camp-20241231

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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FORM 10-K

___________________________________

(Mark One)

For the fiscal year ended December 31, 2024

For the transition period