UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)


☒	ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the fiscal year ended December 31, ~~2024~~2025

     ☐

     TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 FOR
THE TRANSITION PERIOD FROM                      TO

Commission file number 001-39062

Korro Bio, Inc.

(Exact name of registrant as specified in its charter)


Delaware	47-2324450
(State or other jurisdiction of incorporation or organization)	(I.R.S. Employer Identification No.)
60 First Street, 2nd Floor, Suite 250 Cambridge, MA	02141
(Address of principal executive offices)	(Zip Code)

Registrant’s telephone number, including area code: (617) 468-1999

Securities registered pursuant to Section 12(b) of the Act:

     Title of each class

     Trading
Symbol(s)

     Name of each exchange on which registered

     Common stock, par value $0.001 per share

     KRRO

     The Nasdaq Capital Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.


Large accelerated filer	☐	Accelerated filer	☐
Non-accelerated filer	☒	Smaller reporting company	☒
		Emerging growth company	☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive ~~oﬃcers~~officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant, based on the closing price of the shares of common stock on The Nasdaq Capital Market on June 30, ~~2024~~2025, was $~~236~~88,~~755~~968,~~297~~431.

The number of shares of registrant’s Common Stock outstanding as of March 1410, ~~2025~~2026 was 914,~~388~~422,~~902~~571.

DOCUMENTS INCORPORATED BY REFERENCE

The registrant intends to file a definitive proxy statement pursuant to Regulation 14A relating to the ~~2025~~2026 annual meeting of stockholders within 120 days of the end of the registrant’s fiscal year ended December 31, ~~2024~~2025. Portions of such definitive proxy statement are incorporated by reference into Part III of this Annual Report on Form 10-K to the extent stated herein.

Table of Contents

		Page
PART I
Item 1.	Business	1
Item 1A.	Risk Factors	4548
Item 1B.	Unresolved Staff Comments	9397
Item 1C.	Cybersecurity	9397
Item 2.	Properties	9398
Item 3.	Legal Proceedings	9498
Item 4.	Mine Safety Disclosures	9498
PART II
Item 5.	Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities	9599
Item 6.	[Reserved]	9599
Item 7.	Management’s Discussion and Analysis of Financial Condition and Results of Operations	96100
Item 7A.	Quantitative and Qualitative Disclosures About Market Risk	~~103~~109
Item 8.	Financial Statements and Supplementary Data	F-~~105~~110
Item 9.	Changes in and Disagreements with Accountants on Accounting and Financial Disclosure	~~132~~137
Item 9A.	Controls and Procedures	~~132~~137
Item 9B.	Other Information	~~132~~137
Item 9C.	Disclosure Regarding Foreign Jurisdictions that Prevent Inspections	~~133~~137
PART III
Item 10.	Directors, Executive Officers and Corporate Governance	~~134~~138
Item 11.	Executive Compensation	~~134~~138
Item 12.	Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters	~~134~~138
Item 13.	Certain Relationships and Related Transactions, and Director Independence	~~134~~138
Item 14.	Principal Accountant Fees and Services	~~134~~138
PART IV
Item 15.	Exhibit and Financial Statement Schedules	~~135~~139
Item 16.	Form 10-K Summary	~~136~~141

Unless the context otherwise indicates, references in this Annual Report on 10-K to the “Company,” the "combined company," “we,” “our” and “us” refer, collectively, to Korro Bio, Inc., a Delaware corporation, and its consolidated subsidiaries (including Legacy Korro) after completion of our November 2023 business combination. The term “Legacy Korro” refers to privately held Korro Bio Ops, Inc. (formerly known as Korro Bio, Inc.), which we acquired in the November 2023 business combination. The term "Frequency" refers to our company, Frequency Therapeutics, Inc., prior to completion of our November 2023 business combination.

We use various trademarks and trade names in our business, including without limitation our corporate name and logo. All other trademarks or trade names referred to in this Annual Report on Form 10-K are the property of their respective owners. Solely for convenience, the trademarks and trade names in this Annual Report on Form 10-K may be referred to without the ® and ™ symbols, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto.

In this Annual Report, when we refer to our leads or lead candidates, we are referring to our oligonucleotides that we are researching for potential nomination as a development candidate. When we refer to our development candidates, we generally mean an oligonucleotide lead candidate that we have nominated for clinical development.

CAUTIONARY STATEMENT REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K includes statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended, or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act. Our forward-looking statements include, but are not limited to, express or implied statements regarding our or our management team’s expectations, hopes, beliefs, intentions or strategies regarding the future. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. Forward-looking statements in this Annual Report on Form 10-K may include, for example, express or implied statements about:

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the timing, progress, results, and cost of our ~~Phase 1/2a REWRITE clinical trial of~~ KRRO-~~110~~121 development program, including ~~Korro’s~~our ability to ~~complete~~submit ~~the~~a ~~Phase~~regulatory ~~1/2a~~application ~~clinical study and KRRO-110’s best-~~in~~-class~~ ~~potential for~~ the ~~treatment~~second half of ~~Alpha-1~~2026 ~~Antitrypsin~~for ~~Deficiency~~KRRO-121;

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the timing of our expected nomination of a development candidate for our next-generation GalNAc-conjugated alpha-1 antitrypsin deficiency, or AATD, program;

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the initiation, timing, progress, results, cost of and other statements regarding our research and development programs and our current and future preclinical studies and clinical trials, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work, and the period during which the results of the trials will become available;

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our strategy;

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our cash runway and ability to reach meaningful clinical data readouts and data inflection points;

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the ~~therapeutic~~effects ~~and~~of ~~commercial~~our ~~potential~~organizational ofstreamlining ~~our~~and ~~product~~workforce ~~candidates~~reduction;

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the therapeutic and commercial potential of our development candidates;

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our research and development and other expenses;

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our collaboration arrangement with Novo Nordisk A/S, or Novo Nordisk, including effects of the recent pause, and any future collaboration or licensing arrangements;

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our ability to comply with, and the impact of, regulatory requirements, obligations and restrictions on our business and operations;

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our ability to protect our intellectual property and operate our business without infringing upon the intellectual property rights of others, including our ability to obtain and maintain rights to the technologies required to develop and commercialize our ~~product~~development candidates;

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competitive developments, including the impact on our competitive position of rival products and ~~product~~development candidates and our ability to meet such competition; and

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our ability to manage the growth of our business.

These forward-looking statements are subject to known and unknown risks, uncertainties and assumptions about us that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by such forward-looking statements, including those set forth under the heading “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements. Should one or more of the risks or uncertainties described in this Annual Report on Form 10-K, or should underlying assumptions prove incorrect, actual results and plans could differ materially from those expressed in any forward-looking statements. Except as otherwise required by applicable law, we disclaim any duty to update any forward-looking statements, all of which are expressly qualified by the statements in this section, to reflect events or circumstances after the date of this annual report. We qualify all of our forward-looking statements by these cautionary statements.

SUMMARY OF RISK FACTORS

Our business involves significant risks. Below is a summary of the material risks that our business faces, which makes an investment in our securities speculative and risky. This summary does not address all these risks. These risks are more fully described below under the heading “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K. Before making investment decisions regarding our securities, you should carefully consider these risks. The occurrence of any of the events or developments described below could have a material adverse effect on our business, results of operations, financial condition, prospects and stock price. In such event, the market price of our securities could decline, and you could lose all or part of your investment. Further, there are additional risks not described below that are either not currently known to us or that we currently deem immaterial, and these additional risks could also materially impair our business, operations or market price of our securities.

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We have incurred significant losses since inception and expect to incur losses for the foreseeable future and may never achieve or maintain profitability.

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We have never generated revenue from product sales and may never become profitable.

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We will need substantial additional funding. If we are unable to raise capital when needed, we will be forced to delay, reduce, eliminate or prioritize among our research and development programs or future commercialization efforts.

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WeIf ~~have~~preclinical ~~dosed~~studies ~~very~~or ~~few~~clinical ~~participants~~trials inof ~~our~~any ~~Phase~~lead ~~1/2a~~candidates ~~REWRITE~~or ~~clinical~~development ~~trial~~candidates offail ~~KRRO-110~~to ~~for~~demonstrate ~~Alpha-1~~safety ~~Antitrypsin~~and ~~Deficiency,~~efficacy orto ~~AATD,~~the ~~and~~satisfaction ~~not~~of ~~received~~regulatory ~~any~~authorities ~~clinical~~or ~~trial~~do ~~results~~not ~~for~~otherwise ~~any~~produce ofpositive ~~our~~results ~~proposed~~(such ~~delivery~~as ~~methods~~we orexperienced ~~RNA~~in ~~editing~~the ~~approaches~~Phase in1/2a REWRITE clinical ~~trials.~~trial ~~Any~~of ~~favorable~~KRRO-110 ~~results~~for AATD), we may ~~have~~incur ~~may~~additional ~~not~~costs beor ~~predictive~~experience ofdelays ~~results~~in ~~that~~completing, ~~may~~or ultimately be ~~observed~~unable into ~~later~~complete, ~~preclinical~~the ~~studies~~development orand ~~clinical~~commercialization ~~trials~~of such development candidates.

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IfWe ~~preclinical studies or clinical trials of any product candidates we~~ may ~~identify~~not ~~and~~realize ~~develop fail to demonstrate safety and efficacy to~~ the ~~satisfaction~~anticipated benefits of ~~regulatory~~our ~~authorities~~organizational orstreamlining ~~do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development~~ and ~~commercialization~~workforce ~~of such product candidates~~reduction..

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IfThe wegene ~~experience~~editing ~~delays~~field orand ~~difficulties~~RNA editing in ~~the~~particular ~~enrollment~~is ofrelatively ~~patients~~new and is evolving rapidly. We are very early in ~~clinical~~our ~~trials,~~research orand ~~other~~development ~~delays~~efforts and may not be successful in identifying and developing development candidates. It will be many years before we or our ~~clinical~~collaborators ~~trials~~commercialize a development candidate or generate any revenues, ~~our~~if ~~receipt~~ever. ofAdditionally, ~~necessary~~other ~~regulatory~~gene ~~approvals~~editing ~~could~~technologies may be ~~delayed~~discovered orthat ~~prevented~~provide significant advantages over RNA editing, which could materially harm our business.

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The gene editing field and RNA editing in particular is relatively new and is evolving rapidly. We are very early in our research and development efforts and may not be successful in identifying and developing product candidates. It will be many years before we or our collaborators commercialize a product candidate or generate any revenues, if ever. Additionally, other gene editing technologies may be discovered that provide significant advantages over RNA editing, which could materially harm our business.

RNA editing is a novel technology with limited clinical validation for human therapeutic use. The approaches we take to discover and develop novel therapeutics are unproven and may never lead to marketable products.

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We are very early in our development efforts, and our preclinical studies and clinical trials may not be successful. We have yet to successfully complete clinical development of any development candidate, and any favorable results we have may not be predictive of results that may be observed in later preclinical studies or clinical trials, such as our experience in the Phase 1/2a REWRITE clinical trial of KRRO-110 for AATD. If we are unable to commercialize our ~~product~~development candidates or experience significant delays in doing so, our business will be materially harmed.

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Any ~~product~~development candidates we develop may fail in preclinical or clinical development or be delayed to a point where they do not become commercially viable.

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Because we are developing oligonucleotides, which are considered a relatively new class of drugs, there is increased risk that the outcome of our clinical trials will not be sufficient to obtain regulatory approval.

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If we are not able to obtain or protect intellectual property rights related to any of our ~~product~~lead candidates or development candidates, development and commercialization of our ~~product~~oliognucleotide leads or development candidates may be adversely affected.

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We may not be successful in finding strategic collaborators for continuing development of certain of our development candidates or successfully commercializing or competing in the market for certain indications; and we may not see any benefit from our collaboration agreement with Novo Nordisk, which, as of November 2025, is paused for 12 months.

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The price of our common stock is volatile and fluctuates substantially, which could result in substantial losses for our stockholders.

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Our certificate of incorporation and bylaws and provisions under Delaware law could make an acquisition of us more difficult and may prevent attempts by our stockholders to replace or remove our management.

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Our executive officers, directors and principal stockholders have the ability to control or significantly influence all matters submitted to our stockholders for approval.

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Unfavorable global economic conditions could adversely affect our business, financial condition, results of operations or cash flow.

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Our business may be impacted by macroeconomic conditions, including ~~fears concerning the financial services industry,~~ inflation, rising interest rates and volatile market conditions, and other uncertainties beyond our control, including geopolitical events, such as recent U.S. and Israeli military action in Iran, and effects thereof.

iii

PART I

Item 1. Business.

Overview

We are a ~~clinical-stage~~ biopharmaceutical company with a mission to discover, develop and commercialize a new class of genetic medicines based on editing RNA, enabling the treatment of both rare and highly prevalent diseases. We are generating a portfolio of differentiated programs that are designed to harness the body’s natural RNA editing process to effect a precise yet transient change to a single nucleoside (adenosine to an inosine edit). By editing RNA instead of DNA, we are expanding the reach of genetic medicines by delivering additional precision and tunability, which has the potential for increased specificity and improved long-term tolerability. We use an oligonucleotide-based approach and expect to bring our medicines to patients by leveraging our proprietary platform with precedented delivery modalities, including N-acetylgalactosamine, or GalNAc, -conjugated delivery for subcutaneous administration, manufacturing know-how, and established regulatory pathways of approved oligonucleotide medicines. However, the scientific evidence to support the feasibility of developing lead candidates using our RNA editing technology is both preliminary and limited. Moreover, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and limited clinical data has been generated to date.

WeThe ~~are~~versatility ~~generating a portfolio~~ of ~~differentiated~~RNA ~~programs~~editing ~~that~~combined ~~are~~with ~~designed~~our toOPERA ~~harness~~platform broadens the ~~body’s~~therapeutic ~~natural~~target ~~RNA~~space ~~editing~~significantly. ~~process~~The toadvent ~~effect~~of alarge-scale ~~precise~~genome ~~yet~~sequencing ~~transient~~has ~~single~~progressively ~~base~~revealed ~~edit.~~causal Bygenetic ~~editing~~variation ~~RNA~~underlying ~~instead~~several ofhuman ~~DNA~~diseases, weboth ~~are~~rare ~~expanding~~and ~~the~~highly ~~reach~~prevalent. ofGenetic ~~genetic~~mutations, ~~medicines~~including bysingle ~~delivering~~nucleotide ~~additional~~variants, ~~precision~~or ~~and tunability~~SNVs, ~~which~~implicated ~~has~~in ~~the~~disease ~~potential~~have ~~for~~been ~~increased~~found ~~specificity~~to ~~and~~be ~~improved~~diverse ~~long-term~~in ~~tolerability.~~nature ~~Using~~and ancan ~~oligonucleotide-based~~affect ~~approach,~~the wefunction ~~expect~~of togenes ~~bring~~and ~~our~~their ~~medicines~~associated todownstream ~~patients~~biochemical bypathways. ~~leveraging~~Data ~~our~~correlating ~~proprietary~~DNA ~~platform~~to ~~with~~RNA ~~precedented~~to ~~delivery~~disease ~~modalities,~~phenotype ~~manufacturing~~have ~~know-how,~~demonstrated ~~and~~that ~~established~~SNVs ~~regulatory~~lead ~~pathways~~to a loss-of-function ~~approved~~or ~~oligonucleotide~~a ~~medicines.~~gain-of-function ~~However,~~of the ~~scientific~~gene. ~~evidence~~In toaddition, ~~support~~ the ~~feasibility~~majority of ~~developing~~SNVs ~~product~~implicated ~~candidates~~in ~~using~~complex ~~our~~diseases ~~RNA~~are ~~editing~~due ~~technology~~to ismodulation ~~both~~of ~~preliminary~~gene ~~and limited~~function. ~~Moreover,~~By ~~regulators~~editing ~~have~~RNA ~~not~~to ~~yet~~mimic ~~established~~a ~~any~~SNV, ~~definitive~~we ~~guidelines~~believe ~~related~~we towill ~~overall~~be ~~development~~able ~~considerations~~to ~~for~~address ~~RNA~~unmet ~~editing~~patient ~~therapies~~need ~~and~~by ~~limited~~transiently ~~clinical~~modifying ~~data~~gene ~~has~~expression ~~been~~and ~~generated~~the toresultant ~~date~~protein function.

As our understanding of genetic drivers of disease has increased, significant advances have been made in technologies designed to introduce specific yet permanent changes at the DNA level to treat diseases. While these DNA editing approaches offer great promise for the treatment of certain rare diseases, they present significant risks from potential permanent adverse “off-target” edits. Additionally, the complex nature of DNA editing drug products presents multiple challenges including lack of efficient delivery to target cells and scalable manufacturing, impeding their application to treat complex highly prevalent diseases of larger patient populations. These potential limitations have spurred exploration of alternative approaches to genetic medicine development, such as RNA editing.

Mammals and other lower species like cephalopods have an endogenous process of modifying single ~~bases~~nucleosides on RNA, referred to as RNA editing. RNA editing is a natural physiological process, similar to RNA interference, or RNAi, that occurs in cells, including a mechanism mediated by an enzyme called Adenosine Deaminase Acting on RNA, or ADAR. Our RNA editing approach involves co-opting this endogenous editing system via a proprietary engineered ~~oligonucleotide~~oligonucleotides to introduce precise edits to RNA. We iteratively optimize the editing efficiency of our ~~product~~oligonucleotides ~~candidates~~ using a combination of ADAR biology, chemistry and machine learning expertise. Using this approach, we can edit the transcriptome with high efficiency and specificity. The application of such an approach can provide the ability to alter ana ~~SNV~~nucleoside and affect biology in meaningful ways.

WeAs opposed to gene silencing with small interfering RNA, or siRNA, or antisense oligonucleotide, or ASO, gapmers, where oligonucleotides are used to silence and knock-down genes and proteins, we intend to either repair or activate biological pathways by editing RNA. Our pipeline has multiple programs, all of which are focused on modifying proteins to provide clinical benefit. These modification approaches can unlock validated target classes that have ~~assembled~~historically been difficult to drug, enabling us to pursue a ~~suite~~broad range of ~~technologies~~diseases with potentially large addressable patient populations traditionally out-of-scope for other genetic medicine approaches and ~~capabilities~~current totraditional ~~build~~drug modalities. Each of our programs demonstrates the versatility of the oligonucleotide-based RNA editing ~~platform,~~approach ~~Oligonucleotide~~to ~~Promoted~~bring ~~Editing~~additional precision and tunability to address a broad range of ~~RNA,~~rare orand ~~OPERA~~highly prevalent diseases.

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Enabling synthetic rescue through engineering de novo versions of existing proteins: A SNV observed in human genetic association studies has the potential to inform how to transiently modify a small amount of native protein. We can generate this de novo protein with preferred properties using our RNA editing oligonucleotides. In most cases, 10 – 50% of modified version of the native protein is sufficient to provide significant benefit, rather than needing 100% modification. This synthetic rescue approach is designed to restore cellular function without repairing the primary disease-causing genetic mutation. Our lead program, KRRO-121, exemplifies this approach by engineering a de novo version of glutamine synthetase, or GS, that is designed to stabilize the protein and enhance ammonia clearance, overcoming the challenges with a dysfunctional urea cycle.

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~~OPERA~~Repairing ~~integrates~~pathogenic variants: A SNV that is a ~~deep~~pathogenic ~~understanding~~G-to-A ofmutation, ~~ADAR~~leading ~~biology~~to ~~with~~an ~~expertise~~aberrant inamino ~~oligonucleotide~~acid ~~chemistry~~on a protein, ~~machine~~can ~~learning~~be ~~optimization~~repaired ofusing ~~oligonucleotides~~our ~~and~~RNA ~~fit-for-purpose~~editing ~~delivery,~~approach. ~~all~~Such ofan ~~which~~approach ~~are~~is ~~expected~~relevant towhen ~~enable~~the ~~rapid~~patient ~~iteration~~population ofhas ~~our~~a ~~product~~heterogenous ~~candidates~~spectrum ~~across~~of ~~therapeutic~~disease ~~targets.~~manifestations ~~OPERA~~from ~~relies~~mild-to-severe, onand the ~~following~~willingness ~~key~~and ~~components~~utility ~~that~~of ~~enable~~a ustransient torepair ~~generate~~of the ~~proprietary~~protein ~~RNA~~is ~~editing~~preferable ~~oligonucleotides~~to ~~that~~a ~~form~~DNA ~~the~~modification. ~~basis~~Our ofnext-generation ~~our~~GalNAc ~~differentiated~~conjugated ~~product~~lead ~~candidates:~~candidate targeting patients with AATD exemplifies this approach.

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~~Expertise~~Activating inprotein ~~ADAR~~pathways: ~~biology,~~A ~~supported~~single bySNV ~~extensive~~observed ~~preclinical~~in ~~research~~human ~~using~~genetic inassociation ~~vitro~~studies ~~assays~~has ~~and~~the ~~proprietary~~potential ~~mouse~~to ~~models~~inform ashow ~~well~~to astransiently ~~the~~activate ~~fundamental~~a ~~work~~protein ofpathway. ~~our~~We ~~scientific~~can ~~advisors~~generate ~~and~~this ~~founders~~protein totransiently ~~elucidate~~using ~~key~~our ~~insights~~RNA ~~and~~editing ~~know-how~~approach ofwith ~~ADAR~~an ~~biology.~~oligonucleotide, ~~This~~thereby ~~enables~~engineering ana ~~understanding~~de ofnovo ~~ADAR~~protein ~~activity~~with ~~translation~~preferred ~~among~~properties. ~~different~~Our ~~species~~longevity and ~~disease~~liver ~~states,~~health ~~allowing~~program ustargeting toAMP-activated ~~develop~~protein ~~novel~~kinase ~~product~~gamma ~~candidates.~~1 protein, or AMPKγ1, exemplifies this approach.

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Expertise in oligonucleotide chemistry, enabled by the ability to identify and incorporate chemical modifications to generate a fully modified synthetic oligonucleotide. This increases our ability to generate potent oligonucleotides with drug-like properties, thereby increasing the editing and translational efficiency of our product candidates.

Machine learning optimization of oligonucleotides and target identification, driven by data science and computational capabilities for rapid and efficient design and iteration resulting in optimal product candidates for each disease or disease target being pursued.

Leveraging known delivery modalities, made possible by tissue-specific and validated delivery technologies that may potentially derisk our product candidates and enhance biodistribution, specificity, durability and editing efficiency of product candidates.

Such product candidates include Customized High-fidelity Oligonucleotides for RNA Deamination, or CHORDs. CHORDs are single stranded, anti-sense oligonucleotides designed to have high target efficiency and specificity by leveraging the pillars of OPERA.

The versatility of RNA editing combined with our OPERA platform broadens the therapeutic target space significantly. While our approach can be used to repair pathogenic SNVs, as demonstrated by our most advanced clinical-stage program, our AATD development candidate, KRRO-110, we can also engineer de novo SNVs and change amino acids on proteins to endow them with desired properties while preserving their broader functional capabilities as exemplified by three of our other programs (an undisclosed rare metabolic disorder, amyotrophic lateral sclerosis, or ALS, and pain). In preclinical studies, we have demonstrated that single RNA changes can disrupt protein-protein interactions, prevent protein aggregation, selectively modulate ion channels and activate kinases. These modification approaches can unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases with potentially large addressable patient populations traditionally out-of-scope for other genetic medicine approaches and current traditional drug modalities.

Each of our programs demonstrates the versatility of the oligonucleotide-based ADAR-mediated RNA editing approach to bring additional precision and tunability to address a broad range of rare and highly prevalent diseases.

Repairing pathogenic variants: A SNV that is a G to A mutation on DNA, leading to an aberrant amino acid on a protein can be repaired using RNA editing. Such an approach is relevant when the patient population has a spectrum of disease manifestations from mild-to-severe.

Disrupting protein-protein interactions: A single SNV observed in human genetic association studies has the potential to inform how to transiently activate a protein pathway. We can generate this protein variant transiently using our RNA editing product candidates, thereby engineering a de novo SNV with preferred properties.

Other target classes: There are multiple other target classes that can be addressed such as preventing protein aggregation, selectively modulating ion channels and activating kinases that have been traditionally hard to leverage for developing medicines.

~~The~~Figure ~~pipeline~~1: ~~chart~~RNA ~~below demonstrates the breadth of indications and applications enabled by our OPERA platform~~editing, ~~with~~just ana ~~initial~~single ~~focus on four programs that are all wholly~~A-~~owned, along with up~~ to-I ~~two~~nucleoside ~~programs partnered with Novo Nordisk A/S~~change, orcan ~~Novo~~have ~~Nordisk,~~profound ~~for~~impact ~~cardiometabolic~~on ~~diseases~~biological pathways. InThe ~~January~~applications ~~2025~~span wea ~~announced~~multitude ~~the dosing~~ of ~~the~~avenues ~~first~~to ~~participants~~impact ~~in our Phase 1/2a REWRITE clinical trial of KRRO-110 for AATD~~biology. ~~All~~We ~~of our other programs~~ are ~~still~~focused inon ~~the~~activating ~~research or preclinical stage of development~~ and ~~the~~repairing ~~risk~~pathways ofrather ~~failure~~than ofcompeting ~~all~~with ofRNA ~~our~~interference ~~programs is high~~technologies.

~~1De~~Our ~~novo protein variant to prevent toxic gain-of-function (GoF) with TDP43 aggregation and overcome toxic loss-of-function (LoF)~~ Pipeline

WeThe ~~continue~~pipeline tochart ~~make~~below ~~meaningful~~demonstrates ~~advancements across our programs, including recently advancing KRRO-110 into clinical development. Specifically, KRRO-110 is our first clinical-stage product candidate for~~ the ~~treatment~~breadth ~~for~~of ~~AATD that~~indications, ~~using~~with our proprietary RNA editing approach, is intended to repair the amino acid codon. This repair of the endogenous protein has the potential to clear protein aggregates from within liver cells to create a potentially disease-modifying clinically differentiated benefit for liver function and to preserve lung function by providing an ~~adequate~~initial ~~amount~~focus ofon ~~normal~~four ~~alpha~~wholly-1owned ~~antitrypsin~~programs: protein, or AAT. AATD is an inherited genetic disorder that can cause severe progressive lung and liver disease due to a lack of normal AAT, caused by SNV mutations in the SERPINA1 gene. There are an estimated 5.5 million individuals with deficiency allele

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KRRO-121, our hyperammonemia program, targeting the increased clearance of ammonia in multiple indications;

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Our AATD (GalNAc-conjugated delivery) program targeting the repair of the alpha-1 antitrypsin, or AAT, protein;

•

Our longevity and liver health program targeting the activation of AMPKγ1 pathway (GalNAc-conjugated delivery); and

•

Our ALS program targeting the creation of a de novo variant of TDP-43 (with intrathecal delivery).

We may also have up to two programs partnered with Novo Nordisk, which entered a 12-month pause in November 2025. All of our programs are still in the research or preclinical stage of development and the risk of failure of all of our programs is high.

1De novo protein variant to prevent toxic gain-of-function, or GoF, with TDP43 aggregation, and continue downstream signaling by overcoming toxic loss-of-function, or LOF.

KRRO-121 – Hyperammonemia Program

We continue to make meaningful advancements across our programs, including KRRO-121 as a potential first-in-class treatment for hyperammonemia that has the potential to address substantial unmet need in patients with poor ammonia control, including those with urea cycle disorders, or UCD, and hepatic encephalopathy, or HE. KRRO-121 is an RNA-editing oligonucleotide conjugated with GalNAc in preclinical development for the potential treatment of UCDs of any mutational background in adults and adolescents. Utilizing our proprietary platform, we designed KRRO-121 to edit the GS mRNA to generate a stabilized, de novo variant of GS with enhanced ammonia clearance capacity. This synthetic rescue approach creates a compensating protein rather than repairing the underlying urea cycle defect. By editing GS mRNA to create a de novo protein with a single amino acid change that prevents glutamine-induced proteasomal degradation of GS, we aim to maintain consistent ammonia clearance capacity irrespective of the specific enzyme deficiency in patients with UCD and to reduce ammonia levels in patients with HE.

Hyperammonemia, or elevated ammonia in the blood, can lead to neurological impairment that can be potentially permanent, frequent hospitalization, highly restricted diet, elevated infection risk, and additional non-neurological complications. Hyperammonemia can be caused by cirrhosis or urea cycle dysfunction, and clinical studies have shown benefit of lowering ammonia in multiple indications. We believe our approach for treating hyperammonemia has multiple potential advantages:

•

Provides a pan-UCD approach addressing multiple UCD subtypes irrespective of their enzyme deficiencies in the urea cycle.

•

Direct ammonia control through stabilization of GS protein in the liver.

•

Convenient subcutaneous delivery using precedented GalNAc-conjugated technology.

•

Potential for reduction in hyperammonemic crises for UCD patients and reduction in HE events for HE patients.

We have generated compelling preclinical data demonstrating proof of concept across multiple RNA editing oligonucleotides targeting GS, including KRRO-121.

•

KRRO-121 stabilized GS in ornithine transcarbamylase, or OTC, -deficient and argininosuccinate synthase 1, or ASS1, -deficient iPSC-derived hepatocytes, maintaining GS protein levels during ammonia challenge.

•

In both OTC-deficient and CPS-1-deficient mice challenged with ammonia, treatment with a mouse-optimized oligonucleotide reduced ammonia, supporting potential to increase protein intake and dietary liberalization.

•

In a humanized liver mouse model (PXB), KRRO-121 reduced basal ammonia levels and enhanced ammonia clearance following challenge, with production of stabilized de novo GS variant.

•

~~combinations~~In ~~worldwide.~~non-human ~~Despite~~primates, ~~being~~or ~~minimally effective and not fully addressing the needs of many AATD patients~~NHPs, ~~augmentation therapy currently represents approximately $1.4 billion in annual sales worldwide.~~ KRRO-~~110~~121 ~~has~~displayed ~~the~~>90% ~~potential~~delivery to ~~elevate~~liver, ~~the~~confirmed ~~standard~~liver oflocalization ~~care and expand the number of patients on treatment and potential to be a leader~~ with apericentral ~~large market opportunity worldwide. However~~GS, ~~KRRO-110 is in early clinical development~~ and ~~there is~~ no ~~guarantee~~observed ~~that~~changes itin liver or ~~any~~kidney offunction, ~~our~~coagulation, ~~other~~complement, ~~earlier~~platelets, ~~stage~~or ~~programs will be successful~~cytokines.

Additionally, KRRO-~~110~~121 isrepresents a ~~proprietary~~significant ~~oligonucleotide~~market ~~that~~opportunity ~~utilizes~~in aUCD ~~proven~~and ~~lipid~~HE. ~~nanoparticle,~~There orare ~~LNP~~an estimated 4,200 ~~based~~severe ~~delivery~~late-onset ~~system~~UCD ~~administered~~patients ~~intravenously~~in tothe ~~transiently~~United ~~restore~~States, ~~production~~or ofU.S., ~~normal~~and ~~AAT~~5,100 in ~~liver~~the ~~hepatocytes~~European Union, or EU, and United Kingdom, or UK. ByUCD ~~correcting~~patients frequently have ammonia levels greater than 1.5 times the ~~pathogenic~~upper Glimit of normal, leading to Aincreased ~~SNV~~hyperammonemia risk. Ammonia control is highly challenging in ~~the~~UCD ~~SERPINA1~~patients ~~gene~~today, weoften ~~aim~~requiring nitrogen scavengers plus a strict diet that can lead to ~~bring~~malnutrition. ~~individuals~~In ~~with~~addition ~~the~~to ZUCD, ~~mutation~~KRRO-121 has an opportunity to apotentially ~~phenotype~~address ~~where~~significant ~~over~~unmet ~~50%~~need in HE. There are approximately 2.2 million patients with cirrhosis in the United States, of ~~RNA~~which ~~has~~approximately ~~been~~140,000 ~~corrected~~have tosevere ~~produce~~or ~~normal~~recurring ~~AAT~~HE. Up to 80,000 ~~preserving~~addressable ~~lung~~patients ~~and~~in ~~liver~~the ~~function~~United ~~and~~States ~~preventing~~with ~~further~~severe ~~damage~~or recurring HE, high ammonia levels (≥1.5x ~~While~~upper ~~LNPs~~limit ~~have~~of ~~been~~normal), ~~validated~~and ~~clinically~~sufficient toliver ~~deliver~~function ~~oligonucleotides~~may benefit from ammonia-lowering treatment, ~~such~~with asan ~~siRNA~~additional 150,000 ~~they~~patients ~~have~~in ~~not~~the ~~been~~European ~~clinically~~Union ~~proven~~and toUnited ~~deliver~~Kingdom. ~~oligonucleotides~~High ~~for~~ammonia ~~RNA~~significantly ~~editing~~increases hospitalization risk, ~~such~~with asgreater ~~KRRO~~than 2-~~110~~fold increase in HE-related hospitalization for addressable HE patients versus all severe or recurring HE patients, and ~~our~~over ~~other~~$10 ~~product~~billion ~~candidates.~~in inpatient charges for HE in the United States each year.

WeBased on the preclinical data, we believe ~~our~~KRRO-121 ~~approach~~has potential to be a best-in-class treatment for ~~treating~~ammonia ~~AATD~~control. ~~has~~We ~~multiple~~anticipate ~~potential~~a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. The compelling product profile for controlling ammonia is expected to drive strong patient engagement and recruitment. While we believe we can demonstrate many of the key advantages: of our development candidate KRRO-121, we are early in our development efforts and not yet certain of the results we may achieve in humans. Such uncertainties include, but are not limited to, the level of ammonia control needed in a target tissue type to achieve a clinical benefit, and associated safety of the de novo protein variants we create in humans.

~~Provides~~Our aAATD ~~disease modifying therapy for both lung and liver manifestations by transiently editing over 50% of RNA transcripts in hepatocytes to restore normal AAT~~ Program

~~Provides~~We are also developing a next-generation GalNAc-conjugated RNA editing oligonucleotide for the treatment ~~option~~of AATD that ~~can~~has bethe ~~tailored~~potential to ~~address~~be ~~the~~disease-modifying ~~broad~~and ~~spectrum~~provide a differentiated therapeutic option. Following extensive evaluation of ~~severity~~our ~~within~~initial AATD program, KRRO-110, we have strategically pivoted from a lipid nanoparticle, or LNP, based delivery approach to GalNAc-conjugated delivery and made significant improvements on the potency of the next-generation oligonucleotide, to advance a potential best-in-class therapy for AATD ~~population~~patients. We anticipate nominating a development candidate for this program in the second quarter of 2026.

~~Potential~~AATD tois ~~enable~~an ~~physiologic~~inherited ~~regulation~~genetic disorder that can cause severe progressive lung and liver disease due to a lack of normal AAT ~~using~~protein, ~~endogenous~~with ~~ADAR~~varying intensity based on patient genotype and environmental factors. Patients often develop chronic obstructive pulmonary disorder, ~~thereby~~or ~~increasing~~COPD, ~~normal~~in the lungs and cirrhosis of the liver, which can result in liver failure or death. There are an estimated 5.5 million individuals with deficiency allele combinations worldwide. The only U.S. Food and Drug Administration, or FDA, -approved treatment for patients with lung manifestations of AATD is augmentation therapy, which utilizes AAT ~~production~~protein ~~during~~purified ~~inflammation~~from pooled human plasma administered weekly by intravenous infusion. Despite being minimally effective and not fully addressing the needs of many AATD patients, augmentation therapy currently represents approximately $1.4 billion in annual sales worldwide, highlighting the significant unmet medical need and commercial opportunity for a superior therapeutic approach.

~~Fit~~Our next-~~for~~generation GalNAc-~~purpose~~conjugated ~~delivery~~AATD ~~using~~program utilizes a ~~proven~~proprietary ~~LNP~~RNA editing oligonucleotide specifically designed to ~~maximize~~leverage ~~editing~~endogenous ~~efficiency~~ADAR to make a single base edit in SERPINA1 RNA, ~~leading~~correcting the pathogenic G to ~~greater~~A SNV that results in the E342K amino acid substitution. This approach is designed to restore the production of normal AAT protein in liver hepatocytes through convenient subcutaneous administration. Our goal is to bring individuals with the Z allele to a phenotype where over 90% of RNA has been modified to produce normal AAT protein, resulting in levels of AAT consistent with individuals in the upper half of the PiMZ genotype and the fully healthy PiMM genotype. We believe the GalNAc-conjugated delivery approach has the potential ~~clinical~~to ~~benefit~~offer multiple advantages over our previous LNP-based intravenous approach, including improved potency of the next-generation construct, improved delivery to liver cells using GalNAc conjugation, convenient subcutaneous administration that significantly improves patient experience, and potentially enhanced durability of effect.

WeOur preclinical studies have ~~generated~~demonstrated compelling ~~preclinical data demonstrating~~ proof of concept ~~across~~for ~~multiple~~the GalNAc-conjugated approach to AATD treatment. A GalNAc-conjugated RNA editing ~~oligonucleotides~~lead ~~targeting~~candidate achieved greater than 90% editing of the SERPINA1 transcript in vivo in a human transgenic mouse model that expresses the human SERPINA1 gene, ~~including~~with ~~KRRO~~the Z-~~110~~mutation. These results demonstrate both the high efficiency and consistency of our next-generation RNA editing oligonucleotide with the GalNAc-conjugated approach in a well-characterized AATD mouse model. Our potential development candidates have also demonstrated

KRRO-110 has achieved high editing efficiency in vitro (>50% editing in hepatocytes).

KRRO-110 demonstrated high specificity with no bystander effects in MZ human primary hepatocytes.

Intravenous administration of KRRO-110 at 2mg/kg in a human transgenic PiZ mouse model resulted in secretion of approximately 50uM total AAT protein as early as seven days post-single dose.

KRRO-110 increases M-AAT to >70% of total AAT protein in circulation in vivo.

An increase in functional AAT protein with the inhibition of elastase activity was sustained through week 13 when KRRO-110 was dosed every two weeks, demonstrating durability in mice.

Engineered surrogate oligonucleotides that edit RNA at an adjacent site on the SERPINA1 gene relative to KRRO-110 have high translation of RNA editing efficiency from mice to non-human primates, or NHPs, demonstrating the potential applicability of our approach in humans.

In January 2025, we announced dosing of the first participants in our REWRITE clinical program investigating KRRO-110 as a treatment for AATD. REWRITE is a two-part single and multiple dose-escalating Phase 1/2a clinical trial that will evaluate the safety and tolerability of KRRO-110 in up to 64 participants, including healthy adults and clinically stable AATD patients with the PiZZ genotype. Secondary and exploratory endpoints include pharmacokinetic and pharmacodynamic parameters that will guide optimal dose selection for later stage studies. We have completed dosing of the first two single ascending dose cohorts in healthy adult volunteers. We have not observed any serious adverse events as of the date of this annual report on Form 10-K through completion of dosing of the first two cohorts. We continue to progress enrollment, site activation and expansion into other geographies beyond Australia, including the United States. In March 2025, we announced that the FDA has granted orphan drug designation to KRRO-110 for the treatment of AATD. Interim data from single ascending doses in healthy volunteers and AATD patients is expected in the second half of 2025, and completion of the trial is anticipated in 2026. Based on the preclinical data, we believe KRRO-110 has best-in-class potential for the treatment of AATD. However, KRRO-110 is in early clinical development and there is no guarantee that it will be successful.

~~Our~~high ~~Team~~specificity with minimal off-target effects, supporting the potential for a favorable safety profile in clinical development. The editing efficiency achieved with our GalNAc-conjugated approach represents a significant advancement over our earlier studies and positions our program to potentially deliver transformative outcomes for AATD patients. We anticipate nominating a development candidate among our lead candidates for this program in the second quarter of 2026.

~~We were launched in 2018 and were co-founded by Nessan Bermingham, Jean-Francois Formela, Joshua Rosenthal and Andrew Fraley.~~ Our ~~science~~OPERA was based on pioneering research from the laboratory of Joshua Rosenthal, Ph.D., at the Marine Biological Laboratory, or MBL in Woods Hole, Massachusetts. Dr. Rosenthal’s work includes landmark discoveries in RNA editing based on adenosine deamination. Platform

We ~~are~~have ~~led~~assembled bya ansuite ~~experienced team with deep expertise in genetic medicines, development~~ of ~~oligonucleotide-based~~technologies ~~therapeutics, building novel therapeutic platforms,~~ and ~~bringing~~capabilities ~~multiple therapeutics~~ to ~~market.~~build ~~In addition,~~ our ~~executive~~RNA ~~leadership~~editing ~~team has a successful track record of company building and leading biotech companies~~platform, ~~including~~Oligonucleotide ~~Ram~~Promoted ~~Aiyar,~~Editing ~~Ph.D., President and Chief Executive Officer, an experienced executive and company builder with 20 years~~ of ~~diverse industry experience including research~~RNA, ~~business~~or ~~and strategy~~OPERA. We also have an accomplished scientific advisory board comprised of leading experts in the fields of ADAR biology, chemistry, translation medicine, and nucleic acid therapeutics and a clinical advisory board comprised of pulmonary and hepatic experts to support the clinical development and regulatory strategy for KRRO-110.

WeOPERA ~~are~~integrates a ~~mission-driven~~deep ~~organization~~understanding ~~and~~of ~~thrive~~ADAR ~~through~~biology awith ~~strong~~expertise ~~culture~~in ofoligonucleotide ~~scientific~~chemistry, ~~innovation~~machine ~~and~~learning ~~behavior~~optimization ~~that~~of ~~embodies~~oligonucleotides ~~our~~and ~~core~~fit-for-purpose, ~~values~~derisked ~~and~~delivery, ~~principles.~~all Weof which are ~~actively~~expected ~~working~~ to ~~rewrite~~enable ~~the~~rapid ~~future~~iteration of ~~medicine~~our bydevelopment ~~remaining~~candidates onacross ~~the~~therapeutic ~~cutting edge of science and research~~targets. WeOPERA ~~believe~~relies ~~our~~on ~~success~~the isfollowing ~~enabled~~key bycomponents ~~working~~that ~~better~~enable ~~together by being dynamically different, leading~~ us to ~~employ~~generate athe ~~diverse~~proprietary ~~team~~RNA ~~with~~editing ~~varied~~oligonucleotides ~~expertise,~~that ~~enabled~~form bythe ~~kindness,~~basis ~~integrity~~of ~~and~~our ~~respect.~~differentiated development candidates:

•

WeExpertise ~~have~~in ~~attracted~~ADAR abiology, ~~talented~~supported ~~team~~by ofextensive ~~industry~~preclinical ~~experts~~research ~~and~~using ~~experienced~~in ~~scientists~~vitro asassays ~~part~~and ofproprietary amouse ~~high-performing,~~models ~~nimble~~as ~~organization.~~well ~~Our~~as ~~research~~the ~~and~~fundamental ~~development~~work ~~organization~~of isour ~~comprised~~scientific ofadvisors ~~individuals~~and ~~with~~founders ~~expertise~~to inelucidate ~~DNA~~key ~~editing~~insights ~~technologies,~~and ~~RNA~~know-how ~~biology,~~of ~~liver~~ADAR biology,. ~~CNS~~This ~~biology,~~enables ~~medicinal~~an ~~chemistry,~~understanding ~~biochemistry~~of ~~and~~ADAR ~~drug~~activity ~~delivery,~~translation ~~translational~~among ~~medicine,~~different ~~preclinical~~species ~~development, chemistry, manufacturing~~ and ~~controls~~disease states, ~~clinical~~allowing ~~development,~~us ~~clinical~~to ~~operations~~develop ~~and~~novel ~~regulatory~~lead ~~affairs~~candidates.

•

~~Since~~Expertise ~~inception, we have raised $410.9 million~~ in ~~capital~~oligonucleotide chemistry, ~~including~~enabled ~~$70~~by ~~million from~~ the ~~sale~~ability ofto ~~shares~~identify ofand ~~common~~incorporate ~~stock~~chemical ~~issued~~modifications into generate a ~~private~~fully ~~placement~~modified ~~that~~synthetic ~~closed~~oligonucleotide. onThis ~~April~~increases ~~22,~~our ~~2024,~~ability ~~which~~to ~~was~~generate ~~lead~~potent byoligonucleotides ~~leading~~with ~~healthcare~~drug-like ~~investors~~properties, ~~that~~thereby ~~share~~increasing ~~our~~the ~~vision~~editing ofand ~~creating~~translational ~~transformative~~efficiency ~~genetic~~of ~~medicines~~our ~~for~~lead ~~rare and highly prevalent diseases~~candidates.

•

~~Our~~Machine ~~Strategy~~learning optimization of oligonucleotides and target identification, driven by data science and computational capabilities for rapid and efficient design and iteration resulting in optimal lead candidates for each disease or disease target being pursued.

•

~~Our~~Leveraging ~~mission~~known ~~is to discover, develop~~ and ~~commercialize~~derisked adelivery ~~new~~modalities, ~~class~~made ofpossible ~~RNA editing therapies capable of improving the lives of patients with rare and highly prevalent diseases. We do this~~ by ~~applying our proprietary RNA editing platform, OPERA, which combines our unique expertise in ADAR biology and oligonucleotide chemistry with machine learning~~tissue-~~driven~~specific ~~optimization~~ and ~~fit-for-purpose~~validated delivery. ~~Our~~technologies ~~RNA~~that ~~editing~~may ~~product~~potentially ~~candidates~~derisk are designed to harness the body’s natural RNA editing processes to make a precise single base edit. However, this has only been observed in preclinical studies as we only recently dosed the first participants in our ~~Phase~~lead ~~1/2a~~candidates ~~REWRITE clinical trial of KRRO-110 for AATD~~ and weenhance ~~have yet to submit an investigational new drug application~~biodistribution, ~~or IND~~specificity, todurability ~~the U.S. Food~~ and ~~Drug~~editing ~~Administration,~~efficiency ~~or FDA. Our goal is to develop a portfolio~~ of ~~RNA~~lead ~~editing product~~ candidates. ~~with best-in-class properties across a range of diseases by executing on the following key pillars of our strategy:~~

Develop a novel class of RNA editing therapies using learnings from a combination of genetics and approved medicines. We are leveraging significant advances in the understanding of the correlation between DNA, RNA and disease phenotypes to develop novel therapeutic approaches across a range of validated biological targets. This novel class of RNA editing therapeutics combines the precision of genomic therapies with the properties associated with traditional approved drugs, such as titratability and ability to re-dose. In addition, our RNA editing product candidates are structurally similar to other clinically and commercially validated drug modalities such as antisense oligonucleotides, or ASOs, and small-interfering siRNAs, conferring potential advantages in manufacturing, regulatory review and clinical adoption.

Develop and continue to clinically advance a differentiated disease-modifying therapy for patients with AATD. Our first development candidate, KRRO-110, has the potential to provide a differentiated therapeutic option for AATD by addressing both the liver and lung pathologies. Our RNA editing oligonucleotide product candidates, including KRRO-110, have generated compelling preclinical data that demonstrates restoration of normal AAT protein while preventing the aggregation of dysfunctional AAT in the liver. Our preclinical in vivo data has demonstrated durability and high editing efficiency in both mice and NHPs, illustrating the potential applicability in humans. In January 2025, we announced dosing of the first participants in our REWRITE clinical program investigating KRRO-110 as a treatment for AATD. REWRITE is a two-part single and multiple dose-escalating Phase 1/2a clinical trial that will evaluate the safety and tolerability of KRRO-110. We have completed dosing of the first two cohorts of participants. Interim data from single ascending doses in healthy volunteers and AATD patients is expected in the second half of 2025, and completion of the trial is anticipated in 2026. Depending on the evidence of

~~efficacy~~Such ~~and~~lead ~~tolerability,~~candidates weare ~~intend~~single tostranded ~~pursue~~oligonucleotides ~~expedited~~designed ~~regulatory~~to ~~pathways.~~have ~~However,~~high ~~regulators~~target ~~have~~efficiency ~~not~~and ~~yet~~specificity ~~established~~by ~~any~~leveraging ~~definitive~~the ~~guidelines~~pillars ~~related~~of toOPERA. ~~overall~~The ~~development~~versatility ~~considerations~~of ~~for~~ RNA editing ~~therapies.~~combined with our OPERA platform broadens the therapeutic target space significantly.

~~Deploy~~Our ~~our~~Strategy versatile OPERA platform to develop a portfolio of programs that modify proteins transiently to expand into highly prevalent diseases. OPERA has the ability to generate unique RNA editing therapies that can modify protein function or endow proteins with engineered changes that will potentially result in desirable properties to treat disease. In preclinical studies, we have demonstrated that single RNA changes can disrupt a protein-protein interaction, prevent protein aggregation, selectively modulate an ion channel and selectively activate a kinase. These modification approaches can unlock validated target classes that have historically been deemed undruggable, enabling us to pursue a broad range of diseases, including those with high prevalence. We are evaluating potential applications of our OPERA platform for use in other highly prevalent indications including the central nervous system, or CNS, liver, and cardiometabolic therapeutic areas.

~~Continue~~Our tomission ~~optimize~~is ~~and~~to ~~enhance~~discover, ~~our~~develop ~~OPERA~~and ~~platform.~~commercialize Wea ~~believe~~new weclass ~~have~~of ~~built a leading~~ RNA editing ~~company~~therapies ~~through~~capable ~~a combination~~ of ~~our~~improving ~~OPERA~~the ~~platform,~~lives ~~intellectual~~of ~~property~~patients ~~strategy~~with rare and ~~human~~highly ~~capital~~prevalent diseases. ~~Our~~We ~~computationally~~do ~~driven~~this ~~approach~~by ~~enables~~applying ~~rapid~~our ~~design~~proprietary ~~and~~RNA ~~optimization~~editing ofplatform, ~~potential~~OPERA, ~~oligonucleotide~~which ~~product~~combines ~~candidates.~~our Inunique ~~development~~expertise ofin ~~our~~ADAR ~~AATD~~biology ~~program,~~and weoligonucleotide ~~were~~chemistry ~~able~~with tomachine golearning-driven ~~from~~optimization ~~“design-to-data”~~and inleveraging ~~5-6~~existing ~~weeks~~delivery. WeOur ~~intend~~RNA toediting ~~continue~~oligonucleotides toare ~~incorporate~~designed ~~new~~to ~~data~~harness ~~into~~the ~~these~~body’s ~~machine~~natural ~~learning~~RNA ~~models~~editing processes to ~~improve~~make ~~their~~a ~~ability~~precise single A-to-I ~~predict~~edit ~~editing~~on ~~efficiency~~RNA. ~~and~~However, tothis ~~more~~has ~~expeditiously~~primarily ~~optimize~~been ~~and~~observed ~~nominate~~in ~~new~~preclinical ~~product~~studies ~~candidates,~~and ~~although~~in ~~there~~a islimited nonumber ~~guarantee~~of ~~that~~human ~~this~~subjects ~~will~~in ~~result~~our innow anterminated ~~accelerated~~REWRITE ~~development~~clinical orprogram ~~approval~~investigating ~~timeline~~KRRO-110, ifan atLNP-encapsulated ~~all~~oligonucleotide as a treatment for AATD.

~~Maximize~~Our ~~the~~lead ~~potential~~program, ofKRRO-121 ~~our~~for ~~OPERA~~hyperammonemia, ~~platform~~utilizes ~~through~~GalNAc-conjugated ~~collaborations~~delivery ~~and~~with ~~strategic~~a ~~partnerships.~~regulatory Wefiling ~~believe~~anticipated ~~the~~in ~~versatility of our OPERA platform has~~ the ~~potential~~second tohalf ~~create~~of ~~transformative genetic medicines for both rare and highly prevalent diseases~~2026. ToOur ~~fully~~goal ~~realize~~is ~~this potential, we have established and plan~~ to ~~continue~~develop toa ~~actively~~portfolio ~~seek~~of ~~out~~RNA ~~innovative~~editing ~~collaborations~~oligonucleotides, ~~licenses,~~to ~~and~~help ~~strategic~~alleviate ~~alliances~~major ~~with~~unmet ~~clinical leaders, academic~~ medical ~~centers of excellence~~needs, ~~patient advocacy groups, and pioneering companies, including, for example, our collaboration~~ with ~~Novo~~best-in-class ~~Nordisk~~properties ~~for~~by upexecuting toon ~~two partnered programs for cardiometabolic diseases. Given~~ the ~~versatility~~following ~~and~~key ~~broad~~pillars ~~potential~~ of our ~~OPERA~~strategy: platform across therapeutic areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

•

~~Invest~~Develop ina ~~human~~pipeline ~~capital~~of ~~and~~programs ~~encourage~~focused ~~innovation~~on tomodifying ~~maintain~~proteins ato ~~leading~~activate ~~position~~biological ~~and~~pathways ~~advance~~using ~~the~~RNA ~~frontiers of genetic medicines~~editing. We are aleveraging ~~mission-driven~~significant ~~organization,~~advances ~~and~~in wethe ~~thrive~~understanding ~~through~~of athe ~~strong~~relationship ~~culture~~between ~~that~~DNA, ~~embodies~~RNA ~~our~~and ~~core~~disease ~~values.~~phenotypes Weto ~~are~~develop ~~actively~~novel ~~working~~therapeutic toapproaches ~~rewrite~~across ~~the~~a ~~future~~range of ~~medicine~~validated ~~and~~biological ~~remain~~targets. onOur ~~the~~novel ~~cutting~~class ~~edge~~ of ~~science~~RNA ~~and~~editing ~~research~~therapeutics bycombines ~~working~~the ~~better~~precision ~~together~~of ~~and~~genomic ~~being~~therapies ~~dynamically~~with ~~different~~the inproperties ~~employing~~associated ~~a diverse team~~ with ~~varied~~traditional ~~expertise~~approved drugs, ~~enabled~~such byas ~~kindness,~~titratability ~~integrity~~ and ~~respect.~~ability Weto ~~have~~re-dose. ~~attracted~~Using aour ~~talented~~approach, ~~team~~in ofpreclinical ~~industry~~studies, ~~experts~~we ~~and~~have ~~experienced~~demonstrated ~~scientists~~the asability ~~part~~to ofmodify aprotein ~~high-performing~~function ~~and~~or ~~nimble~~engineer ~~organization.~~proteins ~~Our~~to ~~research~~potentially ~~and~~endow ~~development~~them ~~organization~~with isdesirable ~~comprised~~properties ofto ~~individuals~~treat ~~with~~disease. ~~expertise~~This inapproach ~~DNA~~can ~~editing~~unlock ~~technologies,~~validated ~~RNA~~target ~~biology,~~classes ~~liver~~that ~~biology,~~have ~~CNS~~historically ~~biology,~~been ~~medicinal~~deemed ~~chemistry~~undruggable, ~~biochemistry~~enabling ~~and~~us ~~drug~~to ~~delivery,~~pursue ~~translational~~a ~~medicine,~~broad ~~preclinical~~range ~~development,~~of ~~chemistry~~diseases, ~~manufacturing~~including ~~and~~those ~~controls,~~with ~~clinical~~high ~~development, clinical operations and regulatory affairs~~prevalence.

•

Advance KRRO-121 as a potentially first-in-class treatment for hyperammonemia, our first example of synthetic rescue. Our 3lead program, KRRO-2121, has the potential to provide a differentiated therapeutic option for patients with UCD and HE by enhancing ammonia clearance. KRRO-1121 ~~Strategy~~can ~~Through~~potentially ~~End~~achieve this through the stabilization of ~~2027:~~GS, ~~Potential~~specifically in the liver. Our preclinical data has demonstrated proof of concept across multiple in vitro and in vivo models, including a humanized liver mouse model. KRRO-121 utilizes GalNAc-conjugated delivery for ~~Developing~~convenient ~~Differentiated~~subcutaneous ~~Therapies~~administration. We anticipate a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. However, regulators have not yet established any definitive guidelines related to overall development considerations for ~~Patients~~RNA editing therapies.

•

~~Over~~Develop a best-in-class GalNAc-conjugated therapy for patients with AATD. We are advancing a GalNAc-conjugated RNA editing oligonucleotide for AATD that utilizes subcutaneous delivery to repair the ~~next~~protein ~~three~~malfunction ~~years~~caused ~~through~~in the ~~end~~AATD patients, by editing the SERPINA1 RNA in the liver. Our RNA editing lead candidates for AATD have generated compelling preclinical data demonstrating greater than 90% editing of ~~2027~~the SERPINA1 transcript achieved using GalNAc delivery in vivo, thus restoring the production of normal AAT protein. We expect to nominate a development candidate for our ~~goal~~AATD isprogram in the second quarter of 2026. Depending on the evidence of efficacy and tolerability, we intend to: pursue expedited regulatory pathways globally.

•

~~advance~~Continue ~~three~~to ~~product~~optimize and enhance our OPERA platform. We believe we have built a leading RNA editing company through a combination of our OPERA platform, intellectual property strategy and human capital. Our computationally driven approach enables rapid design and optimization of potential lead candidates. We intend to continue to incorporate new data into ~~clinic~~these ~~trials~~machine learning models to improve their ability to predict editing efficiency and to more expeditiously optimize and nominate new development candidates, ~~with~~although ~~KRRO-110~~there ~~being~~is ~~our~~no ~~first~~guarantee that this will result in an accelerated development or approval timeline, if at all.

•

inMaximize the potential of our OPERA platform through collaborations and strategic partnerships. We believe the versatility of our OPERA platform has the potential to create transformative genetic medicines for both rare and highly prevalent diseases. To fully realize this potential, we have established and plan to continue to actively seek out innovative collaborations, licenses, and strategic alliances with clinical leaders, academic medical centers of excellence, patient advocacy groups, and pioneering companies, including, for example, our collaboration with Novo Nordisk for up to two ~~tissue~~partnered ~~types~~programs for cardiometabolic diseases, which entered a 12-month pause in November 2025. Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially

with a single RNA-editing platform.

We refer to this as our 3-2-1 strategy through the end of 2027. We believe RNA editing has potential beyond the treatment of rare genetic diseases and our goal is to apply our OPERA platform to help patients with highly prevalent diseases.

in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

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Invest in human capital and encourage innovation to maintain a leading position and advance the frontiers of genetic medicines. We are a mission-driven organization, and we thrive through a strong culture that embodies our core values. We are actively working to rewrite the future of medicine and remain on the cutting edge of science and research by working better together and being dynamically different in employing a diverse team with varied expertise, enabled by kindness, integrity and respect. We have attracted a talented team of industry experts and experienced scientists as part of a high-performing and nimble organization. Our research and development organization is comprised of individuals with relevant expertise in drug development.

Positioned for Value Creation in 2026 and Beyond

We are well positioned to create significant value in 2026 and beyond with multiple anticipated milestones, with multiple anticipated development candidates:

•

Regulatory filing for KRRO-121 for hyperammonemia anticipated in the second half of 2026.

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Development candidate nomination for our next-generation GalNAc-conjugated AATD program expected in the second quarter of 2026.

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Continued advancement of our longevity and liver health and ALS programs, with cash runway into the second half of 2028 supporting achievement of these milestones

We believe RNA editing has potential beyond the treatment of rare genetic diseases, and our goal is to apply our OPERA platform to help patients with highly prevalent diseases, including HE.

Expanding the Frontiers of Genetic Medicines: RNA Editing

The advent of large-scale genome sequencing has progressively revealed causal genetic variation underlying several human diseases, both rare and highly prevalent. Genetic mutations, including SNVs, implicated in disease have been found to be diverse in nature and can affect the function of genes and their associated downstream biochemical pathways. Natural genetic variations, revealed by population-level genomic studies, have also been shown to protect against or to increase the risk of disease. Beyond these developments, groundbreaking advances in gene therapy, cell therapy and RNA therapeutics have resulted in several approvals that have transformed the treatment of certain genetic diseases and cancers as well as the prevention of infectious diseases, such as COVID-19. In addition, various DNA editing approaches have been developed that introduce specific genetic changes to DNA to treat diseases. First generation CRISPR-Cas9 DNA editing has demonstrated the potential to knockout pathogenic mutations at the single gene level with several programs in clinical development and the first ex vivo DNA editing therapeutic for a rare hematological condition on file at the FDA. Next generation DNA editing approaches have ~~recently~~ entered the clinic and hold the promise to edit DNA at the single nucleotide level.

Despite these advances, significant risks exist with DNA editing approaches. A key concern is the introduction of unwanted DNA modifications (“off-target” edits), which could have permanent adverse effects such as chromosomal integration and non-specific insertions, deletions and substitutions. Additionally, due to the complexity of a multicomponent DNA editing product, delivery to target cells can be challenging and even more so if there is a need to edit multiple genetic loci. Furthermore, manufacturing is highly complex and expanding to commercial scale remains challenging, specifically for a highly prevalent indication. Given these challenges, DNA editing approaches will likely remain a focus for certain rare diseases, while its ability to treat diseases of high prevalence continues to be limited.

ADAR-mediated RNA editing

RNA editing involves altering a sequence of RNA, which intrinsically has the potential to address some of the limitations of DNA editing. RNA editing mediated by adenosine deaminase acting on RNA, or “ADAR-mediated” RNA editing, has ~~recently~~ emerged as a differentiated approach that can generate ~~product~~oligonucleotide ~~candidates~~ having features that combine the precision of genomic therapies with the properties commonly associated with current approved drugs such as titratability and ability to re-dose. Importantly, these drug-like characteristics enable ADAR-mediated RNA editing candidates to be potentially safer and target diseases with high prevalence that would be difficult for DNA editing approaches to address.

ADARs are a family of enzymes present inside a cell, that bind RNA. ADARs bind double-stranded RNA structures, and convert a single base of adenosine (A) on RNA, into an inosine (I) that is typically translated as a guanosine (G), using an enzymatic process. ADAR mediated editing is found at high levels in cephalopods both on the coding and non-coding regions of the RNA. In humans, there are fewer recoding events, and most of the endogenous editing events occur in non-coding regions.

~~ADARs~~enzymatic ~~are essential enzymes for normal physiologic function~~process. ADAR~~-driven~~ ~~RNA~~mediated editing ~~has~~is ~~been~~ found toat behigh ~~critical~~levels ~~for~~in ~~the~~cephalopods ~~function~~both ofon athe ~~number~~coding ofand ~~proteins,~~non-coding ~~such~~regions asof the ~~glutamate ionotropic receptor, which has been found to be almost always~~ RNA~~-edited~~. inIn humans., ~~Given~~there ~~ADARs’~~are ~~natural~~fewer ~~function~~recoding toevents, ~~catalyze~~and ~~A-to-I~~most ~~edits,~~of ~~this~~the endogenous editing ~~system~~events ~~can~~occur bein ~~leveraged~~non-coding ~~to make programmed edits to RNA~~regions. ~~This ability to introduce programmed highly targeted edits into RNA has the potential to expand the reach of genetic medicines with an ability to modify proteins to achieve a desired function.~~

Humans have two known active endogenous ADAR enzymes, ADAR1 and ADAR2. ADAR1 is constitutively expressed and is present in most tissues within the body, whereas ADAR2 is more highly expressed in tissues such as the brain. The ADARs are essential enzymes for normal physiologic function. ADAR-driven RNA editing has been found to be critical for the function of a number of proteins, such as the glutamate ionotropic receptor, which has been found to be almost always RNA-edited in humans. Given ADARs’ natural function to catalyze A-to-I edits, this endogenous editing system can be leveraged to make programmed edits to RNA. This ability to introduce programmed highly targeted edits into RNA has the potential to expand the reach of genetic medicines with an ability to modify proteins to achieve a desired function.

Oligonucleotide-based ADAR-mediated RNA Editing

There are multiple therapeutic approaches to utilize ADAR-mediated RNA editing, including synthetic oligonucleotides, engineered ADARs, and Cas-based editing approaches. Our therapeutic approach delivers oligonucleotides to target tissues and cells to introduce precise edits to RNA through recruitment of endogenous ADAR.

Normally, ADARs are recruited to target RNA editing sites through recognition of specific double-stranded RNA structures such as naturally occurring hairpins or loops in endogenous transcripts. Importantly, one can mimic these double-stranded RNA structures by introducing complementary synthetic oligonucleotides into cells. An oligonucleotide can be engineered to mimic the double-stranded RNA structure such that endogenous ADAR is recruited. Using this targeted approach, a site directed specific A-to-I edit can be introduced.

Figure 12: Mechanism of RNA editing using our proprietary platform

Key Advantages of Oligonucleotide-Based ADAR-Mediated RNA Editing as a Therapeutic Modality

We believe that oligonucleotide-based ADAR-mediated RNA editing is a groundbreaking technology that is ideally suited to expand the application of genetic medicines for indications that DNA editing is unable to address. Over the last two decades, there has been significant research around and development of oligonucleotide-based therapeutics, including modalities such as siRNA and ASOs, that has led to the approval of multiple drugs. Specifically, developments in oligonucleotide chemistry, delivery technologies, tolerability, and manufacturing, combined with better defined regulatory pathways, have led to the approval of oligonucleotide-based therapeutics specific for multiple different tissue types. We believe that oligonucleotide-based ADAR-mediated RNA editing is a groundbreaking technology that is ideally suited to expand the application of genetic medicines for indications that DNA editing is unable to address. We differentiate our approach from DNA-editing by leveraging the know-how from approved oligonucleotide therapies in development of our ~~product~~lead candidates.

While we believe we can demonstrate many of the key advantages of RNA editing, including specificity, delivery, tolerability, manufacturing, and regulatory, we are very early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include, but are not limited to the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

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Specificity: Oligonucleotide-based ADAR-mediated RNA editing enables highly precise edits at the target single nucleotide level on the RNA with low risk of off-target or bystander edits, addressing a key safety concern associated with other DNA editing approaches that carry the risk of permanent insertions and deletions as well as chromosomal integration. Using synthetic oligonucleotides, appropriate chemical modifications can be introduced to increase the overall specificity and targeting efficiency for the site directed RNA editing. The OPERA oligonucleotides are designed to be highly site selective with minimal to no bystander effects or halo effects. To assess global off-target editing, we use a bulk RNA-seq approach to detect base frequency changes at potential off target sites between control and treated samples. We sequence target amplicons via NGS and assess potential A to G editing at all sites across the transcript. In preclinical in vivo studies, we have shown that off-target RNA editing using our technology is negligible and transient.

~~Figure 2. Overview of off-target editing observed in mice across multiple oligonucleotides~~ 8

9integration. Using synthetic oligonucleotides, appropriate chemical modifications can be introduced to increase the overall specificity and targeting efficiency for the site directed RNA editing. The OPERA oligonucleotides are designed to be highly site selective with minimal to no bystander effects or halo effects. To assess global off-target editing, we use a bulk RNA-seq approach to detect base frequency changes at potential off target sites between control and treated samples. We sequence target amplicons via next-generation sequencing and assess potential A to G editing at all sites across the transcript. In preclinical in vivo studies, we have shown that off-target RNA editing using our technology is negligible and transient.

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Delivery: Oligonucleotide-based ADAR-mediated RNA leverages well -established, clinically precedented delivery approaches used in other approved products, such as ~~LNPs and~~ ligand-based approaches. LNP-based delivery of oligonucleotides is a well established and clinically validated delivery approach that provides sustained targeted delivery and editing efficiency, resulting in infrequent dosing and an acceptable tolerability profile. Additionally, LNP delivery of RNA-editing oligonucleotides enhances optimal distribution to targeted cells. One example of a well-established and clinically validated ligand-based delivery approach is GalNAc delivery of oligonucleotides, which provides highly specific and effective delivery to hepatocytes with improved durability and enables convenient subcutaneous administration. Multiple FDA-approved products utilize GalNAc-conjugated delivery, including GIVLAARI and OXLUMO.

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Tolerability: ADAR-mediated RNA editing has a low risk of immunogenicity and can potentially lower off-target editing events resulting in an improved tolerability profile compared to DNA editing approaches. The lower risk of immunogenicity enables the ability to re-dose patients if required, a significant limitation of editing approaches that utilize viral vectors and bacterial Cas systems that carry a higher risk of immunogenicity. The transient and reversible nature of ADAR-based editing confers an ability to modify or cease dosing as needed.

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Manufacturing: Reliance on endogenous ADAR enzymes and the simple drug constructs of oligonucleotide-based therapies has significant advantages over the complexities associated with the manufacturing and delivery of multi-component exogenous complexes used in DNA editing. Manufacturing processes for oligonucleotide-based therapies are well established, cost efficient and scalable to effectively address highly prevalent indications.

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Regulatory: Precedence of marketed oligonucleotide drugs with similar size and types of chemical modifications that therapeutic RNA editing ~~product~~lead candidates exhibit. Guidance for the development of oligonucleotide therapeutics by global agencies, including the FDA, provides for an established pathway for the approval of this class of therapeutics. However, regulators have not yet established any definitive guidelines related to overall development considerations for RNA editing therapies and onlimited clinical data has been generated to date.

Our OPERA – Oligonucleotide Promoted Editing of RNA – Platform

We believe we are the leading RNA editing company and have assembled a suite of technologies and capabilities called OPERA, Oligonucleotide Promoted Editing of RNA, to generate differentiated RNA editing ~~product~~lead candidates~~, or CHORDs~~. A key challenge in developing a therapeutic approach for site-directed RNA editing is to design and optimize oligonucleotides that can drive high-efficiency. This efficiency is facilitated both by the ability to repurpose and optimize oligonucleotide constructs based on existing methods as well as utilizing computational methods to innovate on chemistry and design of the constructs. Our ~~RNA editing product candidates are~~ oligonucleotides capable of forming Watson-Crick base pairing with the target RNA and efficiently inducing the deamination reaction by endogenously recruiting ADAR enzymes.

We have assembled a suite of technologies and capabilities to build our RNA editing platform, Oligonucleotide Promoted Editing of RNA, or OPERA.

OPERA relies on the following key components that enable us to generate our differentiated RNA editing ~~product candidates~~oligonucleotides:

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Expertise in ADAR biology: Our insights and know-how of ADAR biology allow us to design oligonucleotides that efficiently recruit ADARs and promote deamination while maintaining selectivity and stability. RNA editing is dependent on endogenous ADAR expression levels and requires expertise in the physiological role of ADAR, its cell and tissue distribution, the factors that lead to efficient recruitment of ADAR to targeted sites and any consequences that may arise from co-opting ADAR from its normal function. We have developed a cell-free in vitro RNA editing assay with purified human ADAR1 and ADAR2 that predicts the RNA editing activity with our oligonucleotides. With our cell free assay capability, we are able to limit the number of components implicated in screening (target gene, RNA editing product candidates and ADAR), allowing us to measure the kinetics of RNA editing more accurately. Using only three components including the target RNA, oligonucleotide, and ADAR, we have shown that target editing efficiency is correlated with the chemical modification pattern of an oligonucleotide. Furthermore, we have found that this activity predicts the rank order of oligonucleotides in both in vitro cell-based systems and in vivo in rodents. This assay capability supports our understanding of the key steps required to edit RNA at a level of detail that is not possible in cells. These platform biology assay capabilities have enabled detailed mechanistic studies into the tissue distribution and subcellular localization of ADAR proteins and our RNA editing product candidates.

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We have found no evidence that our RNA editing oligonucleotides interfere with endogenous RNA editing occurring naturally in a cell. ADAR naturally edits thousands of targets for a variety of reasons. We have looked at natural editing sites and chose AJUBA, COG and COPA as they have shown to be edited by ADAR to different degrees. In this experiment outlined in Figure 3, ZZ HLC cell lines were transfected with RNA editing ~~product~~oligonucleotides ~~candidates~~ targeting two different genes. The assays were evaluated for % editing for Target A and Target B sites as well as natural editing sites in COG, COPA and AJUBA. As shown below, natural editing sites remained unaffected compared to the

control group, demonstrating that our RNA editing oligonucleotides are not likely to have any effect on the degree of editing of native RNA molecules.

Figure 3. Our RNA editing oligonucleotides show no evidence of interference with endogenous ADAR editing as demonstrated at the above endogenous sites

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Expertise in oligonucleotide chemistry: We have a differentiated ability to create oligonucleotide designs capable of efficiently recruiting endogenous ADAR with chemical modifications that direct high specificity editing. Our oligonucleotides increase the potency and durability of ADAR activation, thereby increasing the editing efficiency and translational efficacy of our RNA editing oligonucleotides. We have identified critical structural, sequence, and chemistry requirements for our RNA editing oligonucleotides that drive efficient recruitment of ADARs and subsequent A-to-I editing. Examples of differentiation include oligonucleotide length for efficient ADAR recruitment, use of precedented and proprietary chemistries within the oligonucleotide, as well as backbone chemistries that provide improved metabolic stability. Additionally, we combine this with 2’ modification chemistries that, together, create oligonucleotides with improved editing efficiency and durability. As RNA editing is an emerging technology, there is a lack of guiding principles to design site-selective RNA editing oligonucleotides. To address this knowledge gap, we developed a robust in-house process using our high-throughput cell-based assay and machine learning capabilities to design and synthesize up to approximately 1,200 oligonucleotides per month and generate up to 6,000 assay data points for any given target.

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Machine learning optimization of oligonucleotides and target identification: We have built data science capabilities and a dedicated team to extract lessons from existing and newly generated experimental data to expeditiously and efficiently design and optimize RNA editing oligonucleotides. Our proprietary machine learning models have been trained to accurately predict oligonucleotide structure and observed levels of editing. We have been able to demonstrate that these models are able to make accurate editing predictions even for previously unseen chemical modifications demonstrating their generalizability across targets. We have demonstrated the utility of our machine learning models through an increase in overall editing efficiency of new RNA editing oligonucleotides. In some cases, we have been able to go from design-to-data in as little as five weeks. However, there is no guarantee that this will result in an accelerated development or approval timeline, if at all.

Figure 4. We have shown our ability to rapidly iterate RNA editing oligonucleotides to maximize editing efficiency

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~~compared~~Structural modeling is another tool that complements our ability to increase the ~~control~~efficiency ~~group~~of our RNA editing oligonucleotides. Detailed structural modeling includes shape, ~~demonstrating~~size and orientation requirements that can lead to successful deamination at the editing site. These aspects have an important impact on our ability to optimize RNA editing ~~product~~oligonucleotides. ~~candidates~~As ~~are~~an ~~not~~example, ~~likely~~a modification predicted by structural analyses led to ~~have~~a ~~any~~conformational ~~effect~~change onthat ~~the~~was ~~degree~~shown ofto improve editing efficiency in the coding region of ~~native~~the ~~RNA~~Target ~~molecules~~A in vivo.

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~~Figure~~Leveraging 3.known delivery modalities: Our RNA editing ~~product~~oligonucleotides utilize short synthetic oligonucleotides, which we believe can be efficiently delivered using technologies such as GalNAc, which is well established and clinically validated and has been developed for precedented modalities such as siRNAs and ASOs. GalNAc has optimal characteristics suited for a given therapeutic application, and we believe has the potential to derisk our lead candidates. ~~show~~Using noRNA ~~evidence~~editing ofoligonucleotides, ~~interference~~we achieved greater than 50% editing in vivo utilizing a ligand-based GalNAc conjugate delivery approach. Ligand-based approaches (e.g., GalNAc for liver hepatocytes) can also be used for effective delivery and to improve durability with ~~endogenous~~OPERA’s ~~ADAR~~RNA editing oligonucleotides, which we have also evaluated in preclinical in vivo models. In contrast to treatments targeting liver hepatocytes where there is a need for a delivery system, our RNA editing oligonucleotides have been delivered intrathecally to the central nervous system without a need for any delivery system in preclinical mouse models. Thus, our choice of delivery system is a fit-for-purpose model that is dependent on the oligonucleotide design as ~~demonstrated~~well atthe suitability for the ~~above~~indication ~~endogenous~~and ~~sites~~tissue localization of the target.

Expertise in oligonucleotide chemistry: We have a differentiated ability to create oligonucleotide designs capable of efficiently recruiting endogenous ADAR with chemical modifications that direct high specificity editing. Our oligonucleotides increase the potency and durability of ADAR activation, thereby increasing the editing efficiency and translational efficacy of our product candidates. We have identified critical structural, sequence, and chemistry requirements for our product candidates that drive efficient recruitment of ADARs and subsequent A-to-I editing. Examples of differentiation include oligonucleotide length for efficient ADAR recruitment, use of precedented and proprietary chemistries within the oligonucleotide, as well as backbone chemistries that provide improved metabolic stability. Additionally, we combine this with 2’ modification chemistries that, together, create oligonucleotides with improved editing efficiency and durability. As RNA editing is an emerging technology, there is a lack of guiding principles to design site-selective RNA editing oligonucleotide product candidates. To address this knowledge gap, we developed a robust in-house process using our high-throughput cell-based assay and machine learning capabilities to design and synthesize up to approximately 1,200 oligonucleotides per month and generate up to 6,000 assay data points for any given target.

Machine learning optimization of oligonucleotides and target identification: We have built data science capabilities and a dedicated team to extract lessons from existing and newly generated experimental data to expeditiously and efficiently design and optimize RNA editing product candidates. Our proprietary machine learning models have been trained to accurately predict oligonucleotide structure and observed levels of editing. We have been able to demonstrate that these models are able to make accurate editing predictions even for previously unseen chemical modifications demonstrating their generalizability across targets. We have demonstrated the utility of our machine learning models through an increase in overall editing efficiency of new product candidates. In some cases, we have been able to go from design-to-data in as little as five weeks. However, there is no guarantee that this will result in an accelerated development or approval timeline, if at all.

Figure 4. We have shown our ability to rapidly iterate product candidates to maximize editing efficiency

Structural modeling is another tool that complements our ability to increase the efficiency of our RNA editing candidates. Detailed structural modeling includes shape, size and orientation requirements that can lead to successful

deamination at the editing site. These aspects have an important impact on our ability to optimize RNA editing product candidates. As an example, a modification predicted by structural analyses led to a conformational change that was shown to improve editing efficiency in the coding region of the Target A in vivo.

Figure 5. We have a demonstrated ability to improve editing in target coding regions

Leveraging known delivery modalities: Our product candidates utilize short synthetic oligonucleotides, which we believe can be efficiently delivered using technologies such as LNP or GalNAc. These delivery technologies are well established and clinically validated and have been developed for precedented modalities such as siRNAs and ASOs. Each of these delivery vehicles has optimal characteristics suited for a given therapeutic application, and we believe have the potential to derisk our product candidates. Using CHORDs, we achieved greater than 50% editing in vivo utilizing both a ligand-based GalNAc conjugate and an LNP-based delivery approach (see Figure 6).

Additionally, LNP mediated delivery of RNA editing product candidates provides sustained delivery and an acceptable tolerability profile that have been manufactured at a scale sufficient to serve the target population. In addition to LNP based delivery approach, ligand-based approaches (ex., GalNAc for liver hepatocytes) can also be used for effective delivery and to improve durability with OPERA’s RNA editing product candidates, which we have also evaluated in preclinical in vivo models. In contrast to treatments targeting liver hepatocytes where there is a need for a delivery system, our RNA editing product candidates have been delivered intrathecally to the central nervous system without a need for any delivery system in preclinical mouse models. Thus, our choice of delivery system is a fit-for-purpose model that is dependent on the oligonucleotide design as well the suitability for the indication and tissue localization of the target. However, this delivery system has not yet been finalized and while LNPs have been validated clinically to deliver oligonucleotides, such as siRNA, they have not been clinically proven to deliver oligonucleotides for RNA editing, such as our product candidates.

Figure 6. Demonstrated greater than 50% editing using GalNAc conjugates in the liver in a preclinical mouse model.

Our Pipeline Demonstrates the Versatility of the OPERA Platform

We are advancing a broad pipeline of four programs that are wholly owned and demonstrate the versatility of our OPERA platform,. ~~along~~We ~~with~~also have the opportunity to advance up to two programs ~~partnered~~under our collaboration with Novo Nordisk, ~~for~~which ~~cardiometabolic~~entered ~~diseases.~~a In12-month ~~January~~pause in November 2025. weOur ~~announced~~most ~~dosing~~advanced ofprogram, ~~the~~KRRO-121 ~~first~~for ~~participants~~hyperammonemia, is advancing toward a regulatory filing anticipated in ~~our~~the ~~Phase~~second ~~1/2a~~half ~~REWRITE~~of ~~clinical~~2026. Our AATD program ofis ~~KRRO~~progressing with a next-~~110~~generation ~~for~~GalNAc-conjugated ~~AATD~~candidate, ~~and~~with wedevelopment candidate nomination expected in the second quarter of 2026. All of our programs are in the research or preclinical stage of development. The risk of failure of all of our programs is high.

1De novo protein variant to prevent toxic GoF with TDP43 aggregation and continue downstream signaling by overcoming toxic LOF

Approximately 85% of the human proteome has historically been considered undruggable through traditional therapeutic modalities as many proteins lack defined small molecule binding sites or are inaccessible by biologics. The versatility of RNA editing, combined with our OPERA platform, addresses a meaningful portion of the undruggable human proteome and broadens the target space. Our target identification and selection for programs is based on strong genetic evidence implicating each target in its disease pathology.

Figure 5: Applications of RNA editing are broad and can be applied in multiple ways to generate a de novo protein with enhanced and augmented properties by just modifying a single amino acid through RNA editing.

Our initial focus is to make edits to the coding region of a transcriptome. Making changes post-transcriptionally, after the mRNA has been created and prior to the protein being translated, provides an exquisite, selective approach for modifying proteins. In preclinical studies, we have demonstrated that single RNA changes can stabilize proteins, disrupt protein-protein interactions, prevent protein aggregation, selectively modulate an ion channel and selectively activate a kinase. These modification approaches have the potential to unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases, including those with high prevalence and large market opportunities.

Stabilize Protein: We are using OPERA to engineer protein stability and enable synthetic rescue. Enabling synthetic rescue provides a novel modality to target intracellular proteins. Our lead program, KRRO-121, exemplifies this synthetic rescue approach by engineering a de novo GS protein with a single amino acid change that is designed to prevent glutamine-induced proteasomal degradation, thereby maintaining ammonia clearance capacity. This approach creates a protein that is engineered to retain full enzymatic activity while resisting the natural degradation pathway, highlighting the broad capabilities of what our OPERA RNA editing platform can accomplish in driving biological change. By focusing specifically on hepatocytes, and delivering our RNA editing oligonucleotides via a GalNAc conjugate, we have the ability to provide control over the cell types on which the GS is stabilized, thereby enhancing the safety profile of the candidate.

Figure 6. KRRO-121 introduces a single amino acid change in GS to enhance ammonia clearance

Repairing pathogenic variants: Our OPERA platform enables the development of RNA editing therapies that can repair SNVs on RNA to express normal proteins through the introduction of precise genetic changes without creating permanent changes to the genome. These normal proteins can be uniquely expressed at desired levels and duration to address both rare and

~~recently~~highly ~~completed~~prevalent ~~dosing~~diseases ofcaused ~~the~~by ~~first~~a ~~two~~pathogenic ~~cohorts~~SNV. ~~All~~This ofapproach ~~our~~is ~~other~~especially ~~programs~~relevant ~~are~~when ~~still in~~ the ~~research~~same orunderlying ~~preclinical~~genetic ~~stage~~SNV ofmanifests ~~development.~~in ~~The~~a ~~risk~~broad ofdisease ~~failure~~phenotype offrom ~~all~~mild ofto ~~our~~severe ~~programs~~forms isof ~~high~~the disease.

~~1De~~Our ~~novo~~program ~~protein~~for ~~variant~~AATD toaddresses ~~prevent~~a ~~toxic~~single ~~gain-~~genetic SNV in the SERPINA1 gene that causes the development of~~-function~~ ~~(GoF)~~AAT deficiency, which has a high unmet medical need and for which there are no disease modifying treatment options. The disease manifests with ~~TDP43~~a ~~aggregation~~heterogenous population having both liver and ~~overcome~~lung ~~toxic~~pathologies. ~~loss-~~By specifically editing a single nucleotide, the normal synthesis of- AAT is restored, resulting in secretion of normal AAT to levels that are predicted to protect the lung from further decline in function. ~~(LoF)~~The correction of a subset of AAT produced also prevents aggregation of AAT protein in the liver, thereby potentially alleviating damage to the liver.

~~Our~~Figure ~~proprietary~~7: ~~oligonucleotides co-opt endogenous ADAR to perform a single~~ A~~-to-I~~ ~~base~~glutamic ~~edit~~acid onwas ~~RNA~~converted to ~~modify~~a ~~protein~~lysine ~~function.~~with ~~Delivery of these proprietary oligonucleotides into~~ a ~~cell~~single ~~forms an oligonucleotide-~~RNA ~~duplex which recruits endogenous ADAR~~edit, ~~ultimately~~leading ~~editing a target adenosine (A)~~ to ~~inosine (I) on RNA. The location of~~ the ~~edit~~correction ~~can lead to a multitude~~ of ~~effects including changes in expression and regulation of mRNA. In~~ the ~~event~~AAT anprotein ~~edit is made~~ in ~~the~~patients ~~coding~~with ~~region~~AATD ~~of the gene, the mRNA is then translated to a protein~~ with ~~the (I) inosine read as~~ a ~~(G)~~at ~~guanosine,~~least ~~resulting in~~ a ~~modified~~single ~~protein. The resultant therapeutic protein can be applied to go beyond repairing pathogenic SNVs by changing amino acids on proteins implicated in disease biology. Single amino acid changes to non~~Z-~~mutated RNA can create de novo modified protein variants with desired altered properties while preserving their broader functional capabilities.~~ allele

~~Repairing~~Other ~~pathogenic~~Target ~~variants~~Classes: ~~Our~~In ~~OPERA~~addition ~~platform enables the development of RNA editing therapies that can repair SNVs on mRNA~~ to ~~express~~engineering ~~normal~~protein ~~proteins~~stability ~~through~~and ~~the~~repairing ~~introduction of precise genetic changes without creating permanent changes to the genome. These normal~~ proteins, ~~can~~we beare ~~uniquely~~also ~~expressed~~advancing atlead ~~desired~~candidates ~~levels and duration~~ to ~~address~~selectively ~~both~~activate ~~rare~~intracellular ~~and~~kinases ~~highly~~in ~~prevalent diseases caused by a pathogenic SNV. This approach is especially relevant when~~ the ~~same~~liver ~~underlying~~and ~~genetic SNV manifests~~ in athe ~~broad~~central ~~disease~~nervous ~~phenotype~~system ~~from mild~~ to ~~severe~~prevent ~~forms~~protein ofaggregation ~~the~~within ~~disease~~neuronal cells.

~~Figure~~Rather 7than treating late-stage disease, we are focused on extending organ health-span, or longevity. ~~RNA~~The ~~editing~~three fundamental reasons as to why organs age are: metabolic dysfunction, oxidative stress, and inflammation accumulation. AMPK, when activated, inhibits anabolic pathways like lipogenesis and protein synthesis, activates catabolic pathways including fatty acid oxidation and autophagy, and regulates glucose homeostasis by enhancing insulin sensitivity. The γ1 subunit—AMPKγ1—represents the optimal liver therapeutic target because of its hepatocyte enrichment. Our longevity and liver health program targeting AMPKγ1 in the liver exemplifies our kinase activation approach, where a single ~~nucleotide~~RNA ~~can~~edit ~~restore~~is ~~normal~~designed ~~protein~~to ~~expression~~activate a master metabolic regulator with the goal of restoring metabolic status and improving liver function.

~~Our~~In ~~lead~~addition to our longevity and liver health program, ~~for~~we ~~AATD~~have ~~addresses~~been focused on creating a ~~single~~de ~~genetic~~novo ~~SNV~~version inof ~~the~~a ~~SERPINA1~~normal ~~gene~~protein that, ~~causes~~under certain disease states, can prevent the ~~development~~aggregation of ~~AAT~~the ~~deficiency~~native version, ~~which~~while ~~has~~preserving the native protein’s intrinsic function. This is a ~~high~~therapeutic ~~unmet~~approach ~~medical~~that ~~need~~has ~~and~~the ~~for~~potential ~~which~~to ~~there~~provide ~~are~~a nodifferentiated ~~disease~~therapeutic ~~modifying~~option ~~treatment~~over ~~options~~knocking down or silencing the protein through alternate mechanisms. ~~The~~Intracellular ~~disease~~protein ~~manifests~~aggregation ~~with~~is a ~~heterogenous~~cause ~~population~~of ~~having~~multiple ~~both~~diseases ~~liver~~across ~~and~~the ~~lung~~body. ~~pathologies~~Specifically in neurodegenerative diseases, accumulation of specific proteins within neurons are pathogenic including Alzheimer’s disease, Parkinson’s disease, and ALS. ByIn ~~specifically~~pathological ~~editing~~conditions, asuch ~~single~~as ~~nucleotide~~ALS, ~~the~~TAR ~~normal~~DNA-binding ~~synthesis~~protein of43, ~~AAT~~or TDP-43, is ~~restored~~depleted from the nucleus and accumulates as protein aggregates in the cytoplasm in hyperphosphorylated, ~~resulting~~ubiquitinated, and cleaved forms. These aggregates are observed in ~~secretion~~more than 90% of ~~normal~~ALS ~~AAT~~patients. A single RNA edit to ~~levels~~TDP-43 ~~which~~transcript ~~are~~is predicted to ~~protect~~lead to the ~~lung~~synthesis ~~from~~of ~~further~~a ~~decline~~de innovo ~~function.~~protein ~~The~~that ~~correction~~does ofnot aaggregate ~~subset~~and ofpreserves ~~AAT~~its ~~produced~~normal ~~also~~function. ~~prevents~~Given ~~aggregation~~TDP-43 ofis ~~AAT~~essential ~~protein~~for inneuronal ~~the liver~~health, ~~thereby~~knocking ~~potentially~~down ~~alleviating~~the ~~damage~~protein tocould ~~the~~be ~~liver~~detrimental.

~~Other~~Figure ~~protein~~8. ~~modifications~~Our lead candidates can reduce pathogenic aggregation of undesirable proteins

~~Approximately~~We ~~85%~~believe ofthat the ~~human~~elegance ~~proteome~~and ~~has~~versatility ~~historically~~of ~~been~~our ~~considered~~RNA ~~undruggable~~editing ~~through~~approach ~~traditional~~will ~~therapeutic~~enable ~~modalities~~a asrobust ~~many~~pipeline ~~proteins~~of ~~lack~~potentially ~~defined~~disease ~~small~~modifying ~~molecule~~development ~~binding~~candidates ~~sites~~to ortreat ~~are~~diseases ~~inaccessible~~previously unattainable by ~~biologics.~~genetic ~~The~~medicine ~~versatility~~approaches. ofWhile ~~RNA~~the ~~editing,~~above ~~combined~~examples ~~with~~demonstrate ~~our~~the ~~OPERA~~breadth ~~platform, addresses a meaningful portion~~ of ~~the~~applications ~~undruggable~~enabled ~~human~~by ~~proteome~~OPERA, ~~and~~we ~~broadens~~believe ~~the~~our ~~target~~RNA ~~space.~~editing ~~Our~~approach ~~target~~will ~~identification~~bring ~~and~~the ~~selection~~first ~~for~~genetic ~~programs~~medicine isto ~~based~~address onthe ~~strong~~complex genetic ~~evidence~~underpinnings ~~implicating~~of ~~each~~highly ~~target~~prevalent ~~in its disease pathology~~diseases.

Our ~~initial~~Hyperammonemia ~~focus~~Program: ~~is to make edits to the coding region of a transcriptome. Making changes post~~KRRO-~~transcriptionally,~~121 ~~after~~– ~~the~~Stabilizing ~~mRNA~~Glutamine ~~has~~Synthetase ~~been created and prior~~ to ~~the~~Clear protein being translated, provides an exquisite, selective approach for modifying proteins. In preclinical studies, we have demonstrated that single RNA changes can disrupt protein-protein interactions, prevent protein aggregation, selectively modulate an ion channel and selectively activate a kinase. These modification approaches have the potential to unlock validated target classes that have historically been difficult to drug, enabling us to pursue a broad range of diseases, including those with high prevalence and large market opportunities. Ammonia

~~Disrupting~~Our ~~Protein-Protein~~development ~~Interaction:~~candidate, ~~Modulating protein~~KRRO-~~protein~~121, ~~interactions~~is ~~provides~~ a ~~novel~~potential ~~modality~~first-in-class totreatment ~~target intracellular proteins specifically~~ for ~~increasing~~hyperammonemia ~~the~~that ~~activity~~could ofaddress ~~the~~substantial ~~protein.~~unmet ~~Single~~need ~~amino~~in ~~acid~~patients ~~changes~~with topoor ~~non-mutated~~ammonia ~~RNA can disrupt binding of inhibitors to target proteins~~control, including ~~transcription~~those ~~factors,~~with ~~promoting~~UCD ~~enhanced~~and ~~biological activity of the target protein~~HE. ~~There~~KRRO-121 ~~are~~is ~~two~~an ~~ways~~RNA-editing ~~this~~oligonucleotide ~~could~~conjugated ~~provide~~with ~~increasing~~GalNAc ~~activation,~~to ~~either~~deliver ~~through~~the aconstruct ~~hyperactive~~specifically ~~protein,~~to orthe ~~through~~liver. ~~the~~Utilizing ~~presence~~our ofproprietary aOPERA ~~longer~~platform, ~~half~~KRRO-~~life~~121 oris ~~both.~~designed ~~Such~~to angenerate ~~approach~~a ~~highlights~~stabilized, ~~the~~de ~~broad~~novo ~~capabilities~~variant of ~~what~~GS anwith ~~RNA~~enhanced ~~editing~~ammonia ~~platform~~clearance ~~can accomplish in driving biological change~~capacity.

~~Figure~~There 8.are ~~Our~~an ~~oligonucleotides~~estimated ~~have~~4,200 severe late-onset UCD patients in United States, and 5,100 in the ~~ability~~European toUnion ~~disrupt~~and ~~protein~~United Kingdom, and there are approximately 80,000 addressable patients in the United States with severe or recurring HE, high ammonia levels (≥1.5x upper limit of normal), and sufficient liver function may benefit from ammonia-~~protein~~lowering ~~interactions~~treatment, ~~using~~with ~~precise~~approximately ~~edits~~an additional 150,000 patients in the European Union and United Kingdom.

~~Other Target Classes:~~ In addition to ~~disrupting~~the ~~protein-protein~~inherent ~~interactions,~~benefits weof ~~are~~ADAR-based ~~also~~RNA ~~advancing~~editing ~~product~~described ~~candidates~~earlier, towe ~~prevent~~believe ~~protein~~our ~~aggregation,~~approach ~~selectively~~for ~~modulate~~potentially ~~ion~~treating ~~channels~~hyperammonemia ~~and~~has ~~activate~~additional ~~kinases.~~potential advantages:

•

~~Intracellular~~Provides ~~protein aggregation is~~ a ~~cause~~pan-UCD ofapproach addressing multiple ~~diseases~~UCD ~~across~~subtypes ~~the~~irrespective ~~body. Specifically in neurodegenerative diseases, accumulation~~ of ~~specific~~their ~~proteins~~enzyme ~~within~~deficiencies ~~neurons~~in ~~are pathogenic including Alzheimer’s disease, Parkinson’s disease, and ALS. Creating a protein variant that can prevent~~ the ~~aggregation,~~urea while preserving its intrinsic function, is a therapeutic approach that has the potential to provide a differentiated therapeutic option over knocking down or silencing the protein through alternate mechanismscycle.

•

Stabilization of GS protein specifically in the liver.

•

Convenient subcutaneous delivery with the potential for >once in 2-week delivery using precedented GalNAc-conjugated technology.

•

Potential for additional benefits including a reduction in hyperammonemic crises and diet liberalization for UCD patients, and a reduction in HE events for HE patients.

We have generated compelling preclinical data demonstrating proof of concept for stabilizing GS using mouse surrogate compounds as well as for KRRO-121 in human systems. KRRO-121 maintains GS protein levels during ammonia challenge in OTC-deficient and ASS1-deficient iPSC-derived hepatocytes. In OTC-deficient mice challenged with ammonia, treatment with a mouse-optimized oligonucleotide reduced ammonia, supporting the potential to both maintain ammonia levels as well as the potential to increase protein intake and dietary liberalization in patients with UCD. In CPS-1 deficient mice, ammonia was reduced post-ammonia challenge, with nonsignificant increase in plasma glutamine levels. In a humanized liver mouse model (PXB), KRRO-121 reduced basal ammonia levels and enhanced ammonia clearance following challenge, with production of stabilized de novo GS variant. In NHPs, KRRO-121 displayed >90% delivery to liver, confirmed liver localization with pericentral GS, and no observed changes in liver or kidney function, coagulation, complement, platelets, or cytokines.

Based on the preclinical data, we believe KRRO-121 has potential to be a first-in-class treatment for ammonia control. We anticipate submitting a regulatory filing to enable commencement of a first-in-human trial in the second half of 2026. The compelling product profile for controlling ammonia is expected to drive strong patient engagement and recruitment. While we

~~Figure~~believe 9we can demonstrate many of the key advantages of RNA editing, we are very early in our development efforts and not yet certain of the results we may achieve. ~~Our~~Such ~~product~~uncertainties ~~candidates~~include, ~~can~~but ~~reduce~~are ~~pathogenic~~not ~~aggregation~~limited to, the level of ~~undesirable~~editing ~~proteins~~efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

~~One~~Hyperammonemia of our programs for disrupting protein aggregation is in early-stage discovery for the treatment of ALS. We are selectively modulating TDP-43, an RNA/DNA-binding protein, which carries out a variety of important functions in healthy neurons including initiation of transcription, pre-mRNA splicing, and miRNA processing. In pathological conditions, such as ALS, TDP-43 is depleted from the nucleus and accumulates as protein aggregates in the cytoplasm in hyperphosphorylated, ubiquitinated, and cleaved forms. These aggregates are observed in more than 90% of ALS patients. A single RNA edit to TDP-43 is predicted to lead to the synthesis of a protein variant that does not aggregate and preserves its normal function. Given TDP-43 is essential for neuronal health, knocking down the protein could be detrimental. Overview

WeAmmonia ~~believe~~is ~~that~~a ~~the~~toxic ~~elegance~~byproduct ~~and versatility~~ of ~~our~~protein ~~RNA~~metabolism. ~~editing~~The ~~approach~~body ~~will~~clears ~~enable~~ammonia athrough ~~robust~~two ~~pipeline~~complementary ofpathways: ~~potentially~~the ~~disease~~urea ~~modifying~~cycle, ~~product~~which ~~candidates~~is toexpressed ~~treat~~primarily ~~diseases~~in ~~previously~~the ~~unattainable~~liver byand ~~genetic~~converts ~~medicine~~ammonia ~~approaches.~~to ~~While~~urea ~~the~~for ~~above~~excretion, ~~examples~~and ~~demonstrate~~ the ~~breadth~~GS ~~of applications enabled by OPERA~~pathway, wewhich ~~believe~~is ~~our~~expressed ~~RNA~~in ~~editing~~many ~~approach~~tissues ~~will~~including ~~bring~~ the ~~first~~liver, ~~genetic~~brain ~~medicine~~and tomuscle, ~~address~~and ~~the~~converts ~~complex~~ammonia ~~genetic~~and ~~underpinnings~~glutamate ofinto ~~highly prevalent diseases~~glutamine.

Hyperammonemia, characterized by elevated levels of toxic ammonia in the blood, is a life-threatening condition resulting from the body’s diminished clearance capacity. When this clearance is compromised, ammonia accumulates systemically, driving pathology across multiple disease states. High ammonia levels are directly linked to severe clinical outcomes. The pathology of hyperammonemia manifests through:

•

Neurological Impairment: Elevated ammonia is neurotoxic, leading to cognitive decline, encephalopathy, and potentially permanent brain damage.

•

Systemic Complications: Beyond the brain, hyperammonemia is associated with elevated infection risks and other non-neurological complications.

•

Severe Lifestyle Restrictions: Patients currently face highly restricted diets to limit protein intake, which can paradoxically lead to malnutrition and metabolic instability.

•

High Healthcare Utilization: Uncontrolled ammonia drives frequent, costly hospitalizations.

Glutamine Synthetase and its function

GS is an enzyme primarily responsible for clearing toxic ammonia from the body. It catalyzes the condensation of glutamate and ammonia to form glutamine. This reaction is a critical, complementary pathway to the urea cycle for detoxifying ammonia. While the urea cycle is expressed primarily in the liver, GS is expressed in many tissues, including the liver, brain, and muscle. GS plays a “scavenging” role, in addition to the urea cycle, to prevent the ammonia from staying in systemic circulation. The stability and activity of GS are tightly regulated by the levels of its product, glutamine. When glutamine levels rise, it drives the degradation of GS protein through known mechanisms. This degradation mechanism involves the acetylation of key N-terminal lysine residues on the GS protein, which tags it for proteasomal degradation. This creates a feedback loop where high glutamine leads to reduced GS levels, diminishing the body’s ammonia clearance capacity. Conversely, when glutamine is low, GS remains stable (without lysine acetylation) to maximize ammonia clearance.

Figure 9. Depicts the glutamine-mediated feedback regulation of GS protein stability, illustrating how elevated glutamine levels trigger degradation of GS, thereby modulating the body’s ammonia clearance capacity.

Urea Cycle Disorders

UCDs are a group of severe, inherited metabolic diseases caused by mutations in the genes that encode one or more of the eight enzymes and transporters necessary to convert ammonia into urea. The inability of the body to properly metabolize ammonia leads to the accumulation of toxic systemic levels in circulation, ultimately resulting in severe health outcomes, such as neurologic disability, seizure and death. UCDs occur across all age groups, from infants to adults, and mild symptoms may go unnoticed until a stressor, such as illness, surgery, protein consumption or environmental stress, overwhelms compensatory functions, resulting in hyperammonemic crisis. The incidence of UCDs in the United States is estimated to be approximately one in 35,000 births. The most common UCD, accounting for approximately 60% of UCD diagnoses, is OTC deficiency. The next two most common genetic subtypes are caused by mutations in the genes coding for the enzymes argininosuccinate lyase, or ASL, and ASS1, affecting approximately 16% and 14% of UCD patients, respectively.

There are approximately 6,500 UCD patients in the United States, of which approximately 4,600 are post-neonatal onset and approximately 4,200 are severe late-onset patients who we believe could benefit from pharmacological therapy. We estimate an additional approximately 5,100 addressable patients exist in the European Union and United Kingdom. There are no FDA-approved, disease-modifying therapies to treat the most prevalent UCDs. The standard of care is supportive in nature and intended to reduce the frequency of, but not eliminate, hyperammonemic crises. Current protocols for patients involve strict adherence to a low-protein diet along with the prophylactic use of nitrogen scavenger agents, which carry an onerous pill regimen and significantly diminish the quality of life for patients. Despite these measures, 20% to 25% of patients experience breakthrough hyperammonemic crises. Liver transplantation is the only definitive treatment option.

Current standard of care for all UCD subtypes are drugs that fall in the class of nitrogen scavengers. These include Sodium phenylbutyrate (NaPBA, Buphenyl®) and Glycerol phenylbutyrate (GPB, Ravicti®), both of which are prodrugs of phenylacetic acid, which is converted to phenylacetyl glutamine and excreted in urine. Both the approved products are an oral suspension taken three times a day. The current approved products have the potential to control ammonia levels in UCD patients; however, it is challenging for multiple reasons including compliance in school age kids and adolescents, severe dietary restrictions where the diets sometimes do not resemble food, and both drugs having a narrow therapeutic index despite the need to take it multiple times a day.

Hepatic Encephalopathy

HE is a brain dysfunction caused by liver insufficiency and/or portal systemic shunting. Because the damaged liver in cirrhosis cannot function normally, neurotoxins such as ammonia are inadequately removed from systemic circulation and travel to the brain, where they affect neurotransmission. This can cause episodes of HE, which may present as alterations in consciousness, cognition, and behavior that range from minimal to severe. Overt HE occurs in 30% to 40% of patients with

cirrhosis at some point during the clinical course of their disease. As the burden of chronic liver disease and cirrhosis is increasing, the frequency of HE is also increasing.

There are approximately 2.2 million patients with cirrhosis in the United States, of whom approximately 140,000 experience severe or recurring HE. We estimate that up to approximately 80,000 of these patients who have high ammonia levels and sufficient liver function could potentially benefit from an ammonia-lowering treatment such as KRRO-121. We estimate an additional approximately 150,000 addressable patients in the European Union and United Kingdom. Current standard of care includes rifaximin and lactulose, which reduce ammonia production by gut bacteria but do not directly address ammonia clearance capacity. The unmet need, like UCD patients, is very high. The current standard of care does not reduce ammonia to levels that is needed, drugs approved for UCD are not used in HE patients as they are not approved and/or the compliance in HE patients is challenging given all of the other drugs needed. HE is also not prioritized for a liver transplant. In addition, the healthcare utilization of these patients is one of the highest for patients with liver disease, making the unmet need high both from a medical and pharmacoeconomic standpoint.

Alternative Treatments in Development for UCD and HE

The treatment landscape for UCD remains an area of active investigation, with multiple modalities in clinical development. Gene therapy and gene editing approaches attempt to deliver a functional copy of the deficient urea cycle gene, most notably OTC. Given the inherent risks associated with DNA-based approaches, both these approaches would likely be most applicable for only the most severe patients, and clinical development is presently limited to only those with OTC deficiency. An mRNA-based approach to deliver functional mRNA to hepatocytes via LNPs has also been tested in patients. However, the requirement for repeated intravenous dosing and the potential for immune responses to the delivery vehicle may limit long-term feasibility and restrict patient independence.

Our approach has distinct potential advantages over these alternative treatments in development, including:

•

Pan-UCD applicability with potential to address all subtypes regardless of genotype.

•

Improved ammonia control complementary to the existing standard of care.

•

Transient, redosable, and titratable approach with convenient subcutaneous administration.

For hepatic encephalopathy, the pipeline remains limited and has faced multiple recent setbacks. Approaches targeting ammonia removal have shown signs of efficacy in early-stage trials, but none appear to be in active clinical development. Microbiome-based approaches have also been tested, but to date, none have successfully progressed through late-stage clinical development for the treatment of HE, and there is limited evidence supporting ammonia-lowering effects of these approaches.

Our Differentiated Approach: Engineering a Stable GS Variant Through Synthetic Rescue

KRRO-121

KRRO-121 exemplifies our synthetic rescue approach, in which a targeted mRNA edit is introduced to compensate for the functional deficiency caused by a primary disease-causing mutation. Rather than attempting to repair the underlying genetic defect in the urea cycle, KRRO-121 is designed to leverage endogenous ADAR to make a single nucleoside edit to GS mRNA, corresponding to a single amino acid change, thereby creating a de novo GS variant that is designed to bypass the degradation vulnerability and restore ammonia clearance capacity. Under normal physiological conditions, GS is subject to glutamine-induced feedback degradation: when glutamine levels rise, key N-terminal lysine residues on GS are acetylated, leading to ubiquitination and proteasomal degradation of the enzyme. This degradation reduces the cell’s capacity to clear ammonia precisely when ammonia clearance is most needed. The modification introduced by KRRO-121 replaces a lysine residue with an arginine, which is resistant to acetylation and therefore resistant to glutamine-induced degradation. The resultant de novo GS protein is intended to retain full enzymatic activity but resist proteasome-mediated degradation, potentially providing sustained ammonia detoxification capacity regardless of the specific UCD enzyme deficiency. This synthetic rescue strategy is engineered to enable KRRO-121 to address hyperammonemia through a pathway independent of the urea cycle, rather than attempting to repair the specific enzyme deficiency. This approach is supported by human genetic evidence. Published genetic studies have identified

patients with start-loss variants in GS that result in loss of N-terminal lysine residues, leading to stabilized GS protein and stable enzymatic activity.

Figure 10. Depicts KRRO-121's lysine residue replacement to create a stabilized de novo GS variant that resists glutamine degradation, intended to maintain ammonia clearance.

We believe our approach has multiple potential advantages:

•

Pan-UCD approach through synthetic rescue: By enhancing ammonia clearance through a pathway independent of the urea cycle, KRRO-121 has the potential to benefit patients with UCD regardless of the specific enzyme deficiency, including OTC, ASL, ASS1 and other subtypes.

•

Dual indication potential: The ammonia-lowering mechanism of KRRO-121 may address both UCD and HE, two distinct conditions with a shared pathology of hyperammonemia.

•

Convenient subcutaneous delivery: KRRO-121 utilizes GalNAc-conjugated delivery, a well-established and clinically validated approach that enables convenient subcutaneous administration with targeted delivery to liver hepatocytes.

•

Potential for dietary liberalization: By providing enhanced ammonia clearance capacity, KRRO-121 may enable relaxation of the strict dietary protein restrictions that significantly diminish quality of life for UCD patients.

Summary of our preclinical studies and data generated leading to KRRO-121 selection

We have generated compelling preclinical data establishing proof of concept for KRRO-121 across multiple model systems:

•

In vitro studies in primary human hepatocytes demonstrated dose-dependent RNA editing.

•

In vitro studies in human induced pluripotent stem cell-derived hepatocytes bearing either the OTC-D175V or the ASS1D309 mutation demonstrated the ability to maintain stable levels of GS under conditions of ammonia overload in two subtypes of UCD.

Figure 11. OTC D175V human iPSC-derived hepatocytes differentiated for 14 days, then treated with oligonucleotide.

•

In vivo activity was demonstrated in OTC mice (OTCspf/ash), with >50% improved ammonia clearance.

Figure 12. Ammonia Reduction in OTC-Deficient Mice

•

In vivo activity in a humanized mouse model (PXB) demonstrated approximately 20% editing at the mRNA level, leading to improved ammonia clearance during hyperammonemia challenge, resulting in approximately 20% of the stabilized protein post ammonia challenge without any significant degradation in the total protein. KRRO-121 significantly reduced ammonia levels in both basal state and following ammonia challenge, while maintaining steady glutamine levels post-challenge.

•

Favorable tolerability profiles were observed in exploratory toxicology studies conducted in mice and NHPs. In NHPs, KRRO-121 displayed >90% delivery to liver, confirmed liver localization with pericentral GS, and no observed changes in liver or kidney function, coagulation, complement, platelets, or cytokines.

While we believe we can demonstrate many of the key advantages of RNA editing, we are early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include, but are not limited to, the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans.

KRRO-121 Next Steps

We anticipate a regulatory filing for KRRO-121 to enable commencement of a first-in-human clinical trial in the second half of 2026. Good laboratory practice, or GLP, -compliant toxicology studies in mouse and monkey are planned to support the proposed first-in-human study. KRRO-121 is being developed for the treatment of UCDs in adults and adolescents, with potential expansion into HE. However, KRRO-121 is in preclinical development and there is no guarantee that it will be successful.

Our AATD Program: RNA Editing to Repair Pathogenic Missense Variant

~~Our~~We ~~clinical-stage~~are ~~development~~developing ~~candidate,~~a ~~KRRO~~next-~~110,~~generation isGalNAc-conjugated inRNA ~~development~~editing asoligonucleotide afor the potential treatment ~~for~~of AATD that has the potential to be disease-modifying and provide a differentiated therapeutic option. AATD is an inherited genetic disorder that can cause severe progressive lung and liver disease due to a lack of normal ~~alpha-1 antitrypsin protein, or~~ AAT, with varying intensity based on patient genotype and environmental factors. Patients often develop chronic obstructive pulmonary disorder, or COPD, in the lungs and cirrhosis of the liver, which can result in liver failure or death.

There are an estimated 5.5 million individuals with deficiency allele combinations worldwide. There is a single approved modality, a once-a-week infusion of pooled human plasma derived AAT, that does not adequately address the lung or liver manifestations of AATD. Within the United States alone, the opportunity to improve the existing standard of care and expand the treated population represents a large market opportunity.

~~KRRO-110~~Our isAATD alead candidates are proprietary RNA editing ~~oligonucleotide~~oligonucleotides ~~that~~conjugated iswith ~~delivered~~GalNAc and administered subcutaneously with delivery to liver ~~cells~~hepatocytes, ~~using~~where anthey ~~established~~co-opt ~~LNP~~endogenous ~~platform~~ADAR to edit a nucleoside in the SERPINA1 transcript and restore production of normal AAT. ~~KRRO~~The GalNAc conjugate approach enables convenient subcutaneous administration with targeted, liver-~~110~~specific delivery to hepatocytes. GalNAc-conjugated delivery is ~~delivered~~a ~~via~~well-established ~~intravenous~~and ~~infusion,~~clinically ~~where~~validated itapproach cothat has been used in multiple FDA-~~opts~~approved ~~endogenous~~products, ~~ADAR~~including toGIVLAARI ~~repair~~and ~~the~~OXLUMO, ~~pathogenic~~providing ~~SNV~~a precedented delivery technology with an established safety and ~~restore~~efficacy ~~production~~profile. ofBy ~~normal~~repairing ~~AAT~~the protein, ~~potentially~~we ~~creating~~aim to bring individuals with the Z mutation to a ~~clinically~~phenotype ~~differentiated~~where ~~benefit~~over ~~for~~90% ~~both~~of ~~liver~~RNA ~~and~~has been corrected to produce normal AAT, preserving lung and liver function inand ~~affected~~preventing ~~individuals.~~further damage.

In addition to the inherent benefits of ADAR-based RNA editing described earlier, we believe our approach has additional potential advantages:, including convenient subcutaneous delivery:

•

Provides a disease modifying therapy for both lung and liver manifestations by transiently editing over 5090% of RNA transcripts in hepatocytes to restore normal AAT protein

•

Provides a treatment option that can be tailored to address the broad spectrum of severity within the AATD population

•

Potential to enable physiologic regulation of AAT using endogenous ADAR, thereby increasing normal AAT production during inflammation

•

~~Fit-for-purpose~~Convenient ~~delivery~~subcutaneous dosing using aprecedented ~~proven~~GalNAc-conjugated ~~LNP~~delivery towith ~~maximize~~liver-targeted ~~editing efficiency, leading to greater potential clinical benefit~~ specificity

15We have generated compelling preclinical data demonstrating proof of concept across multiple RNA editing oligonucleotides targeting the SERPINA1 gene. We have achieved greater than 90% editing of the SERPINA1 transcript using GalNAc delivery in vivo, with results demonstrated in both NSG-PiZ and C57BL/6-PiZ mouse models. We first pursued a development candidate, KRRO-110, for the treatment of AATD, which used an LNP delivery modality. However, following initial results from our REWRITE trial announced in November 2025, we pivoted to a GalNAC delivery modality. See “—Termination of REWRITE Clinical Program” below.

We have generated compelling preclinical data demonstrating proof of concept across multiple RNA editing oligonucleotides targeting the SERPINA1 gene, including KRRO-110. KRRO-110 has achieved targeted durability, high editing efficiency (>50% editing in hepatocytes) and increased expression of normal AAT protein (>70% of total AAT protein in circulation) in an in vivo mouse model. We have also shown that earlier generation oligonucleotides that target a different site on the SERPINA1 gene than KRRO-110 have high translation of RNA editing efficiency from mice to non-human primates, or NHPs, demonstrating the potential applicability of our approach in humans. With regard to KRRO-110, we have shown high specificity with no bystander effects in MZ human primary hepatocytes. Additionally, we have demonstrated that intravenous administration at 2mg/kg resulted in secretion of approximately 50uM functional AAT as early as seven days post-single dose in a human transgenic PiZ mouse model and achieved greater than 60µM total AAT protein and 45µM of M-AAT levels at week 13. An increase in AAT protein and the inhibition of elastase activity were sustained through week 13 when dosed every two weeks, demonstrating durability in mice. Finally, we have shown greater than 40% editing in NHPs utilizing an earlier generation oligonucleotide designed to edit a surrogate SERPINA1 RNA target site.

While we believe we can demonstrate many of the key advantages of RNA editing, we are very early in our development efforts and not yet certain of the results we may achieve. Such uncertainties include, but are not limited to, the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans. Clinical development of KRRO-110 is ongoing and in January 2025 we announced dosing of the first participants in our REWRITE clinical program investigating KRRO-110 as a treatment for AATD. We have completed dosing of the first two cohorts of participants. Interim data from single ascending doses in healthy volunteers and AATD patients is expected in the second half of 2025, and completion of the trial is anticipated in 2026. Depending on the evidence of efficacy and tolerability for our candidate in our first clinical study, we plan to pursue expedited regulatory pathways, including potentially requesting Fast Track Designation and Breakthrough Therapy Designation.

AATD Overview

AAT function

AAT is a protease inhibitor belonging to the Serpin family. It is produced in the liver and circulates in its native state in human blood at approximately 1.5 g/L, one of the highest concentrations observed for protease inhibitors. The main role of AAT is to protect tissue from proteases released by neutrophils, such as neutrophil elastase. Neutrophil elastase is an enzyme that fights infections in the lungs but can also attack normal lung tissue. If not sufficiently inhibited by AAT, neutrophil elastase destroys elastin in the lung, leading to degradation of lung function. Factors that increase lung inflammation, such as smoking or ~~infections, increase the elastase burden in the lung, leading to severe and potentially life-threatening lung damage in AATD patients.~~

infections, increase the elastase burden in the lung, leading to severe and potentially life-threatening lung damage in AATD patients.

Genotypes of AATD

AATD is an inherited, autosomal recessive genetic disorder that is most frequently caused by a single nucleotide variant, or SNV, mutation in the SERPINA1 gene. The most common of these SNVs is the “Z” mutation, corresponding to a mutation of glutamate 342 to lysine, or E342K. A healthy individual typically exhibits an “MM” genotype, or PiMM, while an individual with a single Z allele would exhibit a heterozygous, or PiMZ genotype, and an individual with two Z alleles would exhibit a homozygous, or PiZZ, genotype.

Figure 1013. PiMM genotype (normal liver and lung)

Impact of Z mutations on liver and lung function

The presence of a single Z allele can lead to insufficient production of normal AAT, as well as the production of dysfunctional AAT, causing manifestations of disease in both the lungs and liver. The severity of disease manifestation can vary according to each patient’s genotype, as well as environmental factors, such as exposure to inflammatory respiratory agents or other complications.

PiZZ individuals experience greater manifestations of disease as a result of their very low levels of normal AAT (10% - 15% of normal levels), which are insufficient to prevent lung damage after an influx of neutrophils. They are also at high risk of developing emphysema or COPD, which can present in individuals as early as in their thirties and forties. PiZZ individuals with additional environmental risk factors such as smoking or infection frequently develop COPD as early adults and develop very severe symptoms.

In addition to lung disease, PiZZ individuals can also manifest with liver disease as a result of dysfunctional AAT aggregating in the liver. In adults, this can cause liver inflammation and cirrhosis, ultimately leading to liver failure or cancer. In addition, as many as 10% of newborns with the PiZZ genotype develop cholestatic hepatitis. A quarter of impacted neonates suffer acute liver failure and require an emergency transplant.

Figure 1114. PiZZ genotype that results in fibrotic liver and decreased lung function

Data from the UK Biobank, or UKBB, as well as published literature, have allowed researchers to determine the threshold levels of circulating AAT that are directly linked to the PiMZ and PiZZ genotypes. In Figure 1215 below, the range of AAT levels associated with normal individuals (PiMM) is compared with the range of AAT levels observed in mutated PiMZ and PiZZ patients.

~~Figure 12. Median Levels of AAT and link to outcomes in liver and lung~~ 21

In Figure 1315. ~~below,~~Median ~~the~~Levels ~~Odds~~of ~~Ratios,~~AAT orand ~~OR,~~link ~~associated~~to ~~with~~outcomes ~~developing~~in ~~COPD~~liver and ~~cirrhosis~~lung ~~of the liver are compared across the two genotypes, with key findings summarized below:~~

In Figure 16 below, the Odds Ratios, or OR, associated with developing COPD and cirrhosis of the liver are compared across the two genotypes, with key findings summarized below:

•

COPD: PiMZ individuals have minimal increased risk of developing COPD relative to healthy PiMM individuals, while PiZZ individuals are at very high risk with an OR of 8.8

•

Cirrhosis of the liver: PiMZ individuals have mildly elevated risk of developing cirrhosis of the liver with an OR of 1.5, while PiZZ individuals have significantly elevated risk with an OR of 7.8

17Figure 16. Risk of developing COPD and cirrhosis for different genotypes associated with AATD. Adapted from “The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.” By Nakanishi T, Forgetta V, Handa T, et al. Eur Respir J 2020; 56:2001441

~~Figure~~Based ~~13.~~on ~~Risk~~these findings, we believe that achieving normal AAT protein levels between the ranges of ~~developing~~the PiMZ and PiMM genotypes has the potential to alleviate the increased risk of COPD and cirrhosis ~~for~~of ~~different~~the ~~genotypes~~liver, ~~associated~~and ~~with~~to ~~AATD.~~meaningfully ~~Adapted~~improve ~~from~~clinical ~~“The~~outcomes ~~undiagnosed~~for ~~disease~~PiZZ ~~burden~~patients. ~~associated~~We ~~with~~further ~~alpha-1~~believe ~~antitrypsin~~that ~~deficiency~~by ~~genotypes.”~~achieving Bygreater ~~Nakanishi~~than T,90% ~~Forgetta~~editing V,efficiency ~~Handa~~across Tcells, etwe ~~al.~~can ~~Eur~~reach ~~Respir~~these Jtarget ~~2020;~~levels ~~56:2001441~~and modify disease progression.

Based on these findings, we believe that achieving normal AAT protein levels between the ranges of the PiMZ and PiMM genotypes has the potential to alleviate the increased risk of COPD and cirrhosis of the liver, and to meaningfully improve clinical outcomes for PiZZ patients. We further believe that by achieving >50% editing efficiency across cells, we can reach these target levels and modify disease progression.

Prevalence of AATD and limitations of currently approved therapy

AATD is one of the three most common, potentially lethal, rare diseases affecting those of European descent. Worldwide, there are an estimated 5.5 million individuals with deficiency allele combinations. Studies suggest that clinical unawareness of AATD results in a significant number of patients that go undiagnosed or misdiagnosed. There are currently an estimated 100,000 patients in the United States with a PiZZ genotype, and 125,000 patients across the United Kingdom, Germany, France, Spain and Italy. Studies of PiMZ prevalence suggest as many as one in 49 individuals in the United States and one in 58 individuals across Europe.

The only FDA-approved treatment for patients with lung manifestations of AATD (co-indicated with COPD) is augmentation therapy, which utilizes AAT protein purified from pooled human plasma. The purified AAT is administered weekly by intravenous infusion with the goal of maintaining a serum level of AAT above the 11 µM threshold. Even when the serum level can be maintained at or above this threshold, augmentation therapy has not clearly demonstrated its ability to adequately address lung damage nor liver inflammation caused by AAT aggregation. Augmentation therapy is approved in only a few countries due to its limited efficacy. Lung and/or liver transplantation are the only other available treatment options, outside of standard management of the disease manifestations of AATD.

Despite being minimally effective and not fully addressing the needs of many AATD patients, augmentation therapy currently represents approximately $1.4 billion in annual sales worldwide. ~~KRRO-110 has the potential to elevate the standard of care and expand the number of patients on treatment and potential to be a leader with a large market opportunity worldwide.~~

~~Limitations of~~ Alternative Treatments in Development for AATD

There are a number of therapies in development to treat AATD. Certain DNA editing approaches attempt to add a normal copy of SERPINA1 gene or permanently correct the mutation within the SERPINA1 gene. DNA editing as a treatment would likely be evaluated on a risk-benefit trade-off relative to the severity of the manifestation of AATD, limiting the applicability of DNA editing approaches to the broader AATD patient population.

Additional approaches outside of DNA editing are also in development. There are approaches which attempt to use siRNA to knock-out the production of dysfunctional AAT protein, which only alleviates the liver manifestation of AATD, while potentially worsening the lung manifestation. Replacing plasma derived protein for augmentation therapy with a fusion protein is another approach in development. This fusion protein aims to introduce AAT on an antibody scaffold to improve upon the existing dosing paradigm and activity levels achieved in augmentation therapy. Fusion proteins do not resolve the liver manifestation and are unable to physiologically regulate AAT levels. Lastly, small molecule correctors attempt to promote proper folding of the Z-AAT protein. To date, small molecule correctors have been unable to achieve normal AAT levels and clinical development is focused only on the liver manifestation of AATD.

We believe many of these approaches have inherent limitations including the following:

•

Inability to adequately address the spectrum of clinical pathologies associated with AATD

•

Inability to achieve adequate expression of normal AAT to bring patients back to PiMM genotype

•

Considerable safety and tolerability concerns

•

Potential issues around manufacturability and scalability for the AATD population

Our Approach to Overcome the Limitations: Transiently Correcting the SERPINA1 Variant on RNA

We are developing ~~KRRO~~a GalNAc-~~110~~conjugated RNA editing oligonucleotide to treat patients with AATD. ~~KRRO-110~~ isOur lead candidates are designed to leverage endogenous ADAR to make a single base edit in SERPINA1 mRNA, correcting the amino acid codon created by the pathogenic E342K SNV which stems from a single G-to-A mutation. Specifically, ~~KRRO-110~~our oligonucleotide edits the adenosine (A) to an inosine (I), thereby correcting the faulty amino acid and leading to the production of normal AAT protein.

Our goal is to bring individuals with the Z mutation to a phenotype where over 5090% of RNA has been corrected to produce normal AAT protein. This would result in levels of AAT consistent with individuals in the upper half of the PiMZ genotype and the fully healthy PiMM genotype. Through our GalNAc-conjugated approach in human transgenic mouse models, we have shown our ability to drive the required change in RNA sequence with high efficiency, leading to secretion of AAT at target levels.

We believe our approach has multiple potential advantages, in addition to those conferred by the RNA editing modality:

•

Provides a tailored disease modifying treatment option to address the heterogeneity of the AATD population: We leverage a transient base editing approach leading to restoration of normal AAT. The transient nature of our approach allows us to address a broader AATD patient population, inclusive of PiMZ and PiZZ genotypes. As transient editing is not permanent in nature, we have the ability to adjust dosing and even cease dosing as needed, providing a meaningful benefit in potential safety profile.

•

Provides a disease modifying therapy for both lung and liver manifestations: By transiently editing over 5090% of RNA transcripts in hepatocytes, we believe we can restore levels of normal AAT protein consistent with a PiMZ to PiMM phenotype. These levels of normal AAT have the potential to prevent further lung damage and reduce the risk of dysfunctional AAT aggregating in the liver.

•

Potential to enable physiologic regulation of AAT using endogenous ADAR: Augmentation therapy and other treatments targeting static thresholds for AAT expression do not address the underlying mechanism of AAT regulation, which is endogenously regulated by inflammation and can sometimes lead to as much as 90uM of AAT in humans. During an inflammatory response, there is a simultaneous increase in ADAR levels. Our ADAR-based therapy has the potential to restore natural physiologic regulation by increasing the prevalence of editing during periods of greater AAT production.

Uniform distribution of drug to liver cells to maximize editing: Unlike other modalities that focus on DNA editing, our product candidates, including KRRO-110, have demonstrated a uniform distribution within the liver, including in NHPs. We believe this will allow our therapy to restore production of normal AAT protein in every cell, reducing reliance on the chance of a survival benefit for edited cells as in DNA editing. 23

~~Efficient~~regulation, ~~delivery~~which ~~using a proven LNP: AAT~~ is ~~the~~endogenously ~~fifth~~regulated ~~most~~by ~~abundant~~inflammation ~~protein~~and incan ~~circulation,~~sometimes ~~with~~lead ~~a large number of transcripts that require editing~~ to ~~achieve~~as ~~expression~~much ofas ~~normal~~90uM ~~protein. LNPs provide a significant benefit to delivery~~ of ~~RNA-editing~~AAT ~~oligonucleotides~~in ~~by increasing the likelihood of sufficient distribution into liver cells~~humans. InDuring ~~March 2023, we entered into~~ an ~~agreement~~inflammatory ~~with Genevant Sciences GmbH~~response, orthere ~~Genevant,~~is a ~~well~~simultaneous ~~established~~increase ~~leader~~ in ~~the~~ADAR ~~LNP~~levels. ~~space,~~Our toADAR-based ~~provide~~therapy ~~access~~has tothe ~~clinically~~potential ~~validated~~to ~~LNP~~restore ~~technology~~natural tophysiologic ~~optimize~~regulation ~~delivery~~by ofincreasing ~~KRRO-110.~~the ~~Preclinical~~prevalence ~~studies~~ of ~~this~~editing ~~LNP~~during ~~delivery~~periods ~~technology have shown improved dose-dependent efficacy with reduced clinical chemistry and adverse events. We are pursuing development~~ of ~~KRRO-110~~greater ~~with~~AAT ~~an optimized LNP from Genevant (GVT-1) for delivery~~production.

•

~~KRRO~~Liver-~~110~~targeted delivery using precedented GalNAc-conjugated technology: GalNAc conjugates provide highly specific delivery to hepatocytes with proven clinical track record. This delivery approach enables convenient subcutaneous administration, improving patient experience compared to intravenous infusion.

~~Summary~~Next-Generation ~~of our preclinical studies and data generated to date leading to KRRO~~GalNAc-~~110~~Conjugated ~~nomination~~AATD Program

We ~~have~~are ~~generated~~developing ~~highly~~a ~~compelling~~next-generation ~~preclinical~~GalNAc-conjugated ~~data~~RNA ~~that~~editing ~~forms~~oligonucleotide ~~the basis~~ for ~~our~~AATD ~~proof~~with ofdevelopment ~~mechanism.~~candidate Wenomination ~~have~~anticipated ~~affirmed~~in ~~that~~the ~~multiple~~second ~~disease~~quarter ~~modifying~~of ~~early~~2026. ~~generation~~Our ~~product~~preclinical ~~candidates~~studies have demonstrated compelling proof- of- concept infor ~~in vivo studies leading to~~ the ~~selection of KRRO~~GalNAc-~~110~~conjugated ~~as a development candidate~~approach.

~~Earlier~~We have generated highly compelling preclinical data that forms the basis for our proof of mechanism. We have affirmed that multiple disease modifying early generation ~~product~~lead candidates have ~~independently~~demonstrated ~~achieved~~proof-of-concept ~~clinically~~in ~~meaningful~~in ~~expression~~vivo studies leading to the anticipated selection of ~~normal~~our ~~AAT~~next-generation ~~protein~~GalNAc-conjugated ~~consistent~~development ~~with~~candidate afor ~~PiMZ~~AATD. ~~genotype~~To ~~within~~assess ~~preclinical~~and indifferentiate ~~vivo~~our ~~animal~~GalNAc-conjugated lead candidates in mouse models ~~while~~used ~~using~~widely ~~clinically~~in ~~relevant~~the ~~doses~~AATD ~~administered~~field, onwe aused ~~weekly~~the orNSG-PiZ ~~biweekly~~and ~~basis~~C57BL/6-PiZ transgenic mouse models. ~~Given~~These ~~that~~mice express the human ~~protein~~SERPINA1 ~~half~~gene with the Z-~~life~~mutation. isSubcutaneous ~~much~~administration ~~longer~~of ~~than~~GalNAc-conjugated RNA editing oligonucleotides resulted in >90% editing of SERPINA1 transcript in the NSG-PiZ mouse model following dosing at 10 mg/kg every other ~~species~~day for a total of three doses, wewith ~~believe~~results ~~our~~observed ~~therapies~~one ~~will~~week (seven days) post first dose. This demonstrates the high efficiency and consistency of the GalNAc-conjugated approach across two independent AATD mouse models.

19Figure 17. AATD GalNAC RNA editing in C57BL/6-PiZ and NSG-PiZ mouse models

support a longer dose interval in the clinic. In January 2025 we announced dosing of the first participants in our Phase 1/2a REWRITE clinical program of KRRO-110 for AATD, and we have completed dosing of the first two cohorts of participants. 24

InTermination vitro activity in human cells: Our initial design iterations for RNA-editing oligonucleotides were conducted in in vitro human systems, specifically containing human ADAR and human SERPINA1 genes with a Z allele. By leveraging the capabilities of ~~our~~REWRITE ~~OPERA~~Clinical ~~platform,~~Program ~~we have generated multiple product candidates that achieved increased editing activity in human in vitro systems.~~

~~KRRO-110~~In ~~demonstrates~~November ~~high~~2025, ~~selectivity~~we ~~for~~announced ~~editing~~that atour ~~the~~first-generation ~~E342K~~AATD ~~RNA~~program, ~~site~~KRRO-110, asour ~~shown~~proprietary inRNA ~~Figure~~editing ~~14. No~~oligonucleotide ~~off-target~~with ~~editing~~an ~~was~~LNP ~~observed~~delivery insystem, MZdid ~~primary~~not ~~human~~reach ~~hepatocytes~~projected ~~assessed~~levels atof ~~100~~functional ~~base~~protein ~~sites~~following ~~above~~a ~~and~~single ~~below~~administration. ~~the~~We ~~E342K~~pivoted ~~site,~~to ~~against~~GalNAc ~~background~~delivery ~~levels. A~~for ~~concentration~~AATD ~~gradient~~and ishave ~~observed~~terminated ~~with~~our aREWRITE ~~dose~~clinical program investigating KRRO-~~response~~110 atas ~~the~~a ~~E342K~~treatment ~~edit~~for ~~site~~AATD.

~~Figure~~AATD ~~14.~~GalNAc ~~Negligible~~Program inNext ~~vitro cis off-target editing observed for KRRO-110 in MZ hepatocytes~~Steps

~~Preclinical~~We inexpect ~~vivo~~to ~~activity~~nominate ina ~~mice with KRRO-110: To assess and differentiate our~~ development candidate, ~~KRRO-110,~~for inour aAATD ~~mouse~~GalNAc ~~model~~program ~~used widely~~ in the ~~AATD~~second ~~field,~~quarter weof ~~used a human transgenic NSG-PiZ mouse~~2026. ~~The~~We ~~NSG-PiZ~~are ~~transgenic~~continuing ~~mouse~~to ~~expresses~~design ~~the~~and ~~human~~screen ~~SERPINA1~~additional ~~gene~~oligonucleotides ~~with~~to ~~the~~optimize ~~Z-mutation.~~editing Asefficiency ~~detailed in Figures 15~~ and ~~16 below, intravenous administration of KRRO~~drug-~~110~~like atproperties 2for ~~mg/kg resulted in >50% editing and secretion of approximately 50µM AAT as early as seven days post~~GalNAc-~~single~~conjugated ~~dose~~subcutaneous indelivery. ~~the~~However, ~~NSG-PiZ~~this ~~mouse~~program ~~model.~~is ~~Increase~~ in ~~AAT~~preclinical ~~protein~~development and ~~the~~there ~~inhibition~~is ofno ~~elastase~~guarantee ~~activity~~that ~~were~~it ~~sustained~~will ~~through~~be ~~week 13 when dosed every two weeks, demonstrating durability in mice~~successful.

~~Figure~~Our ~~15.~~Longevity ~~Achieved~~and ~~>50%~~Liver ~~editing in~~Health ~~human~~Program: ~~transgenic mouse~~AMPKγ1 ~~model of Z genotype with a single dose~~Activation

20The longevity space has attracted approximately $8 billion in biotech investment. We've seen combinations of GLP-1 agonists, SGLT2 inhibitors, and PCSK9 inhibitors contributing to meaningful increases in lifespan. Rising U.S. health spending on chronic conditions underscores both the challenge and the opportunity. Top aging experts are pointing to four FDA-approved drugs that hold promise for extending life including GLP-1 agonists. Rather than treating late-stage disease, we are focused on extending organ healthspan and going after three fundamental reasons as to why organs age: metabolic dysfunction, oxidative stress, and inflammation accumulation.

~~Figure~~When 16activated, AMPK inhibits anabolic pathways like lipogenesis and protein synthesis, activates catabolic pathways including fatty acid oxidation and autophagy, and regulates glucose homeostasis by enhancing insulin sensitivity. ~~Secretion~~The γ1 subunit—AMPKγ1—represents the optimal liver therapeutic target because of ~~functional~~its ~~AAT~~hepatocyte ~~(approximately~~enrichment. ~~50uM)~~AMPK asactivation ~~early~~provides asdirect 7metabolic ~~days~~reprogramming—increasing ~~post~~fatty acid oxidation, decreasing lipogenesis, boosting mitochondrial biogenesis, and increasing glucose uptake in an insulin-~~single~~independent ~~dose~~manner, all with minimal central appetite effects. It is hepatocyte-restricted rather than systemically exposed. GLP-1 agonism, by contrast, works primarily through appetite suppression—central satiety signaling, delayed gastric emptying, increased insulin secretion, and decreased glucagon release. These are complementary mechanisms.

~~Preclinical~~We inare ~~vivo~~developing ~~activity~~proprietary inoligonucleotides ~~mice~~designed to activate AMPKγ1, with ~~earlier~~the ~~generation~~goal ~~oligonucleotides:~~of ~~Our~~restoring ~~screening~~metabolic ~~preclinical~~status ~~pharmacology~~and ~~studies~~improving ~~have~~liver ~~been~~function. ~~conducted~~We ~~using~~enable the activation by creating a ~~second~~single ~~C57BL/6-PiZ~~amino ~~mouse~~acid ~~model~~change ~~and~~on ~~licensed~~the bynative usAMPK ~~from~~protein, ~~Dr.~~specifically ~~Jeff~~in ~~Teckman’s~~the ~~laboratory~~liver, atsuch ~~St.~~that ~~Louis~~it ~~University~~stays ~~School~~in ofa ~~Medicine.~~hyper-phosphorylated Drstate, creating an allosteric modulator. ~~Teckman~~This isprogram utilizes GalNAc-conjugated delivery for subcutaneous administration targeting the ~~preeminent~~liver, ~~expert~~thus onavoiding activating AMPK in the ~~study~~rest of ~~AATD~~the body. ~~The~~Prior ~~C57BL/6-PiZ~~programs ~~transgenic~~have ~~mouse~~not ~~model~~moved ~~also~~forward ~~expresses~~due to the ~~human~~systemic ~~SERPINA1~~exposure, ~~gene~~and ~~containing~~the lack of specificity of the ZAMPK ~~mutation~~isoform.

AsWe ~~part~~are ofin ~~our~~early preclinical ~~studies,~~development wefor ~~have~~this ~~evaluated multiple oligonucleotides in varying doses in PiZ mice~~program. ~~KB-0794,~~We anhave ~~earlier~~demonstrated ~~generation~~ oligonucleotide,-mediated ~~demonstrated~~ editing ~~efficiency~~in asmouse ~~high~~hepatocytes aswith 6360% ~~on day four following the administration of a single 3mg/kg dose. Normal M-AAT protein was observed~~ at an100 18nM ~~µM concentration on day four, demonstrating the potential relationship between editing efficiency~~ and ~~secretion~~40% ofat ~~normal~~10 ~~AAT. Upon~~nM ~~observing the high~~ editing ~~efficiency~~resulting ofin KBtwo-~~0794,~~fold weincreases ~~proceeded to conduct an additional preclinical~~ in ~~vivo study where four groups of mice were given a lower dose of 2mg/kg and observed in a multi~~phospho-~~dose~~ACC ~~study that lasted up~~ to ~~four~~total ~~weeks.~~ACC ~~Key takeaways from the multi-dose study included the following:~~

~~Achieved up to 54% editing efficiency with up to 20uM of normal AAT, constituting 72% of total protein in circulation~~ 25

~~Liver~~ratio ~~polymers~~in ~~associated~~vivo ~~with~~in ~~the~~wild ~~dysfunctional~~type ~~AAT~~mice, ~~protein~~demonstrating ~~were~~in ~~reduced~~vivo atfunctional ~~day~~downstream ~~28,~~signaling. ~~pointing~~We toare apromoting ~~potential~~allosteric activation of the γ1 subunit to ~~provide~~enable ~~liver~~sustained ~~benefit~~activation, ~~through~~what ~~clearing~~we ofbelieve ~~aggregates~~is needed for durable therapeutic benefit.

~~The~~Figure ~~half-life~~18. ofHepatic ~~AAT in mice and NHPs has been observed to be around~~ AMPKγ1-2 ~~days~~activation ~~and~~improved ~~2-4~~liver ~~days,~~function ~~respectively. Human AAT has a longer half-life of 4-6 days, and when coupled with the optimization of our oligonucleotide drug product and the accumulation of drug product observed~~ in ~~the~~obese multi-dose preclinical studies, we believe that we will be able to achieve greater durability and a longer dosing interval in the clinic than the current once weekly or biweekly interval conducted in our preclinical studies. mice

Our ~~preclinical~~GalNAc-conjugated ~~screening~~oligonucleotides ~~studies~~enable toliver-specific ~~identify~~targeting. ~~product~~In ~~candidates~~diet-induced ~~were~~obesity ~~originally~~mice, ~~conducted~~we ~~using~~dosed anonce ~~LNP~~daily ~~delivery~~for ~~vehicle~~five ~~comprising~~days ~~lipids~~at ~~used~~10 mg/kg. We achieved 23.9% editing in ~~the~~liver ~~approved~~with ~~product~~ALT ~~ONPATTRO®.~~dropping ~~Over~~from ~~the~~230 ~~past~~to ~~decade,~~122 U/L (back toward the ~~field~~lean mouse range of ~~LNP~~60) ~~delivery~~and ~~has~~AST ~~made~~improving ~~advancements~~from as208 ~~measured~~to by108 ~~safety~~(approaching ~~profile~~the lean mouse level of 100). Liver function was improved and ~~tolerability~~metabolic signaling restored without affecting food intake. ~~Our~~The ~~product~~body ~~candidates~~weight curves were essentially identical, ~~when~~and ~~combined~~food ~~with~~consumption ~~current~~was ~~generation~~unchanged, ~~LNP~~highlighting ~~delivery~~a ~~technology~~direct ~~from~~metabolic ~~Genevant~~reprogramming, ~~have~~not ~~demonstrated~~appetite ~~optimized~~suppression. ~~editing~~Our ~~efficiency~~GalNAc-conjugated oligonucleotide is fundamentally different from GLP-1s, ~~safety~~which ~~and~~we ~~tolerability.~~believe potentially makes it an ideal combination partner.

In a preclinical study to compare the editing efficiency of a previous generation LNP (the comparator LNP) and current generation Genevant LNPs (GVT-1 and GVT-2), we evaluated C57BL/6-PiZ mice after receiving a single 2mg/kg dose of KB-0794 via each of the three delivery vehicles. GVT-1 and GVT-2 achieved comparable or higher editing of 37% and 65%, respectively, as compared to 29% editing for the comparator LNP. Post a single LNP dose, the percentage of normal-AAT increased to 66% for GVT-1 and 85% for GVT-2, compared to 56% for the comparator LNP, showing potential for disease-modifying effects.

Selection of KRRO-110

The above data demonstrates the highly compelling preclinical data that forms the basis for our proof of mechanism and therapeutic approach. Additionally, we have generated non-GLP toxicology data and affirmed that multiple disease modifying

early generation product candidates have demonstrated proof-of-concept in in vivo studies. The complete data set has led to the nomination of KRRO-110 as a development candidate, and which program is now our lead clinical-stage product candidate.

Translation to NHPs

In addition to our preclinical in vivo studies conducted using the PiZ mouse models described above, we have also generated a translational model to validate the potential for delivery and ability to edit the SERPINA1 gene in NHPs with an earlier generation oligonucleotide. Because the human SERPINA1 gene in NHPs does not harbor the E342K mutation, we are demonstrating our oligonucleotide’s ability to edit within the coding region of the SERPINA1 gene and the ability to translate that preclinical in vivo editing from the PiZ mouse model to NHPs.

Figure 17. Editing de novo adenosine on cyno SERPINA1 to elucidate editing in higher species

We evaluated the potential editing efficiency of GVT-1 and GVT-2 for the SERPINA1 coding region in NHPs. The observed editing rate of GVT-2 was meaningfully higher at 34%, relative to 13% in the historical MC3 study. ALT levels, a measure of safety and tolerability, were meaningfully lower in GVT-1 and on par between GVT-2 and the LNP comparator. These results show that our product candidates, when combined with current generation Genevant LNPs, can demonstrate a desirable safety profile while increasing the editing efficiency.

Optimization of our NHP surrogate led to KB-1494 formulated in the current generation Genevant LNP (GVT-1). Upon receiving a 2mg/kg intravenous dose, liver editing was measured 4, 7, and 14 days after the initial dose in mice and 5 and 15 days after the initial dose in NHPs. As depicted in Figure 18, the observed degree of editing from KB-1494 in NHPs was statistically higher than what was observed in mouse. The observations could be recovered using a minimal PK/PD model and allometric scaling of the liver half-life for KB-1494. The same PK/PD modeling was then used to simulate predicted editing in humans. Based on the prediction in our simulation in Figure 18, we believe the editing in humans will achieve a higher peak with a more sustained response compared to our observations in nonclinical species. However, we have not received any clinical trial results for our RNA editing approach and favorable preclinical results we may have may not be predictive of results that may be observed in later preclinical studies or clinical trials.

Figure 18. Editing of SERPINA1 coding region in NHPs and C57BL/6-PiZ model showed correlation

Rewrite Clinical Program and Next Steps

Our Rare Metabolic Disorder Program: De Novo Protein to Prevent Degradation

We are developing proprietary oligonucleotides targeting the mRNA for a rare metabolic disorder to create de novo modified protein variants.

Our Differentiated Approach

We are engineering de novo SNVs enabling single amino acid changes to non-mutated RNA to create a de novo modified protein variant with desired altered properties while preserving their broader functional capabilities to prevent protein degradation for a number of related rare metabolic disorders. Our objective is for the resultant therapeutic protein to go beyond repairing pathogenic SNVs by changing amino acids on proteins implicated in disease biology in these metabolic disorders.

Next Steps

We are continuing to design and screen additional oligonucleotides to identify proprietary oligonucleotides for further evaluation. WeFurthermore, ~~expect~~we toare ~~nominate~~identifying aand ~~development~~characterizing ~~candidate~~metabolic ~~for~~dysfunction-associated ~~our~~steatohepatitis, ~~rare~~or ~~metabolic~~MASH, ~~disorder~~and ~~program~~liver ~~targeting~~fibrosis ~~the~~models ~~liver~~and ~~(GalNAc)~~patient ~~with~~cell ~~subcutaneous~~lines, ~~delivery~~ to ~~create~~test the efficacy of de novo AMPK γ1 protein ~~variants~~in bydisease ~~the~~models. ~~end~~We ofanticipate ~~2025~~progressing this program towards achieving a development candidate.

Our Amyotrophic Lateral Sclerosis Program: Disrupting Protein Aggregation

We are developing proprietary oligonucleotides targeting the mRNA for TAR DNA binding protein 43, or TDP-43, a protein associated with the etiology of ALS.

Amyotrophic Lateral Sclerosis

ALS is an adult-onset, progressive, and fatal neurodegenerative disorder that causes muscle weakness, paralysis, and ultimately death. The majority of ALS patients die from respiratory failure within three to five years after symptom appearance, with a small percentage of patients surviving beyond 10 years. Despite being classified as a rare disease by the FDA and the European Medicines Agency, or EMA, ALS is considered one of the more common neurodegenerative diseases worldwide. Prevalence estimates vary, but it is widely accepted that there are approximately 30,000 ALS patients in the United States. There is currently no cure for ALS, and currently approved therapies either only provide symptomatic relief or slow the overall progression of the disease.

Our Differentiated Approach and Results

Our approach is to selectively modulate TDP-43, an RNA/DNA-binding protein, which carries out a variety of important functions in healthy neurons, including initiation of transcription, pre-mRNA splicing and miRNA processing. Hyper-phosphorylated and ubiquitinated TDP-43 deposits form inclusion bodies in the brain and spinal cord of patients with ALS and frontotemporal dementia, or FTD. The majority of ALS and FTD cases are sporadic, and more than 90% and 45% of ALS and FTD patients, respectively, have TDP-43 aggregations in neurons. Less than 10% of ALS cases are familial, and mutations in TARDBP, the gene encoding TDP-43, are responsible for approximately 4% of familial ALS. Given the importance of the role of TDP-43’s ~~role~~ in maintaining healthy neurons, the generation of a protein variant with the desired non-aggregating property could potentially have therapeutic benefit for the majority of ALS and FTD patients. We believe that by leveraging the ability of RNA ~~editing to affect a single base edit in TARDBP, we can lead to the synthesis of a TDP-43 protein variant that does not aggregate, thereby restoring our normal function.~~

2326

Weediting ~~have~~to ~~created~~affect a ~~series of TDP-43 variants that contain~~ single ~~amino~~base ~~acid~~edit ~~changes~~in ~~designed to alter post-translational modification by phosphorylation~~TARDBP, ~~ubiquitination,~~we ~~acetylation~~can orlead ~~cleavage with the intent of reducing the ability~~ to ~~aggregate while maintaining function in RNA metabolism. We believe that modulating TDP-43 through~~ the ~~introduction~~synthesis of ~~specific~~a ~~amino acid changes into~~ TDP-43 ~~mRNA sequence is preferable to other approaches that try to address~~ protein ~~aggregates~~variant ~~after they form, to non-specifically prevent stress granule formation, or to target a single TDP-43 downstream target. We have engineered mutations amenable to an RNA edit using our OPERA platform~~ that ~~limit~~does ~~the~~not ~~formation of TDP-43 inclusion bodies in vitro. Additionally~~aggregate, wethereby ~~have~~restoring ~~demonstrated~~normal ~~meaningful editing of TDP-43 targets sites with our product candidates in a human neuroblastoma-derived cell line (SK-N-AS) as demonstrated in Figure 19 below~~function.

Figure 19. ~~Editing~~Continued splicing of ~~TDP-43~~factors ~~mRNA~~downstream ~~using~~of ~~our product candidates (100 nM)~~ TDP-43

We ~~intend~~have created a series of TDP-43 variants that contain single amino acid changes designed to ~~initially~~alter ~~pursue~~post-translational ~~ALS~~modification by phosphorylation, ubiquitination, acetylation or cleavage with ~~this~~the ~~approach~~intent ~~and~~of ~~have~~reducing the ~~opportunity~~ability to ~~expand~~aggregate ~~our~~while ~~pipeline~~maintaining function in RNA metabolism. We believe that modulating TDP-43 through the introduction of specific amino acid changes into TDP-43 mRNA sequence is preferable to other ~~neurodegenerative~~approaches ~~diseases~~that try to address protein aggregates after they form, ~~such~~to asnon-specifically ~~FTD~~prevent stress granule formation, or to target a single TDP-43 downstream target. In preclinical studies, our TDP-43 variant demonstrated reduced mis-splicing of critical genes (maintaining STMN2 and POLDIP3 expression) and decreased cytosolic mis-localization of TDP-43 protein in iPSC-derived motor neurons under cell stress conditions. These results support the potential of our approach to reduce pathogenic aggregation of TDP-43 while preserving its normal cellular functions.

Figure 20. Re-localization of the TDP43 protein inside the nucleus

Next Steps

We are continuing to design and screen additional oligonucleotides ~~in SK-N-AS cells~~ to identify proprietary oligonucleotides for further evaluation ~~in aggregation assays~~. Furthermore, we are identifying and characterizing ALS cell lines including genetic-induced models and patient cell lines, to test the efficacy of TDP-43 protein variants in disease models.

Our Pain Program: Selective Modulation of Ion Channels

We are developing proprietary oligonucleotides that selectively modulate ion channels associated with pain.

Overview of Pain Indications

Pain is a condition that millions of patients experience and is often a component of rare and highly prevalent diseases. Pain can be generally classified as either acute or chronic and can be further segmented into subcategories including nociceptive or neuropathic pain. There are several classes of therapeutics to target the numerous pathways that cause pain, including opioids, nerve growth factors and ion channel blockers. Many of these treatment methods involve non-specific targeting of pathways that lead to off-target effects. Despite a large commercial market opportunity, there remains significant unmet needs for safe and effective pain management, including non-opioid therapeutics.

Several classes of drugs, including local anesthetics, such as lidocaine, are ion channel blockers, although they do not show a high degree of specificity and thus inhibit many types of sodium channels rather than selectively blocking NaV1.7. No highly selective small molecule product candidates have been FDA-approved as therapeutics. One of the challenges in developing a small molecule inhibitor of NaV1.7 is the high degree of homology with other voltage gated sodium channels, inhibition of which has been linked to safety concerns.

Our Differentiated Approach and Results

The introduction of genetic changes into the mRNA encoding NaV1.7 demonstrates the potential of RNA editing to create highly differentiated and selective therapeutics for ion channels. NaV1.7 is a voltage-gated sodium channel that plays a critical role in the generation and conduction of action potentials and is thus important for electrical signaling in the nervous system. NaV1.7 is highly expressed in the pain sensing dorsal root ganglion neuron. Genetic inactivation of SCN9A, the gene encoding NaV1.7, in mice results in the inability to sense pain from inflammatory stimuli. In humans, mutations that lead to inactivation of

NaV1.7 function result in a genetic condition known as Channelopathy-associated insensitivity to pain, or CIP. Individuals with CIP have severely diminished ability to sense pain. By contrast, mutations that activate NaV1.7 result in intense pain.

Through our RNA editing technology, we have generated a series of site-specific changes in NaV1.7 that modulate our ion channel function such that it mimics a small molecule sodium channel blocker. We believe that using RNA editing to introduce these changes in patients has the potential to deliver potent analgesic activity without the dose-limiting toxicities that have been observed by other sodium channel blockers.

We have demonstrated that rationally designed single amino acid changes to unique target sites are sufficient to decrease the activity of NaV1.7. Electrophysiology studies performed in CHO cells transfected with plasmids expressing channel variants demonstrated biophysical properties that are associated with a decrease in NaV1.7 channel activity compared to fully functional NaV1.7. Additionally, we have demonstrated meaningful editing for these target sites in SK-N-AS cells as shown in Figure 21 below.

Figure 21. Editing of NaV1.7 using our product candidates (100nM)

Next Steps

We are optimizing and screening our proprietary oligonucleotides in electrophysiology assays. Furthermore, we will perform a high throughput screen of NaV1.7 variants to identify potential novel ion channel variants with enhanced crippling of electrophysiology activity.

Pioneering RNA Editing to Deliver the Future of Medicine

Each of our programs demonstrate the versatility of the ADAR-mediated RNA editing approach. Importantly, we are able to not only address classes of diseases caused by deleterious effects of misfolded or misdirected proteins, but we can also potentially utilize genetics to identify highly prevalent diseases where therapeutic benefit can be generated through alteration of protein function or expression. We will continue to selectively identify and pursue additional targets and indications based on a range of technical, clinical, and commercial factors to build a robust and differentiated pipeline. However, RNA editing is a novel technology that is not yet clinically validated for human therapeutic use. The approaches we take to discover and develop novel therapeutics are unproven and may never lead to marketable products. While limited clinical data for RNA editing therapies has been generated to date, we are not aware of any clinical trials for safety or efficacy having been completed by any third party using RNA editing and nor are we aware of any RNA editing therapeutic product that has been approved in the United States or Europe. It will be many years before we commercialize aan ~~product~~approved ~~candidate~~product, if ever.

Collaborations

We believe the versatility of our OPERA platform has the potential to create transformative genetic medicines for both rare and highly prevalent diseases. To fully realize this potential, we have established and plan to continue to actively seek out innovative collaborations, licenses, and strategic alliances with clinical leaders, academic medical centers of excellence, patient advocacy groups, and pioneering companies. Given the versatility and broad potential of our OPERA platform across therapeutic areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

areas, especially in diseases with high prevalence, we may enter into additional strategic partnerships with external parties that have complementary capabilities to broaden and accelerate access to our RNA editing therapies.

Novo Nordisk

In September 2024, we entered into a research collaboration and license agreement with Novo Nordisk, pursuant to which we granted Novo Nordisk an exclusive worldwide license under certain intellectual property rights to research, develop, manufacture, commercialize or otherwise exploit certain licensed compounds and licensed products for an initial target in the cardiometabolic field and for a second target (to be nominated by Novo Nordisk within a specified time period as set forth in the agreement). Under the agreement, we are responsible for certain research and development activities with respect to licensed compounds and licensed products directed against the initial target and the second target (if nominated by Novo Nordisk), and we are eligible to receive cost reimbursement from Novo Nordisk for our performance of such research and development activities under the agreement with respect to such target(s). Novo Nordisk may undertake subsequent worldwide development, manufacturing, marketing and commercialization of the licensed products directed against the initial target and the second target (if applicable). In November 2025, the collaboration entered a 12-month pause. For additional information relating to the financial terms of such agreement, see Note 1312 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

Manufacturing and Supply Arrangements

We currently have no commercial manufacturing capabilities. For our initial wave of clinical programs, we intend to use qualified third-party CMOs with relevant manufacturing experience in genetic medicines. weWe plan to partner with suppliers and CMOs to produce or process critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for investigational new drug, or IND, -supporting activities and early-stage clinical trials. At the appropriate time in the product development process, we will determine whether to establish in-house good manufacturing practice capabilities for some core technologies or continue to rely on third parties to manufacture commercial quantities for any products that we may successfully develop.

We also in-license technology for our fit-for-purpose delivery systems, including LNP delivery systems. For example, in March 2023, we entered into a collaboration and license agreement with Genevant, a well established leader in the LNP space, to provide access to clinically validated LNP technology to optimize delivery of our ~~AATD~~now ~~product~~terminated ~~candidate,~~REWRITE ~~KRRO-110.~~clinical ~~Preclinical~~program ~~studies~~investigating ~~of this LNP delivery technology have shown improved dose~~KRRO-~~dependent~~110 ~~efficacy~~as ~~with~~a ~~reduced~~treatment ~~clinical~~for ~~chemistry and adverse events~~AATD. For additional information relating to the financial terms of such agreement, see Note 1312 to our audited consolidated financial statements included elsewhere in this Annual Report on Form 10-K.

Competition

The pharmaceutical and biotechnology industries, including the gene therapy and gene editing fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property. While we believe that our differentiated technology, scientific expertise, and intellectual property position provide us with competitive advantages, we face potential competition from a variety of companies in these fields. There are several companies using synthetic oligonucleotide or base editing technology, including ~~Beam Therapeutics~~AIRNA, ~~Verve~~Beam Therapeutics, Prime Medicine, ~~AIRNA~~ProQR, ~~ProQR~~Tessera Therapeutics, ~~and~~Verve Therapeutics, Wave Life Sciences, and YolTech Therapeutics. Several additional companies utilize other editing technologies, including Edigene and Shape Therapeutics. In addition, we face competition from companies utilizing gene therapy, oligonucleotides, and DNA editing technologies such as base and prime editing.

Any ~~product~~development candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our ~~product~~development candidates. This may include other types of therapies, such as small molecule, antibody, and/or protein therapies.

In addition, many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials and approved products than we do today. Mergers and acquisitions in the pharmaceutical, biotechnology and gene therapy industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. We also compete with these companies in recruiting, hiring and retaining qualified scientific and management talent, establishing clinical trial sites and patient registration for clinical trials, obtaining manufacturing slots at contract manufacturing organizations, and in acquiring technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, particularly if they represent cures, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety, convenience, and availability of reimbursement.

Intellectual Property

Overview

We strive to protect the proprietary technology that we believe is important to our business, including seeking and maintaining patent protection in the United States and internationally for our current and future ~~product~~lead candidates and development candidates. We also rely on trademarks, copyrights, trade secrets, confidentiality procedures, employee disclosure, invention assignment agreements, know-how, continuing technological innovation and in-licensing opportunities to develop and maintain our proprietary position.

We seek to obtain domestic and international patent protection, and endeavor to promptly file patent applications for new commercially valuable inventions. We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

We plan to continue to expand our intellectual property estate by filing patent applications directed to platform technologies and pipeline programs, including composition of matter, pharmaceutical compositions, methods of treatment, and methods of manufacture. Our success will depend on our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how related to our business, defend and enforce any patents that we may obtain, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

The patent positions of companies like us are generally uncertain and involve complex legal, scientific and factual questions. In addition, the coverage claimed in a patent may be challenged in courts after issuance. Moreover, many jurisdictions permit third parties to challenge issued patents in administrative proceedings, which may result in further narrowing or even cancellation of patent claims. We cannot guarantee that our pending patent applications, or any patent applications that we may in the future file or license from third parties, will result in the issuance of patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or at all, whether the claims of any patent applications, should they issue, will cover our ~~product~~lead candidates and development candidates, or whether the claims of any issued patents will provide sufficient protection from competitors or otherwise provide any competitive advantage. We cannot predict the scope of claims that may be allowed or enforced in our patents. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our product candidates.

the scope of claims that may be allowed or enforced in our patents. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Consequently, we may not obtain or maintain adequate patent protection for any of our lead candidates and development candidates.

Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months or potentially even longer, and because publication of discoveries in the scientific or patent literature often lags behind actual discoveries and patent application filings, we cannot be certain of the priority of inventions covered by pending patent applications. Accordingly, we may not have been the first to invent the subject matter disclosed in some of our patent applications or the first to file patent applications covering such subject matter, and we may have to participate in derivation proceedings declared by the U.S. Patent and Trademark Office, or USPTO, to determine priority of invention. Further, periodic maintenance fees, renewal fees, annuity fees and various other government fees on patents and/or applications will be due to be paid to the USPTO and various government patent agencies outside of the United States over the lifetime of our patents and patent applications. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Patent Portfolio

We strive to protect our proprietary RNA editing platform, OPERA, and related technologies, and our ~~product~~lead candidates and development candidates, including seeking and maintaining patent protection intended to cover various target-specific editing strategies, the composition of matter of our ~~product~~lead candidate and development candidates, their methods of use, related delivery technologies, and other inventions. The intellectual property that is available to us is critical to our business, and we strive to protect it, including by obtaining, maintaining, defending, and enforcing patent protection in the United States and internationally. As of December 31, ~~2024~~2025, our patent portfolio in total consisted of 3342 patent families, with ~~five~~six U.S. patents and ~~three~~five patents in foreign jurisdictions (e.g., ~~Canada~~Australia, Japan and Taiwan), including pending U.S. provisional patent applications, pending Patent Cooperation Treaty, or PCT, applications, and various pending non-provisional applications world-wide (e.g., United States, Australia, Canada, China, Europe, South Korea, and Japan).

Our patent portfolio relates to our RNA editing platform OPERA, as well as numerous disease programs listed below. Patents and pending applications in the portfolio are directed to various oligonucleotide formats, nucleotide compositions, oligonucleotide chemistries, modifications, specific linkage chemistries, oligonucleotides having a specific structures, methods of deaminating an adenosine using such oligonucleotides, methods of oligonucleotide delivery, and methods of treating disease by administering such oligonucleotides.

We have three patent families with pending applications directed to specific oligonucleotide structures useful in ADAR editing oligonucleotides. Each of these three families have pending applications in Australia, Canada, China, Europe, Japan, South Korea and the United States. Absent any term extensions available via patent term extension or patent term adjustment, patents in these families will expire in 2040. These patent families include three granted U.S. patents: U.S. Patent No. 11,479,575 directed to specific oligonucleotide structures and expires in 2040; U.S. Patent No. 11,453,878 directed to methods of deamination of an adenosine in an mRNA using oligonucleotide with specific structures and also expires in 2040; and U.S. Patent No. 12,031,131 directed to specific oligonucleotide structures and expires in 2040.

In addition to the patent families described above, we also have other patent families directed to additional target-specific editing strategies, oligonucleotide compositions and their methods of use, related delivery technologies, and other inventions related to early-stage research and development efforts not reflected in our pipeline. Patents issued from or issuing from applications in these families will expire between 2041 and ~~2045~~2046, absent any available additional term for patent term extension or patent term adjustment~~, and includes Canadian Patent No~~. ~~3,162,416, which will expire in 2042.~~

In addition to platform and non-target specific patent families, we also have patent families pending that are directed to specific target programs.

Our patent portfolio that relates to our ~~AAT~~hyperammonia program includes ~~three~~two patent families ~~with pending patent applications~~ directed to specific ~~oligonucleotides~~target sites and ~~compositions~~oligonucleotides that ~~target~~edit ~~SERPINA1~~the ~~for editing to treat AAT~~target. The first patent family ~~includes~~consists ~~pending~~of ~~applications~~PCT inpatent ~~Australia, Canada, China, Europe, Japan, South Korea~~ and ~~the~~issued ~~United~~patents ~~States. Patents issuing from applications~~ in this family ~~will~~would expire in ~~2041~~2045, absent any available additional term for patent term extension or patent term adjustment. The second patent family ~~comprises~~is adirected ~~pending~~to ~~PCT~~oligonucleotides ~~application~~that ~~and~~direct ~~any~~editing ~~issued~~of ~~patents~~the ~~in this family would expire in 2044, absent any available additional term for patent term extension or patent term adjustment~~target. ~~The~~This ~~third~~second patent family ~~has~~consists ~~been~~of ~~filed~~two ~~as a~~ provisional patent ~~application~~applications, and if ~~refiled~~re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in ~~2045, absent any available additional term for patent term extension or patent term adjustment~~2046.

Our patent portfolio that relates to our ~~rare~~AATD ~~metabolic disorder~~ program includes aone patent family ~~directed~~with toa ~~specific~~pending ~~target~~U.S. ~~sites~~provisional ~~and~~patent ~~oligonucleotides that edit the target~~application. This patent family ~~consists~~has ofbeen ~~one~~filed as a provisional patent application, and if ~~re-filed~~refiled as PCT or non-provisional applications, and issued, patents in this family would expire in ~~2045~~2046, absent any available additional term for patent term extension or patent term adjustment.

Our patent portfolio that relates to our ALS program includes a patent family directed to specific target sites and oligonucleotides that edit TDP-43. This patent family consists of one provisional patent application, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in 2045, absent any available additional term for patent term extension or patent term adjustment. 30

Our patent portfolio that relates to our ~~Nav1.7~~longevity and liver health program includes atwo patent families. The first patent family is directed to specific target sites. This first patent family consists of one PCT patent application, and issued patents in this family would expire in 2046, absent any available additional term for patent term extension or patent term adjustment. The second patent family is directed to oligonucleotides that ~~edit~~direct ~~Nav1~~editing of AMPKγ1.7. This second patent family consists of one provisional patent application, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in ~~2045, absent any available additional term for patent term extension or patent term adjustment~~2046.

Our patent portfolio that relates to our ALS program includes two patent families directed to specific target sites and oligonucleotides that direct edit TDP-43. The first patent family consists of one PCT issued patents in this family would expire in 2045, absent any available additional term for patent term extension or patent term adjustment. The second patent family is directed to oligonucleotides that direct editing of TDP-43. This second patent family consists of one provisional patent application, and if re-filed as PCT or non-provisional applications, and issued, patents in this family would expire in 2046.

Patent Term

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, including the United States, the base term is 20 years from the filing date of the earliest-filed non-provisional patent application from which the patent claims priority. The term of a U.S. patent can be lengthened by patent term adjustment, which compensates the owner of the patent for administrative delays at the USPTO. In some cases, the term of a U.S. patent is shortened by terminal disclaimer that reduces its term to that of an earlier-expiring patent. The term of a U.S. patent may be eligible for patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act, to account for at least some of the time the drug is under development and regulatory review after the patent is granted. With regard to a drug for which FDA approval is the first permitted marketing of the active ingredient, the Hatch-Waxman Act allows for extension of the term of one U.S. patent that complies with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other regulatory requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale.

We may become subject to administrative or judicial sanctions or other legal consequences. These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending FDA applications, issuance of clinical holds for ongoing studies, suspension or revocation of approved at least one claim covering the composition of matter of such an FDA-approved drug, an FDA-approved method of treatment using the drug and/or a method of manufacturing the FDA-approved drug. The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug, and a patent cannot be extended more than once or for more than a single product. During the period of extension, if granted, the scope of exclusivity is limited to the approved product for approved uses. Some foreign jurisdictions, including Europe and Japan, have analogous patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

28In the future, if and when our development candidates receive FDA approval, we expect to apply, if appropriate, for patent term extension on patents directed to those development candidates, their methods of use and/or methods of manufacture. However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

product. During the period of extension, if granted, the scope of exclusivity is limited to the approved product for approved uses. Some foreign jurisdictions, including Europe and Japan, have analogous patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

In the future, if and when our product candidates receive FDA approval, we expect to apply, if appropriate, for patent term extension on patents directed to those product candidates, their methods of use and/or methods of manufacture. However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Reservation of Rights by the U.S. Government

Our in-licensed patent rights may be subject to a reservation of rights by one or more third parties, including the U.S. government. Pursuant to the Bayh-Dole Act of 1980, the U.S. government has certain rights in inventions developed with government funding. These U.S. government rights include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. When new technologies are developed with government funding, in order to secure ownership of patent rights related to the technologies, the recipient of such funding is required to comply with certain government regulations, including timely disclosing the inventions claimed in such patent rights to the U.S. government and timely electing title to such inventions. A failure to meet these obligations may lead to a loss of rights or the unenforceability of relevant patents or patent applications. In addition, the U.S. government has the right, under certain limited circumstances, to require the licensor to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions to a third party if it determines that: (1) adequate steps have not been taken to commercialize the invention; (2) government action is necessary to meet public health or safety needs; or (3) government action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”). While the U.S. government has not successfully exercised its march-in rights to date, recent developments in regulatory pharmaceutical product pricing schemes indicate that these march-in rights could be exercised to affect pricing.

as “march-in rights”). While the U.S. government has not successfully exercised its march-in rights to date, recent developments in regulatory pharmaceutical product pricing schemes indicate that these march-in rights could be exercised to affect pricing.

If the U.S. government exercised its march-in rights in our future intellectual property rights that are generated through the use of U.S. government funding or grants, we could be forced to license or sublicense intellectual property that we license on terms unfavorable to us, and there can be no assurance that we would receive compensation from the U.S. government for the exercise of such rights. If the U.S. government decides to exercise these march-in rights, it is not required to engage us as its contractor in connection with doing so. The U.S. government’s rights may also permit it to disclose the funded inventions and technology, which may include our confidential information, to third parties and to exercise march-in rights to use or allow third parties to use the technology that was developed using U.S. government funding. Intellectual property generated under a government funded program is also subject to certain reporting requirements, compliance with which may require us to expend substantial resources. In addition, the U.S. government requires that any products embodying any of these inventions or produced through the use of any of these inventions be manufactured substantially in the United States. This preference for U.S. industry may be waived by the federal agency that provided the funding if the owner or assignee of the intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the United States or that under the circumstances domestic manufacture is not commercially feasible. This preference for U.S. industry may limit our ability to contract with non-U.S. product manufacturers for products covered by such intellectual property. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Trade Secrets

In addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position. We typically rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection. We protect trade secrets and know-how by establishing confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and collaborators. These agreements provide that all confidential information developed or made known during the course of an individual or entities’ relationship with us must be kept confidential during and after the relationship. These agreements also provide that all inventions resulting from work performed for us or relating to our business and conceived or completed during the period of employment or assignment, as applicable, shall be our exclusive property. In addition, we take other appropriate precautions, such as physical and technological security measures, to guard against misappropriation of our proprietary information by third parties.

Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. For more information regarding the risks related to our intellectual property, see Item 1A “Risk Factors—Risks Related to Our Business—Risks Related to Intellectual Property.”

Governmental Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, clinical trial, testing, manufacture, quality control, import, export, safety, efficacy, labeling, packaging, storage, distribution, recordkeeping, approval, distribution, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs. We, along with our vendors, contract research organizations, or CROs, clinical investigators and CMOs will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our ~~product~~development candidates. The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

Overview of U.S. Drugs Development Process

In the United States, the FDA regulates drug products under the Federal Food, Drug and Cosmetic Act, or FD&C Act, and its implementing regulations. Drugs are also subject to other federal, state and local statutes and regulations. If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or judicial sanctions or other legal consequences. These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending applications, warning or untitled letters, product withdrawals or recalls, product seizures, relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

Our product candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States. For drug product candidates regulated under the FD&C Act, FDA must approve a New Drug Application, or an NDA. The process generally involves the following: 32

~~completion~~judicial ofsanctions ~~extensive~~or ~~preclinical~~other ~~studies~~legal inconsequences. ~~accordance~~These ~~with~~sanctions ~~applicable~~or ~~regulations~~consequences could include, ~~including~~among ~~studies~~other ~~conducted~~things, inthe ~~accordance~~FDA’s ~~with~~refusal ~~good~~to ~~laboratory~~approve ~~practice~~pending applications, warning or ~~GLP~~untitled letters, ~~requirements~~product ~~and~~withdrawals ~~applicable~~or ~~requirements~~recalls, ~~for~~product ~~the~~seizures, ~~humane~~relabeling ~~use~~or ofrepackaging, ~~laboratory~~total ~~animals~~or partial suspensions of manufacturing or ~~other~~distribution, ~~applicable~~injunctions, ~~regulations;~~fines, civil penalties or criminal prosecution.

Our development candidates must be approved for therapeutic indications by the FDA before they may be marketed in the United States. For drug development candidates regulated under the FD&C Act, FDA must approve a New Drug Application, or an NDA. The process generally involves the following:

•

completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP requirements and applicable requirements for the humane use of laboratory animals or other applicable regulations;

•

completion of the manufacture, under current good manufacturing practice, or cGMP, conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

•

submission to the FDA of an IND which must become effective before clinical trials may begin;

•

payment of user fees for FDA review of the NDA;

•

approval by an institutional review board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

•

performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

•

preparation and submission to the FDA of an NDA;

•

a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

•

satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced to assess compliance with cGMP requirements to assure that the facilities, methods and controls are adequate to preserve the drug product’s identity, strength, quality and purity;

•

satisfactory completion of potential FDA audit of the preclinical study clinical trial sites that generated the data in support of the NDA; and

•

FDA review and approval of the NDA, including, where applicable, consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug in the United States.

Preclinical Studies and Clinical Trials for Drugs

Before testing any drug in humans, the ~~product~~development candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluations of product chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use. The conduct of preclinical studies is subject to federal and state regulation and requirements, including GLP requirements for safety/toxicology studies. The results of the preclinical studies, together with manufacturing information and analytical data, must be submitted to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before clinical trials may begin. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials. The IND also includes the results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. Some long-term preclinical testing may continue after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions about the conduct of the clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks, and imposes a full or partial clinical hold. FDA must notify the sponsor of the grounds for the hold and any identified deficiencies must be resolved before the clinical trial can begin. Submission of an IND may result in the FDA not allowing clinical trials to commence or not allowing clinical trials to commence on the terms originally specified in the IND. A clinical hold can also be imposed once a trial has already begun, thereby halting the trial until the deficiencies articulated by FDA are corrected.

The clinical stage of development involves the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, who generally are physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirements that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters and criteria to be used in monitoring safety and evaluating effectiveness. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable compared to the anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. The FDA, the IRB, or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trials to public registries. Information about clinical trials, including results for clinical trials other than Phase 1 investigations, must be submitted within specific timeframes for publication on www.ClinicalTrials.gov, a clinical trials database maintained by the National Institutes of Health. 33

The clinical stage of development involves the administration of the development candidate to healthy volunteers or patients under the supervision of qualified investigators, who generally are physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirements that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters and criteria to be used in monitoring safety and evaluating effectiveness. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND. Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable compared to the anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. The FDA, the IRB, or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk. There also are requirements governing the reporting of ongoing clinical trials and completed clinical trials to public registries. Information about clinical trials, including results for clinical trials other than Phase 1 investigations, must be submitted within specific timeframes for publication on www.ClinicalTrials.gov, a clinical trials database maintained by the National Institutes of Health.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board or committee. This group provides authorization for whether or not a clinical trial may move forward at designated check points based on access that only the group maintains to available data from the trial and may recommend halting the clinical trial if it determines that the participants or patients are being exposed to an unacceptable health risk or other grounds, such as no demonstration of efficacy. Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.

A sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a foreign clinical trial is not conducted under an IND, FDA will nevertheless accept the results of the study in support of an NDA if the study was well-designed and well-conducted in accordance with GCP requirements, including that the clinical trial was performed by a qualified investigator(s); the data are applicable to the U.S. population and U.S. medical practice; and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials to evaluate therapeutic indications to support NDAs for marketing approval are typically conducted in three sequential phases, which may overlap.

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Phase 1 – Phase 1 clinical trials involve initial introduction of the investigational product in a limited population of healthy human volunteers or patients with the target disease or condition. These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, excretion the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness.

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Phase 2 – Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the drug’s potential efficacy, to determine the optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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Phase 3 – Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling. Generally, two adequate and well-controlled Phase 3 trials are required by the FDA for approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials or post-marketing studies, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a clinical setting. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of NDA approval.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA. Written IND safety reports must be submitted to the FDA and the investigators fifteen days after the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human volunteers and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information. During the development of a new drug product, sponsors have the opportunity to meet with the FDA at certain points, including prior to submission of an IND, at the end of Phase 2 and before submission of an NDA. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice on the next phase of development.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life. 34

before submission of an NDA. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date and for the FDA to provide advice on the next phase of development.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the development candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the development candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the development candidate does not undergo unacceptable deterioration over its shelf life.

U.S. Review and Approval Process for Drugs

Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. An NDA is a request for approval to market a new drug for one or more specified indications and must contain proof of the drug’s safety and efficacy for the requested indications. The marketing application is required to include both negative and ambiguous results of preclinical studies and clinical trials, as well as positive findings. Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational drug, to the satisfaction of the FDA. FDA must approve an NDA before a drug may be marketed in the United States.

The FDA reviews all submitted NDAs to ensure they are sufficiently complete to permit substantive review before it accepts them for filing and may request additional information rather than accepting the NDA for filing. The FDA must make a decision on accepting an NDA for filing within 60 days of receipt, and such decision could include a refusal to file by the FDA. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the NDA. The FDA reviews an NDA to determine, among other things, whether the product is safe and effective for the indications sought and whether the facility in which it is manufactured, processed, packaged or held meets standards, including cGMP requirements, designed to assure and preserve the product’s continued identity, strength, quality and purity. Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of a new molecular entity NDA and respond to the applicant, and six months from the filing date of a new molecular entity NDA for priority review. The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

Further, under PDUFA, as amended, each NDA must be accompanied by a substantial user fee. The FDA adjusts the PDUFA user fees on an annual basis. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

32The FDA also may require submission of a risk evaluation and mitigation strategy, or REMS, if it believes that a REMS is necessary to ensure that the benefits of the drug outweigh its risks. A REMS can include use of risk evaluation and mitigation strategies like medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, special monitoring or other risk-minimization tools.

The FDA also may require submission of a REMS if it believes that a REMS is necessary to ensure that the benefits of the drug outweigh its risks. A REMS can include use of risk evaluation and mitigation strategies like medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, special monitoring or other risk-minimization tools.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, which reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter. A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval. A Complete Response Letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response Letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the Complete Response Letter, the FDA may require additional clinical or preclinical testing or recommend other actions, such as requests for additional information or clarification, that the applicant might take in order for the FDA to reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

the application is not ready for approval. A Complete Response Letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response Letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the Complete Response Letter, the FDA may require additional clinical or preclinical testing or recommend other actions, such as requests for additional information or clarification, that the applicant might take in order for the FDA to reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

Even if the FDA approves a product, depending on the specific risk(s) to be addressed it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan drug designation to a drug intended to treat a rare disease or condition, which is a disease or condition with either a patient population of fewer than 200,000 individuals in the United States, or a patient population of 200,000 or more individuals in the United States when there is no reasonable expectation that the cost of developing and making the product available in the United States for the disease or condition will be recovered from sales of the product. Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in or shorten the duration of the regulatory review and approval process, though companies developing orphan products are eligible for certain incentives, including tax credits for qualified clinical testing and user-fee waivers.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to a seven-year period of marketing exclusivity during which the FDA may not approve any other applications to market the same therapeutic agent for the same approved use or indication, except in limited circumstances, such as a subsequent product’s showing of clinical superiority over the product with orphan exclusivity or where the original applicant cannot produce sufficient quantities of product. Competitors, however, may receive approval of different therapeutic agents for the indication for which the orphan product has exclusivity or obtain approval for the same therapeutic agent for a different indication than that for which the orphan product has exclusivity. Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same approved use or indication before we do, unless we are able to demonstrate that our product is clinically superior. If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity. Further, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity. Further, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

The FDA may further reevaluate its regulations and policies under the Orphan Drug Act. It is unclear as to how, if at all, the FDA may change the orphan drug regulations and policies in the future.

Expedited Development and Review Programs for Drugs

The FDA maintains several programs intended to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening diseases or conditions. These programs include Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval, and the purpose of these programs is to either expedite the development or review of important new drugs to get them to patients more quickly than standard FDA review timelines typically permit.

A new drug is eligible for Fast Track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition. Fast track designation applies to the combination of the product candidate and the specific indication for which it is being studied. Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed. Rolling review means that the FDA may review portions of the marketing application before the sponsor submits the complete application. 36

A new drug is eligible for Fast Track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition. Fast track designation applies to the combination of the development candidate and the specific indication for which it is being studied. Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed. Rolling review means that the FDA may review portions of the marketing application before the sponsor submits the complete application.

In addition, a new drug may be eligible for Breakthrough Therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug, alone or in combination with one or more other drugs, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Breakthrough Therapy designation provides all the features of Fast Track designation in addition to intensive guidance on an efficient product development program beginning as early as Phase 1, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review staff in a cross-disciplinary review, where appropriate.

Any product submitted to the FDA for approval, including a product with Fast Track or Breakthrough Therapy designation, may also be eligible for additional FDA programs intended to expedite the review and approval process, including Priority Review designation and Accelerated Approval. A product is eligible for Priority Review, once an NDA is submitted, if the product that is the subject of the marketing application has the potential to provide a significant improvement in safety or effectiveness in the treatment, diagnosis or prevention of a serious disease or condition. Under priority review, the FDA’s goal date to take action on the marketing application is six months compared to ten months for a standard review.

Products are eligible for Accelerated Approval if they can be shown to have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or an effect on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, which is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Accelerated Approval is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, adequate and well-controlled additional post-approval confirmatory studies to verify and describe the product’s clinical benefit, and under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Further, under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a product or an indication approved under Accelerated Approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product. In addition, for products being considered for Accelerated Approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or publication within 120 days of marketing approval be submitted to the agency for review during the pre-approval review period. After the 120-day period has passed, all advertising and promotional materials must be submitted at least 30 days prior to the intended time of initial dissemination or publication.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened. Furthermore, Fast Track designation, Breakthrough Therapy designation, Priority Review and Accelerated Approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval, though they may expedite the development or review process.

U.S. Post-Approval Requirements for Drugs

Drugs manufactured or distributed pursuant to FDA approvals are subject to continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, reporting of adverse experiences with the product, complying with promotion and advertising requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe approved products for off-label uses, manufacturers may not market or promote such uses. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, including not only by company employees but also by agents of the company or those speaking on the company’s behalf, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Promotional materials for approved drugs must be submitted to the FDA in conjunction with their first use or first publication. Further, if there are any modifications to the drug, including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.

including changes in indications, labeling or manufacturing processes or facilities, the applicant may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the development of additional data or preclinical studies and clinical trials.

The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-market testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization. In addition, manufacturers and their subcontractors involved in the manufacture and distribution of approved drugs and those supplying products, ingredients and components of them, are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMPs, which impose certain procedural and documentation requirements on sponsors and their CMOs. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that a sponsor may use. Additionally, manufacturers and other parties involved in the drug supply chain for prescription drugs must also comply with product tracking and tracing requirements and for notifying FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States. Accordingly, manufacturers must continue to expend time money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. Failure to comply with statutory and regulatory requirements may subject a manufacturer to possible legal or regulatory action, such as warning letters, suspension of manufacturing, product seizures, injunctions, civil penalties or criminal prosecution. There is also a continuing, annual program user fee for any marketed product.

The FDA may withdraw approval of a product if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS. Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product;

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fines, warning letters or holds on post-approval clinical trials;

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refusal of the FDA to approve applications or supplements to approved applications, or suspension or revocation of product approvals;

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product seizure or detention, or refusal to permit the import or export of products;

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injunctions or the imposition of civil or criminal penalties;

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consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; and

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mandated modification of promotional materials and labeling and issuance of corrective information.

U.S. Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of FDA approval of our future ~~product~~development candidates, some of our United States patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit restoration of the patent term of up to five years as compensation for patent term lost during the FDA regulatory review process. Patent term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date and only those claims covering such approved drug product, a method for using it or a method for manufacturing it may be extended. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond a patent’s current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

extension or restoration. In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond a patent’s current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

Marketing exclusivity provisions under the FD&C Act also can delay the submission or the approval of certain drug product applications. The FD&C Act provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an Abbreviated New Drug Application, or ANDA, or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FD&C Act also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Privacy and Cybersecurity

Our operations entail the collection, use, disclosure, transfer, and processing of sensitive and personal information. These operations subject us to privacy and data security laws and regulations in the United States, Europe and internationally. Our operations extend to commercial partnerships and third-party processors, each of which may be governed by their distinct privacy regulations and data security laws. These laws are constantly evolving and subject to varying interpretations, requiring us to periodically update our policies and measures to maintain compliance.

With respect to Europe, we are subject to the European data protection laws where we collect and use personal information relating to Europe in certain circumstances, including to conduct and enroll subjects in clinical trials in the United Kingdom, or the UK, European Union, or the EU, or the European Economic Area, or the EEA. This includes the EU General Data Protection Regulation, or EU GDPR, the UK General Data Protection Regulation, or UK GDPR, as well as applicable data protection laws in effect in the Member States of the EEA and in the UK (including the UK Data Protection Act 2018) that govern the processing of personal information (known as “personal data” under the GDPR) in connection with the offering goods or services to individuals in the EEA and UK; monitoring the behavior of individuals in the EEA and UK; or the activities of an establishment in the EEA and UK. The UK’s data protection regime is independent from but aligned to the EU’s data protection regime. In this Annual Report on Form 10-K, “GDPR” refers to both the EU GDPR and the UK GDPR, unless specified otherwise. The GDPR is wide-ranging in scope and imposes numerous obligations on companies that process personal information, including (i) stringent requirements on the processing of health and other sensitive data, (ii) providing information to individuals regarding data processing activities; (iii) ensuring a legal basis or condition applies to the processing of personal data and, where applicable, obtaining consent from individuals to whom the data processing relates; (iv) responding to data subject requests; (v) imposing requirements to notify the competent national data protection authorities and data subjects of personal data breaches; (vi) implementing safeguards in connection with the security and confidentiality of the personal data; (vii) accountability requirements; and (viii) taking certain measures when engaging third-party processors. The GDPR’s definition of personal data includes coded data, and it requires changes to informed consent practices and detailed notices for clinical trial subjects and investigators. The GDPR also imposes strict rules on the transfer of personal data to countries outside of the EEA and the UK that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses, or the SCCs, and the UK International Data Transfer Agreement or Addendum, or the UK IDTA, have been put in place. Where relying on the SCCs or the UK IDTA for data transfers, transfer impact assessments are required to assess whether the recipient is subject to local laws which allow public authority access to personal data. Failure to implement valid mechanisms for personal data transfers from Europe may result in increased exposure to regulatory actions, substantial fines and injunctions against processing personal data from Europe. Inability to export personal data may also: (i) restrict our activities outside Europe; (ii) limit the ability to collaborate with partners as well as other service providers, contractors and other companies outside of Europe; and/or (iii) require us to increase our processing capabilities within Europe at significant expense or otherwise cause us to change the geographical location or segregation of our relevant systems and operations – any or all of which could adversely affect our operations or financial results.

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~~valid~~The GDPR ~~transfer~~provides ~~mechanism~~that ~~(for~~EU ~~example,~~member ~~the~~states ~~European~~or ~~Commission~~the ~~approved~~UK ~~Standard~~may ~~Contractual~~make ~~Clauses,~~their orown ~~the~~further ~~SCCs,~~laws and ~~the~~regulations UKlimiting ~~International~~the ~~Data~~processing ~~Transfer~~of ~~Agreement~~personal ~~or Addendum~~data, orincluding ~~the~~genetic, ~~UK IDTA~~biometric, ~~have~~or ~~been~~health ~~put in place~~data. ~~Where~~In ~~relying~~addition, onfollowing the ~~SCCs or the~~ UK’s ~~IDTA~~exit ~~for~~from ~~data~~the ~~transfers~~EU, ~~transfer~~or ~~impact~~Brexit, ~~assessments~~there ~~are~~is ~~required~~increasing toscope ~~assess~~for ~~whether~~divergence ~~the~~in ~~recipient~~application, isinterpretation ~~subject~~and toenforcement ~~local~~of ~~laws~~the ~~which~~data ~~allow~~protection ~~public~~laws ~~authority~~between ~~access~~these ~~to personal data~~territories. ~~Failure~~For toexample, ~~implement~~the ~~valid~~UK ~~mechanisms~~has ~~for~~recently ~~personal~~introduced ~~data~~a ~~transfers~~new ~~from~~Data ~~Europe~~(Use ~~may~~and ~~result~~Access) inBill. ~~increased~~This ~~exposure~~development tocould ~~regulatory~~reshape ~~actions,~~the ~~substantial~~UK’s ~~fines~~data ~~and~~protection ~~injunctions~~landscape, ~~against~~distancing ~~processing~~it ~~personal data~~ from ~~Europe.~~the ~~Inability~~EU’s todata ~~export~~protection ~~personal~~regime ~~data~~and ~~may~~threaten ~~also:~~the ~~(i)~~UK ~~restrict~~adequacy ~~our~~decision ~~activities~~from ~~outside~~the ~~Europe;~~EU ~~(ii)~~Commission ~~limit~~allowing the ~~ability~~free toflow ~~collaborate~~of ~~with~~personal ~~partners~~data asfrom ~~well~~the asUK ~~other~~to ~~service~~the ~~providers~~EEA, ~~contractors~~which ~~and~~may ~~other~~lead ~~companies~~to ~~outside~~additional ofcompliance ~~Europe;~~costs and~~/or~~ ~~(iii)~~could ~~require~~increase usour tooverall ~~increase~~risk. ~~our~~This ~~processing~~lack ~~capabilities~~of ~~within~~clarity ~~Europe~~on atfuture ~~significant~~UK ~~expense~~laws orand ~~otherwise~~regulations ~~cause~~and ustheir tointeraction ~~change~~with ~~the~~those ~~geographical~~of ~~location~~the orEU ~~segregation~~could ofadd ~~our~~legal ~~relevant~~risk, ~~systems~~uncertainty, complexity, and ~~operations~~cost; –and any orresulting ~~all~~divergence ofin ~~which~~laws could ~~adversely~~increase ~~affect~~ our ~~operations~~risk orprofile ~~financial~~and ~~results~~necessitate further compliance measures.

The GDPR provides that EU member states or the UK may make their own further laws and regulations limiting the processing of personal data, including genetic, biometric, or health data. In addition, following the UK’s exit from the EU, or Brexit, there is increasing scope for divergence in application, interpretation and enforcement of the data protection laws between these territories. For example, the UK has recently introduced a new Data (Use and Access) Bill . This development could reshape the UK’s data protection landscape, distancing it from the EU’s data protection regime and threaten the UK adequacy decision from the EU Commission allowing the free flow of personal data from the UK to the EEA, which may lead to additional compliance costs and could increase our overall risk. This lack of clarity on future UK laws and regulations and their interaction with those of the EU could add legal risk, uncertainty, complexity, and cost; and any resulting divergence in laws could increase our risk profile and necessitate further compliance measures.

Failure to comply with the GDPR can result in significant practical, legal, and financial repercussions, including the destruction of improperly gathered or used personal data, substantial fines of up to €20 million (£17.5 million for the UK) or 4% of the company’s global annual turnover, mandatory audits, orders to cease or modify data use, and a private right of action enabling data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

In the United States, privacy and security of personal information are regulated by various federal and state laws, such as health information privacy laws, comprehensive state privacy laws, security breach notification laws, and consumer protection laws. At the state level, numerous states now have comprehensive privacy laws in effect, adding complexity, variation in requirements, restrictions and potential legal risk requiring additional investment of resources in compliance programs. These laws impose certain obligations on covered businesses, including obligations to provide specific disclosures in privacy notices and affording individuals certain rights concerning their personal data. While existing state comprehensive privacy laws exempt some data processed in the context of clinical trials, these developments may further complicate compliance efforts, and increase legal risk and compliance costs for us and the third parties upon whom we rely.

Federal and state legislators and regulators in the United States are also imposing new and heightened protections for health and other sensitive information that could impact our business. For example, the Federal Trade Commission, or the FTC, has imposed stringent requirements on the collection and disclosure of sensitive categories of personal information, including health information, and has expanded the application of its Health Breach Notification Rule. Through executive and legislative action, the federal government has also taken steps to restrict data transactions involving certain sensitive data categories – including health data, genetic data, and biospecimens – with persons affiliated with China, Russia, and other countries of concern. Additionally, a small number of states have passed or are considering laws governing the privacy of consumer health data. Washington’s My Health My Data Act, which went into effect in March 2024, requires regulated entities to obtain consent to collect health information, grants consumers certain rights, including to request deletion, and provides for robust enforcement mechanisms, including enforcement by the state attorney-general and by litigants through a private right of action for consumer claims. These current and future data privacy laws and regulations may require us to modify our data collection or processing practices and policies, incur substantial costs and expenses in an effort to comply and increase our potential exposure to regulatory enforcement, reputational damage, and/or litigation.

Further, regulators and legislators in the United States are increasingly scrutinizing and restricting certain personal data transfers and transactions involving foreign countries. For example, the ~~executive~~Department ~~order~~of Justice’s January 8, 2025, rule on “Preventing Access to ~~Americans’~~U.S. ~~Bulk~~ Sensitive Personal Data and ~~United States~~ Government-Related Data by Countries of Concern asor ~~implemented~~Covered ~~by Department of Justice regulations issued in December 2024~~Persons,” prohibits data brokerage transactions involving certain sensitive personal data categories, including health data, genetic data, and biospecimens, to countries of concern, including China. The regulations also restrict certain investment agreements, employment agreements and vendor agreements involving such data and countries of concern, absent specified cybersecurity controls. Actual or alleged violations of these regulations may be punishable by criminal and/or civil sanctions, and may result in exclusion from participation in federal and state programs.

There is a further risk that we may not be able to adequately protect our information systems from cyberattacks. Such security breaches, incidents and compromises could result in the disclosure of confidential, protected, or personal information, damage our reputation, and expose us to significant financial and legal exposure, including potential civil fines and penalties, litigation, and regulatory investigations or enforcement actions under laws such as HIPAA and the GDPR. Further, all 50 states in the United States have laws including obligations to provide notification of unauthorized acquisition of personal information to affected individuals, state officers and others. Some laws may also impose physical and electronic security requirements regarding the safeguarding of personal information. In order to comply with privacy and information security laws, we have confidentiality and information security standards and procedures in place for our business activities.

37Compliance with these multifaceted privacy and data security laws can be time-consuming, and failure to comply with any of these regulations could lead to significant fines and penalties (potentially including criminal prosecution), adversely affecting our reputation, business, financial condition, and operational results. Changes in statutes, regulations, or interpretations of existing

Compliance with these multifaceted privacy and data security laws can be time-consuming, and failure to comply with any of these regulations could lead to significant fines and penalties (potentially including criminal prosecution), adversely affecting our reputation, business, financial condition, and operational results. Changes in statutes, regulations, or interpretations of existing regulations could impose additional requirements on our operations, such as modifications to data processing arrangements, changes to privacy policies, recall or discontinuation of certain data processing methods, or additional recordkeeping requirements. These changes could adversely affect the operation of our business. 40

regulations could impose additional requirements on our operations, such as modifications to data processing arrangements, changes to privacy policies, recall or discontinuation of certain data processing methods, or additional recordkeeping requirements. These changes could adversely affect the operation of our business.

In addition to the risks outlined above, the legal or regulatory actions may also divert our management from their primary operations. Prohibitions, restrictions, or allegations of violations of these laws could materially and adversely affect our business. Hence, ensuring consistent compliance with privacy and data security laws and regulations remains a critical operational imperative for us.

Other Regulatory Matters

Manufacturing, labeling, packaging, distribution, sales, promotion and other activities of ~~product~~development candidates following product approval, where applicable, or commercialization are also potentially subject to federal and state consumer protection and unfair competition laws, among other requirements to which we may be subject. Additionally, the activities associated with the commercialization of ~~product~~development candidates are subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human Services, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

The distribution of pharmaceutical drugs is subject to additional requirements and regulations, including extensive recordkeeping, licensing, storage and security requirements intended to prevent the unauthorized sale of such pharmaceutical products.

The failure to comply with any of these laws or regulatory requirements may subject firms to legal or regulatory action. Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines or other penalties, injunctions, exclusion from federal healthcare programs, requests for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, relabeling or repackaging, or refusal to allow a firm to enter into supply contracts, including government contracts. Any claim or action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business. Prohibitions or restrictions on marketing, sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

Changes in statutes, regulations, or the interpretation of existing regulations could impact our business in the future by requiring, for example: (i) changes to our manufacturing arrangements; (ii) additions or modifications to product labeling or packaging; (iii) the recall or discontinuation of our products; or (iv) additional recordkeeping requirements. If any such changes were to be imposed, they could adversely affect the operation of our business.

Regulation Outside of the United States

In addition to regulations in the United States, we are subject to a variety of regulations in other jurisdictions governing clinical studies, commercial sales, and distribution of our products. Most countries outside of the United States require that clinical trial applications be submitted to and approved by the local regulatory authority for each clinical study. Whether or not we obtain FDA approval for a product, we must obtain approval of a product by the comparable regulatory authorities of countries outside the United States before we can commence marketing of the product in those countries. The approval process and requirements vary from country to country, so the number and type of nonclinical, clinical, and manufacturing studies needed may differ, and the time may be longer or shorter than that required for FDA approval.

Regulatory Framework in the EU and United Kingdom

In the EU an application must be submitted to the national competent authority and an independent ethics committee in each country in which we intend to conduct clinical trials, much like the FDA and IRB, respectively. Under the new CTR (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022, a single application is now made through the Clinical Trials Information System, or CTIS, for clinical trial authorization in up to 30 EU/EEA countries at the same time and with a single set of documentation.

The assessment of applications for clinical trials is divided into two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation). Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted, or Member States concerned of a draft report prepared by a Reference Member State. Part II is assessed separately by each

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or Member ~~States concerned of a draft report prepared by a Reference Member~~ State. ~~Part II is assessed separately by each Member State~~ concerned. The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the Member State concerned, however overall related timelines are defined by the CTR. The new CTR also provides for simplified reporting procedures for clinical trial sponsors.

To obtain regulatory approval of our medicinal products under the EU’s regulatory system, we are required to submit a marketing authorization application, or MAA, to be assessed in the centralized procedure. The centralized procedure allows applicants to obtain a marketing authorization, or MA, that is valid throughout the EU, and the additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway), or EEA. It is compulsory for medicinal products manufactured using biotechnological processes, orphan medicinal products, advanced therapy medicinal products (gene-therapy, somatic cell-EU and which is intended for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, auto-immune and other immune dysfunctions, viral diseases or diabetes). The centralized procedure is optional for any other products containing new active substances not authorized in the EU or for products which constitute a significant therapeutic, scientific, or technical innovation or for which a centralized authorization is in the interests of patients at EU level. When a company wishes to place on the market a medicinal product that is eligible for the centralized procedure, it sends an application directly to the European Medicines Agency, or EMA, to be assessed by the Committee for Medicinal Products for Human Use, or CHMP. The CHMP is responsible for conducting the assessment of whether a medicine meets the required quality, safety, and efficacy requirements, and whether the product has a positive risk/benefit profile. Once the CHMP has completed its assessment, the CHMP will give a favorable or unfavorable opinion as to whether to grant the authorization. The time limit for the evaluation procedure is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP). The EMA then has fifteen days to forward its opinion to the European Commission, which will make a binding decision on the grant of an MA within 67 days of the receipt of the CHMP opinion.

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States. Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as an orphan medicinal product if it is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition that affects no more than five in 10,000 persons in the EU when the application is made. In addition, orphan designation can be granted if the product is intended for a life threatening, seriously debilitating, or serious and chronic condition in the EU and when, without incentives, it is unlikely that sales of the product in the EU would be sufficient to justify the necessary investment in its development. Orphan designation is only available if there is no other satisfactory method approved in the EU of diagnosing, preventing, or treating the applicable orphan condition, or if such a method exists, the proposed orphan medicinal product will be of significant benefit to patients affected by such condition, as defined in Regulation (EC) 847/2000.

Orphan designation provides opportunities for fee reductions, protocol assistance, and access to the centralized procedure. In addition, if a product which has an orphan designation subsequently receives a centralized MA for the indication for which it has such designation, the product is entitled to orphan market exclusivity, which means the EMA may not approve any other application to market a similar medicinal product for the same indication for a period of ten years. A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication. The exclusivity period may be reduced to six years if, at the end of the fifth year, it is shown that the designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity. Additionally, an MA may be granted to a similar medicinal product for the same indication at any time if:

•

the second applicant can establish that its product, although similar to the authorized product, is safer, more effective or otherwise clinically superior;

•

the MA holder of the authorized product consents to a second orphan medicinal product application; or

•

the MA holder of the authorized product cannot supply enough orphan medicinal product.

A pediatric investigation plan, or PIP, in the EUEuropean Union is aimed at ensuring that the necessary data are obtained to support the authorization of a medicine for children, through studies in children. All applications for MAs for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when an MA holder wants to add a new indication, pharmaceutical form, or route of administration for a medicine that is already authorized and covered by intellectual property rights. Several rewards and incentives for the development of pediatric medicines for children are available in the EU. Medicines authorized across the EU with the results of studies from a PIP included in the product information are eligible for an extension of their supplementary protection certificate, or SPC, by six months (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to two years before the SPC expires). This is the case even when the studies’ results are negative. For orphan medicinal products, the incentive is an additional two years of market exclusivity. Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines.

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In March 2016, the EMA launched an initiative, the Priority Medicines scheme, or the PRIME scheme, to facilitate development of ~~product~~development candidates in indications, often rare, for which few or no therapies currently exist. The PRIME scheme is intended to encourage development of products in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies on the basis of compelling non-clinical data and tolerability data from initial clinical trials. Many benefits accrue to sponsors of ~~product~~development candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and potentially accelerated MAA assessment once a dossier has been submitted. Importantly, once a candidate medicine has been selected for the PRIME scheme, a dedicated contact and rapporteur from the CHMP or from the Committee for Advanced Therapies, or CAT, are appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level. An initial meeting with the CHMP/CAT rapporteur initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies. PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designation or eligibility will result in expedited review or approval. The aforementioned EU rules are generally applicable in the EEA. The United Kingdom left the EU on January 31, 2020.

The United Kingdom have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021. The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of United Kingdom and EU pharmaceutical regulations. At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended). Except in respect of the new EU Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with current EU medicines regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of United Kingdom and EU pharmaceutical legislation. However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework which will be put in place by the Medicines and Healthcare products Regulatory Agency, or MHRA, the United Kingdom’s medicines regulator, from January 1, 2024, the MHRA will take into account decisions on the approval of MAs from the EMA (and certain other regulators) when considering an application for a Great Britain MA.

On February 27, 2023, the United Kingdom government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”. This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the United Kingdom. In particular, the MHRA will be responsible for approving all medicinal products destined for the United Kingdom market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland. A single United Kingdom-wide MA will be granted by the MHRA for all medicinal products to be sold in the United Kingdom, enabling products to be sold in a single pack and under a single authorization throughout the United Kingdom. On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply after January 1, 2025.

There is now no pre-MA orphan designation in Great Britain. Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MAA. The criteria are essentially the same, but have been tailored for the Great Britain market, i.e., the prevalence of the condition in Great Britain (rather than the EU) must not be more than five in 10,000. Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in Great Britain or the EU, wherever is earliest.

Regulatory Framework in Australia

~~Our~~We conducted the REWRITE Phase 1/2a ~~clinical~~ trial ~~for~~in ~~KRRO-110~~Australia isand ~~being~~may, ~~conducted~~in the future, conduct additional clinical trials in Australia. The Therapeutic Goods Administration, or TGA, and the National Health and Medical Research Council set the legislative, regulatory and good clinical practice requirements for conducting clinical research in Australia, and compliance with these laws and codes is mandatory. Australia has also adopted international codes, such as those promulgated by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH. The ICH guidelines, as annotated by teh TGA, must be complied with across all fields of clinical research, including those related to pharmaceutical quality, nonclinical and clinical data requirements and trial designs. The basic requirements for preclinical data to support a first-in-human trial under ICH guidelines are applicable in Australia, and will form part of the Common Technical Document for the registration of medicines. Requirements related to adverse event reporting in Australia are similar to those required in other major jurisdictions.

The Therapeutic Goods Act 1989 and related regulations establish and maintain the national system of controls relating to the efficacy, quality, safety and timely availability of drugs and medical devices in Australia. The TGA is the Australian regulatory authority for therapeutic goods. The TGA describes its remit as being to safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods. The TGA administers two pathways for 43

40The Therapeutic Goods Act 1989 and related regulations establish and maintain the national system of controls relating to the efficacy, quality, safety and timely availability of drugs and medical devices in Australia. The TGA is the Australian regulatory authority for therapeutic goods. The TGA describes its remit as being to safeguard and enhance the health of the Australian community through effective and timely regulation of therapeutic goods. The TGA administers two pathways for clinical trials, the Clinical Trials Notification, or CTN, and Clinical Trials Approval, or CTA, schemes. These provide an avenue through which 'unapproved' therapeutic goods may be lawfully supplied for use solely for experimental purposes in humans. The choice of which route to use (CTN or CTA) lies firstly with the Australian clinical trial sponsor and then with the Human Research Ethics Committee, or HREC, that approves the protocol. The CTA pathway, requiring prior regulatory approval, is generally designed for high-risk or novel treatments where there is no or limited knowledge of safety.

clinical trials, the Clinical Trials Notification, or CTN, and Clinical Trials Approval, or CTA, schemes. These provide an avenue through which 'unapproved' therapeutic goods may be lawfully supplied for use solely for experimental purposes in humans. The choice of which route to use (CTN or CTA) lies firstly with the Australian clinical trial sponsor and then with the Human Research Ethics Committee, or HREC, that approves the protocol. The CTA pathway, requiring prior regulatory approval, is generally designed for high-risk or novel treatments where there is no or limited knowledge of safety.

Clinical trials of medicines and biologicals typically proceed through 'phases' of development, which generally follow: Phase 1 (human pharmacology), Phase 2 (therapeutic exploratory), and Phase 3 (therapeutic confirmatory). Phase 4 may be conducted for post-marketing surveillance or resolution of treatment uncertainties. Clinical development pathways are becoming less rigid with respect to phase and seamless adaptive trial designs and other cross-phase studies exist.The use of therapeutic goods in any clinical trial must be in accordance with the Guideline for Good Clinical Practice, the National Statement on Ethical Conduct in Human Research and the protocol approved by the HREC responsible for monitoring the conduct of the trial. The trial sponsor must also comply with the requirements of any other Commonwealth and/or state and territory legislation in relation to clinical trials and the supply of therapeutic goods.

Approval for inclusion in the Australian Register of Therapeutic Goods, or ARTG, is required before a pharmaceutical product that is not otherwise the subject of a relevant exemption or exclusion may be marketed (or imported, exported, manufactured or supplied) in Australia. In order to obtain registration of the product on the ARTG, it is required that:

•

adequate and well-controlled clinical trials demonstrate the quality, safety and efficacy of the therapeutic product;

•

evidence is compiled which demonstrates that the manufacture of the therapeutic product complies with the principles of cGMP;

•

manufacturing and clinical data is derived to submit to the relevant independent advisory committee to the TGA, which makes recommendations as to whether or not to grant approval to include the therapeutic product in the ARTG; for example, the Advisory Committee on Medicines; and

•

an ultimate decision is made by the Secretary of the Department of Health and Aged Care, via the TGA, whether to include the therapeutic product in the ARTG.

Therapeutic goods need to be entered on the ARTG before they can be supplied in Australia, unless a relevant exemption or exclusion applies. However, aside from use during an approved clinical trial, there are a limited ways that patients may gain access to such products or indications that have not been approved for use in Australia, for example:

•

the Special Access Scheme allows a health practitioner to access an unapproved therapeutic good for an individual patient on a case-by-case basis;

•

medical professionals can apply to the TGA to become an Authorised Prescriber of a specific unapproved good to specific patients with a particular medical condition. In some instances, doctors also need to have their application approved by a human research ethics committee or endorsed by a specialist college.

~~Patients~~Pharmaceutical ~~Rely on Insurance~~ Coverage ~~by Third-Party Payors (third-party payors include Medicare~~ and ~~Medicaid~~Reimbursement ~~(government payors) and commercial insurance companies such as Blue Cross Blue Shield, Humana, Cigna, etc.) to Pay for Products~~

InPatients in the United States and markets in other countries, ~~patients~~ generally rely on third-party payors to cover and reimburse all or part of the costs associated with their treatment, including the cost of drugs. Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance for any product that we may commercialize. Our ability to successfully commercialize our ~~product~~development candidates will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

Additionally, the process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which products they will pay for and establish reimbursement levels. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. ~~Third-party~~(for ~~payors~~example, ~~may~~formularies, ~~limit~~prior ~~coverage~~authorization, tostep ~~specific products on an approved list~~therapy, ~~also~~quantity ~~known as a formulary~~limits, which might not include all of the approved products for a particular indication. Net prices for products may also be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and ~~by any future relaxation~~ site-of ~~laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States. Increasingly, third~~-~~party~~care ~~payors are requiring that pharmaceutical companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. As a result~~restrictions, ~~the coverage determination~~

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among other). Third-party payors may limit coverage for a product for narrower patient subpopulations or might not include all of the approved products for a particular indication. Net prices for products may also be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States. Increasingly, third-party payors are requiring that pharmaceutical companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained. Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment.

~~Outside~~There ~~the~~is ~~United States, ensuring coverage and adequate payment for a product~~ also ~~involves~~significant ~~challenges.~~uncertainty ~~Pricing~~related ~~of prescription pharmaceuticals is subject~~ to ~~government control in many countries. In some foreign countries,~~ the ~~proposed~~insurance ~~pricing~~coverage ~~for~~and areimbursement ~~drug~~of ~~must~~newly be approved ~~before~~products itand coverage may be ~~lawfully~~more ~~marketed.~~limited ~~The~~than ~~requirements governing drug pricing vary widely from country to country. For example,~~ the ~~European~~purposes ~~Union provides options~~ for ~~its~~which ~~Member States to restrict~~ the ~~range~~medicine ofis ~~medicinal~~approved ~~products~~by ~~for which their national health insurance systems provide reimbursement and to control~~ the ~~prices~~FDA ofor ~~medicinal~~comparable ~~products~~foreign ~~for~~regulatory ~~human use~~authorities. ToIn ~~obtain~~the ~~reimbursement~~United ~~or pricing approval~~States, ~~some of these countries may require~~ the ~~completion~~principal ofdecisions ~~clinical~~about ~~trials~~reimbursement ~~that~~for ~~compare~~new ~~the~~medicines ~~cost~~are ~~effectiveness~~typically ofmade aby ~~particular product candidate to currently available therapies~~CMS. ACMS ~~Member~~decides ~~State~~whether ~~may~~and ~~approve~~to awhat ~~specific~~extent ~~price for the medicinal product or it may instead adopt~~ a ~~system~~new ofmedicine ~~direct~~will ~~or indirect controls on the profitability of the company placing the medicinal product on the market. There can~~ be nocovered ~~assurance~~and ~~that~~reimbursed ~~any~~under ~~country~~Medicare ~~that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement~~ and ~~pricing~~private ~~arrangements~~payors ~~for~~tend ~~any~~to ~~of our product candidates. Historically, products launched in the European Union do not~~ follow ~~U.S.~~CMS ~~price structures and generally prices tend~~ to bea ~~significantly~~substantial ~~lower~~degree.

No Uniform Policy Exists for Coverage and Reimbursement in the United States

There is also significant uncertainty related to the insurance coverage and reimbursement of newly approved products and coverage may be more limited than the purposes for which the medicine is approved by the FDA or comparable foreign regulatory authorities. In the United States, the principal decisions about reimbursement for new medicines are typically made by the CMS, an agency within the U.S. Department of Health and Human Services that implements the Medicare program. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.

We currently expect that any drugs we develop may need to be administered under the supervision of a physician on an outpatient basis. Under currently applicable U.S. law, certain drugs that are not usually self-administered (such as most injectable drugs) may be eligible for coverage under the Medicare Part B program if:

•

they are incident to a physician’s services;

•

they are reasonable and necessary for the diagnosis or treatment of the illness or injury for which they are administered according to accepted standards of medical practice; and

•

they have been approved by the FDA and meet other requirements of the statute.

Pharmaceutical companies whose products are reimbursed under Medicare Part B must calculate and report certain price reporting metrics to the government, such as average sales price, and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely. Further, these prices for ~~product~~development candidates may be reduced by mandatory discounts or rebates required by government healthcare programs.

~~Further,~~Outside ~~during~~ the ~~COVID-19~~United ~~pandemic~~States, ~~millions~~ensuring ofcoverage ~~individuals~~and ~~lost~~adequate ~~employer-based~~payment ~~insurance~~for ~~coverage~~a product also involves challenges. ItPricing of prescription pharmaceuticals is ~~unclear~~subject ~~what~~to ~~effect~~government control in many countries. In some foreign countries, ifthe ~~any~~proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. For example, the ~~American~~European ~~Rescue~~Union ~~Plan~~provides ~~will~~options ~~have~~for onits Member States to restrict the ~~number~~range of ~~covered~~medicinal ~~individuals,~~products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. To obtain reimbursement or pricing approval, some of these countries may ~~adversely~~require ~~affect~~the ~~our~~completion ~~ability~~of clinical trials that compare the cost effectiveness of a particular development candidate to ~~commercialize~~currently available therapies. A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our development candidates. Historically, products launched in the European Union do not follow U.S. price structures and generally prices tend to be significantly lower.

Other Healthcare Laws

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business that may constrain the financial arrangements and relationships through which we research, as well as sell, market and distribute any products for which we obtain marketing authorization. Such laws include, without limitation, ~~state~~(i) fraud and abuse laws, such as the federal ~~anti~~Anti-~~kickback,~~Kickback ~~fraud~~Statute and ~~abuse,~~federal and state false claims, and ~~transparency~~related laws (including the False Claims Act and ~~regulations~~Civil ~~related~~Monetary toPenalties ~~drug~~Law); ~~pricing~~(ii) ~~and~~healthcare ~~payments~~fraud and ~~other~~false ~~transfers~~statement ofstatutes; ~~value~~(iii) ~~made~~privacy toand ~~physicians~~security ~~and~~requirements ~~other~~for ~~healthcare~~health ~~providers.~~information Ifunder ~~our~~HIPAA, ~~operations~~as ~~are~~amended ~~found~~by toHITECH, beand inanalogous ~~violation~~state ofand ~~any~~foreign ofdata ~~such~~protection laws; or(iv) ~~any~~transparency ~~other~~and ~~governmental~~reporting ~~regulations~~requirements, ~~that~~including ~~apply,~~the wefederal ~~may~~Physician bePayments ~~subject~~Sunshine toAct ~~penalties,~~and ~~including,~~state ~~without~~equivalents; ~~limitation,~~(v) ~~administrative,~~federal ~~civil~~and state drug price reporting and ~~criminal~~disclosure ~~penalties,~~laws; ~~damages,~~and ~~fines,~~(vi) ~~disgorgement~~anti-corruption laws, including the ~~curtailment~~Foreign orCorrupt ~~restructuring~~Practices ofAct ~~operations,~~and ~~integrity~~similar ~~oversight~~foreign requirements. Many state and ~~reporting~~foreign ~~obligations,~~laws ~~exclusion~~are ~~from~~broader ~~participation~~than intheir federal ~~and~~counterparts, ~~state~~may ~~healthcare~~apply ~~programs~~regardless ~~and~~of ~~responsible~~payor, ~~individuals~~and may beimpose ~~subject~~additional toor ~~imprisonment~~different obligations. If our operations are found to be in violation of any of such laws or any other governmental

4245

~~Affordable~~regulations ~~Care~~that ~~Act~~apply, we may be subject to penalties, including, without limitation, administrative, civil and ~~Legislative~~criminal ~~Reform~~penalties, ~~Measures~~damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and responsible individuals may be subject to imprisonment.

~~Payors,~~Healthcare ~~whether~~Reform ~~domestic~~Measures or foreign, or governmental or private, are developing increasingly sophisticated methods of controlling healthcare costs and those methods are not always specifically adapted for new technologies such as gene therapy and therapies addressing rare diseases such as those we are developing. In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products profitably. In particular, in 2010, the ACA was enacted, which, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations; subjected manufacturers to new annual fees and taxes for certain branded prescription drugs; created a Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; and provided incentives to programs that increase the federal government’s comparative effectiveness research.

~~Since its enactment~~Payors, ~~there~~whether ~~have~~domestic ~~been~~or ~~numerous judicial~~foreign, ~~administrative,~~or ~~and~~governmental ~~executive~~or private, ~~challenges~~are todeveloping ~~certain~~increasingly ~~aspects~~sophisticated methods of ~~the~~controlling ~~ACA.~~healthcare Incosts ~~addition,~~and ~~other~~those ~~legislative~~methods ~~changes~~are ~~have~~not ~~been~~always ~~proposed~~specifically ~~and~~adapted ~~adopted~~for innew ~~the~~technologies ~~United~~such ~~States~~as ~~since~~gene ~~the~~therapy ~~ACA~~and ~~was~~therapies ~~enacted.~~addressing ~~For~~rare ~~example,~~diseases ~~the~~such ~~American~~as ~~Rescue~~those ~~Plan~~we ~~Act~~are ofdeveloping. ~~2021~~In ~~eliminates~~both the ~~statutory~~United ~~Medicaid~~States ~~drug~~and ~~rebate~~certain ~~cap~~foreign jurisdictions, ~~currently~~there ~~set~~have atbeen ~~100%~~a number of alegislative ~~drug’s~~and ~~average~~regulatory ~~manufacturer~~changes ~~price,~~to ~~for~~the ~~single~~health ~~source~~care ~~and~~system ~~innovator~~that ~~multiple~~could ~~source~~impact ~~drugs,~~our ~~beginning~~ability ~~January~~to 1,sell ~~2024.~~our ~~Further,~~products ~~the~~profitably. ~~Budget~~In ~~Control~~particular, ~~Act~~in of2010, ~~2011~~the ~~and~~ACA ~~subsequent~~was ~~legislation~~enacted, which, among other things, ~~created~~addressed ~~measures~~a ~~for~~new ~~spending~~methodology ~~reductions~~by which rebates owed by ~~Congress~~manufacturers ~~that~~under ~~include~~the ~~aggregate~~Medicaid ~~reductions~~Drug ofRebate ~~Medicare~~Program ~~payments~~are tocalculated ~~providers~~for ofdrugs 2%that ~~per~~are ~~fiscal~~inhaled, ~~year~~infused, ~~which~~instilled, ~~remain~~implanted inor ~~effect~~injected; ~~through~~increased ~~2031.~~the ~~Due~~minimum toMedicaid ~~the~~rebates ~~Statutory~~owed ~~Pay-As-You-Go~~by ~~Act~~most ofmanufacturers ~~2010,~~under ~~estimated~~the ~~budget~~Medicaid ~~deficit~~Drug ~~increases~~Rebate ~~resulting~~Program; ~~from~~extended the ~~American~~Medicaid ~~Rescue~~Drug ~~Plan~~Rebate ~~Act~~program to utilization of ~~2021,~~prescriptions ~~and~~of ~~subsequent~~individuals ~~legislation,~~enrolled ~~Medicare~~in ~~payments~~Medicaid managed care organizations; subjected manufacturers to ~~providers~~new ~~will~~annual befees ~~further~~and ~~reduced~~taxes ~~starting~~for incertain ~~2025~~branded ~~absent~~prescription ~~further~~drugs; ~~legislation.~~created ~~The~~a ~~U.S.~~Medicare ~~American~~Part ~~Taxpayer~~D ~~Relief~~coverage ~~Act~~gap ofdiscount ~~2012~~program, ~~further~~in ~~reduced~~which ~~Medicare~~manufacturers ~~payments~~were required to ~~several~~agree ~~types~~to ofoffer ~~providers~~70% ~~and~~point-of-sale ~~increased~~discounts ~~the~~off ~~statute~~negotiated prices of ~~limitations~~applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the ~~government~~manufacturer’s outpatient drugs to ~~recover~~be ~~overpayments~~covered tounder ~~providers~~Medicare ~~from~~Part ~~three~~D (later replaced under the Inflation Reduction Act with the Manufacturer Discount Program); and provided incentives to ~~five~~programs ~~years~~that increase the federal government’s comparative effectiveness research.

~~The~~Since ~~Inflation~~its ~~Reduction~~enactment, ~~Act~~there ofhave ~~2022,~~been ornumerous ~~IRA~~judicial, ~~includes~~administrative, ~~several~~and ~~provisions~~executive, ~~that~~challenges ~~may impact our business~~ to ~~varying~~certain ~~degrees,~~aspects ~~including~~of ~~provisions that reduce~~ the ~~out-of-pocket~~ACA. ~~cap~~In ~~for Medicare Part D beneficiaries to $2~~addition,~~000~~ ~~starting~~other inlegislative ~~2025;~~changes ~~impose~~have ~~new~~been ~~manufacturer~~proposed ~~financial~~and ~~liability~~adopted onin ~~certain~~the ~~drugs~~United ~~under~~States ~~Medicare~~since ~~Part~~the D;ACA ~~allow~~was ~~the U~~enacted.S. ~~government~~For toexample, ~~negotiate~~the ~~Medicare~~American ~~Part~~Rescue BPlan ~~and~~Act ~~Part~~of D2021 ~~price~~eliminated ~~caps~~the ~~for~~statutory ~~certain~~Medicaid ~~high-cost~~drug ~~drugs~~rebate ~~without~~cap, ~~generic~~currently ~~competition;~~set ~~require~~at ~~companies~~100% toof ~~pay~~a ~~rebates~~drug’s toaverage ~~Medicare~~manufacturer price, for ~~certain~~single ~~drug~~source ~~prices~~and ~~that~~innovator ~~increase~~multiple ~~faster~~source ~~than~~drugs, ~~inflation;~~effective ~~and delay until~~ January 1, ~~2032 the rebate rule that would limit the fees that pharmacy benefit managers can charge~~2024. Further, ~~under~~ the ~~IRA,~~Budget ~~orphan~~Control ~~drugs~~Act ~~are~~of ~~exempted~~2011 ~~from~~and ~~the~~subsequent ~~Medicare~~legislation, ~~drug~~among ~~price~~other ~~negotiation program~~things, ~~but~~created ~~only~~measures ~~if they have one orphan designation and~~ for ~~which~~spending ~~the~~reductions ~~only~~by ~~approved~~Congress ~~indication is for~~ that ~~disease~~include oraggregate ~~condition.~~reductions Ifof aMedicare ~~product~~payments ~~receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption. Further, judicial challenges~~ to ~~the~~providers ~~IRA may have an impact on the implementation~~ of ~~the~~2% ~~IRA’s~~per ~~provisions;~~fiscal ~~and~~year, ~~the~~which ~~overall~~remain ~~effects of the IRA on our business and the healthcare industry~~ in ~~general~~effect isthrough ~~not~~fiscal ~~yet~~year ~~known~~2032.

AtThe aU.S. ~~federal~~American ~~level,~~Taxpayer ~~the~~Relief ~~current~~Act ~~executive reversed some~~ of ~~the~~2012 ~~prior~~also ~~administration’s~~further ~~executive~~reduced ~~orders~~Medicare ~~including~~payments ~~rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans.” New executive orders may be designed~~ to ~~impact~~several ~~drug~~types ~~pricing. A number~~ of ~~these~~providers and ~~other~~increased ~~proposed~~the ~~measures~~statute ~~may~~of ~~require~~limitations ~~authorization~~period ~~through~~for ~~additional~~the ~~legislation~~government to ~~become~~recover ~~effective.~~overpayments ~~Congress and the new administration have indicated that they will continue~~ to ~~seek~~providers ~~new~~from ~~legislative~~three ~~measures~~ to ~~control~~five ~~drug costs~~years.

~~Individual~~The ~~states~~Inflation inReduction ~~the~~Act ~~United~~of ~~States~~2022, ~~have~~or ~~also~~IRA, ~~become~~includes ~~increasingly~~several ~~active~~provisions inthat ~~passing~~may ~~legislation~~impact ~~and~~our ~~implementing~~business ~~regulations~~to ~~designed~~varying todegrees, ~~control~~including ~~pharmaceutical~~provisions ~~and~~that ~~biological~~reduce ~~product~~the ~~pricing,~~out-of-pocket ~~including~~cap ~~price~~for orMedicare ~~patient~~Part ~~reimbursement~~D ~~constraints,~~beneficiaries ~~discounts~~to $2,000 ~~restrictions~~starting in 2025; impose new manufacturer financial liability on certain ~~drug~~drugs ~~access~~under Medicare Part D; allow the U.S. government to negotiate Medicare Part B and ~~marketing~~Part D price caps for certain high-cost ~~disclosure~~drugs ~~and~~without ~~transparency~~generic ~~measures,~~competition; ~~and~~require ~~designed~~companies to ~~encourage~~pay ~~importation~~rebates ~~from~~to ~~other~~Medicare ~~countries~~for ~~and~~certain ~~bulk~~drug ~~purchasing.~~prices ~~Legally~~that ~~mandated~~increase ~~price~~faster ~~controls~~than oninflation; ~~payment~~and ~~amounts~~delay byuntil ~~third-party~~January ~~payors~~1, or2032 ~~other~~the ~~restrictions~~rebate ~~could~~rule ~~harm~~that ~~our~~would ~~business,~~limit ~~financial~~the ~~condition,~~fees ~~results~~that ofpharmacy ~~operations~~benefit ~~and~~managers ~~prospects~~can charge. InFurther, ~~addition~~under the IRA, ~~regional~~orphan ~~healthcare~~drugs ~~authorities~~are ~~and~~exempted ~~individual~~from ~~hospitals~~the ~~are~~Medicare ~~increasingly~~drug ~~using~~price ~~bidding~~negotiation ~~procedures~~program, tobut ~~determine~~only ~~what~~if ~~pharmaceutical~~they ~~products~~have one or more orphan designations and for which ~~suppliers~~the ~~will~~only beapproved ~~included~~indication inor ~~their~~indications ~~prescription~~are ~~drug~~for ~~and~~a ~~other~~rare ~~healthcare~~disease ~~programs~~or condition. ~~This~~Further, ~~could~~judicial ~~reduce~~challenges to the ~~ultimate~~IRA ~~demand~~may ~~for~~have ~~our~~an ~~drugs~~impact oron ~~put~~the ~~pressure~~implementation onof ~~our~~the ~~drug~~IRA’s ~~pricing,~~provisions; ~~which~~and ~~could~~the ~~negatively~~overall ~~affect~~effects of the IRA on our business, ~~financial~~and ~~condition,~~the ~~results~~healthcare ofindustry ~~operations~~in ~~and~~general ~~prospects~~is not yet known.

~~These~~Recently, ~~laws~~there ~~and~~has ~~regulations~~been ~~may~~heightened ~~result~~governmental scrutiny over the manner in ~~additional~~which ~~reductions~~manufacturers set prices for their marketed products. Such scrutiny has resulted in ~~Medicare~~several recent U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to, among other ~~healthcare~~things, ~~funding~~bring more transparency to drug pricing, review the relationship between pricing and ~~otherwise~~manufacturer ~~affect~~patient programs, reduce the ~~prices~~cost weof ~~may~~drugs ~~obtain~~under Medicare, and reform government program reimbursement methodologies for ~~any~~pharmaceutical ~~product~~products. ~~candidates~~The costs of drugs have also been the subject of considerable discussion in the United States. To date, there have been several recent U.S. congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for ~~which~~drug weproducts. ~~may~~The ~~obtain~~current U.S. administration has issued executive orders and supported proposed regulatory ~~approval~~initiatives orin 2025 that could have a significant impact on the ~~frequency~~prices ~~with~~that ~~which~~we, or any ~~such~~collaborators, ~~product~~may ~~candidate~~receive isfor ~~prescribed~~any orapproved ~~used~~development candidates.

43Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain drug access and marketing cost disclosure and transparency measures, and designed to encourage importation from other countries and bulk purchasing. Legally mandated price controls on payment amounts by

third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. This could reduce the ultimate demand for our drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any development candidates for which we may obtain regulatory approval or the frequency with which any such development candidate is prescribed or used.

Other U.S. Environmental, Health and Safety Laws and Regulations

We may be subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may also produce hazardous waste products. Even if we contract with third parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials. In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

We maintain workers’ compensation insurance to cover costs and expenses we may incur due to injuries to our employees as well as insurance for environmental liability, but this insurance may not provide adequate coverage against potential liabilities. However, we do not maintain insurance for toxic tort claims that may be asserted against us.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and regulations may impair our research, development or production efforts. In addition, failure to comply with these laws and regulations may result in substantial fines, penalties or other sanctions.

Employees and Human Capital Resources

As of December 31, ~~2024~~2025, we had ~~104~~58 full-time employees, including 7044 who hold Ph.D. degrees or other advanced degrees; 7239 employees are engaged in research and development and 3219 employees are engaged in management or general and administrative activities. None of our employees are subject to a collective bargaining agreement or represented by a trade or labor union. We consider our relationship with our employees to be good. We also employ consultants from time to time.

Our human capital objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees. The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

Corporate Information

We were incorporated as a Delaware corporation, on November 13, 2014 under the name “Frequency Therapeutics, Inc.”. On November 3, 2023, we completed a business combination and changed our name to Korro Bio, Inc. Our principal executive office is located at 60 First Street, 2nd Floor, Suite 250, Cambridge, MA 02141, and our telephone number is 617-468-1999. Our website address is https://www.korrobio.com/. The information contained on, or that can be accessed through, our website is not incorporated by reference into this Annual Report on Form 10-K or in any other report or document we have filed or may file with the Securities and Exchange Commission, or SEC, and any reference to our website address is intended to be an inactive textual reference only. We will make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC. The SEC maintains an Internet site, http://www.sec.gov, containing reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC.

4447

Item 1A. Risk Factors.

You should consider carefully the risks and uncertainties described below, together with all of the other information in this Annual Report on Form 10-K and in our other filings with the Securities and Exchange Commission, or SEC. We operate in a dynamic and rapidly changing industry that involves numerous risks and uncertainties. The risks and uncertainties described below are not the only ones we face. Other risks and uncertainties, including those that we do not currently consider material, may impair our business. If any of the risks discussed below actually occur, our business, financial condition, operating results or cash flows could be materially adversely affected. This Annual Report on Form 10-K also contains forward-looking statements that involve risks and uncertainties. Our actual results could differ materially from those anticipated in these forward-looking statements as a result of certain factors, including the risks we face as described below and elsewhere in this Annual Report on Form 10-K. See “Cautionary Statement Regarding Forward Looking Statements.”.

Risks Related to Our Business

We have incurred significant losses since inception. We expect to incur losses for the foreseeable future and may never achieve or maintain profitability.

Since inception, we have incurred significant operating losses. Our net loss was $83117.63 million and $8183.26 million for the years ended December 31, ~~2024~~2025 and ~~2023~~2024, respectively. As of December 31, ~~2024~~2025, we had an accumulated deficit of $~~266~~383.68 million. We have financed our operations primarily through private placements of our convertible preferred stock and more recently, common stock in ~~the~~our ~~private~~November ~~placement~~2023, ~~that~~April ~~closed~~2024 ~~immediately~~and ~~prior~~March to2026 ~~the~~private ~~November~~placements, ~~2023~~and ~~business~~sales ~~combination~~under ~~and~~ our ~~April~~at-the-market ~~2024~~offering ~~private placement~~program. Substantially all of our losses have resulted from expenses incurred in connection with our research and development and from general and administrative costs associated with our operations, and most recently, a $30.9 million impairment charge in the fourth quarter of 2025 related to our operating lease right-of-use asset and fixed assets. We expect to continue to incur significant expenses, increasing operating losses, and negative operating cash flows for the foreseeable future. The net losses we incur may fluctuate significantly from quarter to quarter. We anticipate that our expenses will increase substantially if and as we:

•

progress our development candidates, including KRRO-~~110~~121, through clinical development;

•

continue current research programs and preclinical and clinical development of any ~~product~~lead candidates or development candidates we may identify;

•

seek to identify additional research programs and ~~product~~lead candidates and nominate development candidates;

•

further develop ~~Oligonucleotide Promoted Editing of RNA, or~~ OPERA, our RNA editing platform;

•

maintain, expand, enforce, defend and protect our intellectual property portfolio;

•

seek marketing approvals for any ~~product~~development candidates that successfully complete clinical trials;

•

develop, maintain and enhance a sustainable, scalable, reproducible and transferable manufacturing process for the ~~product~~ candidates we may develop;

•

ultimately establish a sales, marketing and distribution infrastructure to commercialize any products for which we may obtain marketing approval;

•

hire additional personnel as we grow our business;

•

acquire or in-license ~~product~~lead candidates, development candidates, intellectual property and technologies;

•

establish and maintain collaborations;

•

should we decide to do so, build and maintain a commercial-scale current good manufacturing practices, or cGMP, manufacturing facility; and

•

operate as a public company.

We expect that it will be many years, if ever, before we have a RNA editing product ready for commercialization. To become and remain profitable, we must develop and, either directly or through collaborators, eventually commercialize a product or products with market potential. This will require us to be successful in a range of challenging activities, including identifying ~~product~~lead candidates, completing preclinical studies and clinical trials of ~~product~~development candidates, obtaining marketing approval for these product candidates, manufacturing, marketing and selling those products for which we may obtain marketing approval and satisfying any post-marketing requirements. We may never succeed in these activities and, even if we do, may never generate revenues that are significant or large enough to achieve profitability.

We have transitioned from discovery, research and development to clinical stage for our product candidate, KRRO-110, and in January 2025, we announced the dosing of the first participants in our Phase 1/2a REWRITE clinical trial 48

45these development candidates, manufacturing, marketing and selling those products for which we may obtain marketing approval and satisfying any post-marketing requirements. We may never succeed in these activities and, even if we are, may never generate revenues that are significant or large enough to achieve profitability.

In November 2025, we announced that we did not reach projected levels of protein in patients in our Phase 1/2a REWRITE clinical trial of KRRO-110 for AATD and our other programs are in early stages of development. In addition, we undertook workforce reductions in May 2025 and November 2025, and in the fourth quarter of 2025, as result of identified indicators of impairment for our long-lived assets, primarily including our operating lease right-of-use, or ROU, asset, and property and equipment, we recognized a non-cash, long-lived asset impairment charge of $30.9 million. Because of the numerous risks and uncertainties associated with developing ~~oligonucleotide~~lead ~~product~~candidates and development candidates, and the risks associated with conducting preclinical studies and clinical trials, we are unable to predict the extent of any future losses or when we will become profitable, if at all. If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise capital, maintain our research and development efforts, expand business or continue our operations. A decline in our value could also cause you to lose all or part of your investment. Further, we may not even experience the expected benefits of our May 2025 and November 2025 workforce reductions or our decision to discontinue clinical development of KRRO-110. Further, the long-lived asset impairment charges recognized may affect how investors, analysts, and counterparties assess our financial position and prospects, potentially making it more difficult or expensive to raise capital or enter into collaborations on favorable terms.

We have never generated revenue from product sales and may never become profitable.

Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with collaborative partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, ~~product~~ candidates we may identify for development. We do not anticipate generating revenues from product sales for many years, if ever. Our ability to generate future revenues from product sales depends heavily on our, or our collaborators’, ability to successfully:

•

identify ~~product~~lead candidates and successfully complete research and development of such ~~product~~lead candidates;

•

seek and obtain regulatory and marketing approvals for any ~~product~~development candidates for which we complete clinical trials;

•

launch and commercialize any ~~product~~development candidates for which we may obtain regulatory and marketing approval by establishing a sales force, marketing and distribution infrastructure, or alternatively, collaborating with a commercialization partner;

•

qualify for adequate coverage and reimbursement by government and third-party payors for any ~~product~~development candidates for which we may obtain regulatory and marketing approval;

•

establish and maintain supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for any ~~product~~development candidates for which we obtain regulatory and marketing approval;

•

develop, maintain and enhance a sustainable, scalable, reproducible and transferable manufacturing process for the ~~product~~development candidates we may develop;

•

address competing technological and market developments;

•

negotiate favorable terms in any existing or future collaboration, licensing or other arrangements and perform our obligations in such collaborations;

•

receive market acceptance by physicians, patients, healthcare payors, and others in the medical community;

•

maintain, protect, enforce, defend and expand our portfolio of intellectual property and other proprietary rights, including patents, trade secrets and know-how;

•

defend against third party intellectual property claims of infringement, misappropriation or other violation; and

•

attract top talent and retain qualified personnel.

Our expenses could increase beyond expectations if we are required by the FDA, the EMA, HREC, or TGA, or other regulatory authorities to perform clinical and other studies in addition to those that we currently anticipate. Even if one or more of the product candidates we may develop are approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate. Additionally, such products may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives. Even if we are able to generate revenues from the sale of any approved product candidates, we may not become profitable and may need to obtain additional funding to continue operations.

the candidates we may develop are approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved development candidate. Additionally, such products may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives. Even if we are able to generate revenues from the sale of any approved development candidates, we may not become profitable and may need to obtain additional funding to continue operations.

We expect our expenses to continue to increase in connection with our ongoing activities, particularly as we identify, continue the research and development of, initiate preclinical studies and clinical trials of, and seek marketing approval for, ~~product~~our lead candidates and development candidates. Because we have limited financial and managerial resources, we have prioritized our research programs and ~~lead~~oligonucleotide optimization efforts in specific indications among many potential options. Specifically, our initial development programs target liver and central nervous systems indications, amongst others. As a result of this prioritization, we may forego or delay pursuit of opportunities with other lead candidates or development candidates or for other indications that later prove to have greater clinical or commercial potential and we may need to reprioritize our focus in the future. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. For example, KRRO-110, which used an LNP delivery system, did not reach projected levels of protein in patients in our Phase 1/2a REWRITE clinical trial for AATD and we have since transitioned to a GalNAc-conjugated delivery system for our AATD program. Our spending on current and future research and development programs, lead candidates and development candidates for specific indications may not yield any commercially viable products.

46In addition, if we obtain marketing approval for any candidates we may develop, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of a collaborator. Furthermore, we expect to continue to incur additional costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and product development programs or future commercialization efforts.

~~pursuit~~As of ~~opportunities~~December ~~with~~31, ~~other~~2025, ~~product~~our ~~candidates~~cash, orcash ~~for~~equivalents ~~other~~and ~~indications~~marketable ~~that~~securities ~~later~~were ~~prove~~$85.2 tomillion, ~~have~~excluding ~~greater~~restricted ~~clinical~~cash, or ~~commercial~~$88.6 ~~potential~~million, including restricted cash. We believe our existing cash, cash equivalents and wemarketable ~~may~~securities, ~~need~~together with the net proceeds raised under sales under our at-the-market offering program and March 2026 private placement, will be sufficient to ~~reprioritize~~fund our ~~focus~~operating inexpenses and capital expenditure requirements through several value-creating milestones and into the ~~future~~second half of 2028. ~~Our~~However, ~~resource~~our ~~allocation~~operating ~~decisions~~plan may ~~cause~~change usas toa ~~fail~~result of factors currently unknown, and expectations regarding our cash runway and ability to ~~capitalize~~reach data inflection points are based on ~~viable~~numerous ~~commercial~~assumptions ~~products~~that ormay ~~profitable~~prove ~~market~~to ~~opportunities~~be untrue. ~~Our~~As ~~spending~~a onresult, ~~current~~we ~~and~~may ~~future~~be ~~research~~required ~~and~~to ~~development~~raise ~~programs~~capital sooner than anticipated and ~~product~~our ~~candidates~~exposure ~~for~~to ~~specific~~certain ~~indications~~contingent liabilities and contractual obligations may ~~not~~be ~~yield~~greater ~~any~~than ~~commercially~~anticipated. ~~viable~~Our ~~products~~future capital requirements will depend on many other factors, including those discussed in the risk factor entitled “We have incurred significant losses since inception. We expect to incur losses for the foreseeable future and may never achieve or maintain profitability.”

InAny ~~addition~~additional fundraising efforts may divert our management from their day-to-day activities, ifwhich wemay ~~obtain~~adversely ~~marketing~~affect ~~approval~~our ~~for~~ability to develop and commercialize any ~~product~~development candidates we may develop,. weWe ~~expect~~cannot tobe ~~incur~~certain ~~significant~~that ~~commercialization~~additional ~~expenses~~funding ~~related~~will tobe ~~product~~available ~~sales,~~on ~~marketing,~~acceptable ~~manufacturing~~terms ~~and~~or ~~distribution~~at toall. ~~the~~Although ~~extent~~we ~~that~~have ~~such~~an ~~sales,~~effective ~~marketing,~~shelf ~~manufacturing~~registration statement and ~~distribution~~an ~~are~~at-the-market offering program, we have not sold any shares under the ~~responsibility~~program and we have no committed source of aadditional ~~collaborator~~capital. ~~Furthermore,~~If we ~~expect~~are unable to ~~incur~~raise additional ~~costs~~capital ~~associated~~in ~~with~~sufficient ~~operating~~amounts asor aon ~~public~~terms ~~company.~~acceptable ~~Accordingly~~to us, we ~~will~~may ~~need~~have to ~~obtain~~significantly ~~substantial~~delay, ~~additional~~scale ~~funding~~back inor ~~connection~~discontinue ~~with~~the ~~our~~development ~~continuing~~or ~~operations~~commercialization of any development candidates or other research and development initiatives. IfWe wecould ~~are~~be ~~unable~~required to ~~raise~~seek ~~capital~~collaborators ~~when~~for ~~needed~~potential orlead oncandidates ~~attractive~~earlier ~~terms,~~than we would otherwise plan or on terms that are less favorable than might otherwise be ~~forced~~available. toWe ~~delay,~~could ~~reduce~~also be required to relinquish or ~~eliminate~~license our ~~research~~rights ~~and~~to ~~product~~lead ~~development~~candidates ~~programs~~on orunfavorable ~~future~~terms in certain markets where we otherwise would seek to pursue development or commercialization ~~efforts~~ourselves.

~~As of December 31, 2024, our cash, cash equivalents and marketable securities were $163.1 million, excluding restricted cash, or $166.5 million, including restricted cash.~~ We ~~believe~~did ~~our~~not ~~existing~~reach ~~cash,~~projected ~~cash~~levels ~~equivalents~~of ~~and~~protein ~~marketable~~in ~~securities~~patients ~~will~~in ~~be sufficient to fund~~ our ~~operating expenses and capital expenditure requirements through several value-creating milestones (including completion of the~~ Phase 1/2a REWRITE clinical trial of KRRO-110) ~~and~~for ~~into~~AATD ~~the~~and ~~second~~have ~~half~~transitioned ofto ~~2026.~~GalNAc-conjugated ~~However,~~delivery for our ~~operating~~AATD ~~plan~~program, and may ~~change~~experience asdelays ain ~~result~~developing ofa ~~factors~~potential ~~currently~~treatment ~~unknown,~~for ~~and~~AATD. ~~expectations~~We ~~regarding~~have ~~our~~not ~~cash~~completed ~~runway~~any ~~and~~clinical ~~ability~~trials tonor ~~reach~~reported ~~data~~any ~~inflection~~clinical ~~points~~trial ~~are~~results ~~based~~for onany ~~numerous~~of ~~assumptions~~our ~~that~~proposed ~~may~~delivery ~~prove~~methods toor beRNA ~~untrue~~editing approaches. AsAny afavorable ~~result,~~results we may behave ~~required~~from toour ~~raise~~earlier ~~capital~~preclinical ~~sooner~~studies ~~than~~may ~~anticipated~~not ~~and~~be ~~our~~predictive ~~exposure~~of toresults ~~certain~~that ~~contingent liabilities and contractual obligations~~ may be ~~greater~~observed ~~than anticipated. Our future capital requirements will depend on many other factors, including those discussed~~ in ~~the~~later ~~risk~~preclinical ~~factor~~studies ~~entitled “We have incurred significant losses since inception. We expect to incur losses for the foreseeable future and may never achieve~~ or ~~maintain~~clinical ~~profitability~~trials.”

~~Any~~The ~~additional~~scientific ~~fundraising~~evidence ~~efforts may divert our management from their day-~~to~~-day~~ ~~activities,~~support which may adversely affect our ability to develop and commercialize any product candidates we may develop. We cannot be certain that additional funding will be available on acceptable terms or at all. Although we have an effective shelf registration statement and an at-the~~-market~~ ~~offering~~feasibility ~~program, we have not sold any shares under the program and we have no committed source~~ of ~~additional~~developing ~~capital. If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we may have to significantly delay, scale back or discontinue the~~ development ~~or commercialization of any product~~ candidates orusing ~~other~~our ~~research~~proprietary ~~and~~RNA ~~development~~editing ~~initiatives.~~technology Weis ~~could~~both bepreliminary ~~required~~and ~~to seek collaborators for potential product candidates earlier than we would otherwise plan or on terms that are less favorable than might otherwise be available~~limited. We ~~could~~dosed ~~also~~very befew ~~required~~participants toin ~~relinquish or license~~ our ~~rights~~Phase to1/2a ~~product~~REWRITE ~~candidates~~clinical ontrial ~~unfavorable terms in certain markets where we otherwise would seek to pursue development or commercialization ourselves.~~

We have dosed very few participants in our Phase 1/2a REWRITE clinical trial of KRRO-110 for AATD and not received any clinical trial results for any of our proposed delivery methods or RNA editing approaches in clinical trials and any favorable results we may have may not be predictive of results that may be observed in later preclinical studies or clinical trials. 50

~~The~~of ~~scientific~~KRRO-110 ~~evidence~~for toAATD. ~~support~~Although ~~the~~we ~~feasibility~~observed functional protein in AATD patients following a single administration of ~~developing~~KRRO-110, ~~product~~we ~~candidates~~did ~~using~~not ~~our~~reach ~~proprietary~~projected ~~RNA~~levels ~~editing~~of ~~technology~~protein isin ~~both~~patients ~~preliminary~~as ~~and~~of ~~limited~~the data cut off date. We have ~~dosed~~not ~~very~~completed ~~few~~any ~~participants~~clinical intrials ~~our~~for ~~Phase~~any ~~1/2a~~of ~~REWRITE~~our ~~clinical~~proposed ~~trial~~delivery ofmethods ~~KRRO-110~~or ~~for~~RNA ~~AATD~~editing approaches, and we have ~~not~~transitioned ~~yet~~from ~~received~~LNP ~~any~~to ~~clinical~~GalNAc-conjugated ~~trial~~delivery ~~results.~~for ~~For~~our ~~example~~AATD program. Accordingly, ~~KRRO-110~~we ~~uses~~may ~~LNPs~~experience asdelays in developing a ~~delivery~~potential ~~modality~~treatment ~~and~~for AATD. In the future, we may use other delivery modalities to deliver our other ~~product~~lead candidates. While LNPs have been validated clinically to deliver oligonucleotides, such as siRNA, they ~~have~~were not ~~been~~ clinically proven to deliver oligonucleotides for RNA editing, such as KRRO-110 and our other ~~product~~lead candidates. Similarly, while GalNAc-conjugated delivery has been validated in multiple FDA-approved oligonucleotide therapeutics, there are no FDA-approved GalNAc-conjugated RNA editing oligonucleotide therapeutics. Both of our most advanced programs, KRRO-121 and our AATD program, utilize GalNAc-conjugated delivery. If GalNAc-conjugated delivery fails to effectively deliver our RNA editing oligonucleotides, multiple programs in our pipeline could be adversely affected.

In addition, our proprietary RNA editing technology itself may lead to other issues, such as inability to deliver the desired efficacy or safety-related consequences as it is tested in clinical trials. ~~We have not generated any clinical trial results to date.~~ The design of a clinical trial can determine whether its results will support approval of a ~~product~~development candidate and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. Furthermore, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their ~~product~~development candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their ~~product~~development candidates. Many ~~product~~lead candidates that initially showed promise in early stage testing for treating a variety of diseases have later been found to lack efficacy or to cause side effects that prevented further clinical development ~~of the product candidates~~. Accordingly, any favorable results we may have from our earlier preclinical studies may not be predictive of results that may be observed in further preclinical studies or clinical trials.

47If preclinical studies or clinical trials of any lead candidate or development candidate we may identify fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such development candidate.

IfBefore ~~preclinical~~obtaining ~~studies~~marketing orapproval ~~clinical~~from ~~trials~~regulatory authorities for the sale of any ~~product~~development candidates we may identify and develop, ~~fail~~we must complete preclinical development and then conduct extensive clinical trials to demonstrate safety and efficacy in humans. Clinical testing is expensive, difficult to design and implement, can take many years to complete, and the ~~satisfaction~~outcome ofis ~~regulatory~~uncertain. ~~authorities~~A failure of one or domore ~~not~~clinical ~~otherwise~~trials ~~produce~~can ~~positive~~occur ~~results,~~at weany ~~may~~stage ~~incur~~of ~~additional~~development. ~~costs~~The oroutcome ~~experience~~of ~~delays~~preclinical intesting ~~completing,~~and orearly ~~ultimately~~clinical betrials ~~unable~~may tonot ~~complete,~~be predictive of the ~~development~~success of later clinical trials, and ~~commercialization~~interim results of ~~such~~a ~~product~~clinical ~~candidates~~trial do not necessarily predict final results.

~~Before obtaining marketing approval from regulatory authorities for the sale of any product candidates we may identify and develop~~Moreover, ~~we must complete~~ preclinical ~~development~~ and ~~then~~clinical ~~conduct~~data ~~extensive~~are ~~clinical~~often ~~trials~~susceptible to ~~demonstrate~~varying ~~the~~interpretations ~~safety~~ and ~~efficacy in humans~~analyses. ~~Clinical~~Many ~~testing~~companies isthat ~~expensive,~~have ~~difficult~~believed totheir ~~design~~lead ~~and~~candidates ~~implement,~~or ~~can~~development ~~take~~candidates ~~many~~performed ~~years~~satisfactorily toin ~~complete,~~preclinical studies and ~~is uncertain as to outcome. A failure of one or more~~ clinical trials ~~can~~have ~~occur~~nonetheless atfailed, ~~any~~preventing ~~stage~~marketing approval of ~~testing.~~their ~~The~~development ~~outcome~~candidates. ofFor ~~preclinical~~example, ~~testing~~despite ~~and~~our ~~early~~preclinical ~~clinical~~data, ~~trials~~we ~~may~~did not bereach ~~predictive~~projected oflevels ~~the success~~ of ~~later~~protein ~~clinical~~in ~~trials,~~AATD ~~and~~patients ~~interim~~in ~~results~~our ofREWRITE aPhase 1/2a clinical trial ~~do not necessarily predict final results~~.

~~Moreover,~~We ~~preclinical~~ and ~~clinical~~our ~~data~~collaborators, ~~are~~if ~~often~~any, ~~susceptible~~may toexperience ~~varying~~numerous ~~interpretations~~unforeseen ~~and~~events ~~analyses.~~during, ~~Many~~or ~~companies~~as ~~that~~a ~~have~~result ~~believed~~of, ~~their~~clinical ~~product~~trials ~~candidates~~that ~~performed~~could ~~satisfactorily~~delay inor ~~preclinical~~prevent ~~studies~~our ~~and~~ability ~~clinical~~to ~~trials~~receive ~~have~~marketing ~~nonetheless~~approval ~~failed~~or tocommercialize ~~obtain~~any ~~marketing~~development ~~approval~~candidates ofwe ~~their~~may ~~product~~identify ~~candidates.~~and develop, including:

•

We and our collaborators, if any, may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize any product candidates we may identify and develop, including:

delays in reaching a consensus with regulators on trial design;

•

regulators, institutional review boards, or IRBs, or independent ethics committees may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;

•

delays in reaching or failing to reach agreement on acceptable clinical trial contracts or clinical trial protocols with prospective CROs and clinical trial sites;

•

clinical trials of any ~~product~~development candidates we may develop may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical trials or abandon product development or research programs;

•

difficulty in designing well-controlled clinical trials due to ethical considerations that may render it inappropriate to conduct a trial with a control arm that can be effectively compared to a treatment arm;

•

difficulty in designing clinical trials and selecting endpoints for diseases that have not been well-studied and for which the natural history and course of the disease is poorly understood;

the number of patients required for clinical trials of any product candidates we may develop may be larger than we anticipate; enrollment of suitable participants in these clinical trials, which may be particularly challenging for some of the rare genetically defined diseases we are targeting in our most advanced programs, may be delayed or slower than we anticipate; or patients may drop out of these clinical trials at a higher rate than we anticipate; 51

•

the number of patients required for clinical trials may be larger than we anticipate; enrollment of suitable participants in these clinical trials, which may be particularly challenging for some of the rare genetically defined diseases such as UCD, may be delayed or slower than we anticipate; or patients may drop out of these clinical trials at a higher rate than we anticipate;

•

our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all;

•

regulators, IRBs, or independent ethics committees may require that we or our investigators suspend or terminate clinical research or clinical trials of any ~~product~~development candidates we may develop for various reasons, including noncompliance with regulatory requirements, a finding of undesirable side effects or other unexpected characteristics, or that the participants are being exposed to unacceptable health risks or after an inspection of our clinical trial operations or trial sites;

•

the cost of clinical trials of any ~~product~~development candidates we may ~~develop may~~ be greater than we anticipate;

•

the supply or quality of any ~~product~~development candidates ~~we may develop~~ or other materials necessary to conduct clinical trials of any ~~product~~development candidates we may ~~develop may~~ be insufficient or inadequate, including as a result of delays in the testing, validation, manufacturing, and delivery of any ~~product~~development candidates ~~we may develop~~ to the clinical sites by us or by third parties with whom we have contracted to perform certain of those functions;

•

delays in having patients complete participation in a trial or return for post-treatment follow-up;

•

clinical trial sites dropping out of a trial;

•

selection of clinical endpoints that require prolonged periods of clinical observation or analysis of the resulting data;

•

48occurrence of serious adverse events associated with any development candidates that are viewed to outweigh their potential benefits;

•

occurrence of serious adverse events associated with any product candidates we may develop that are viewed to outweigh their potential benefits;

occurrence of serious adverse events in trials of the same class of agents conducted by other sponsors; and

•

changes in regulatory requirements and guidance that require amending or submitting new clinical protocols.

If we or our collaborators are required to conduct additional clinical trials or other testing of any ~~product~~development candidates ~~we may develop~~ beyond those that we currently contemplate, if we or our collaborators are unable to successfully complete clinical trials or other testing of any ~~product~~development candidates ~~we may develop~~, or if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we or our collaborators may:

•

be delayed in obtaining marketing approval for any such ~~product~~development candidates ~~we may develop~~ or not obtain marketing approval at all;

•

choose to, or be required to, revise or transition strategy for our development candidates or protocols;

•

obtain approval for indications or patient populations that are not as broad as intended or desired;

•

obtain approval with labeling that includes significant use or distribution restrictions or safety warnings, including boxed warnings;

•

be subject to changes in the way the product is administered;

•

be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;

•

have regulatory authorities withdraw, or suspend, their approval of the product or impose restrictions on our distribution in the form of a REMS or through modification to an existing REMS;

•

be sued; or

•

experience damage to our reputation.

Product development costs will also increase if we or our collaborators experience delays in clinical trials or other testing or in obtaining marketing approvals. We do not know whether any clinical trials will begin as planned, will need to be restructured, or will be completed on schedule, or at all. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize any ~~product~~development candidates we may develop, could allow our competitors to bring products to market before we do, and could impair our ability to successfully commercialize any product candidates we may develop, any of which may harm our business, financial condition, results of operations, and prospects.

products to market before we do, and could impair our ability to successfully commercialize any development candidates we may develop, any of which may harm our business, financial condition, results of operations, and prospects.

Our business is substantially dependent on the success of KRRO-121, our lead development candidate, and if KRRO-121 fails to advance successfully, our business would be materially and adversely affected.

We have concentrated a significant portion of our current resources and efforts on the advancement of KRRO-121, our lead development candidate for the treatment of hyperammonemia, including UCD and HE. KRRO-121 is in preclinical development and has not been tested in humans. KRRO-121 utilizes GalNAc-conjugated delivery and is designed to generate a stabilized, de novo variant of GS with enhanced ammonia clearance capacity. We anticipate submitting a regulatory filing to enable commencement of a first-in-human clinical trial in the second half of 2026. However, there can be no assurance that KRRO-121 will demonstrate safety or efficacy in humans, that our regulatory filing will be accepted, or that we will be able to initiate or complete clinical trials on our anticipated timeline. If KRRO-121 fails to demonstrate safety or efficacy, or if we experience significant delays in its regulatory filing or clinical development, our business, financial condition, results of operations and prospects would be materially and adversely affected. Following the termination of our REWRITE clinical program investigating KRRO-110 for AATD, KRRO-121 is our only nominated development candidate, which increases the concentration of risk in a single program. Our other programs, including our AATD GalNAc-conjugated program, our longevity and liver health program targeting AMPKγ1, and our ALS program targeting TDP-43, are in earlier stages of preclinical development and may not advance to clinical development on a timely basis, or at all.

If we experience delays or difficulties in the enrollment of patients in clinical trials, or other delays in our clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

Clinical trials of a new ~~product~~development candidate require the enrollment of a sufficient number of patients, including patients who are suffering from the disease the ~~product~~development candidate is intended to treat and who meet other eligibility criteria. Rates of patient enrollment are affected by many factors, including the stage and severity of disease, the nature and requirements of the protocol, the proximity of patients to clinical sites, the availability of effective treatments for the relevant disease, and the eligibility criteria for the clinical trial, possible adverse effects from treatments, the existence of competing clinical trials, the involvement of patient advocacy groups, the availability of new or alternative treatments, lack of efficacy, personnel issues and ease of participation in our clinical trials, among others. Clinical trials can also be impacted by other events unrelated to our business, such as ~~the~~geopolitical ~~Russian~~events ~~invasion~~and ~~of Ukraine~~unrest, ~~recent~~such ~~turmoil~~as inrecent ~~the~~hostilities ~~Middle~~involving ~~East~~Iran, ~~or other geopolitical events or~~ global pandemics (~~such~~e.g., ~~as what occurred during~~ COVID-19), or economic uncertainty, including imposition of tariffs that impact the supply chain, or disruptions due to government shutdowns, which can impact regulatory reviews. In April 2025, the United States imposed tariffs on imports on its trading partners and tariff policy (and trading partners subject to such tariffs) has continued to evolve. Historically, tariffs have led to increased costs, political and trade tensions, which negatively affect global supply chains. These types of events can disrupt clinical trial sites and delay patient enrollment, all of which would have a negative impact on our business and ability to obtain regulatory approval. Delays or difficulties in patient enrollment or difficulties retaining trial participants, including as a result of the availability of existing or other investigational treatments, can result in increased costs, longer development times or termination of a clinical trial.

Risks Related to Discovery, Development and Commercialization

The gene editing field and RNA editing in particular is relatively new and is evolving rapidly. We are very early in our development efforts and may not be successful in identifying and developing ~~product~~any candidates. It will be many years before we or our collaborators commercialize a ~~product~~development candidate or generate any revenues, if ever. Additionally, other ~~gene~~genetic ~~editing~~medicine technologies may be discovered that provide significant advantages over RNA editing, which could materially harm our business.

The success of our business depends primarily upon our ability to identify, develop and commercialize ~~product~~development candidates. We are very early in our development efforts and have focused our research and development efforts to date on developing OPERA, our RNA editing platform, and identifying our initial targeted disease indications. We currently only ~~recently~~have ~~commenced~~one ~~dosing~~nominated development candidate in our ~~first~~pipeline, KRRO-~~in-human~~121 ~~trial~~as terminated further development of KRRO-110 ~~for~~after ~~AATD~~it failed to reach projected levels of protein in our first in-human clinical trial. Although we believe we can demonstrate many of the key advantages of RNA editing, because we are very early in our development efforts, we are not yet certain of the results we may achieve, which may be important for registration and commercialization of ~~our~~any ~~products~~candidates we successfully develop. Such uncertainties include, but are not limited to, the level of editing efficiency needed in a target tissue type to achieve a clinical benefit, and associated safety of our edits in humans. We have also not yet shown that preclinical editing activity can result in ~~clinically important effects, nor that the data generated by our preclinical studies can translate into positive results in clinical trials.~~

We only have one product candidate, KRRO-110, in a Phase 1/2a clinical trial. All of our other product development programs are still in the research or preclinical stage of development. Our research methodology may be unsuccessful in identifying product candidates, our product candidates may be shown to have harmful side effects in preclinical in vitro experiments or animal model studies, they may not show promising signals of therapeutic effect in such experiments or studies or they may have other characteristics that may make the product candidates impractical to manufacture, unmarketable, or unlikely to receive marketing approval. 53

~~The~~clinically ~~pharmacological~~important ~~properties~~effects, ~~ascribed~~nor tothat the ~~product~~data ~~candidates~~generated weby ~~are~~our ~~testing in~~ preclinical studies ~~may~~can ~~not~~translate beinto ~~positively~~positive ~~demonstrated~~results in clinical trials ~~in patients, and they may interact with human biological systems in unforeseen, ineffective or harmful ways~~. If our product candidates prove to be ineffective, unsafe or commercially unviable, OPERA and our pipeline would have little, if any, value, which would substantially harm our business, financial condition, results of operations and prospects. In addition, our approach, which focuses on using oligonucleotides for drug development, as opposed to multiple or other, more advanced proven technologies, and new products and technologies that may enter the market, may expose us to additional financial risks and make it more difficult to raise additional capital if we are not successful in developing one or more product candidates that receive regulatory approval. Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development and eventual commercialization of any product candidates we may discover, which may never occur. We currently generate no revenue from sales of any product, and we may never be able to develop or commercialize a marketable product.

InAll ~~addition,~~of ~~although~~our weproduct ~~believe~~development ~~OPERA,~~programs ~~our~~are ~~RNA~~still ~~editing~~in ~~platform,~~the ~~will~~research ~~position~~or uspreclinical tostage ~~expand~~of ~~our~~development. ~~portfolio~~Our ofresearch ~~product~~methodology ~~candidates~~may ~~beyond~~be ~~the~~unsuccessful ~~initial~~in ~~product~~identifying lead candidates, weour development candidates may ~~develop,~~be weshown to have harmful side effects in preclinical in vitro experiments or animal model studies, they may not ~~yet~~show ~~successfully~~promising ~~developed~~signals ~~any~~of ~~product~~therapeutic ~~candidate~~effect ~~and~~in ~~our~~such ~~ability~~experiments toor ~~expand~~studies ~~our~~or ~~portfolio~~they may ~~never~~have ~~materialize~~other characteristics that may make the development candidates impractical to manufacture, unmarketable, or unlikely to receive marketing approval.

~~Commencing~~The ~~clinical~~pharmacological ~~trials~~properties inascribed to the ~~United~~lead ~~States~~candidates iswe ~~also~~are ~~subject~~testing toin ~~acceptance~~preclinical bystudies ~~the~~may ~~FDA~~not ofbe ~~any~~positively ~~future~~demonstrated ~~investigational~~in ~~new~~clinical ~~drug~~trials ~~applications~~in patients, orand ~~INDs~~they may interact with human biological systems in unforeseen, ~~and~~ineffective ~~finalization~~or ofharmful ~~trial~~ways ~~designs~~(such ~~based~~as onwe ~~discussions~~experienced ~~with~~in ~~the~~our ~~FDA~~REWRITE ~~and~~Phase ~~other~~1/2a ~~regulatory~~clinical ~~authorities~~trial). ~~Even~~If ~~after~~our wedevelopment ~~receive~~candidates ~~and~~prove ~~incorporate~~to ~~guidance~~be ~~from~~ineffective, ~~these~~unsafe ~~regulatory~~or ~~authorities~~commercially unviable, ~~the~~OPERA ~~FDA~~and orour ~~other~~pipeline ~~regulatory~~would ~~authorities~~have ~~could~~little, ~~disagree~~if ~~that~~any, wevalue, ~~have~~which ~~satisfied~~would ~~their~~substantially ~~requirements~~harm toour ~~commence~~business, ~~any~~financial ~~clinical~~condition, ~~trial~~results orof ~~change~~operations ~~their~~and ~~position~~prospects. In addition, our approach, which focuses on ~~the~~using ~~acceptability~~oligonucleotides offor ~~our~~drug ~~trial~~development, ~~designs~~as opposed to multiple or ~~any~~other, ~~clinical~~more ~~endpoints~~advanced ~~selected~~proven technologies, ~~which~~and new products and technologies that may ~~require~~enter the market, may expose us to ~~complete~~ additional ~~studies~~financial orrisks ~~trials~~and ormake ~~impose~~it ~~stricter~~more ~~approval~~difficult ~~conditions~~to ~~than~~raise weadditional ~~expect.~~capital ~~There~~if we are ~~equivalent~~not ~~processes~~successful ~~and~~in ~~risks~~developing ~~applicable~~one or more development candidates that receive regulatory approval. Our ability to ~~clinical~~generate ~~trial~~product ~~applications~~revenue, orwhich ~~CTAs,~~we indo ~~other~~not ~~countries,~~expect ~~including~~will inoccur ~~Europe,~~for ~~the~~many ~~United~~years, ~~Kingdom~~if ever, orwill ~~UK.~~depend heavily on the successful development and ~~Australia,~~eventual ~~where~~commercialization of any development candidates we ~~recently~~may ~~dosed~~discover, ~~the~~which ~~first~~may ~~participants~~never inoccur. ~~our~~We ~~Phase~~currently ~~1/2a~~generate ~~REWRITE~~no ~~clinical~~revenue ~~trial~~from sales of ~~KRRO-110~~any ~~for~~product, ~~AATD~~and we may never be able to develop or commercialize a marketable product.

~~Even~~In ifaddition, although we ~~complete~~believe ~~the necessary clinical trials~~OPERA, weour ~~cannot~~RNA ~~predict~~editing ~~when~~platform, ~~or if, we~~ will ~~obtain~~position ~~regulatory~~us ~~approval~~ to ~~commercialize~~expand ~~KRRO-110~~our orportfolio ~~any~~of ~~other~~development ~~product~~ candidates inbeyond the ~~United~~initial ~~States~~candidates ~~or any other jurisdiction, and any such approval may be for a narrower indication than~~ we ~~seek. In addition, clinical trials conducted in one country~~ may ~~not be accepted by regulatory authorities in other countries~~develop, ~~and~~we ~~regulatory~~have ~~approval in one country does~~ not ~~guarantee~~yet ~~regulatory~~successfully ~~approval~~developed in any ~~other~~candidate ~~country.~~and ~~We are conducting~~ our ~~Phase~~ability ~~1/2a REWRITE clinical trial in Australia, and may in the future decide~~ to ~~conduct~~expand ~~other~~our ~~clinical~~portfolio ~~trials with one or more trial sites that are located outside the United States. Although the FDA~~ may ~~accept~~never data from clinical trials conducted outside the United States, acceptance of these data is subject to conditions imposed by the FDA, and there can be no assurance that the FDA will accept data from our Phase 1/2a REWRITE clinical trial or any other clinical trials conducted outside of the United Statesmaterialize. If the FDA does not accept the data from our Phase 1/2a REWRITE trial or any other clinical trial that we conduct outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and could delay or permanently halt our development of KRRO-110 or the other applicable product candidates. Similarly, marketing approval by the FDA in the United States, if obtained, does not ensure approval by regulatory

authorities in other countries or jurisdictions. Approval processes vary among countries and can involve additional product candidate testing and validation and additional administrative review periods.

Commercialization of any product candidates we may develop will also require obtaining manufacturing supply, capacity and expertise; building of a commercial organization; and significant marketing efforts. If we do not successfully commercialize any product candidates we may develop, we could experience a material harm to our business.

We are focused on developing products based on RNA editing. Although there have been significant advances in the field of gene editing in recent years, RNA editing technologies are new and largely unproven. The technologies that we have developed have not yet ~~been~~completed ~~clinically tested, nor are we aware of any~~ clinical ~~trials for safety or efficacy having been completed by third parties using RNA editing or similar technologies~~development. The scientific evidence to support the feasibility of developing ~~product~~development candidates based on these technologies is both preliminary and limited. Successful development of ~~product~~development candidates by us will require solving a number of issues, including optimizing the efficiency and specificity of such ~~product~~development candidates, and ensuring the therapeutic selectivity of such ~~product~~development candidates. There can be no assurance we will be successful in solving any or all of these issues.

We have concentrated our research efforts to date on preclinical work to bring therapeutics to the clinic for our initial indications, and our future success is highly dependent on the successful development of OPERA, our RNA editing platform, as well as cellular delivery methods and therapeutic applications of that technology. While some of the existing, non-RNA editing, gene editing technologies developed by third parties have progressed to clinical trials, they continue to suffer from various limitations, and such limitations may affect our future success. While a number of clinical trials for oligonucleotide products conducted by other companies have not been successful, some have received regulatory approval. The pharmacological properties ascribed to the ~~product~~development candidates we are testing or will test in the future may not be positively demonstrated in clinical trials in patients, and they may interact with human biological systems in unforeseen, ineffective or harmful ways. If our ~~product~~development candidates prove to be ineffective, unsafe or commercially unviable, our OPERA platform and our pipeline would have little, if any, value, which would substantially harm our business, financial condition, results of operations and prospects. We may decide to alter or abandon our initial programs as new data becomes available and we gain experience in developing base editing therapeutics. We cannot be sure that our technologies will yield satisfactory products that are safe and effective, scalable or profitable in our initial indications or any other indication we pursue.

Development activities in the field of RNA editing are currently subject to a number of risks related to the ownership and use of certain intellectual property rights that are subject to patent reexamination and inter partes proceedings in the United States and opposition proceedings in Europe. For additional information regarding the risks that may apply to our and our licensors’ intellectual property rights, see “—Risks Related to Intellectual Property.”

We are very early in our development efforts, and our preclinical studies and clinical trials may not be successful. If we are unable to commercialize our product candidates or experiences significant delays in doing so, our business will be materially harmed. 54

We are very early in our development ~~of product candidates and have focused our~~ efforts ~~to date on platform development~~, ~~discovery, research,~~ and ~~preclinical development. We have only recently dosed the first participants in~~ our ~~Phase~~preclinical ~~1/2a~~studies ~~REWRITE~~and clinical ~~trial~~trials ofmay ~~KRRO-110~~not ~~for~~be ~~AATD~~successful. ~~and~~If ~~all~~we ~~of our other programs~~ are ~~still~~unable ~~in the research or preclinical stage of development. Our ability~~ to ~~generate~~commercialize ~~product~~our ~~revenues, which we do not expect will occur for many years, if ever, will depend heavily on the successful~~ development, ~~marketing approval and eventual commercialization of our product~~ candidates, ~~which~~or ~~may~~experience ~~never~~significant ~~occur.~~delays Wein ~~have~~doing ~~not yet generated revenue from product sales or otherwise~~so, ~~and~~our webusiness ~~may~~will ~~never~~ be ~~able~~materially ~~to develop or commercialize a marketable product~~harmed.

~~Commencing~~We ~~clinical~~are ~~trials~~very early in ~~the~~our ~~United~~development ~~States~~of isdevelopment ~~subject~~candidates toand ~~acceptance~~have byfocused ~~the~~our ~~FDA~~efforts ofto andate ~~IND~~primarily ~~and~~on ~~finalizing~~platform ~~the~~development, ~~trial~~discovery, ~~design~~research, ~~based~~and onpreclinical ~~discussions~~development ~~with~~and ~~the~~had ~~FDA~~only ~~and~~dosed ~~other~~a ~~regulatory~~small ~~authorities.~~number Inof ~~the~~participants ~~event~~in ~~that~~our ~~the~~terminated ~~FDA~~Phase ~~requires~~1/2a usREWRITE toclinical ~~complete~~trial ~~additional~~of ~~preclinical~~KRRO-110 ~~studies~~for orAATD. weOur ~~are~~development ~~required~~candidate, toKRRO-121, ~~satisfy~~is ~~other~~advancing ~~FDA~~toward ~~requests~~a ~~prior~~regulatory tofiling ~~commencing~~anticipated ~~clinical~~in ~~trials,~~ the ~~start~~second half of ~~our~~2026. ~~first~~All ~~clinical~~of ~~trials~~our ~~may~~other beprograms ~~delayed~~are orstill wein ~~may~~the beresearch ~~unsuccessful~~or ~~obtaining~~preclinical ~~clearance~~stage toof ~~proceed into clinical~~ development. ~~Even~~Our ~~after~~ability weto ~~receive~~generate ~~and~~product ~~incorporate guidance from these regulatory authorities~~revenues, ~~the~~which ~~FDA or other regulatory authorities could disagree that~~ we ~~have~~do ~~satisfied~~not ~~their~~expect ~~requirements~~will tooccur ~~commence~~for ~~any~~many ~~clinical~~years, ~~trial~~if orever, ~~change~~will ~~their~~depend ~~position~~heavily on the ~~acceptability~~successful ofdevelopment, ~~our~~marketing ~~trial~~approval ~~designs~~and oreventual ~~the~~commercialization ~~clinical~~of ~~endpoints~~our ~~selected~~development candidates, which may ~~require~~never usoccur. toWe ~~complete~~have ~~additional~~not ~~preclinical~~yet ~~studies~~generated orrevenue ~~clinical~~from ~~trials,~~product ~~delay~~sales ~~the~~or ~~enrollment of our clinical trials~~otherwise, ~~abandon~~and ~~our clinical development plans or meet stricter approval conditions than~~ we ~~currently~~may ~~expect.~~never ~~There~~be ~~are~~able ~~equivalent processes and risks applicable~~ to ~~CTAs~~develop inor ~~other~~commercialize ~~countries,~~a ~~including~~marketable ~~countries~~product. ~~in the~~

51Commencing clinical trials in the United States is subject to acceptance by the FDA of an IND and finalizing the trial design based on discussions with the FDA and other regulatory authorities. In the event that the FDA requires us to complete additional preclinical studies or we are required to satisfy other FDA requests prior to commencing clinical trials, the start of our first clinical trials may be delayed or we may be unsuccessful obtaining clearance to proceed into clinical development. Even after we receive and incorporate guidance from these regulatory authorities, the FDA or other regulatory authorities could disagree that we have satisfied their requirements to commence any clinical trial or change their position on the acceptability of our trial designs or the clinical endpoints selected, which may require us to complete additional preclinical studies or clinical trials, delay the enrollment of our clinical trials, abandon our clinical development plans or meet stricter approval conditions than we currently expect. There are equivalent processes and risks applicable to clinical trial applications, or CTAs, in other countries, including countries in the European Union, United Kingdom and Australia.

~~European~~Even ~~Union~~if we complete the necessary clinical trials, we cannot predict when, or EUif, ~~and~~we ~~Australia~~will obtain regulatory approval to commercialize any development candidates in the United States or any other jurisdiction, ~~where~~and any such approval may be for a narrower indication than we ~~recently~~seek. ~~dosed~~In ~~the~~addition, ~~first~~clinical ~~participants~~trials conducted in ~~our~~one ~~Phase~~country ~~1/2a~~may ~~REWRITE~~not be accepted by regulatory authorities in other countries, and regulatory approval in one country does not guarantee regulatory approval in any other country. We may in the future decide to conduct other clinical trials with one or more trial sites that are located outside the United States. Although the FDA may accept data from clinical trials conducted outside the United States, acceptance of ~~KRRO-110~~these data is subject to conditions imposed by the FDA, and there can be no assurance that the FDA will accept data from any clinical trials conducted outside of the United States. If the FDA does not accept the data from any clinical trial that we conduct outside the United States, it would likely result in the need for ~~AATD~~additional trials, which would be costly and time-consuming and could delay or permanently halt our development of the applicable development candidates. Similarly, marketing approval by the FDA in the United States, if obtained, does not ensure approval by regulatory authorities in other countries or jurisdictions. Approval processes vary among countries and can involve additional development candidate testing and validation and additional administrative review periods.

Commercialization of any ~~product~~development candidates we may develop will require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions, including by the FDA, the EMA, HREC and TGA; manufacturing supply, capacity and expertise; a commercial organization; and significant marketing efforts. The success of our ~~product~~development candidates will depend on many factors, including the following:

•

timely and successful completion of preclinical studies, including toxicology studies, biodistribution studies and minimally efficacious dose studies in animals, where applicable;

•

effective INDs or comparable foreign applications that allow commencement of our planned clinical trials or future clinical trials for any ~~product~~development candidates we may develop;

•

successful enrollment and completion of clinical trials, including under the FDA’s current GCPs, current GLPs, and any additional regulatory requirements from foreign regulatory authorities;

•

positive results from our future clinical trials that support a finding of safety and effectiveness and an acceptable risk-benefit profile in the intended populations;

•

receipt of marketing approvals from applicable regulatory authorities;

•

establishment of arrangements through our own facilities or with third-party manufacturers for clinical supply and, where applicable, commercial manufacturing capabilities;

•

establishment, maintenance, defense and enforcement of patent, trademark, trade secret and other intellectual property protection or regulatory exclusivity for any ~~product~~development candidates we may develop;

~~commercial launch of any product candidates we may develop, if approved, whether alone or in collaboration with others;~~55

•

~~acceptance~~commercial oflaunch ~~the benefits and use~~ of ~~the~~any ~~product~~development candidates we may develop, ~~including method of administration,~~ if ~~and when~~ approved, bywhether ~~patients,~~alone ~~the~~or ~~medical~~in ~~community~~collaboration ~~and~~with ~~third-party payors~~others;

•

acceptance of the benefits and use of the development candidates we may develop, including method of administration, if and when approved, by patients, the medical community and third-party payors;

•

effective competition with other products;

•

maintenance of a continued acceptable safety, tolerability and efficacy profile of any ~~product~~development candidates we may develop following approval; and

•

establishment and maintenance of healthcare coverage and adequate reimbursement by payors.

If we do not succeed in one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize any ~~product~~development candidates we may develop, which would materially harm our business.

Any ~~product~~development candidates we develop may fail in preclinical or clinical development or be delayed to a point where they do not become commercially viable.

Before obtaining regulatory approval for the commercial distribution of any of our ~~product~~development candidates, we must conduct, at our own expense, extensive preclinical studies and clinical trials to demonstrate the safety and efficacy in humans of our ~~product~~development candidates. Preclinical and clinical testing are expensive, difficult to design and implement, can take many years to complete, are uncertain as to outcome, and the historical failure rate for drugs in preclinical and clinical development is high. For example, we depend on the availability of ~~non-human~~NHPs ~~primates~~ to conduct certain preclinical studies. Over the past several years there has been an increasing global shortage of ~~non-human~~NHPs ~~primates~~ available for drug development that has matured into an acute global supply chain issue. The supply of these ~~non-human~~NHPs ~~primates~~ is currently constrained due to factors such as their limited worldwide availability, domestic regulatory restrictions and trade relations. If we are unable to obtain access to a sufficient supply of these ~~non-human~~NHPs ~~primates~~ in a timely manner or at all, our timelines and our ability to complete preclinical testing and submit IND or CTA applications may be adversely affected.

The development of one or more of our ~~product~~development candidates can fail at any stage of testing. We may experience numerous unforeseen events during, or as a result of, preclinical studies and clinical trials that could delay or prevent regulatory approval or our ability to commercialize our ~~product~~development candidates, including:

•

our preclinical studies or clinical trials may produce negative or inconclusive results, including results that may not meet the level of significance or clinical benefit required by the FDA, the EMA, HREC, TGA or other regulators, and we may decide, or regulators may require us, to conduct additional preclinical studies or clinical trials, or we may abandon projects that we had expected to be promising;

•

we may decide, or regulators may require us, to conduct additional preclinical studies or clinical trials, or we may abandon projects that we had expected to be promising;

delays in filing INDs or comparable foreign applications or delays or failure in obtaining the necessary approvals from regulators or IRBs in order to commence a clinical trial at a prospective trial site, or their suspension or termination of a clinical trial once commenced;

•

conditions imposed on us by the FDA, the EMA, HREC, TGA or comparable foreign authorities regarding the scope or design of our clinical trials;

•

divergent views between FDA and other homologue regulatory authorities as to the objectives and/or design of the clinical trials required in support of marketing registration;

•

problems in obtaining or maintaining IRB approval of trials;

•

delays in enrolling patients or volunteers into clinical trials, and variability in the number and types of patients eligible for clinical trials;

•

an inability to open study sites, or enroll, treat, and monitor patients due to local restrictions, including as a result of any pandemic or endemic or other ~~events, such as the Russian invasion of Ukraine or the ongoing conflict in the Middle East, or other~~ geopolitical events that can disrupt supply chains, such as announced tariffs, hostilities in Iran, or other evolving economic policies;

•

high drop-out rates for patients in clinical trials and substantial missing data;

•

negative or inconclusive results from our clinical trials or the clinical trials of others for ~~product~~development candidates similar to ours;

•

failure of future clinical trials to confirm positive results, if any, from earlier preclinical studies and clinical trials;

•

inability to consistently manufacture, inadequate supply, or unacceptable quality of ~~product~~development candidate materials or other materials necessary for the conduct of our clinical trials;

•

greater than anticipated clinical trial costs;

•

serious and unexpected side effects that may or may not be related to the ~~product~~development candidate being tested that are experienced by participants in our clinical trials or by individuals using drugs similar to our ~~product~~development candidates;

•

poor or disappointing effectiveness of our ~~product~~development candidates during clinical trials;

•

unfavorable outcome of FDA, EMA, HREC, TGA or other regulatory agency inspection and review of a manufacturing or clinical trial site or other records relating to the clinical investigation;

•

failure of our third-party contractors, investigators, or collaboration partners to comply with regulatory requirements or otherwise meet their contractual obligations in a timely manner, or at all;

•

governmental or regulatory delays and changes in regulatory requirements, policy and guidelines, including the imposition of additional regulatory oversight around manufacturing, preclinical, or clinical testing generally or with respect to our ~~product~~development candidates class, in particular; or

•

varying interpretations of data by the FDA and similar foreign regulatory agencies.

If we do not successfully conduct clinical development, we will not be able to market and sell products derived from our ~~product~~development candidates or generate product revenues. Even if we do successfully complete clinical trials, those results are not necessarily predictive of results of additional trials that may be needed before we can submit an application for regulatory approval to the FDA or foreign regulatory agencies. If the development of any of our ~~product~~development candidates fails or is delayed to a point where such ~~product~~development candidate is no longer commercially viable, our business may be materially harmed.

We may not be able to conduct clinical trials successfully due to various process-related factors that could negatively impact our business plans.

The successful initiation and completion of any of our clinical trials, ~~including our REWRITE Phase 1/2a clinical trial of KRRO-110 for AATD,~~ within timeframes consistent with our business plans, is dependent on various factors, which include, but are not limited to, our ability to:

•

retain and recruit employees, contractors or consultants with the required level of knowledge and experience;

•

retain and recruit, in a timely manner, a sufficient number of patients necessary to conduct a clinical trial;

•

manufacture and maintain a sufficient amount of clinical material, internally or through third parties;

•

ensure adherence to trial designs and protocols agreed upon and approved by regulatory authorities and applicable regulatory and legal guidelines;

•

apply the appropriate pharmacovigilance measures in case of adverse effects emerging during a clinical trial;

•

execute clinical trial designs and protocols approved by regulatory authorities without deficiencies;

•

timely and effectively contract with (under reasonable terms), manage and work with investigators, institutions, hospitals and the CROs involved in the clinical trial;

•

negotiate contracts and other related documents with clinical trial parties and IRBs, CRO agreements and site agreements, which can be subject to extensive negotiations that could cause significant delays in the clinical trial process, with terms possibly varying significantly among different trial sites and CROs and possibly subjecting us to various risks; and

•

conduct clinical trials in a cost-effective manner, including management of foreign currency risk in clinical trials conducted in foreign jurisdictions and cost increases due to unforeseen or unexpected complications such as enrollment delays, or needing to outsource certain functions during the clinical trial.

If we are not able to manage the clinical trial process successfully, our business plans could be delayed or be rendered unfeasible for us to execute within our planned or required time frames, or at all.

If we cannot successfully manufacture our product candidates for our research and development and preclinical activities, or manufacture sufficient amounts of our product candidates to meet our clinical requirements and timelines, our business may be materially harmed. 57

InIf ~~order~~we tocannot ~~develop~~successfully manufacture our ~~product~~development candidates, ~~apply~~ for ~~regulatory~~our ~~approvals~~research and ~~commercialize~~development ~~our~~and ~~product~~preclinical ~~candidates~~activities, ~~we will need to develop, contract for,~~ or ~~otherwise arrange for the necessary manufacturing and supply capabilities. In addition to the oligonucleotides that we~~ manufacture ~~internally,~~sufficient weamounts ~~may utilize CMOs to manufacture the oligonucleotides required for our preclinical studies and clinical trials. There are a limited number~~ of ~~manufacturers that supply oligonucleotides. There are risks inherent in pharmaceutical manufacturing that could affect~~ our ~~ability~~development orcandidates ~~the ability of our CMOs~~ to meet ~~delivery time requirements or provide adequate amounts of material to meet~~ our clinical trial demands on our projected timelines. Included in these risks are potential synthesis and purification failures and/or contamination during the manufacturing process, as well as other issues with our facility or the CMOs’ facilities and ability to comply with the applicable manufacturing requirements and ~~quality standards, which could result in unusable product and cause delays in our manufacturing~~ timelines ~~and ultimately delay our clinical trials~~, ~~as well as result in additional expense. To manufacture~~ our ~~oligonucleotides,~~business ~~we rely on third parties to supply the required raw materials. We will likely need to secure alternative suppliers for these raw materials, and such alternative suppliers are limited and~~ may ~~not~~ be readily available, or we may be unable to enter into agreements with them on reasonable terms and in a timely manner. For example, we source certain materials used in the manufacture of our products from China and other countries outside of the United States; supply chain disruptions (including as a result of recently announced tariffs, other geopolitical events or global health pandemics) could impact our business. Additionally, our cost of goods development is at an early stage. The actual cost to manufacture and process our product candidates could be greater than expected and could materially ~~and adversely affect the commercial viability of our product candidates~~harmed.

~~Moreover~~In order to develop our development candidates, apply for regulatory approvals and commercialize our development candidates, we ~~license~~will need to develop, contract for, or otherwise arrange for the ~~LNP~~necessary ~~technology~~manufacturing ~~used~~and supply capabilities. In addition to ~~deliver~~the ~~KRRO-110~~oligonucleotides ~~from~~that we manufacture internally, we may utilize CMOs to manufacture the oligonucleotides required for our preclinical studies and clinical trials. There are a ~~third~~limited ~~party~~number of manufacturers that supply oligonucleotides. ~~Although~~There are risks inherent in pharmaceutical manufacturing that could affect our ~~current~~ability ~~partner,~~or ~~Genevant~~the ~~Sciences~~ability ~~GmbH,~~of our CMOs to meet delivery time requirements or ~~Genevant,~~provide isadequate aamounts ~~well~~of ~~established~~material ~~leader~~to meet our clinical trial demands on our projected timelines. Included in these risks are potential synthesis and purification failures and/or contamination during the ~~LNP~~manufacturing ~~space~~process, ~~and~~as ~~our~~well ~~preclinical~~as ~~studies~~other ofissues ~~this~~with ~~LNP~~our ~~delivery~~facility ~~technology~~or ~~have~~the ~~shown~~CMOs’ ~~improved~~facilities ~~dose-dependent~~and ~~efficacy~~ability to comply with ~~reduced~~the ~~clinical~~applicable ~~chemistry~~manufacturing requirements and ~~adverse~~quality ~~events~~standards, ~~there~~which iscould noresult ~~guarantee~~in ~~that~~unusable ~~this~~product ~~will~~and because ~~replicated~~delays in our manufacturing timelines and ultimately delay our clinical trials., ~~There~~as iswell ~~also~~as noresult ~~guarantee~~in ~~that~~additional expense. To manufacture our oligonucleotides, we ~~will~~rely ~~continue~~on third parties to ~~source~~supply the ~~LNP~~required ~~delivery~~raw ~~system~~materials. We will likely need to secure alternative suppliers for ~~KRRO-110~~these ~~from~~raw ~~Genevant.~~materials, ~~The~~and ~~process~~such ofalternative ~~establishing~~suppliers are limited and ~~maintaining~~may ~~collaborative~~not ~~relationships~~be readily available, or we may be unable to enter into agreements with them on reasonable terms and ~~identifying~~in a timely manner. For example, we source certain materials used in the manufacture of our products from China and ~~securing~~other ~~access~~countries tooutside ~~optimized~~of ~~delivery~~the ~~systems~~United ~~that~~States; ~~are~~supply ~~fit-for-purpose~~chain isdisruptions ~~difficult~~(including as a result of announced tariffs, ~~time-consuming~~other geopolitical events or global health pandemics) could impact our business. Additionally, our cost of goods development is at an early stage. The actual cost to manufacture and ~~involves~~process our development candidates could be greater than expected and could materially and adversely affect the commercial viability of our development candidates.

significant uncertainty. If the current arrangement with Genevant is terminated, our clinical development, manufacturing, or commercialization efforts for KRRO-110 could be delayed or terminated, while we secure an alternative delivery system, which could have a material adverse impact on our clinical development plans and business.

The process of manufacturing oligonucleotides is complex and we may encounter difficulties in production, particularly with respect to process development or scaling-up of our manufacturing capabilities.

The process of manufacturing oligonucleotides is complex, highly-regulated and subject to multiple risks. The complex processes associated with the manufacture of our ~~product~~development candidates expose us to various manufacturing challenges and risks, which may include delays in manufacturing adequate supply of our ~~product~~development candidates, limits on our ability to increase manufacturing capacity, and the potential for product failure and product variation in quality that may interfere with preclinical studies and clinical trials, along with additional costs. We may also make changes to our manufacturing process or the delivery system we use at various points during development, and even after commercialization, for various reasons, such as optimizing costs, achieving scale, decreasing processing time, increasing manufacturing success rate, or other reasons. Such changes carry the risk that they will not achieve their intended objectives, and any of these changes could cause our ~~product~~development candidates to perform differently and affect the results of current or future clinical trials, or the performance of the product, once commercialized. In some circumstances, changes in the manufacturing or delivery system may require us to perform ex vivo comparability studies, and/or conduct animal studies, and to collect additional data from patients prior to undertaking more advanced clinical trials. For instance, changes in our manufacturing process during the course of clinical development may require us to show the comparability of the product used in earlier clinical trials or at earlier portions of a trial to the product used in later clinical trials or later portions of the trial. We may also make further changes to our manufacturing or delivery system before or after commercialization, and such changes may require us to show the comparability of the resulting product to the product produced via earlier manufacturing processes and supplied or delivery system used in clinical studies. We may be required to collect additional preclinical and/or clinical data from any modified process prior to obtaining marketing approval for the ~~product~~development candidate produced with such modified process. If preclinical and/or clinical data are not ultimately comparable to those seen in the earlier trials, we may be required to make further changes to our process and/or undertake additional clinical testing, either of which could significantly delay the clinical development or commercialization of the associated ~~product~~development candidate.

Although we continue to build on our experience in manufacturing oligonucleotides, we have limited experience as a company manufacturing ~~product~~development candidates for commercial supply. We may never be successful in manufacturing ~~product~~development candidates in sufficient quantities or with sufficient quality for commercial use. Our manufacturing capabilities could be affected by cost-overruns, unexpected delays, equipment failures, labor shortages, operator error, natural disasters, unavailability of qualified personnel, difficulties with logistics and shipping, problems regarding yields or stability of product, contamination or other quality control issues, power failures, and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

Furthermore, compliance with cGMP requirements and other quality issues may arise during any internal efforts to scale-up manufacturing, and with our current or any future CMOs. If contaminants are discovered in our supply of our ~~product~~development candidates or in the manufacturing facilities of our CMOs, such manufacturing facilities may need to be closed for an extended period of time to investigate and remedy the contamination. We cannot assure you that any stability failures or other issues relating to the manufacture of our product candidates will not occur in the future. Additionally, our CMOs may experience manufacturing difficulties due to resource constraints or as a result of labor disputes or unstable political environments. If our CMOs were to encounter any of these difficulties, our ability to provide our product candidate to patients in clinical trials, or to provide product for treatment of patients once approved, would be jeopardized.

We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success. 58

~~Because~~period weof ~~have~~time ~~limited~~to ~~financial~~investigate ~~resources,~~and weremedy ~~intend~~the tocontamination. ~~focus~~We oncannot ~~developing~~assure ~~product~~you ~~candidates~~that ~~for~~any ~~specific~~stability ~~indications~~failures ~~that~~or weother ~~identify~~issues asrelating ~~most likely~~ to ~~succeed,~~the inmanufacture ~~terms~~ of ~~both~~our ~~regulatory~~development ~~approval and commercialization. As a result, we may forego or delay pursuit of opportunities with other product~~ candidates orwill ~~for~~not ~~other~~occur ~~indications~~in ~~that~~the ~~may prove to have greater commercial potential~~future. ~~Our~~Additionally, ~~resource~~our ~~allocation~~CMOs ~~decisions~~ may ~~cause~~experience usmanufacturing todifficulties ~~fail~~due to ~~capitalize~~resource onconstraints ~~viable commercial products~~ or ~~profitable~~as ~~market~~a ~~opportunities.~~result ~~Our~~of ~~spending~~labor ondisputes ~~current~~or ~~and~~unstable ~~future~~political ~~research and development programs and product candidates for specific indications may not yield any commercially viable products~~environments. If weour doCMOs ~~not~~were ~~accurately~~to ~~evaluate~~encounter ~~the~~any ~~commercial~~of ~~potential~~these ordifficulties, ~~target~~our ~~market~~ability ~~for~~to aprovide ~~particular~~our ~~product~~development candidate, ~~we may relinquish valuable rights~~ to ~~that~~patients ~~product~~in ~~candidate~~clinical ~~through collaboration~~trials, ~~licensing~~ or ~~other~~to ~~royalty~~provide ~~arrangements~~product ~~in cases in which we would have been more advantageous~~ for ustreatment toof ~~retain~~patients ~~sole~~once ~~development~~approved, ~~and~~would ~~commercialization~~be ~~rights to such product candidate~~jeopardized.

55We may expend our limited resources to pursue a particular development candidate or indication and fail to capitalize on development candidates or indications that may be more profitable or for which there is a greater likelihood of success.

~~Our~~Because ~~product~~we ~~candidates~~have ~~may~~limited ~~cause~~financial ~~undesirable~~resources, ~~and~~we ~~unforeseen~~intend ~~side~~to ~~effects~~focus oron bedeveloping ~~perceived~~development bycandidates ~~the~~for ~~public~~specific indications that we identify as ~~unsafe~~most likely to succeed, ~~which~~in ~~could~~terms of both regulatory approval and commercialization. As a result, we may forego or delay pursuit of opportunities with other development candidates or ~~prevent~~for ~~their~~other ~~advancement~~indications ~~into~~that ~~clinical~~may ~~trials~~prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or ~~regulatory~~profitable ~~approval,~~market ~~limit~~opportunities. Our spending on current and future research and development programs and development candidates for specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or ~~result~~target market for a particular development candidate, we may relinquish valuable rights to that development candidate through collaboration, licensing or other royalty arrangements in ~~significant~~cases ~~negative~~in ~~consequences.~~which we would have been more advantageous for us to retain sole development and commercialization rights to such development candidate.

WeOur ~~have~~development ~~dosed~~candidates ~~very~~may ~~few~~cause ~~participants~~undesirable ~~in our Phase 1/2a REWRITE clinical trial of KRRO-110 for AATD~~ and ~~have~~unforeseen ~~not~~side ~~received~~effects ~~any~~or ~~results~~be ~~for~~perceived ~~any~~by ofthe ~~our~~public ~~product~~as ~~candidates in human clinical trials. Moreover~~unsafe, ~~there~~which ~~have~~could ~~been~~delay ~~only~~or aprevent ~~limited~~their ~~number~~advancement ofinto clinical trials ~~involving the use of gene editing technologies and RNA editing technology similar to our technology. It is impossible to predict when,~~ or ~~if,~~regulatory ~~any product candidates we may develop will prove safe in humans. In the genetic medicine field~~approval, ~~there~~limit ~~have been several significant adverse events from gene therapy treatments in~~ the ~~past,~~commercial ~~including~~potential ~~reported cases of leukemia and death. There can be no assurance that RNA editing technologies will not cause undesirable side effects, such as lymphoma, leukemia,~~ or ~~other~~result ~~cancers,~~in orsignificant ~~other~~negative ~~aberrantly functioning cells~~consequences.

IfWe ~~any~~have ~~such~~dosed ~~adverse~~very ~~events~~few ~~occur,~~participants with our ~~future~~development ~~clinical~~candidates ~~trials~~in ~~could~~human beclinical ~~suspended or terminated~~trials. IfMoreover, wethere ~~are~~have ~~unable~~been toonly ~~demonstrate~~a ~~that~~limited ~~any~~number ~~adverse~~of ~~events~~clinical ~~were~~trials ~~caused~~involving by the ~~administration~~use ~~process~~of orgenetic ~~related~~medicine ~~procedures,~~technologies ~~the~~and ~~FDA,~~RNA ~~the~~editing ~~EMA,~~technology ~~HREC,~~similar ~~TGA~~to orour ~~other~~technology. ~~regulatory~~It ~~authorities~~is ~~could~~impossible ~~order us~~ to ~~cease~~predict ~~further development of~~when, or ~~deny approval of~~if, any ~~product~~development candidates ~~for any or all targeted indications. Even if~~ we ~~can~~may ~~demonstrate~~develop ~~that~~will ~~all~~prove ~~future~~safe ~~serious~~in ~~adverse~~humans. ~~events~~In ~~are not product-related, such occurrences could affect patient recruitment or~~ the ~~ability~~genetic ofmedicine ~~enrolled patients to complete any future trial. Moreover~~field, ifthere wehave ~~elect,~~been orseveral ~~are~~significant ~~required,~~adverse toevents ~~not~~from ~~initiate,~~gene ~~delay,~~therapy ~~suspend~~treatments orin ~~terminate~~the ~~any future clinical trial of any of our product candidates~~past, ~~the~~including ~~commercial~~reported ~~prospects~~cases of ~~such~~leukemia ~~product candidates may be harmed~~ and ~~our~~death. ~~ability~~There tocan ~~generate product revenues from any of these product candidates may~~ be ~~delayed~~no orassurance ~~eliminated.~~that ~~Any~~RNA ofediting ~~these~~technologies ~~occurrences~~will ~~may~~not ~~harm~~cause ~~our~~undesirable ~~ability~~side toeffects, ~~develop~~such ~~other~~as ~~product~~lymphoma, ~~candidates~~leukemia, ~~and~~or ~~may~~other ~~adversely affect our business~~cancers, ~~financial~~or ~~condition,~~other ~~results~~aberrantly offunctioning ~~operations and prospects significantly~~cells.

~~Additionally~~If any such adverse events occur, ifour ~~KRRO-110~~future clinical trials could be suspended or terminated. If we are unable to demonstrate that any ofadverse ~~our~~events ~~future~~were ~~product~~caused ~~candidates~~by ~~receives~~the ~~marketing~~administration ~~approval~~process or related procedures, the FDA, the EMA, HREC, TGA or other regulatory authorities could ~~require~~order us to ~~adopt~~cease afurther ~~REMS~~development toof, ~~ensure~~or ~~that~~deny ~~the~~approval ~~benefits~~ of, ~~the~~any ~~product~~development ~~outweigh~~candidates ~~its~~for ~~risks,~~any ~~which~~or ~~may~~all ~~include,~~targeted ~~for~~indications. ~~example~~Even if we can demonstrate that all future serious adverse events are not product-related, asuch ~~Medication~~occurrences ~~Guide~~could ~~outlining~~affect ~~the~~patient ~~risks~~recruitment ofor the ~~product~~ability ~~for~~of ~~distribution~~enrolled patients to ~~patients~~complete ~~and~~any afuture ~~communication~~trial. ~~plan~~Moreover, if we elect, or are required, to ~~health~~not ~~care~~initiate, ~~practitioners~~delay, suspend or ~~other~~terminate ~~elements~~any tofuture ~~assure~~clinical ~~safe~~trial ~~use~~of any of ~~the~~our ~~product.~~development ~~Furthermore~~candidates, ifthe wecommercial orprospects ~~others~~of ~~later~~such ~~identify~~development ~~undesirable~~candidates ~~side~~may ~~effects~~be ~~caused~~harmed byand our ability to generate product revenues from any of these development candidates may be delayed or eliminated. Any of these occurrences may harm our ~~product~~ability to develop other development candidates, ~~several~~and ~~potentially~~may ~~significant~~adversely ~~negative~~affect ~~consequences~~our ~~could~~business, ~~result~~financial condition, ~~including:~~results of operations and prospects significantly.

~~regulatory~~Additionally, ~~authorities~~if any of our development candidates receives marketing approval, the FDA could require us to adopt a REMS to ensure that the benefits of the product outweigh its risks, which may ~~suspend~~include, for example, a Medication Guide outlining the risks of the product for distribution to patients and a communication plan to health care practitioners, or ~~withdraw~~other ~~approvals~~elements to assure safe use of ~~such~~the product. ~~candidate;~~Furthermore, if we or others later identify undesirable side effects caused by any of our development candidates, several potentially significant negative consequences could result, including:

•

weregulatory authorities may besuspend ~~required~~or towithdraw ~~change~~approvals ~~the~~of ~~way~~such adevelopment ~~product~~ candidate ~~is administered or conduct additional clinical trials~~;

•

we may be required to change the way a development candidate is administered or conduct additional clinical trials;

•

we could be sued and held liable for harm caused to patients; and

•

our reputation may suffer.

Any of these occurrences may harm our business, financial condition, results of operations and prospects significantly.

If we are unable to successfully identify patients who are likely to benefit from therapy with any product candidates we develop, or experience significant delays in doing so, we may not realize the full commercial potential of any products we may develop. 59

If we are unable to successfully identify patients who are likely to benefit from therapy with any development candidates we develop, or experience significant delays in doing so, we may not realize the full commercial potential of any products we may develop.

Our success may depend, in part, on our ability to identify patients who are likely to benefit from therapy with any products we may develop, which may require those potential patients to have their DNA analyzed for the presence or absence of a particular sequence. If we, or any third parties that we engage to assist us, are unable to successfully identify such patients, or experience delays in doing so, then:

•

our ability to develop any ~~product~~development candidates may be adversely affected if we are unable to appropriately select patients for enrollment in our clinical trials; and

•

we may not realize the full commercial potential of any ~~product~~development candidates we develop that receive marketing approval if, among other reasons, we are unable to appropriately select patients who are likely to benefit from therapy with our products.

As a result of these factors, we may be unable to successfully develop and realize the commercial potential of any ~~product~~development candidates we may identify and develop, and our business, financial condition, results of operations, and prospects would be materially adversely affected.

If we are unable to establish sales and marketing capabilities or enter into agreements with third parties to market and sell any ~~product~~development candidates, we may be unable to generate any revenues.

We currently do not have an organization for the sales, marketing and distribution of any ~~product~~development candidates and the cost of establishing and maintaining such an organization may exceed the cost-effectiveness of doing so. To market any products that may be approved, we must build our sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. With respect to certain of our current programs as well as future programs, we may rely completely on an alliance partner for sales and marketing. In addition, although we intend to establish a sales organization if we are able to obtain approval to market any development candidates, we may enter into strategic alliances with third parties to develop and commercialize any development candidates, including in markets outside of the United States or for other large markets that are beyond our resources. This will reduce the revenue generated from the sales of these products.

56Any future strategic alliance partners may not dedicate sufficient resources to the commercialization of our development candidates or may otherwise fail in their commercialization due to factors beyond our control. If we are unable to establish effective alliances to enable the sale of our development candidates to healthcare professionals and in geographical regions, including the United States, that will not be covered by our own marketing and sales force, or if our potential future strategic alliance partners do not successfully commercialize the development candidates, our ability to generate revenues from product sales will be adversely affected.

may be approved, we must build our sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. With respect to certain of our current programs as well as future programs, we may rely completely on an alliance partner for sales and marketing. In addition, although we intend to establish a sales organization if we are able to obtain approval to market any product candidates, we may enter into strategic alliances with third parties to develop and commercialize any product candidates, including in markets outside of the United States or for other large markets that are beyond our resources. This will reduce the revenue generated from the sales of these products.

Any future strategic alliance partners may not dedicate sufficient resources to the commercialization of our product candidates or may otherwise fail in their commercialization due to factors beyond our control. If we are unable to establish effective alliances to enable the sale of our product candidates to healthcare professionals and in geographical regions, including the United States, that will not be covered by our own marketing and sales force, or if our potential future strategic alliance partners do not successfully commercialize the product candidates, our ability to generate revenues from product sales will be adversely affected.

If we are unable to establish adequate sales, marketing and distribution capabilities, whether independently or with third parties, we may not be able to generate sufficient product revenue and may not become profitable. We will be competing with many companies that currently have extensive and well-funded marketing and sales operations. Without an internal team or the support of a third party to perform marketing and sales functions, we may be unable to compete successfully against these more established companies.

Even if we receive regulatory approval to market our ~~product~~development candidates, the market may not be receptive to our ~~product~~development candidates upon their commercial introduction, which will prevent us from becoming profitable.

Our ~~product~~development candidates are based upon new discoveries, technologies and therapeutic approaches. Key participants in pharmaceutical marketplaces, such as physicians, third-party payors and consumers, may not adopt a product intended to improve therapeutic results that is based on the technology employed by oligonucleotides. As a result, it may be more difficult for us to convince the medical community and third-party payors to accept and use our product, or to provide favorable reimbursement.

Other factors that we believe will materially affect market acceptance of our ~~product~~development candidates include:

•

the timing of our receipt of any regulatory approvals, the terms of any approvals and the countries in which approvals are obtained;

•

the ability to consistently manufacture our products within acceptable quality standards;

~~the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any;~~ 60

•

the safety and efficacy of our development candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any;

•

the incidence, seriousness and severity of any side effects;

•

the relative convenience and ease of administration of our ~~product~~development candidates;

•

the willingness of patients to accept potentially new routes of administration and their risk tolerance as it relates to potentially serious side effects;

•

the success of our physician education programs;

•

the availability of government and third-party payor coverage and adequate reimbursement;

•

the pricing of our products, particularly as compared to alternative treatments; and

•

the availability of alternative effective treatments for the diseases that ~~product~~development candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.

In addition, our estimates regarding the potential market size may be materially different from what we currently expect by the time we commence commercialization, which could result in significant changes in our business plan and may significantly harm our results of operations and financial condition.

The pharmaceutical industry is intensely competitive. If we are unable to compete effectively with existing drugs, new treatment methods and new technologies, we may be unable to commercialize successfully any drugs that we develop.

The pharmaceutical industry is intensely competitive and rapidly changing. Many large pharmaceutical and biotechnology companies, academic institutions, governmental agencies and other public and private research organizations are pursuing the development of novel drugs for the same diseases that we are targeting or expect to target, including UCD, HE and AATD. Many of our competitors have:

•

much greater financial, technical and human resources than we have at every stage of the discovery, development, manufacture and commercialization of products;

•

more extensive experience in designing and conducting preclinical studies and clinical trials, obtaining regulatory approvals, and manufacturing, marketing and selling pharmaceutical products;

•

~~product~~development candidates that are based on previously tested or accepted technologies;

•

products that have been approved or are in late stages of development; and

•

collaborative arrangements in our target markets with leading companies and research institutions.

We will face intense competition from drugs that have already been approved and accepted by the medical community for the treatment of the conditions for which we may develop products. We also expect to face competition from new drugs that enter the market. We believe a significant number of drugs are currently under development, and may become commercially available in the future, for the treatment of conditions that our current or future ~~product~~development candidates are or may be designed to treat. These drugs may be more effective, safer, less expensive, or marketed and sold more effectively, than any products we develop. Following our transition to GalNAc-conjugated delivery for our AATD program, we may be further behind in our development efforts than our competitors, which could negatively impact our ability to develop a commercially viable product for such indication.

Our competitors may develop or commercialize products with significant advantages over any products we are able to develop and commercialize based on many different factors, including:

•

the safety and effectiveness of our products relative to alternative products, if any;

•

the ease with which our products can be administered and the extent to which patients accept relatively new routes of administration;

•

the timing and scope of regulatory approvals for these products;

•

the availability and cost of manufacturing, marketing and sales capabilities;

•

price;

•

more extensive coverage and higher levels of reimbursement; and

•

patent position.

Our competitors may therefore be more successful in commercializing their products than we are, which could adversely affect our competitive position and business. Competitive products may make any products we develop obsolete or noncompetitive before we can recover the expenses of developing and commercializing our ~~product~~development candidates. Such competitors could also recruit our employees, which could negatively impact our level of expertise and our ability to execute on our business plan.

~~The~~Healthcare ~~pricing,~~legislative ~~insurance coverage and reimbursement status of newly approved products is uncertain. Failure to obtain~~ or ~~maintain~~regulatory ~~adequate~~reform ~~coverage~~measures ~~and~~may ~~reimbursement~~have ~~for~~a ~~our~~negative ~~product~~impact ~~candidates,~~on ~~if approved, could limit~~ our ~~ability~~business ~~to market those products~~ and ~~decrease~~results ~~our~~of ~~ability to generate product revenue~~operations.

WeIn ~~expect~~the ~~that~~United ~~coverage~~States and ~~reimbursement~~some byforeign ~~third-party~~jurisdictions, ~~payors~~there ~~will~~have bebeen, ~~essential~~and ~~for~~continue ~~most patients~~ to be, ~~able~~several tolegislative ~~afford~~and ~~any~~regulatory ~~gene~~changes ~~therapies~~and ~~for~~proposed ~~which~~changes weregarding ~~are~~the ~~able~~healthcare tosystem ~~successfully~~that ~~complete~~could ~~clinical~~prevent ~~development.~~or ~~Accordingly,~~delay ~~sales~~marketing approval of ~~any~~development ~~future~~candidates, ~~products~~restrict ~~will~~or ~~depend~~regulate ~~substantially~~post-approval activities, ~~both domestically~~ and ~~internationally,~~affect onour ~~the~~ability ~~extent~~ to ~~which~~profitably ~~the~~sell ~~costs of~~ any ~~such~~development ~~products~~candidates ~~will~~for bewhich ~~paid~~we byobtain ~~health~~marketing ~~maintenance,~~approval. ~~managed care~~Payors, ~~pharmacy~~whether ~~benefit~~domestic ~~and~~or ~~similar healthcare management organizations~~foreign, or ~~will~~governmental beor ~~reimbursed~~private, byare ~~government~~developing ~~authorities,~~increasingly ~~private~~sophisticated ~~health~~methods ~~coverage~~of ~~insurers~~controlling ~~and~~healthcare ~~other~~costs. ~~third-party~~Recent ~~payors.~~and ~~Even~~proposed ifhealthcare ~~coverage~~reform ismeasures ~~provided,~~in the ~~approved~~United ~~reimbursement~~States ~~amount~~have ~~may~~focused ~~not~~in beparticular ~~high~~on ~~enough~~prescription todrug ~~allow us to establish or maintain~~ pricing, ~~sufficient~~reimbursement, toand ~~realize~~manufacturer afinancial ~~sufficient~~obligations ~~return~~under ongovernment ishealthcare ~~investment~~programs. IfThese wemeasures ~~are~~include ~~unable~~statutory tochanges, ~~establish~~executive oractions, ~~sustain coverage~~ and ~~adequate~~proposed ~~reimbursement~~regulations ~~for~~that ~~any~~may ~~future~~affect ~~product~~pricing, ~~candidates~~coverage, ~~from~~reimbursement ~~third-party payors~~methodologies, ~~the~~and ~~adoption~~market ofaccess ~~those~~for ~~product~~pharmaceutical ~~candidates~~ and ~~sales~~biological ~~revenue~~products. ~~will~~For bea ~~adversely~~more ~~affected,~~complete ~~which,~~discussion inof ~~turn,~~healthcare ~~could~~reform ~~adversely~~and ~~affect~~regulatory ~~the~~developments ~~ability~~that tomay ~~market~~affect orour ~~sell~~business, ~~those~~see ~~product~~Item ~~candidates~~1, if“Business—Government ~~approved~~Regulation—Healthcare Reform Measures.”

There ishas ~~significant~~been ~~uncertainty~~increasing ~~related~~legislative, regulatory, and enforcement interest in the United States with respect to prescription drug pricing practices. Specifically, there has been heightened governmental scrutiny over the ~~insurance~~manner ~~coverage~~in ~~and~~which ~~reimbursement~~manufacturers ofset ~~newly~~prices ~~approved~~for their marketed products, which has resulted in ~~both~~several ~~the~~U.S. ~~United~~Congressional ~~States~~inquiries and ~~globally.~~proposed ~~Outside~~and ~~the~~enacted ~~United~~federal ~~States~~and state legislation designed to, ~~international~~among ~~operations~~other ~~are~~things, ~~generally~~bring ~~subject~~more transparency to ~~extensive~~drug ~~governmental~~pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs.

58The continuing efforts of the government, insurance companies, managed care organizations and other payers of healthcare services to contain or reduce costs of healthcare may adversely affect:

•

~~price controls and other market regulations, and we believe~~ the ~~increasing~~demand emphasis on cost-containment initiatives in the United States, the European Union, Canada and other countries has and will continue to put pressure on the pricing and usage of therapeutics such as our product candidates. Moreover, increasing efforts by governmental and third-party payors, in the United States and internationally, to cap or reduce healthcare costs may cause such organizations to limit both coverage and level of reimbursement for ~~new products approved and, as a result, they may not cover or provide adequate payment for our product candidates. We expect to experience pricing pressures in connection with the sale of~~ any of our ~~product~~development candidates ~~due to the trend toward managed healthcare~~, ~~the~~if increasing influence of certain third-party payors, such as health maintenance organizations, and additional legislative changes. For an overview and discussion of the regulatory framework for pricing and reimbursement, see Item 1 “Business—Government Regulation—Patients Rely on Insurance Coverage by Third-Party Payors (third-party payors include Medicare and Medicaid (government payors) and commercial insurance companies such as Blue Cross Blue Shield, Humana, Cigna, etc.) to Pay for Products.”approved;

•

If the ~~market~~ability ~~opportunities~~to ~~for~~set ~~any~~a ~~product~~price ~~candidates~~that we ~~may~~believe ~~develop~~is ~~are~~fair ~~smaller~~for ~~than~~any weof ~~believe they are,~~ our ~~potential~~development ~~revenues may be adversely affected~~candidates, ~~and~~if ~~our business may suffer.~~ approved;

•

Our projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with product candidates we may develop, are based on estimates. These estimates may prove to be incorrect and new studies may change the estimated incidence or prevalence of these diseases. Additionally, our ~~estimates~~ability regarding the potential market size may be materially different from what we currently expect by the time we commence commercialization. The number of patients in the United States, Europe, and elsewhere may turn out to begenerate ~~lower~~revenues ~~than expected,~~ and ~~patients~~achieve ~~may not be amenable to treatment with our product candidates,~~ or ~~may~~maintain ~~become increasingly difficult to identify or gain access to, all of which would adversely affect our business, financial condition, results of operations, and prospects.~~ profitability;

•

~~While we intend to seek designations for our product candidates with~~ the ~~FDA~~level ~~and~~of ~~comparable~~taxes ~~foreign regulatory authorities~~ that ~~are intended to confer benefits such as a faster development process or an accelerated regulatory pathway, there can be no assurance that~~ we ~~will successfully obtain such designations. In addition, even if one or more of our product candidates~~ are ~~granted~~required ~~such designations, we may not be able~~ to ~~realize~~pay; ~~the intended benefits of such designations.~~ and

•

~~The FDA and comparable foreign regulatory authorities offer certain designations for product candidates that are designed to encourage~~ the ~~research~~availability ~~and development~~ of ~~product candidates that are intended to address conditions with significant unmet medical need~~capital. These designations include fast track, or breakthrough therapy, among others, and may confer benefits such as additional interaction with regulatory authorities, a potentially accelerated regulatory pathway and priority review. However, there can be no assurance that we will successfully obtain such designations for any product candidates. See Item 1 “Business—Government Regulation—Expedited Development and Review Programs for Drugs” for more information regarding these designations. While such designations could expedite the development or approval process, they generally do not change the standards for approval. Even if we obtain such designations for one or more of our product candidates, there can be no assurance that we will realize their intended benefits.

InWe ~~the~~expect ~~future,~~that weadditional ~~may~~healthcare ~~also~~reform ~~seek~~measures ~~approval~~will ofbe ~~product~~adopted ~~candidates~~in ~~under~~ the ~~FDA’s~~future, ~~accelerated approval pathway or request priority review. There can be no assurance that FDA would allow~~ any of ~~the~~which ~~product~~could ~~candidates~~result wein ~~may~~reduced ~~develop~~demand tofor ~~proceed~~our ondevelopment ancandidates ~~accelerated approval pathway~~ or ~~grant~~additional ~~priority~~pricing ~~review,~~pressures. ~~and~~These ~~even~~cost ifcontainment ~~FDA~~measures ~~did allow such pathway, there can~~ (be noit ~~assurance~~federal ~~that such submission~~ or ~~application~~state ~~will~~regulations, ~~be accepted~~ or ~~that~~regional ~~any~~bidding ~~expedited development~~processes, ~~review~~ or ~~approval~~most-favored-nation ~~will~~pricing ~~be granted on a timely basis~~practices, or atotherwise) ~~all.~~could ~~Moreover,~~reduce ~~even~~the ifultimate wedemand ~~received~~for ~~accelerated approval,~~ any ~~post-approval~~approved ~~studies~~development ~~required~~candidates ~~to confirm~~ and ~~verify~~or ~~clinical~~put ~~benefit~~pressure ~~may~~on ~~not~~our ~~show such benefit~~pricing, which could ~~lead~~negatively toaffect ~~withdrawal~~our ofbusiness, ~~any~~financial ~~approvals~~condition, weresults ~~have~~of ~~obtained.~~operations ~~Receiving~~and ~~accelerated approval does not assure that the product’s accelerated approval will eventually be converted to a traditional approval~~prospects.

In addition, ina ~~the~~2024 ~~European~~U.S. ~~Union,~~Supreme weCourt decision may ~~seek~~increase toregulatory ~~participate~~uncertainty inand ~~The~~litigation ~~PRIority~~risk ~~MEdicines,~~and orcould ~~PRIME,~~delay ~~scheme~~or ~~for~~complicate ~~our~~FDA ~~product~~regulatory ~~candidates.~~review, ~~The~~policymaking, ~~PRIME~~or ~~scheme~~implementation ~~is intended to encourage drug development in areas~~ of ~~unmet~~regulatory ~~medical~~initiatives. ~~need~~We ~~and~~cannot ~~provides~~predict ~~accelerated~~the ~~assessment~~full impact of ~~products~~this ~~representing substantial innovation~~decision, ~~where~~future ~~the~~judicial ~~marketing~~challenges ~~authorization~~brought ~~application~~against ~~will be made through~~ the ~~centralized~~FDA, ~~procedure~~or in the ~~European~~nature ~~Union.~~or ~~There~~extent isof nogovernment ~~guarantee,~~regulation ~~however,~~ that ~~our~~may ~~product~~arise ~~candidates~~from ~~would~~future belegislation ~~deemed~~or ~~eligible~~administrative ~~for~~action. ~~the~~Any ~~PRIME~~such ~~scheme~~challenges, ~~and even~~ if ~~we do participate in the PRIME scheme~~successful, ~~where~~could ~~during~~have ~~the~~an ~~course~~impact ofon ~~development~~our ~~a medicine no longer meets the eligibility criteria~~business, ~~support~~and ~~under~~any ~~the~~such ~~PRIME~~impact ~~scheme~~could ~~may~~ be ~~withdrawn~~material. ~~PRIME~~In ~~eligibility~~addition ~~does~~to ~~not~~potential ~~change~~changes ~~the~~to ~~standards~~regulations ~~for product approval,~~ and ~~there~~agency isguidance noas ~~assurance~~a ~~that~~result ~~any~~of ~~such~~legal ~~designation~~challenges, orthese ~~eligibility~~decisions ~~will~~may result in ~~expedited~~increased ~~review~~regulatory oruncertainty ~~approval.~~and ~~For~~delays ~~more~~in ~~information~~and ~~regarding~~other ~~PRIME~~impacts ~~and~~to the EUagency ~~regulatory~~rulemaking ~~framework~~process, ~~see~~any ~~Item~~of 1which ~~“Business—Government~~could ~~Regulation—Regulation~~adversely ~~Outside~~impact ofour ~~the~~business ~~United~~and ~~States~~operations.”

5962

If the market opportunities for any development candidates we may develop are smaller than we believe they are, our potential revenues may be adversely affected, and our business may suffer.

Our projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with development candidates we may develop, are based on estimates. These estimates may prove to be incorrect and new studies may change the estimated incidence or prevalence of these diseases. Additionally, our estimates regarding the potential market size may be materially different from what we currently expect by the time we commence commercialization. The number of patients in the United States, Europe, and elsewhere may turn out to be lower than expected, and patients may not be amenable to treatment with our development candidates, or may become increasingly difficult to identify or gain access to, all of which would adversely affect our business, financial condition, results of operations, and prospects.

While we intend to seek designations for our development candidates with the FDA and comparable foreign regulatory authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway, there can be no assurance that we will successfully obtain such designations. In addition, even if one or more of our development candidates are granted such designations, we may not be able to realize the intended benefits of such designations.

The FDA and comparable foreign regulatory authorities offer certain designations for development candidates that are designed to encourage the research and development of development candidates that are intended to address conditions with significant unmet medical need. These designations include fast track, or breakthrough therapy, among others, and may confer benefits such as additional interaction with regulatory authorities, a potentially accelerated regulatory pathway and priority review. However, there can be no assurance that we will successfully obtain such designations for any development candidates. See Item 1 “Business—Government Regulation—Expedited Development and Review Programs for Drugs” for more information regarding these designations. While such designations could expedite the development or approval process, they generally do not change the standards for approval. Even if we obtain such designations for one or more of our development candidates, there can be no assurance that we will realize their intended benefits.

In the future, we may also seek approval of development candidates under the FDA’s accelerated approval pathway or request priority review. There can be no assurance that FDA would allow any of the development candidates we may develop to proceed on an accelerated approval pathway or grant priority review, and even if FDA did allow such pathway, there can be no assurance that such submission or application will be accepted or that any expedited development, review or approval will be granted on a timely basis, or at all. Moreover, even if we received accelerated approval, any post-approval studies required to confirm and verify clinical benefit may not show such benefit, which could lead to withdrawal of any approvals we have obtained. Receiving accelerated approval does not assure that the product’s accelerated approval will eventually be converted to a traditional approval.

In addition, in the European Union, we may seek to participate in The PRIority MEdicines, or PRIME, scheme for our development candidates. The PRIME scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the marketing authorization application will be made through the centralized procedure in the European Union. There is no guarantee, however, that our development candidates would be deemed eligible for the PRIME scheme and even if we do participate in the PRIME scheme, where during the course of development a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn. PRIME eligibility does not change the standards for product approval, and there is no assurance that any such designation or eligibility will result in expedited review or approval. For more information regarding PRIME and the EU regulatory framework, see Item 1 “Business—Government Regulation—Regulation Outside of the United States.”

Risks Related to Regulatory, Legal, and Clinical Trials

The FDA and comparable ex-U.S. regulatory agencies have relatively limited experience with oligonucleotides, which may increase the complexity, uncertainty and length of the regulatory review process for any ~~product~~development candidates. Even though the FDA issued two draft guidance documents in December 2021 relating to IND submissions for individualized antisense oligonucleotide drugs for severely debilitating or life-threatening genetic diseases, one with clinical focus, the other with chemistry manufacturing and controls focus, and in June 2024 final guidance on clinical pharmacology considerations for the development of oligonucleotide therapeutics, the FDA and its foreign counterparts have not yet established any definitive policies, practices or guidelines in relation to overall development considerations for RNA editing oligonucleotide therapies. The general lack of policies, practices or guidelines specific to oligonucleotides may hinder or slow review by the FDA or other foreign homologues of any regulatory filings that we may submit. Moreover, the FDA or other foreign homologues may respond to these submissions by defining requirements we may not have anticipated. Addressing such requirements could lead to significant delays in the development of our product candidates. In addition, because there may be approved treatments for some of the diseases for which we may seek approval, in order to receive regulatory approval, we may need to demonstrate through clinical trials that the product candidates we develop to treat these diseases, if any, are not only safe and effective, but safer or more effective than existing products. Furthermore, in recent years, there has been increased public and political pressure on the FDA with respect to the approval process for new drugs. As a result of the foregoing factors, we may never receive regulatory approval to market and commercialize any product candidate. Even if we obtain regulatory approval, the approval may be for disease indications or patient populations that are not as broad as we intended or desired or may require labeling that includes significant use or distribution restrictions or safety warnings. We may be required to perform additional or unanticipated clinical trials to obtain regulatory approval or be subject to additional post-marketing studies or other requirements to maintain such approval. As a result, we may never succeed in developing a marketable product, we may not become profitable and the value of our common stock could decline.

~~Enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product candidates and may affect the prices we may set.~~ 63

~~Existing~~foreign regulatory ~~policies~~agencies of any regulatory filings that we may ~~change~~submit. ~~and~~Moreover, ~~additional~~the ~~government~~FDA ~~regulations~~or other foreign regulatory agencies may berespond ~~enacted~~to ~~that~~these submissions by defining requirements we may not have anticipated. Addressing such requirements could ~~prevent,~~lead ~~limit~~to orsignificant ~~delay~~delays ~~regulatory~~in ~~approval~~the development of our ~~product~~development candidates. WeIn ~~cannot~~addition, ~~predict~~because ~~the~~there ~~likelihood,~~may ~~nature~~be orapproved ~~extent~~treatments for some of ~~government~~the ~~regulation~~diseases ~~that~~for which we may ~~arise~~seek ~~from~~approval, ~~future~~in ~~legislation~~order orto ~~administrative~~receive ~~action~~regulatory approval, ~~including~~we asmay aneed ~~result~~to ofdemonstrate ~~shifting~~through ~~policy~~clinical ~~priorities~~trials ofthat the ~~current~~development ~~presidential~~candidates ~~administration~~we develop to treat these diseases, if any, are not only safe and effective, but safer or more effective than existing products. Furthermore, in recent years, there has been increased public and political ~~appointees~~pressure ~~tasked~~on the FDA with respect to ~~oversee~~the approval process for new drugs. As a result of the ~~regulatory~~foregoing ~~agencies~~factors, ~~either~~we inmay ~~the~~never ~~United~~receive ~~States~~regulatory orapproval ~~abroad~~to market and commercialize any development candidate. IfEven if we ~~are~~obtain ~~slow~~regulatory approval, the approval may be for disease indications or ~~unable~~patient topopulations ~~adapt~~that toare ~~changes~~not inas ~~existing~~broad ~~requirements~~as we intended or ~~the~~desired ~~adoption~~or ofmay ~~new~~require ~~requirements~~labeling that includes significant use or ~~policies,~~distribution restrictions or ifsafety wewarnings. ~~are~~We ~~not~~may ~~able~~be required to ~~maintain~~perform additional or unanticipated clinical trials to obtain regulatory ~~compliance,~~approval weor ~~may~~be ~~lose~~subject ~~any~~to additional post-marketing studies or other requirements to maintain such approval. ~~that~~As a result, we may ~~have~~never ~~obtained~~succeed ~~and~~in developing a marketable product, we may not ~~achieve~~become orprofitable ~~sustain~~and ~~profitability.~~the ~~For~~value ~~more~~of ~~information,~~our ~~see~~common ~~Item~~stock 1could ~~“Business—Governmental Regulation~~decline.”

WeBecause ~~cannot~~we ~~predict~~are ~~the~~developing ~~ultimate~~development ~~content,~~candidates ~~timing~~in orthe ~~effect~~field of ~~any~~genetic ~~healthcare~~medicines ~~reform~~in ~~legislation~~which orthere ~~the~~is ~~impact~~little ofclinical ~~potential legislation on us. In addition~~experience, ~~other~~there ~~legislative~~is ~~changes~~increased ~~have~~risk ~~been~~that ~~proposed and adopted since~~ the ~~Patient Protection and Affordable Care Act~~FDA, or the ~~ACA~~EMA, ~~was~~HREC, ~~enacted.~~TGA Weor ~~may~~other ~~choose~~regulatory toauthorities ~~seek~~may annot ~~expanded~~consider ~~access~~the ~~program~~endpoints ~~for~~of our ~~product~~clinical ~~candidates,~~trials or to ~~utilize~~provide ~~comparable~~clinically ~~rules~~meaningful inresults ~~other~~and ~~countries~~ that ~~allow~~these ~~the~~results ~~use~~may ofbe adifficult ~~drug,~~to ~~on a named patient basis or under a compassionate use program~~analyze.

WeIn ~~expect~~order ~~that~~to ~~the~~proceed ~~ACA~~into clinical development of any development candidates we identify, aswe ~~well~~will asneed ~~other~~to ~~healthcare~~submit ~~reform~~INDs ~~measures~~or ~~that~~comparable ~~may~~foreign beapplications ~~adopted~~to inregulatory authorities and obtain regulatory clearance to commence clinical development. Because the ~~future~~development candidates we identify are based on novel gene-editing technology, we may ~~result~~be unsuccessful in ~~more~~obtaining ~~rigorous~~clearance ~~coverage~~from ~~criteria~~regulatory ~~and~~authorities into ~~additional~~proceed ~~downward~~into ~~pressure~~clinical ondevelopment. ~~the~~In ~~price~~order ~~that~~to commence clinical development, we ~~receive~~will ~~for~~need ~~any~~to ~~approved~~identify ~~product.~~success ~~Payors,~~criteria ~~whether~~and ~~domestic~~endpoints orsuch ~~foreign~~that the FDA, orthe ~~governmental~~EMA or ~~private,~~other ~~are~~regulatory ~~developing~~authorities ~~increasingly~~will ~~sophisticated~~be ~~methods~~able ofto ~~controlling~~determine ~~healthcare~~the ~~costs~~clinical efficacy and ~~those~~safety ~~methods~~profile ~~are~~of ~~not~~any ~~always~~development ~~specifically~~candidates ~~adapted~~we ~~for~~may ~~new~~develop. ~~technologies~~As ~~such~~we asare ~~gene~~initially ~~therapy~~seeking to identify and ~~therapies~~develop ~~addressing~~development ~~rare~~candidates to treat diseases ~~such~~in aswhich ~~those~~there weis ~~are~~little ~~developing.~~clinical ~~Any~~experience ~~reduction~~using innew ~~reimbursement~~technologies, ~~from~~and ~~Medicare~~while orwe ~~other~~may ~~government~~have ~~programs~~opportunities ~~may~~to ~~result~~discuss inour aclinical ~~similar~~development ~~reduction~~plans inwith ~~payments~~regulatory ~~from~~authorities ~~private~~prior ~~payors.~~to ~~The~~commencing ~~implementation~~clinical ofdevelopment, ~~cost~~there ~~containment~~is ~~measures~~heightened risk that the FDA, the EMA, HREC, TGA or other ~~healthcare~~regulatory ~~reforms~~authorities may ~~prevent~~not usconsider ~~from~~the ~~being~~clinical ~~able~~trial endpoints that we propose to ~~generate~~provide ~~revenue,~~clinically ~~attain~~meaningful ~~profitability~~results (reflecting a tangible benefit to patients). In addition, orthe ~~commercialize~~resulting ~~our~~clinical ~~product~~data ~~candidates~~and results may be difficult to analyze.

~~Legislative~~Even ~~and~~if ~~regulatory~~the ~~proposals~~FDA ~~have~~does ~~been~~find ~~made~~our success criteria to ~~expand~~be ~~post-approval~~sufficiently ~~requirements~~validated and ~~restrict~~clinically ~~sales~~meaningful, ~~and~~we ~~promotional~~may ~~activities~~not ~~for~~achieve ~~pharmaceutical~~the ~~products.~~pre-specified Weendpoints ~~cannot~~to bea ~~sure~~degree ~~whether~~of ~~additional~~statistical ~~legislative~~significance. ~~changes~~Furthermore, ~~will~~even beif ~~enacted,~~we ordo ~~whether~~achieve ~~FDA~~the ~~regulations~~pre-specified criteria, ~~guidance~~we ormay ~~interpretations~~produce ~~will~~results bethat ~~changed,~~are unpredictable or ~~what~~inconsistent with the ~~impact~~results of ~~such~~the ~~changes~~non-primary onendpoints ~~the~~or ~~marketing~~other ~~approvals~~relevant data. The FDA also weighs the benefits of ~~our~~a product ~~candidates,~~against ifits ~~any~~risks, and the FDA may ~~be.~~view Inthe ~~addition,~~efficacy ~~increased~~results ~~scrutiny~~in bythe context of safety as not being supportive of regulatory approval. Other regulatory authorities in the UEuropean Union and other countries may make similar comments with respect to these endpoints and data.S. ~~Congress~~Any ofdevelopment candidates we may develop will be based on a novel technology that makes it difficult to predict the ~~FDA’s~~time and cost of development and of subsequently obtaining regulatory approval. ~~process~~No ~~may~~RNA ~~significantly~~editing ~~delay~~therapeutic product has been approved in the United States or ~~prevent~~in ~~marketing~~Europe. ~~approval~~Within the broader genome product field, asonly ~~well~~a aslimited ~~subject~~number usof togene ~~more~~therapy ~~stringent~~products ~~product~~have ~~labeling~~received ~~and~~marketing ~~post-~~authorization or marketing ~~testing~~approval from the European Commission or the FDA. Some of these products have taken years to register and ~~other~~have ~~requirements~~had to deal with significant issues in their post-marketing experience.

60Even if we complete the necessary preclinical studies and clinical trials, we cannot predict when, or if, we will obtain regulatory approval to commercialize a development candidate and the approval may be for a narrower indication than we seek.

~~Because~~Prior weto ~~are~~commercialization, ~~developing~~any ~~product~~of our development candidates must be approved by the FDA pursuant to a new drug application, or NDA, in the ~~field~~United States and pursuant to similar marketing applications by the EMA and similar regulatory authorities outside the United States. The process of ~~genetic~~obtaining ~~medicines~~marketing approvals, both in ~~which~~the ~~there~~United States and abroad, is ~~little~~expensive ~~clinical~~and ~~experience~~takes many years, ~~there~~if approval is ~~increased~~obtained ~~risk~~at ~~that~~all, ~~the~~and ~~FDA~~can vary substantially based upon a variety of factors, including the ~~EMA~~type, ~~HREC,~~complexity ~~TGA~~and ornovelty ~~other~~of ~~regulatory~~the ~~authorities~~development ~~may~~candidates ~~not~~involved. ~~consider~~Failure to obtain marketing approval for a development candidate will prevent us from commercializing the ~~endpoints~~development candidates. We have not received approval to market any of our ~~clinical~~development ~~trials~~candidates tofrom ~~provide~~regulatory ~~clinically~~authorities ~~meaningful~~in ~~results~~any jurisdiction. We have no experience in submitting and supporting the applications necessary to gain marketing approvals, and, in the event regulatory authorities indicate that ~~these~~we ~~results~~may submit such applications, we may be ~~difficult~~unable to ~~analyze~~do so as quickly and efficiently as desired.

InSecuring ~~order~~marketing toapproval ~~proceed~~requires ~~into~~the clinical development of any product candidates we identify, we will need to submit INDs or comparable foreign applications to regulatory authorities and obtain regulatory clearance to commence clinical development, such as our recent regulatory submission ~~to HREC to conduct our first-in-human clinical trial~~ of ~~KRRO-110~~extensive ~~for~~preclinical AATD. Because the product candidates we identify are based on novel gene-editing technology, we may be unsuccessful in obtaining clearance from regulatory authorities to proceed into clinical development. In order to commence clinical development, we will need to identify success criteria and ~~endpoints such that the FDA, the EMA or other regulatory authorities will be able to determine the~~ clinical ~~efficacy~~data and ~~safety~~supporting ~~profile~~information ~~of any product candidates we may develop. As we are initially seeking~~ to identify and develop product candidates to treat diseases in which there is little clinical experience using new technologies, and while we may have opportunities to discuss our clinical development plans with regulatory authorities ~~prior~~for toeach ~~commencing~~therapeutic ~~clinical~~indication ~~development, there is heightened risk that the FDA, the EMA, HREC, TGA or other regulatory authorities may not consider the clinical trial endpoints that we propose~~ to ~~provide~~establish ~~clinically meaningful results (reflecting a tangible benefit to patients). In addition,~~ the ~~resulting~~development ~~clinical~~candidate’s ~~data~~safety and ~~results may be difficult to analyze~~efficacy. Securing

Even if the FDA does find our success criteria to be sufficiently validated and clinically meaningful, we may not achieve the pre-specified endpoints to a degree of statistical significance. Furthermore, even if we do achieve the pre-specified criteria, we may produce results that are unpredictable or inconsistent with the results of the non-primary endpoints or other relevant data. The FDA also weighs the benefits of a product against its risks, and the FDA may view the efficacy results in the context of safety as not being supportive of regulatory approval. Other regulatory authorities in the European Union and other countries may make similar comments with respect to these endpoints and data. Any product candidates we may develop will be based on a novel technology that makes it difficult to predict the time and cost of development and of subsequently obtaining regulatory approval. No RNA editing therapeutic product has been approved in the United States or in Europe. Within the broader genome product field, only a limited number of gene therapy products have received marketing authorization or marketing approval from the European Commission or the FDA. Some of these products have taken years to register and have had to deal with significant issues in their post-marketing experience. 64

~~Even~~marketing ifapproval wealso ~~complete~~requires the ~~necessary~~submission ~~preclinical~~of ~~studies~~information about the product manufacturing process to, and ~~clinical~~inspection ~~trials~~of manufacturing facilities by, wethe ~~cannot~~regulatory ~~predict~~authorities. ~~when~~Our development candidates may not be effective, may be only moderately effective or ifmay prove to have undesirable or unintended side effects, wetoxicities ~~will~~or ~~obtain~~other ~~regulatory~~characteristics that may preclude us from obtaining marketing approval toor ~~commercialize~~prevent aor ~~product~~limit ~~candidate~~commercial ~~and~~use. Regulatory authorities have substantial discretion in the approval process and may berefuse to accept or file any application or may decide that our data is insufficient for aapproval ~~narrower~~and ~~indication~~require ~~than~~additional wepreclinical, ~~seek~~clinical or other studies. In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a development candidate.

~~Prior~~Approval toof ~~commercialization,~~ any of our ~~product~~development candidates ~~must~~may be ~~approved~~delayed ~~by the FDA pursuant to a new drug application,~~ or ~~NDA,~~refused infor the United States and pursuant to similar marketing applications by the EMA and similar regulatory authorities outside the United States. The process of obtaining marketing approvals, both in the United States and abroad, is expensive and takes many ~~years~~reasons, ~~if approval is obtained at all, and can vary substantially based upon a variety of factors,~~ including: the type, complexity and novelty of the product candidates involved. Failure to obtain marketing approval for a product candidate will prevent us from commercializing the product candidate. We have not received approval to market any of our product candidates from regulatory authorities in any jurisdiction. We have no experience in submitting and supporting the applications necessary to gain marketing approvals, and, in the event regulatory authorities indicate that we may submit such applications, we may be unable to do so as quickly and efficiently as desired.

•

Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy. Securing marketing approval also requires the submission of information about the product manufacturing process to, and inspection of manufacturing facilities by, the regulatory authorities. Our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude us from obtaining marketing approval or prevent or limit commercial use. Regulatory authorities have substantial discretion in the approval process and may refuse to accept or file any application or may decide that our data is insufficient for approval and require additional preclinical, clinical or other studies. In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate.

Approval of any of our product candidates may be delayed or refused for many reasons, including:

the FDA or comparable foreign regulatory authorities may disagree with the design or implementation of our clinical trials;

•

We may be unable to demonstrate, to the satisfaction of the FDA or comparable foreign regulatory authorities, that our ~~product~~development candidates are safe and effective for any of their proposed indications;

•

the results of clinical trials may not meet the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval;

•

We may be unable to demonstrate that our ~~product~~development candidates’ clinical and other benefits outweigh their safety risks;

•

the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data from preclinical programs or clinical trials;

•

the data collected from clinical trials of our ~~product~~development candidates may not be sufficient to support the submission of an NDA or other comparable submission in foreign jurisdictions or to obtain regulatory approval in the United States or elsewhere;

•

the facilities of third-party manufacturers with which we contract or procure certain service or raw materials, may not be adequate to support approval of our ~~product~~development candidates; and

•

the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval.

Even if our ~~product~~development candidates meet their safety and efficacy endpoints in clinical trials, the regulatory authorities may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval. Additional delays may result if an FDA Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process.

Regulatory authorities also may approve a ~~product~~development candidate for more limited indications than requested or they may impose significant limitations in the form of narrow indications, warnings or REMS. These regulatory authorities may require precautions or contra-indications with respect to conditions of use or they may grant approval subject to the performance of costly post-marketing clinical trials. In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our ~~product~~development candidates. Any of the foregoing scenarios could materially harm the commercial prospects for our ~~product~~development candidates and adversely affect our business, financial condition, results of operations and prospects.

We may be unable to obtain regulatory approval in the United States or foreign jurisdictions and, as a result, be unable to commercialize our ~~product~~development candidates and our ability to generate revenue will be materially impaired.

Our ~~product~~development candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, quality, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, packaging, advertising and promotion, pricing, marketing and distribution of drugs. Rigorous preclinical studies and clinical trials, and an extensive regulatory approval process are required to be successfully completed in the United States and in many foreign jurisdictions before a new drug can be marketed. Satisfaction of these and other regulatory requirements is costly, time consuming, uncertain, and subject to a continuously evolving regulatory environment and unanticipated delays. It is possible that none of the ~~product~~development candidates we may develop will obtain the regulatory approvals necessary for us or our collaborators to begin selling them.

The time required to obtain FDA and other approvals is unpredictable but typically takes many years following the commencement of clinical trials, depending upon the type, complexity and novelty of the product candidate. The standards that the FDA and its foreign counterparts use when regulating companies such as ours are not always applied predictably or uniformly and can change. Any analysis we perform of data from chemistry, manufacturing and controls, preclinical and clinical activities is subject to confirmation and interpretation by regulatory authorities, which could delay, limit or prevent regulatory approval. We may also encounter unexpected delays or increased costs due to new government regulations, for example, from future legislation or administrative action, or from changes in FDA policy during the period of product development, clinical trials and FDA regulatory review. It is impossible to predict whether legislative changes will be enacted, or whether FDA or foreign regulations, guidance or interpretations will be changed, or what the impact of such changes, if any, may be. 65

~~Any~~The ~~delay~~time orrequired ~~failure~~to inobtain ~~obtaining~~FDA ~~required~~and other approvals ~~could~~is ~~adversely~~unpredictable ~~affect~~but ~~our~~typically ~~ability~~takes tomany ~~generate~~years ~~revenues~~following ~~from~~ the ~~particular~~commencement ~~product~~of ~~candidate~~clinical ~~for~~trials, ~~which~~depending weupon ~~are~~the ~~seeking~~type, ~~approval.~~complexity ~~Furthermore,~~and ~~any~~novelty ~~regulatory~~of ~~approval~~the todevelopment ~~market~~candidate. aThe ~~product~~standards ~~may~~that bethe ~~subject~~FDA toand ~~limitations~~its onforeign ~~the~~counterparts ~~approved~~use ~~uses~~when ~~for~~regulating ~~which~~companies wesuch ~~may~~as ~~market~~ours ~~the~~are ~~product~~not oralways ~~the~~applied ~~labeling~~predictably or ~~other~~uniformly ~~restrictions~~and can change. InAny ~~addition~~analysis we perform of data from chemistry, ~~the~~manufacturing ~~FDA~~and ~~has~~controls, ~~the~~preclinical ~~authority~~and toclinical ~~require~~activities ais ~~REMS~~subject asto aconfirmation ~~condition~~and ofinterpretation ~~approval~~by regulatory authorities, which could delay, limit or prevent regulatory approval. We may ~~impose~~also ~~further~~encounter ~~requirements~~unexpected delays or ~~restrictions~~increased oncosts ~~the~~due ~~distribution~~to new government regulations, for example, from future legislation or ~~safe~~administrative ~~use~~action, ofor anfrom ~~approved~~changes ~~drug~~in FDA policy during the period of product development, ~~such~~clinical astrials ~~limiting~~and ~~prescribing~~FDA ~~rights~~regulatory review. It is impossible to ~~certain~~predict ~~physicians~~whether orlegislative ~~medical~~changes ~~centers~~will ~~that~~be ~~have~~enacted, ~~undergone~~or ~~specialized~~whether ~~training~~FDA or foreign regulations, ~~limiting~~guidance ~~treatment~~or tointerpretations ~~patients~~will asbe ~~specially~~changed, ~~defined~~or bywhat the ~~indication~~impact ~~statement~~of orsuch ~~who~~changes, ~~meet~~if any, may be.

62Any delay or failure in obtaining required approvals could adversely affect our ability to generate revenues from the particular development candidates for which we are seeking approval. Furthermore, any regulatory approval to market a product may be subject to limitations on the approved uses for which we may market the product or the labeling or other restrictions. In addition, the FDA has the authority to require a REMS as a condition of approval, which may impose further requirements or restrictions on the distribution or safe use of an approved drug, such as limiting prescribing rights to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients as specially defined by the indication statement or who meet certain safe-use criteria, and requiring treated patients to enroll in a registry, among other requirements. These limitations and restrictions may limit the size of the market for the product and affect reimbursement by third-party payors.

certain safe-use criteria, and requiring treated patients to enroll in a registry, among other requirements. These limitations and restrictions may limit the size of the market for the product and affect reimbursement by third-party payors.

We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and payment. The foreign regulatory approval process varies among countries and may include all of the risks associated with FDA approval described above, as well as risks attributable to the satisfaction of local regulations in foreign jurisdictions. Approval by the FDA does not ensure approval by comparable regulatory authorities outside of the United States and vice versa.

Any ~~product~~development ~~candidate~~candidates for which we obtain marketing approval will be subject to extensive post-marketing regulatory requirements and could be subject to post-marketing restrictions or withdrawal from the market, and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our ~~product~~development candidates, when and if any of them are approved.

Our ~~product~~development candidates and the activities associated with their development and potential commercialization, including their testing, manufacturing, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, are subject to comprehensive regulation by the FDA and other U.S. and international regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, including cGMPs, quality control, quality assurance and corresponding maintenance of records and documents, including periodic inspections by the FDA and other regulatory authorities and requirements regarding the distribution of samples to providers and recordkeeping.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of any approved product. The FDA closely regulates the post-approval marketing and promotion of drugs to ensure drugs are marketed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding use of their products. If we promote our ~~product~~development candidates in a manner inconsistent with FDA-approved labeling or otherwise not in compliance with FDA regulations, we may be subject to enforcement action. Violations of the Federal Food, Drug, and Cosmetic Act relating to the promotion of prescription drugs may lead to investigations alleging violations of federal and state healthcare fraud and abuse laws, as well as state consumer protection laws and similar laws in international jurisdictions.

In addition, later discovery of previously unknown adverse events or other problems with our ~~product~~development candidates, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may yield various results, including:

•

restrictions on such ~~product~~development candidates, manufacturers or manufacturing processes;

•

restrictions on the labeling or marketing of a product;

•

restrictions on product distribution or use;

•

requirements to conduct post-marketing studies or clinical trials;

•

warning or untitled letters;

•

withdrawal of any approved product from the market;

•

refusal to approve pending applications or supplements to approved applications that we may submit;

•

recall of ~~product~~development candidates;

•

fines, restitution or disgorgement of profits or revenues;

•

suspension or withdrawal of marketing approvals;

•

refusal to permit the import or export of our ~~product~~development candidates;

•

product seizure; or

•

injunctions or the imposition of civil or criminal penalties.

Non-compliance with European Union requirements regarding safety monitoring or pharmacovigilance, and with requirements related to the development of products for the pediatric population, can also result in significant financial penalties. Similarly, failure to comply with the European Union’s requirements regarding the protection of personal information can also lead to significant penalties and sanctions.

Even if we obtain regulatory approvals, our marketed drugs will be subject to ongoing regulatory oversight. If we fail to comply with continuing U.S. and foreign requirements, our approvals, if obtained, could be limited or withdrawn, we could be subject to other penalties, and our business would be seriously harmed.

Following any initial regulatory approval of any drugs we may develop, we will also be subject to continuing regulatory oversight, including the review of adverse drug experiences and safety data that are reported after our drug products are made commercially available. This would include results from any post-marketing studies or surveillance to monitor the safety and efficacy of the drug product required as a condition of approval or agreed to by us. Any regulatory approvals that we receive for our ~~product~~development candidates may also be subject to limitations on the approved uses for which the product may be marketed. Other ongoing regulatory requirements include, among other things, submissions of safety and other post-marketing information and reports, registration and listing, as well as continued maintenance of our marketing application, compliance with cGMP requirements and quality oversight, compliance with post-marketing commitments, applicable product tracking and tracing requirements and compliance with GCP for any clinical trials that we conduct post-approval. Failure to comply with these requirements could result in warning or untitled letters, criminal or civil penalties, recalls, or product withdrawals. In addition, we intend to seek approval to market our ~~product~~development candidates in jurisdictions outside of the United States, and therefore will be subject to, and must comply with, regulatory requirements in those jurisdictions.

The FDA has significant post-market authority, including, for example, the authority to require labeling changes based on new safety information and to require post-market studies or clinical trials for a variety of reasons. The FDA also has the authority to require a REMS plan after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug.

We, our CMOs, and the manufacturing facilities we use to make our ~~product~~development candidates will also be subject to ongoing assessment of product quality, compliance with cGMP, and periodic inspection by the FDA and potentially other regulatory agencies. We or our CMOs may not be able to comply with applicable cGMP regulations or similar regulatory requirements outside of the United States. Our failure, or the failure of our CMOs, to comply with applicable regulations could result in regulatory actions, such as the issuance of FDA Form 483 notices of observations, warning letters or sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of ~~product~~development candidates or drugs, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products. We may not have the ability or capacity to manufacture material at a broader commercial scale in the future. We and our CMOs currently manufacture a limited supply of clinical trial materials. Reliance on CMOs entails risks to which we would not be subject if we manufactured all of the material ourselves, including reliance on the CMO for regulatory compliance. Our product promotion and advertising will also be subject to regulatory requirements and continuing regulatory review.

If we or our collaborators, manufacturers or service providers fail to comply with applicable continuing regulatory requirements in the United States or foreign jurisdictions in which we may seek to market our products, we or they may be subject to, among other things, fines, warning letters, holds on clinical trials, refusal by the FDA or comparable foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, consent decree, civil penalties and criminal prosecution.

~~Any~~The ~~drugs~~insurance wecoverage ~~develop~~and ~~may~~reimbursement ~~become~~status ~~subject~~of tonewly-approved ~~unfavorable~~products ~~pricing~~is ~~regulations,~~uncertain. ~~third-party~~Failure ~~reimbursement~~to ~~practices~~obtain or ~~healthcare~~maintain ~~reform~~adequate ~~initiatives,~~coverage ~~thereby~~and ~~harming~~reimbursement for our ~~business~~development candidates could limit our product revenues.

Because our ~~product~~development candidates represent new approaches to the treatment of genetic-based diseases, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our ~~product~~development candidates or assure that coverage and reimbursement will be available for any product that we may develop. The regulations that govern marketing approvals, pricing and reimbursement for new drugs vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. We are monitoring these regulations as several of our programs move into later stages of development; however, many of our programs are currently in the earlier stages of development and we will not be able to assess the impact of price regulations for a number of years. As a result, we might obtain regulatory approval for a product in a particular country, but then be subject to price regulations that could delay our commercial launch of the product and negatively impact any potential revenues we may be able to generate from the sale of the product in that country and potentially in other countries due to reference pricing. For more information, see Item 1 “Business – Government Regulation – NoPharmaceutical ~~Uniform Policy Exists for~~ Coverage and Reimbursement ~~in the U~~.S.” and "– Patients Rely on Insurance Coverage by Third-Party Payors (third-party payors include Medicare and Medicaid (government payors) and commercial insurance companies such as Blue Cross Blue Shield, Humana, Cigna, etc.) to Pay for Products.”

64Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement/payment for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Even if we succeed in bringing one or more products to the market, these products may not be considered medically necessary and/or cost-effective, and the amount reimbursed for any products may be insufficient to allow us to sell our products on a competitive basis. At this time, we are unable to determine their cost effectiveness or the likely level or method of reimbursement for our development candidates. Increasingly, third-party payors, such as government and private insurance plans, are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts paid for pharmaceutical products. If the price we are able to charge for any products we develop, or the payments provided for such products, is inadequate in light of our development and other costs, our return on investment could be adversely affected.

Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement/payment for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations. Even if we succeed in bringing one or more products to the market, these products may not be considered medically necessary and/or cost-effective, and the amount reimbursed for any products may be insufficient to allow us to sell our products on a competitive basis. At this time, we are unable to determine their cost effectiveness or the likely level or method of reimbursement for our product candidates. Increasingly, third-party payors, such as government and private insurance plans, are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts paid for pharmaceutical products. If the price we are able to charge for any products we develop, or the payments provided for such products, is inadequate in light of our development and other costs, our return on investment could be adversely affected.

There may be significant delays in obtaining coverage for newly-approved drugs, and coverage may be more limited than the indications for which the drug is approved by the FDA or comparable foreign regulatory authorities. Patients who are prescribed medications for the treatment of their conditions, and their prescribing physicians, generally rely on third-party payors to pay all or part of the costs associated with their prescription drugs. Patients are unlikely to use our products unless coverage is provided and payment is adequate to cover all or a significant portion of the cost of our products. Therefore, coverage and adequate payment is critical to new product acceptance. Coverage decisions may depend upon clinical and economic standards that disfavor new drug products when more established or lower cost therapeutic alternatives are already available or subsequently become available. Moreover, eligibility for coverage does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Interim payments for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement may be based on payments allowed for lower-cost drugs that are already reimbursed, may be incorporated into existing payments for other services and may reflect budgetary constraints or imperfections in Medicare data. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates. However, no uniform policy requirement for coverage and reimbursement for drug products exists among third-party payors in the United States. Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor. As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. Our inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for new drugs that we develop and for which we obtain regulatory approval could adversely affect our operating results, our ability to raise capital needed to commercialize products, and our overall financial condition.

We believe that the efforts of governments and third-party payors to contain or reduce the cost of healthcare and legislative and regulatory proposals to broaden the availability of healthcare will continue to affect the business and financial condition of pharmaceutical and biopharmaceutical companies. A number of legislative and regulatory changes in the healthcare system in the United States and other major healthcare markets have been proposed and/or adopted in recent years, and such efforts have expanded substantially in recent years. At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. It is unclear how any additional healthcare reform measures may increase the pressure on drug pricing or limit the availability of coverage and adequate reimbursement for our future candidates. We expect ongoing initiatives in the United States to increase pressure on drug pricing and reimbursement. Such reforms could have an adverse effect on anticipated revenues from product candidates that we may successfully develop and for which we may obtain regulatory approval, and may affect our overall financial condition and ability to further develop product candidates. For more information on these changes, see Item 1 “Business—Governmental Regulation—Affordable Care Act and Legislative Reform Measures.” 68

We ~~may~~believe ~~not~~that bethe ~~able~~efforts toof ~~obtain~~governments ~~orphan~~and ~~drug~~third-party ~~exclusivity~~payors ~~for~~to ~~one~~contain or ~~more~~reduce the cost of ~~our~~healthcare ~~product~~and ~~candidates,~~legislative and ~~even~~regulatory ifproposals weto ~~do,~~broaden ~~that~~the ~~exclusivity~~availability ~~may~~of ~~not~~healthcare ~~prevent~~will ~~the~~continue ~~FDA~~to oraffect the ~~EMA~~business ~~from~~and ~~approving~~financial ~~other~~condition ~~competing~~of ~~products~~pharmaceutical and biopharmaceutical companies.

~~Under~~We ~~the Orphan Drug Act, the FDA~~ may ~~designate~~not abe ~~product~~able ~~candidate~~to asobtain an orphan drug ifexclusivity itfor isone ~~a drug intended to treat a rare disease~~ or ~~condition.~~more ~~A similar regulatory scheme governs approval~~ of ~~orphan~~our ~~product~~development candidates, byand ~~the~~even ~~EMA in the European Union. Generally,~~ if awe ~~product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation~~do, ~~the~~that ~~product is entitled to a period of marketing~~ exclusivity, ~~which~~may ~~precludes~~not prevent the FDA or the EMA from approving ~~another~~other ~~marketing~~competing ~~application for another product candidate for the same orphan therapeutic indication for that time period~~products. ~~The applicable period is seven years in the United States and ten years in the European Union. The~~

65Under the Orphan Drug Act, the FDA may designate a development candidate as an orphan drug if it is a drug intended to treat a rare disease or condition. A similar regulatory scheme governs approval of orphan development candidates by the EMA in the European Union. Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA or the EMA from approving another marketing application for another development candidates for the same orphan therapeutic indication for that time period. The applicable period is seven years in the United States and ten years in the European Union. The exclusivity period in the European Union can be reduced to six years if a product no longer meets the criteria for orphan designation, in particular if the product is sufficiently profitable so that market exclusivity is no longer justified.

The FDA’s standards for granting orphan drug exclusivity ~~period~~in the gene therapy context are unclear and evolving. In order for the FDA to grant orphan drug exclusivity to one of our development candidates, the agency must find that the development candidates is indicated for the treatment of a condition or disease that affects fewer than 200,000 individuals in the ~~European~~United ~~Union~~States ~~can~~or that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the development candidate available for the disease or condition will be ~~reduced~~recovered tofrom ~~six~~sales ~~years~~of the product in the United States. The FDA may conclude that the condition or disease for which we seek orphan drug exclusivity does not meet this standard. Even if we obtain orphan drug exclusivity for a ~~product~~development nocandidate, ~~longer~~that ~~meets~~exclusivity may not effectively protect the ~~criteria~~development candidates from competition because different development candidates can be approved for the same approved use or condition. In addition, even after an orphan ~~designation~~drug is approved, inthe ~~particular~~FDA can subsequently approve the same development candidates for the same approved use or condition if the ~~product~~FDA concludes that the later development candidates is ~~sufficiently~~clinically ~~profitable~~superior soin that ~~market~~it is shown to be safer, more effective or makes a major contribution to patient care compared with the product that has orphan exclusivity. Orphan drug exclusivity may also be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is nounable ~~longer~~to ~~justified~~assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition.

The FDA’s standards for granting orphan drug exclusivity in the gene therapy context are unclear and evolving. In order for the FDA to grant orphan drug exclusivity to one of our product candidates, the agency must find that the product candidate is indicated for the treatment of a condition or disease that affects fewer than 200,000 individuals in the United States or that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making the product candidate available for the disease or condition will be recovered from sales of the product in the United States. The FDA may conclude that the condition or disease for which we seek orphan drug exclusivity does not meet this standard. Even if we obtain orphan drug exclusivity for a product candidate, that exclusivity may not effectively protect the product candidate from competition because different product candidates can be approved for the same condition. In addition, even after an orphan drug is approved, the FDA can subsequently approve the same product candidate for the same condition if the FDA concludes that the later product candidate is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care compared with the product that has orphan exclusivity. Orphan drug exclusivity may also be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition.

In August 2017, the Congress passed the FDA Reauthorization Act of 2017, or FDARA. FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation, to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity. The law reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority. Moreover, in the Consolidated Appropriations Act of 2021, Congress did not further change this interpretation when it clarified that the interpretation codified in FDARA would apply in cases where FDA issued an orphan designation before the enactment of FDARA but where product approval came after the enactment of FDARA. The FDA may further reevaluate the Orphan Drug Act and its regulations and policies. We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business. Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.

If we do not comply with laws regulating the protection of the environment and health and human safety, our business could be adversely affected.

Our research, development and manufacturing processes involve the use of hazardous materials. We maintain quantities of various flammable and toxic chemicals in our facilities that are required for our research, development and manufacturing activities. We are subject to federal, state and local laws and regulations governing the use, manufacture, storage, handling and disposal of these hazardous materials. Our procedures for storing, handling and disposing of these materials are reviewed against the relevant guidelines and laws of the jurisdictions in which our facilities are located on a regular basis. Although we believe that our safety procedures for handling and disposing of these materials sufficiently mitigate the risk of accidental contamination or injury from these materials, the risk cannot be completely eliminated. If an accident occurs, we could be held liable for resulting damages, which could be substantial. We are also subject to numerous environmental, health and workplace safety laws and regulations, including those governing laboratory procedures, exposure to blood-borne pathogens and the handling of biohazardous materials. Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of these materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological or hazardous materials. Additional federal, state and local laws and regulations affecting our operations may become applicable in the future. We may incur substantial costs to comply with, and substantial fines or penalties if we violate any of, these laws or regulations.

against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological or hazardous materials. Additional federal, state and local laws and regulations affecting our operations may become applicable in the future. We may incur substantial costs to comply with, and substantial fines or penalties if we violate any of, these laws or regulations.

If we or our collaborators, manufacturers, service providers or other third parties fail to comply with applicable healthcare laws and regulations, we could be subject to enforcement actions, which could affect our ability to develop, market and sell our products and may harm our reputation.

We are currently, orand may in the future, be, subject to extensive federal, state, local, and comparable foreign healthcare laws and regulations, including those relating to ~~areas~~fraud ~~such~~and asabuse, ~~fraud~~anti-kickback restrictions, false claims, transparency and ~~abuse~~reporting, patient privacy and ~~patients’~~data ~~rights.~~protection, ~~These~~and ~~laws~~anti-bribery and related requirements, which may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we research, develop, market, sell, and distribute our products for which we obtain marketing approval. ~~For~~The ~~more~~scope ~~information~~and onenforcement of these laws is uncertain, subject to rapid change, and dependent on evolving government and industry interpretations, and authorities have increased scrutiny of interactions between healthcare companies and healthcare providers and third-party payors. If our operations are found to be in violation of applicable requirements, we may be subject to penalties and other sanctions, which may include civil or criminal penalties, criminal prosecution, monetary damages, disgorgement, contractual damages, reputational harm, curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs (including Medicare and Medicaid), the imposition of a corporate integrity agreement, suspension or withdrawal of product approvals, restrictions or prohibitions on marketing, and other enforcement actions. Any investigation or enforcement action, even if ultimately resolved favorably, could cause us to incur significant legal and compliance expenses, divert management attention, and adversely affect our business, financial condition, results of operations, and prospects. We intend to develop and implement a comprehensive corporate compliance program prior to commercialization; however, compliance programs can mitigate but cannot eliminate the risk of noncompliance and related enforcement. For more information, see Item 1, “Business—Governmental Regulation—Other Healthcare Laws.”

66Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Given the breadth of the laws and regulations, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, governmental authorities may possibly conclude that our business practices may not comply with healthcare laws and regulations. The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform. Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry. Moreover, federal, state or foreign laws or regulations are subject to change, and while we, our collaborators, manufacturers and/or service providers currently may be compliant, that could change due to changes in interpretation, prevailing industry standards or other reasons.

IfThe ~~our~~provision ~~operations are found to be in violation~~ of ~~any~~benefits ~~such~~or ~~requirements,~~advantages weto ~~may~~physicians ~~be subject~~ to ~~penalties,~~induce ~~including civil~~ or ~~criminal~~encourage ~~penalties, criminal prosecution, monetary damages,~~ the ~~curtailment or restructuring of our operations~~prescription, ~~loss of eligibility to obtain approvals from the FDA~~recommendation, ~~exclusion from participation in federal healthcare programs including Medicare and Medicaid~~endorsement, ~~the imposition of a corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services~~purchase, ~~disgorgement~~supply, ~~individual imprisonment~~order, ~~contractual~~or ~~damages,~~use ~~reputational harm, and diminished profits and future earnings, any~~ of ~~which~~medicinal ~~could~~products ~~adversely~~is ~~affect~~prohibited ~~our~~in ~~financial results and adversely affect our ability to operate our business. We intend to develop and implement a comprehensive corporate compliance program prior to~~ the ~~commercialization of our product candidates~~EU. ~~Although~~The ~~effective~~provision ~~compliance programs can mitigate the risk~~ of ~~investigation~~benefits ~~and prosecution for violations of these laws, these risks cannot be entirely eliminated. Any action against us for an alleged~~ or ~~suspected~~advantages ~~violation could cause us~~ to ~~incur~~physicians ~~significant~~is ~~legal~~also ~~expenses,~~governed ~~could~~by ~~divert~~the ~~our~~national ~~management’s~~anti-bribery ~~attention~~laws ~~from the operation~~ of ~~our~~European ~~business,~~Union ~~and~~Member ~~could harm our reputation~~States, ~~even~~such ifas ~~our~~the ~~defense is successful~~U.K. InBribery ~~addition,~~Act ~~achieving~~2010. ~~and~~Infringement ~~sustaining~~of ~~compliance~~these ~~with applicable~~ laws ~~and~~could ~~regulations~~result ~~may be costly to us~~ in ~~terms~~substantial offines ~~money, time~~ and ~~resources~~imprisonment.

IfPayments wemade orto ~~our~~physicians ~~collaborators,~~in ~~manufacturers~~certain orEuropean ~~service~~Union ~~providers~~Member ~~fail~~States tomust ~~comply~~be publicly disclosed. Moreover, agreements with ~~applicable~~physicians ~~federal~~often must be the subject of prior notification and approval by the physician’s employer, ~~state~~his or ~~foreign~~her ~~laws~~competent orprofessional ~~regulations~~organization, weand/or ~~could~~the beregulatory ~~subject~~authorities toof ~~enforcement~~the ~~actions,~~individual ~~which~~European ~~could~~Union ~~affect~~Member ~~our~~States. ~~ability~~These torequirements ~~develop~~are provided in the national laws, ~~market~~industry ~~and~~codes, ~~sell~~or ~~our~~professional ~~products~~codes ~~successfully~~of ~~and~~conduct ~~could~~applicable ~~harm~~in ~~our~~the ~~reputation~~European ~~and~~Union ~~lead~~Member States. Failure to ~~reduced~~comply ~~acceptance~~with ofthese ~~our~~requirements ~~products~~could byresult ~~the~~in ~~market.~~reputational ~~These~~risk, ~~enforcement~~public ~~actions~~reprimands, ~~include~~administrative penalties, ~~among~~fines ~~others:~~or imprisonment.

adverse regulatory inspection findings;

warning and/or untitled letters;

voluntary or mandatory product recalls or public notification or medical product safety alerts to healthcare professionals;

restrictions on, or prohibitions against, marketing our products;

restrictions on, or prohibitions against, importation or exportation of our products;

suspension of review or refusal to approve pending applications or supplements to approved applications;

exclusion from participation in government-funded healthcare programs;

exclusion from eligibility for the award of government contracts for our products;

suspension or withdrawal of product approvals;

product seizures;

injunctions;

consent decrees; and

civil and criminal penalties, up to and including criminal prosecution resulting in fines, exclusion from healthcare reimbursement programs and imprisonment.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform. Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry. Moreover, federal, state or foreign laws or regulations are subject to change, and while we, our collaborators, manufacturers and/or service providers currently may be compliant, that could change due to changes in interpretation, prevailing industry standards or other reasons.

Our employees, consultants and collaborators may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements.

We are exposed to the risk of fraud and other misconduct by our employees, consultants and collaborators. Such misconduct could include intentional failures to comply with FDA and other foreign agency regulations, provide accurate information to the FDA, comply with manufacturing standards required by the FDA or us, comply with federal and state healthcare fraud and abuse laws and regulations, report financial information or data accurately or disclose unauthorized activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Such misconduct could also involve the improper use of information obtained in the course of

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or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Such misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. It is not always possible to identify and deter such misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

Product liability lawsuits against us could cause us to incur substantial liabilities and could limit commercialization of any medicines that we may develop.

We face an inherent risk of product liability exposure related to the testing in human clinical trials of any ~~product~~development candidates we may develop and will face an even greater risk if we commercially sell any products that we may develop. If we cannot successfully defend ourselves against claims that our ~~product~~development candidates or medicines caused injuries, we could incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:

•

decreased demand for any products that we may develop;

•

injury to our reputation and significant negative media attention;

•

withdrawal of clinical trial participants;

•

significant time and costs to defend the related litigation;

•

substantial monetary awards to trial participants or patients;

•

loss of revenue; and

•

the inability to commercialize any medicines that we may develop.

We anticipate that we will need to increase our insurance coverage when we begin clinical trials and if we successfully commercialize any product. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

Our internal computer and information systems, or those used by our CROs, CMOs or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our development programs.

Despite the implementation of appropriate security measures, our internal computer and information systems and those of our current and any future CROs, CMOs and other contractors or consultants may become vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. If such an event were to occur and cause interruptions in our operations, it could result in a disruption of our development programs and our business operations, whether due to a loss of our trade secrets or other proprietary information or other similar disruptions. For example, the loss of data from completed or future preclinical studies or clinical trials could result in significant delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed and the further development and commercialization of our ~~product~~development candidates could be significantly delayed.

We may be unable to adequately protect our information systems from cybersecurity incidents or data breaches, which could result in the disclosure of confidential information, damage our reputation, and subject us to significant financial and legal exposure.

We and the third parties upon which we rely face a variety of evolving threats, which could cause cybersecurity incidents or data breaches. Cybersecurity incidents and data breaches are increasing in their frequency, sophistication and intensity, and have become increasingly difficult to detect. Cybersecurity incidents and data breaches could include wrongful conduct by hostile foreign governments, industrial espionage, wrongful conduct by employees or vendors, human error, wire fraud and other forms of cyber fraud, the deployment of harmful malware or ransomware, denial-of-service attacks, social engineering fraud (including successful phishing attacks) or other means to threaten data confidentiality, integrity and availability. A cybersecurity incident or data breach could cause serious negative consequences for us, including, without limitation, the disruption of operations, the misappropriation of confidential business information, including financial information, trade secrets, financial loss and the disclosure of corporate strategic plans. To date, we have not experienced a material compromise of our data or information systems but we have from time to time experienced, and may in the future continue to experience, threats and cybersecurity incidents relating to our and our third-party vendors’ information systems. Although we devote resources to protect our information systems, we realize that cybersecurity incidents are a threat, and there can be no assurance that our efforts will prevent information security breaches that could result in business,

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~~legal,~~misappropriation ~~financial~~of orconfidential ~~reputational~~business ~~harm to us~~information, orincluding ~~would~~financial ~~have~~information, atrade ~~material~~secrets, ~~adverse~~financial ~~effect~~loss onand ~~our~~the ~~results~~disclosure of ~~operations~~corporate ~~and~~strategic ~~financial condition~~plans.

~~Our~~Like ~~failure~~other companies in our industry, we and our third party vendors, have experienced, or may experience, threats and cybersecurity incidents relating to ~~obtain~~our ~~regulatory~~and ~~approval~~our third-party vendors’ information systems and infrastructure. Although we devote resources to protect our information systems, there can be no assurance that our efforts will prevent cybersecurity incidents or data breaches that could result in ~~international~~business, ~~jurisdictions~~legal, financial or reputational harm to us, or would ~~prevent~~have a material adverse effect on our results of operations and financial condition. Attempts to disrupt or gain unauthorized access to our and our third-party vendors’ information systems from malicious third parties or insider threats may incorporate widely varying and frequently changing tactics, which may be enhanced or facilitated by artificial intelligence. Further, our contracts may not contain limitations of liability, and even where they do, there can be no assurance that limitations of liability in our contracts are sufficient to protect us from ~~marketing~~liabilities, damages, or claims related to our ~~product~~privacy ~~candidates~~and ~~outside~~data ~~the~~security ~~United~~obligations. ~~States~~Although we maintain cyber liability insurance, this insurance may not provide adequate coverage against potential liabilities related to any experienced cybersecurity incident or breach. For additional information on our cybersecurity obligations as well as our cybersecurity program, see Item 1 “Business—Government Regulation—Privacy and Cybersecurity” and Item 1C “Cybersecurity.”

ToOur ~~market~~failure ~~and~~to ~~sell our future product candidates in other jurisdictions, we must~~ obtain ~~separate marketing approvals and comply with numerous and varying~~ regulatory ~~requirements. The~~ approval ~~procedure~~in ~~varies~~international ~~among~~jurisdictions ~~countries~~would ~~and~~prevent ~~can~~us ~~involve additional testing. The time required to obtain approval may differ substantially~~ from ~~that~~marketing ~~required~~our todevelopment ~~obtain~~candidates ~~FDA approval. The regulatory approval process~~ outside the United States ~~generally includes all of the risks associated with obtaining FDA approval~~. In addition, in many countries outside the United States, we must secure product reimbursement approvals before regulatory authorities will approve the product for sale in that country. Failure to obtain foreign regulatory approvals or non-compliance with foreign regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the introduction of our product candidates in certain countries.

IfTo market and sell our future development candidates in other jurisdictions, we ~~fail~~must toobtain separate marketing approvals and comply with ~~the~~numerous and varying regulatory requirements. inThe ~~international~~approval ~~markets~~procedure varies among countries and ~~receive~~can ~~applicable~~involve ~~marketing~~additional ~~approvals,~~testing. ~~our~~The ~~target~~time ~~market~~required ~~will~~to beobtain ~~reduced~~approval ~~and~~may ~~our~~differ ~~ability~~substantially from that required to ~~realize~~obtain FDA approval. The regulatory approval process outside the ~~full~~United ~~market~~States ~~potential~~generally includes all of ~~our~~the ~~product~~risks ~~candidates~~associated ~~will~~with beobtaining ~~harmed~~FDA ~~and~~approval. ~~our~~In ~~business~~addition, ~~will~~in bemany ~~adversely~~countries ~~affected.~~outside Wethe ~~may~~United ~~not~~States, ~~obtain~~we ~~foreign~~must ~~regulatory~~secure product reimbursement approvals onbefore aregulatory ~~timely~~authorities ~~basis,~~will ifapprove atthe ~~all.~~product ~~Our~~for ~~failure~~sale in that country. Failure to obtain ~~approval~~foreign ofregulatory ~~any~~approvals ofor ~~our~~non-compliance ~~product~~with ~~candidates~~foreign by regulatory ~~authorities~~requirements could result in ~~another~~significant ~~country~~delays, ~~may~~difficulties ~~significantly~~and ~~diminish~~costs ~~the~~for ~~commercial~~us ~~prospects~~and ofcould ~~that~~delay ~~product~~or ~~candidate~~prevent ~~and~~the introduction of our ~~business~~development ~~prospects~~candidates ~~could~~in ~~decline~~certain countries.

~~Disruptions~~If atwe fail to comply with the ~~FDA~~regulatory ~~and~~requirements ~~other~~in ~~government~~international ~~agencies~~markets ~~caused~~and byreceive ~~funding~~applicable ~~shortages~~marketing orapprovals, ~~global~~our ~~health~~target ~~concerns~~market ~~could~~will ~~hinder~~be ~~their~~reduced and our ability to ~~hire,~~realize ~~retain~~the orfull ~~deploy~~market ~~key~~potential ~~leadership~~of ~~and~~our ~~other~~development ~~personnel,~~candidates orwill ~~otherwise~~be ~~prevent~~harmed ~~new~~and orour ~~modified~~business ~~products~~will ~~from~~be ~~being~~adversely ~~developed,~~affected. ~~approved,~~We ormay ~~commercialized~~not inobtain foreign regulatory approvals on a timely ~~manner~~basis, orif at all,. ~~which~~Our ~~could~~failure ~~negatively~~to ~~impact~~obtain approval of any of our development candidates by regulatory authorities in another country may significantly diminish the commercial prospects of that development candidates and our business prospects could decline.

~~The~~Disruptions ~~ability~~at of the FDA, toSEC ~~review~~ and ~~approve~~other ~~new~~government ~~products~~agencies ~~can~~caused ~~be affected~~ by astaffing ~~variety of factors~~cuts, ~~including government budget and~~ funding ~~levels,~~shortages ~~statutory,~~or ~~regulatory,~~global ~~and~~health ~~policy~~concerns ~~changes,~~could ~~the~~hinder ~~FDA’s~~their ability to hire, ~~and~~ retain ~~key~~or ~~personnel~~deploy ~~and~~key ~~accept~~leadership ~~the payment of user fees,~~ and other ~~events~~personnel, ~~that~~or ~~may~~ otherwise ~~affect~~prevent ~~the~~new ~~FDA’s~~or ~~ability~~modified toproducts ~~perform~~from ~~routine~~being ~~functions. Average review times at the agency have fluctuated in recent years as a result. In addition~~developed, ~~government funding of other government agencies that fund research and development activities is subject to the political process~~approved, ~~which~~or iscommercialized ~~inherently fluid and unpredictable. Currently, federal agencies~~ in ~~the United States are operating under~~ a ~~continuing~~timely ~~resolution~~manner ~~that~~or is set to expire on September 30, 2025. Without appropriation of additional funding to federal agencies, our business operations related to our product development activities for the U.S. market could be impacted. Disruptions at ~~the FDA and other agencies may also slow the time necessary for new drugs or modifications to approved drugs to be reviewed and/or approved by necessary government agencies~~all, which ~~would~~could ~~adversely~~negatively ~~affect~~impact our business. ~~For example, the U.S. government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical FDA employees and stop critical activities.~~

The ability of the FDA to review and approve new products can be affected by a variety of factors, including staffing, government budget and funding levels, statutory, regulatory, and policy changes, the FDA’s ability to hire and retain key personnel and accept the payment of user fees, and other events that may otherwise affect the FDA’s ability to perform routine functions. Average review times at the agency have fluctuated in recent years as a result. In addition, government funding of other government agencies that fund research and development activities is subject to the political process, which is inherently fluid and unpredictable. Without appropriation of funding to federal agencies, our business operations related to our product development activities for the U.S. market could be impacted.

Disruptions at the FDA and other federal agencies, including substantial leadership departures, personnel cuts, and policy changes, may also slow the time necessary for new drugs to be reviewed and/or approved, which would harm our business. Changes and cuts in FDA staffing also could result in delays in the FDA’s responsiveness or in its ability to review regulatory submissions or applications, issue regulations or guidance, or implement or enforce regulatory requirements in a timely fashion or at all. For example, over the last several years, the U.S. government has shut down several times, including for a 43-day period that began on October 1, 2025, and certain regulatory agencies, such as the FDA, have had to furlough critical FDA employees and stop critical activities. If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA and the SEC to timely review and process our submissions, which could have a material adverse effect on our business and our timelines.

In addition, government funding of other agencies on which our operations may rely, including those that fund research and development activities and clinical trials, is subject to the political process, which is inherently fluid and unpredictable. Changes to such agencies’ budgets, may negatively impact our operations and ongoing clinical trials. Future shutdowns or other disruptions could also affect other government agencies such as the SEC, which may also impact our business by delaying review of our public filings, to the extent such review is necessary, and our ability to access the public markets.

With the change in the U.S. presidential administration in 2025, there is substantial uncertainty as to the extent and manner in which the U.S. government will seek to modify or revise the requirements and policies of the FDA and other regulatory agencies with jurisdiction over our development candidates and any products for which we obtain approval. This uncertainty could present new challenges and/or opportunities as we navigate development and approval of our development candidates. Additionally, the current administration could issue or promulgate executive orders, regulations, policies or guidance that adversely affect us or create a more challenging or costly environment to pursue the development of new therapeutic candidates. Also, state governments may seek to address or react to changes at the federal level with changes to their regulatory frameworks in a manner that could impact our operations.

We, our collaborators and our service providers may be subject to a variety of privacy and data security laws, regulations and contractual obligations, and our failure to comply with them could harm our business.

We maintain a large quantity of sensitive information, including confidential business and patient health information in connection with our preclinical studies, and are subject to laws and regulations governing the privacy and security of such information. In the United States, there are numerous federal and state privacy and data security laws and regulations governing the collection, use, disclosure and protection of personal information, including federal and state health information privacy laws, federal and state security breach notification laws, and federal and state consumer protection laws. Each of these laws is subject to varying interpretations and new laws continue to be proposed. Outside of the United States, many jurisdictions have enacted stringent privacy and data protection laws. The collection, use, disclosure, transfer or other processing of personal data originating from the European Economic Area, or EEA, and United Kingdom is governed by the General Data Protection Regulation, or EU GDPR, and the UK General Data Protection Regulation, or UK GDPR, which, together with the EU GDPR, is referred to as the GDPR. For additional information on these regimes, see Item 1 “Business—Government Regulation—Privacy and Cybersecurity”. Compliance with these and any other applicable privacy and data security laws and regulations is a rigorous and time-intensive process, and we may be required to put in place additional mechanisms to ensure compliance, and despite those efforts, if we fail to comply with any such laws or regulations, we may face significant fines and penalties that could adversely affect our reputation, business, financial condition and results of operations.

The use of new and evolving technologies, such as artificial intelligence, or AI, in our offerings may result in spending material resources and presents risks and challenges that can impact our business including by posing security and other risks to our confidential information, proprietary information and personal information, and as a result we may be exposed to reputational harm and liability.

~~The~~We may use and ~~integration~~integrate of AI ~~presents~~into ~~risks and challenges that could affect its adoption, and therefore~~ our business. ~~The~~processes ~~use~~both ofin ~~certain~~our ~~artificial~~own ~~intelligence~~development ~~technology can give rise to intellectual property risks, including compromises to proprietary intellectual property~~ and ~~intellectual~~implementation ~~property~~of ~~infringement.~~AI ~~Additionally, we expect to see increasing government~~ and ~~supranational~~through ~~regulation related to artificial intelligence use and ethics, which may also significantly increase~~ the ~~burden~~adoption ~~and cost~~ of ~~research,~~commercially ~~development~~available ~~and~~tools. ~~compliance~~Use inof this ~~area.~~technology ~~For~~could ~~example~~pose cybersecurity, indata ~~the United States~~privacy, ~~a number of states have proposed and passed laws regulating various uses of AI. In Europe~~IT, ~~the~~intellectual ~~EU’s Artificial Intelligence Act~~property, ~~or AI Act~~regulatory, ~~entered into force in 2024 and~~legal, ~~with some exceptions~~operational, ~~will begin to apply in August 2026. This legislation imposes significant obligations on providers and deployers of high risk artificial intelligence systems~~competitive, ~~and~~reputational ~~encourages providers~~ and ~~deployers~~other ofrisks ~~artificial intelligence systems to account for EU ethical principles in their development~~ and ~~use~~challenges ~~of these systems. If we develop or deploy AI systems~~ that ~~are~~could ~~governed~~affect byour ~~the~~business. ~~AI Act~~Specifically, werisks ~~may~~related ~~be required~~ to ~~adopt~~accuracy, ~~higher~~bias, ~~standards~~artificial ofintelligence ~~data quality~~hallucinations, ~~transparency~~discrimination, ~~and~~harmful ~~human~~content, ~~oversight~~misinformation, ~~and adhere to specific and potentially burdensome and costly ethical~~fraud, ~~accountability~~scams, ~~and~~targeted ~~administrative~~attacks ~~requirements.~~(including ~~The~~model ~~rapid~~poisoning evolution of AI will require the application of significant resources to help ensure that AI is implemented in accordance with applicable law and regulation and in a socially responsible manner and to minimize any real or ~~perceived~~data ~~unintended harmful impacts. Our vendors may in turn incorporate AI tools into their own offerings~~poisoning), ~~and the providers of these AI tools may not meet existing or rapidly evolving regulatory or industry standards~~surveillance, ~~including with respect to privacy and~~ data ~~security. Further~~leakage, ~~bad actors around the world use increasingly sophisticated methods~~inequality, ~~including~~environmental ~~the use of AI~~harms, ~~to engage in illegal activities involving the theft~~ and ~~misuse~~other ofharms ~~personal~~may ~~information,~~flow ~~confidential~~from ~~information and intellectual property. Any of these effects could damage~~ our ~~reputation~~development, ~~result~~use, inor ~~the~~deployment ~~loss~~ of ~~valuable~~AI ~~property and information, cause us to breach applicable laws and regulations, and adversely impact our business~~technologies.

The use of certain AI technology can give rise to intellectual property risks, including by disclosing or otherwise compromising our confidential or proprietary intellectual property and intellectual property infringement, or by undermining our ability to assert or defend ownership rights in intellectual property created with the assistance of AI tools.

Additionally, we expect to see increasing government and supranational regulation related to AI use and ethics, which may also significantly increase the burden and cost of research, development and compliance in this area. For example, the European Union began implementing the Artificial Intelligence Act, or AI Act, with a significant part of the law scheduled to come into effect in August 2026. As currently enacted, the AI Act, which may be amended, imposes significant obligations on providers and deployers of high risk AI systems, and encourages providers and deployers of AI systems to account for EU ethical principles in their development and use of these systems.

In the United States, the AI regulatory environment is complex and uncertain. Over the past year, states have advanced, and in some cases passed, dozens of laws focusing on AI governance and regulation, including on deployment of AI in healthcare

settings. At the federal level, the current U.S. administration has endorsed a federal moratorium on the enforcement of state AI laws, including through a December 2025 executive order. So far, these efforts have not been successful at curtailing state action on AI regulation, contributing to a complicated legislative patchwork, which may be litigated in state and federal courts. If we develop or deploy AI systems that are governed by these laws or regulations, we will need to adopt higher standards of data quality, transparency, and human oversight, and adhere to specific and potentially burdensome and costly ethical, accountability, and administrative requirements. We may also be subject to significant enforcement or litigation in the event of any perceived non-compliance.

The rapid evolution of AI will require the application of significant resources to help ensure that AI is implemented in accordance with applicable law and regulation and in a socially responsible manner and to minimize any real or perceived unintended harmful impacts. If we enable or offer solutions that draw controversy due to perceived or actual negative societal impact, we may experience brand or reputational harm, competitive harm or legal liability. Our vendors may in turn incorporate AI tools into their own offerings, and the providers of these AI tools may not meet existing or rapidly evolving regulatory or industry standards, including with respect to privacy and data security. Further, bad actors around the world use increasingly sophisticated methods, including the use of AI, to engage in illegal activities involving the theft and misuse of personal information, confidential information and intellectual property. In addition, the use of generative AI models in our internal or third-party systems may create new attack surfaces or methods for adversaries, which could impact us and our vendors. Any of these effects could damage our reputation, result in the loss of valuable property and information, cause us to breach applicable laws and regulations, and adversely impact our business.

Risks Related to Our Third Party Relationships

We may be subject to claims that we or our employees or consultants have wrongfully used or disclosed alleged trade secrets of employees’ or consultants’ former employers or their clients. These claims may be costly to defend and if we do not successfully do so, we may be required to pay monetary damages and may lose valuable intellectual property rights or personnel.

Many of our employees were previously employed at universities or biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although no claims against us are currently pending, we may be subject to claims that these employees or we have inadvertently or otherwise used or disclosed trade secrets or other proprietary information of their former employers. Litigation may be necessary to defend against these claims. If we fail in defending such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. A loss of key research personnel or their work product could hamper our ability to commercialize, or prevent us from commercializing, our ~~product~~development candidates, which could severely harm our business. Even if we are successful in defending against these claims, litigation could result in substantial costs and be a distraction to management.

We expect to rely on third parties to conduct our clinical trials and some aspects of our research, as well as some aspects of our delivery methods, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials, research or testing.

We currently, and expect to continue to, rely on third parties, such as CROs, clinical data management organizations, medical institutions, preclinical laboratories and clinical investigators, to conduct some aspects of our research. For example, we may rely on a third ~~party~~parties to ~~supply LNPs, or to~~ conduct some of our preclinical animal experiments and supply key materials for our programs. Any of these third parties may terminate their engagements with us at any time under certain criteria. If we need to enter into alternative arrangements, we may delay our product development activities.

Our reliance on these third parties for research and development activities will reduce our control over these activities but will not relieve us of our responsibilities. For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the trial. Moreover, the FDA, the EMA and other regulatory authorities require us and the study sites and investigators we work with to comply with standards, commonly referred to as GLPs and GCPs for conducting, recording and reporting the results of preclinical studies and clinical trials to assure, amongst other things, that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected.

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We may not be successful in finding strategic collaborators for continuing development of certain of our ~~product~~development candidates or successfully commercializing or competing in the market for certain indications; and we may not see any benefit from our collaboration agreement with Novo Nordisk, which is currently on hold.

In September 2024 we entered into a collaboration agreement with Novo Nordisk and in the future, we may decide to collaborate with non-profit organizations, universities, pharmaceutical and other biotechnology companies for the development and potential commercialization of existing and new ~~product~~development candidates. We face significant competition in seeking appropriate collaborators. Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors. Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject ~~product~~development ~~candidate~~candidates, the costs and complexities of manufacturing and delivering such ~~product~~development ~~candidate~~candidates to patients, the potential of competing drugs, the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge and industry and market conditions generally. The collaborator may also consider alternative ~~product~~development candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for its ~~product~~development ~~candidate~~candidates. The terms of any additional collaborations or other arrangements that we may establish may not be favorable to us. Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business combinations among large pharmaceutical companies that have resulted in a reduced number of potential future collaborators.

We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all. If we are unable to do so, we may have to curtail the development of the ~~product~~development candidate for which we are seeking to collaborate, reduce or delay our development program or one or more of our other development programs, delay our potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to increase our expenditures to fund development or commercialization activities on our own, we may need to obtain additional capital, which may not be available to us on acceptable terms or at all. If we do not have sufficient funds, we may not be able to further develop our ~~product~~development candidates or bring them to market and generate product revenue.

The success of any potential collaboration arrangements, including our ~~recent~~ collaboration agreement with Novo Nordisk, which as of November 2025 is on pause, will depend heavily on the efforts and activities of our collaborators. Collaborators generally have significant discretion in determining the efforts and resources that they will apply to these collaborations. For example, in November 2025, we agreed on a 12-month hold under our collaboration agreement with Novo Nordisk. Disagreements between parties to a collaboration arrangement regarding clinical development and commercialization matters can lead to delays in the development process or commercializing the applicable ~~product~~development ~~candidate~~candidates and, in some cases, termination of such collaboration arrangements. These disagreements can be difficult to resolve if neither of the parties has final decision-making authority. Collaborations with pharmaceutical or biotechnology companies and other third parties often are terminated or allowed to expire by the other party. Any such termination or expiration would adversely affect us financially and could harm our business reputation.

Future acquisitions or strategic alliances could disrupt our business and harm our financial condition and results of operations.

We may acquire additional businesses or drugs, form strategic alliances or create joint ventures with third parties that we believe will complement or augment our existing business. If we acquire businesses with promising markets or technologies, we may not be able to realize the benefit of acquiring such businesses if we are unable to successfully integrate them with our existing operations and company culture. We may encounter numerous difficulties in developing, manufacturing and marketing any new drugs resulting from a strategic alliance or acquisition that delay or prevent us from realizing their expected benefits or enhancing our business. We cannot assure you that, following any such acquisition, we will achieve the expected synergies to justify the transaction. The risks we face in connection with acquisitions, include:

•

diversion of management time and focus from operating our business to addressing acquisition integration challenges;

•

program divestitures due to potential exclusivity obligations;

•

coordination of research and development efforts;

•

retention of key employees from the acquired company;

•

changes in relationships with strategic partners as a result of product acquisitions or strategic positioning resulting from the acquisition;

•

cultural challenges associated with integrating employees from the acquired company into ours;

•

the need to implement or improve controls, procedures, and policies at a business that prior to the acquisition may have lacked sufficiently effective controls, procedures and policies;

•

liability for activities of the acquired company before the acquisition, including intellectual property infringement claims, violation of laws, commercial disputes, tax liabilities, and other known liabilities;

•

unanticipated write-offs or charges; and

•

litigation or other claims in connection with the acquired company, including claims from terminated employees, customers, former stockholders or other third parties.

Our failure to address these risks or other problems encountered in connection with our past or future acquisitions or strategic alliances could cause us to fail to realize the anticipated benefits of these transactions, cause us to incur unanticipated liabilities and harm our business generally. There is also a risk that future acquisitions will result in the incurrence of debt, contingent liabilities, amortization expenses or incremental operating expenses, any of which could harm our financial condition or results of operations.

We rely, and anticipate that we will rely, on third parties to design, conduct, supervise and monitor our preclinical studies and clinical trials, and if those third parties perform in an unsatisfactory manner, it may harm our business.

We rely, and anticipate that we will rely, on third party clinical investigators, CROs, clinical data management organizations and consultants to design, conduct, supervise and monitor preclinical studies and clinical trials of our ~~product~~development candidates. Because we rely on third parties and do not have the ability to conduct preclinical studies or clinical trials independently, we have less control over the timing, quality and other aspects of preclinical studies and clinical trials than we would if we conducted them on own, including our inability to control whether sufficient resources are applied to our programs. If any of our CROs are acquired or consolidated, these concerns are likely to be exacerbated and our preclinical studies or clinical trials may be further impacted due to potential integration, streamlining, staffing and logistical changes. These investigators, CROs and consultants are not our employees and we have limited control over the amount of time and resources that they dedicate to our programs. These third parties may have contractual relationships with other entities, some of which may be our competitors, which may draw time and resources from our programs. Further, these third parties may not be diligent, careful or timely in conducting our preclinical studies or clinical trials, resulting in the preclinical studies or clinical trials being delayed or unsuccessful.

If we cannot contract with acceptable third parties on commercially reasonable terms, or at all, or if these third parties do not carry out their contractual duties, satisfy legal and regulatory requirements for the conduct of preclinical studies or clinical trials or meet expected deadlines, our preclinical and clinical development programs could be delayed and otherwise adversely affected. In all events, we are responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the general investigational plan and protocols for the trial. The FDA and other health authorities require certain preclinical studies to be conducted in accordance with GLP, and clinical trials to be conducted in accordance with GCP, including conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected. If we or our CROs fail to comply with these requirements, the data generated in our clinical trials may be deemed unreliable or uninterpretable and the FDA and other health authorities may require us to perform additional clinical trials. Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements. In the United States, we are also required to register certain clinical trials and post the results of completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within certain timeframes. Failure to do so can result in fines, adverse publicity and civil and criminal sanctions. Any such event could adversely affect our business, financial condition, results of operations and prospects.

We rely on third parties in the supply and manufacture of our ~~product~~lead candidates and development candidates for our research, preclinical and clinical activities, and may do the same for commercial supplies of our ~~product~~lead or development candidates.

We have not yet manufactured our ~~product~~development candidates on a commercial scale, and may not be able to do so for any of our ~~product~~development candidates. We currently rely on third parties in the supply and manufacture of materials for our research, preclinical and clinical activities and may continue to do so for the foreseeable future, including if we received regulatory approval for any ~~product~~development ~~candidate~~candidates. We may do the same for the commercial supply of our drug product. We use third parties to perform additional steps in the manufacturing process, such as the filling, finishing and labeling of vials and storage of our product candidates and we expect to do so for the foreseeable future. There can be no assurance that our supply of research, preclinical and clinical development drug candidates and other materials will not be limited, interrupted or restricted or will be of satisfactory quality or continue to be available at acceptable prices. Replacement of any of the third parties we may engage could require significant

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parties to perform additional steps in the manufacturing process, such as the filling, finishing and labeling of vials and storage of our development candidates and we expect to do so for the foreseeable future. There can be no assurance that our supply of research, preclinical and clinical development drug candidates and other materials will not be limited, interrupted or restricted or will be of satisfactory quality or continue to be available at acceptable prices. Replacement of any of the third parties we may engage could require significant effort and expertise because there may be a limited number of qualified replacements. In addition, raw materials, reagents, and components used in the manufacturing process, particularly those for which we have no other source or supplier, may not be available, may not be suitable or acceptable for use due to material or component defects, or may introduce variability into the supply of our ~~product~~development candidates. Furthermore, with the increase of companies developing nucleic acid therapeutics, there may be increased competition for the supply of the raw materials that are necessary to make our oligonucleotides, which could severely impact the manufacturing of our ~~product~~development candidates.

We may be unable to identify manufacturers on acceptable terms or at all because the number of potential manufacturers is limited and they must be acceptable to the FDA or approved by foreign regulatory authorities. Suppliers and manufacturers, including us, must meet applicable manufacturing requirements, including compliance with cGMP regulations, and undergo rigorous facility and process validation tests required by regulatory authorities in order to comply with regulatory standards. In the event that any of our suppliers or manufacturers fail to comply with such requirements or to perform their obligations to us in relation to quality, timing or otherwise, some of which may be out of their or our control, or if our supply of components or other materials becomes limited or interrupted for other reasons, we may be forced to increase the manufacturing of the materials ourself, for which we currently have limited capabilities and resources, or enter into an agreement with another third party, which we may not be able to do on reasonable terms, if at all. Any interruption of the development or operation of the manufacturing of our ~~product~~development candidates, such as order delays for equipment or materials, equipment malfunction, quality control and quality assurance issues, regulatory delays and possible negative effects of such delays on supply chains and expected timelines for product availability, production yield issues, shortages of qualified personnel, discontinuation of a facility or business or failure or damage to a facility resulting from natural disasters, could result in the cancellation of shipments, loss of product in the manufacturing process or a shortfall in available ~~product~~lead and development candidates or materials. In some cases, the technical skills or technology required to manufacture our ~~product~~lead and development candidates may be unique or proprietary to the original manufacturer and we may have difficulty, or there may be contractual restrictions prohibiting us from, transferring such skills or technology to another third party and a feasible alternative may not exist. These factors would increase our reliance on such manufacturer or require us to obtain a license from such manufacturer in order to have another third party manufacture our ~~product~~lead and development candidates. If we are required to change manufacturers for any reason, we will be required to verify that the new manufacturer maintains facilities and procedures that comply with quality standards and with all applicable regulations and guidelines. The delays associated with the verification of a new manufacturer could negatively affect our ability to develop ~~product~~lead and development candidates in a timely manner or within budget.

We may also be required to enter into long-term manufacturing agreements that contain exclusivity provisions and/or substantial termination penalties which could have a material adverse effect on our business prior to or after commercialization of any of our ~~product~~development candidates. If we are unable to obtain or maintain third-party manufacturing for ~~product~~development candidates, or to do so on commercially reasonable terms, we may not be able to develop and commercialize our ~~product~~development candidates successfully. Failure to execute on our manufacturing requirements, either by us or by one of our third-party vendors, could adversely affect our business.

Our relationships with healthcare providers, physicians, and third-party payors will be subject to applicable anti-kickback, fraud and abuse, anti-bribery and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm, and diminished profits and future earnings.

Healthcare providers, physicians, and third-party payors play a primary role in the recommendation and prescription of any product candidates that we may develop for which we obtain marketing approval. Our future arrangements with third-party payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell, and distribute our medicines for which we obtain marketing approval. Restrictions under applicable federal and state healthcare laws and regulations listed in the section above titled “Risks Related to Regulatory, Legal, and Clinical Trials”, including certain laws and regulations applicable only if we have marketed products.

Some state laws also require pharmaceutical companies to comply with specific compliance standards, restrict financial interactions between pharmaceutical companies and healthcare providers or require pharmaceutical companies to report information related to payments to health care providers or marketing expenditures.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs. Given the breadth of the laws and regulations, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, governmental authorities may possibly conclude that our business practices may not comply with healthcare laws and regulations. If our operations are found to be in violation of any of the laws described above or any other government regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, damages, fines, exclusion from participation in government health care programs, such as Medicare and Medicaid, imprisonment, and the curtailment or restructuring of our operations, any of which could adversely affect our business, financial condition, results of operations, and prospects.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order, or use of medicinal products is prohibited in the EU. The provision of benefits or advantages to physicians is also governed by the national anti-bribery laws of European Union Member States, such as the U.K. Bribery Act 2010. Infringement of these laws could result in substantial fines and imprisonment.

Payments made to physicians in certain European Union Member States must be publicly disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization, and/or the regulatory authorities of the individual European Union Member States. These requirements are provided in the national laws, industry codes, or professional codes of conduct applicable in the European Union Member States. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

Risks Related to Our Personnel, Operations and Growth

If we are unable to attract and retain qualified key management and scientists, staff, consultants and advisors, our ability to implement our business plan may be adversely affected.

We are highly dependent upon our senior management and our scientific, clinical and medical staff and advisors. The loss of the service of any of the members of our senior management or other key employees could delay our research and development programs and materially harm our business, financial condition, results of operations and prospects. InAlthough ~~addition~~we implemented workforce reductions in May 2025 and in November 2025, we expect that we will continue to have an increased need to recruit and hire qualified personnel as we advance our programs and expand operations. Our recent workforce reductions could impede future recruiting and hiring efforts. Failure to successfully recruit and retain personnel could impact our anticipated development plans and timelines. For example, we have faced challenges in retaining and attracting employees to support our research and development efforts, and our failure to do so could have an adverse effect on our ability to execute on our business plan. We are dependent on the continued service of our technical personnel because of the highly technical and novel nature of our ~~product~~lead and development candidates, platform and technologies and the specialized nature of the regulatory approval process. Replacing such personnel may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully execute our business strategy, and we cannot assure you that we will be able to identify or employ qualified personnel for any such position on acceptable terms, if at all. Many of the biotechnology and pharmaceutical companies with whom we compete for qualified personnel have greater financial and other resources, different risk profiles and longer histories in the industry than we do. Because our management team and key employees are not obligated to provide us with continued service, they could terminate their employment with us at any time without penalty. We do not maintain key person life insurance policies on any of our management team members or key employees. Our future success will depend in large part on our continued ability to attract and retain highly qualified scientific, technical and management personnel, as well as personnel with expertise in preclinical and clinical testing, manufacturing, governmental regulation and commercialization. In order to do so, we may need to pay higher compensation or fees to our employees or consultants than we currently expect, and such higher compensation payments may have a negative effect on our operating results. We face increased competition for personnel from other companies, universities, public and private research institutions, government entities and other organizations. If we are unable to attract and retain qualified personnel, the rate and success at which we may be able to discover and develop our product candidates and implement our business plan will be limited.

We expect to expand our research, development, delivery, manufacturing, commercialization, regulatory and future sales and marketing capabilities over time, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations. 77

Asbiotechnology ofand ~~December~~pharmaceutical ~~31,~~companies ~~2024,~~with whom we ~~had~~compete ~~104~~for ~~full-time~~qualified ~~employees,~~personnel ~~including~~have 70greater ~~who~~financial ~~hold~~and ~~Ph.D.~~other ~~degrees~~resources, ordifferent ~~other~~risk ~~advanced~~profiles ~~degrees;~~and 72longer ~~employees~~histories ~~are~~in ~~engaged~~the inindustry ~~research~~than ~~and~~we ~~development~~do. Because our management team and 32key employees are ~~engaged~~not inobligated ~~management~~to orprovide ~~general~~us ~~and~~with ~~administrative~~continued ~~activities.~~service, Inthey ~~connection~~could ~~with~~terminate ~~the~~their ~~growth~~employment ~~and~~with ~~advancement~~us ofat ~~our~~any ~~pipeline,~~time wewithout ~~expect~~penalty. toWe ~~increase~~do ~~the~~not ~~number~~maintain ofkey ~~our~~person ~~employees~~life ~~and~~insurance ~~the~~policies ~~scope~~on any of our ~~operations,~~management ~~particularly~~team inmembers ~~the~~or ~~areas~~key ofemployees. ~~drug~~Our ~~development,~~future ~~regulatory~~success ~~affairs,~~will ~~and~~depend asin ~~any~~large ~~product~~part ~~candidates~~on ~~near~~our ~~later~~continued ~~stage~~ability ~~clinical~~to ~~trials~~attract and ~~potential~~retain ~~commercialization~~highly byqualified usscientific, ~~and~~technical ~~sales~~ and ~~marketing.~~management Topersonnel, ~~manage~~as ~~our~~well ~~anticipated~~as ~~future~~personnel ~~growth,~~with weexpertise ~~must~~in ~~continue~~preclinical ~~to implement~~ and ~~improve~~clinical ~~our~~testing, ~~managerial~~manufacturing, ~~operational~~governmental regulation and ~~financial~~commercialization. ~~systems,~~In ~~expand~~order ~~our~~to ~~facilities~~do so, ~~and~~we ~~continue~~may need to ~~recruit~~pay ~~and~~higher ~~train~~compensation ~~additional~~or ~~qualified~~fees ~~personnel. Due~~ to our ~~limited~~employees ~~financial~~or ~~resources~~consultants ~~and~~than ~~the~~we ~~limited~~currently ~~experience~~expect, ofand ~~our~~such ~~management~~higher ~~team~~compensation inpayments ~~managing~~may have a ~~company~~negative ~~with~~effect ~~such~~on ~~anticipated~~our ~~growth,~~operating weresults. ~~may~~We ~~not~~face beincreased ~~able~~competition tofor ~~effectively~~personnel ~~manage~~from ~~the~~other ~~expected~~companies, ~~expansion~~universities, ofpublic ~~our operations or recruit~~ and ~~train~~private ~~additional~~research ~~qualified personnel. Moreover~~institutions, ~~our~~government ~~current~~entities ~~physical~~and ~~laboratory~~other ~~space~~organizations. ~~may~~If bewe ~~insufficient~~are ~~for~~unable ~~our~~to ~~near-term~~attract ~~research~~ and ~~development~~retain ~~hiring~~qualified ~~plans~~personnel, ~~and~~ the ~~expected~~rate ~~physical~~and ~~expansion~~success ofat ~~our~~which ~~operations~~we may ~~lead~~be able to ~~significant~~discover ~~costs~~ and ~~may~~develop ~~divert~~ our ~~management and business~~ development ~~resources.~~candidates ~~Any~~and ~~inability~~implement ~~to manage growth could delay the execution of~~ our business ~~plans~~plan orwill ~~disrupt~~be ~~our operations~~limited.

AsWe aexpect ~~growing~~to ~~biotechnology~~need ~~company,~~to weexpand ~~are~~our ~~actively~~research, ~~pursuing~~development, ~~new~~delivery, ~~platforms~~manufacturing, commercialization, regulatory and ~~product~~future ~~candidates~~sales inand ~~many~~marketing ~~therapeutic~~capabilities ~~areas~~over time, and ~~across~~as a ~~wide~~result, ~~range~~we ofmay ~~diseases.~~encounter ~~Successfully~~difficulties ~~developing~~in ~~product~~managing ~~candidates~~our ~~for~~future ~~and~~growth, ~~fully~~which ~~understanding~~could ~~the~~disrupt ~~regulatory~~our operations.

74As of December 31, 2025, we had 58 full-time employees, including 44 who hold Ph.D. degrees or other advanced degrees; 39 employees are engaged in research and development and 19 employees are engaged in management or general and administrative activities. In May 2025, we announced a workforce reduction and organizational streamlining and in November 2025, we announced a further workforce reduction to extend our cash runway. In connection with the growth and advancement of our pipeline, we expect that we will need to increase the number of our employees and the scope of our operations, particularly in the areas of drug development, regulatory affairs, and as any development candidates near later stage clinical trials and potential commercialization by us, and sales and marketing. To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities, and continue to recruit and train additional qualified personnel. Our workforce reduction may make these efforts more challenging. Due to our limited financial resources and the limited experience of our management team in managing a company with such anticipated growth, we may not be able to effectively manage the expected future expansion of our operations or recruit and train additional qualified personnel. Any inability to manage growth could delay the execution of our business plans or disrupt our operations.

As a pre-commercial biotechnology company, we are actively pursuing new platforms and lead candidates in many therapeutic areas and across a wide range of diseases. Successfully developing development candidates for and fully understanding the regulatory and manufacturing pathways to all of these therapeutic areas and disease states requires a significant depth of talent, resources and corporate processes in order to allow simultaneous execution across multiple areas. Due to our limited resources and recent workforce reductions, we may not be able to effectively manage this simultaneous execution and the expansion of our operations or, when appropriate, recruit and train additional qualified personnel. This may result in weaknesses in our infrastructure, give rise to operational mistakes, legal or regulatory compliance failures, loss of business opportunities, further loss of employees and reduced productivity among remaining employees. The physical expansion of our operations may lead to significant costs and may divert financial resources from other projects, such as the development of our potential ~~product~~development candidates. If our management is unable to effectively manage the expected development and expansion, our expenses may increase more than expected, our ability to generate or increase our revenue could be reduced and we may not be able to implement our business strategy. Our future financial performance and our ability to compete effectively and commercialize any ~~product~~development candidates we may develop will depend in part on our ability to effectively manage our future development and expansion.

Risks Related to Intellectual Property

If we are not able to obtain or protect intellectual property rights related to any of our ~~product~~lead candidates and development candidates, development and commercialization of our

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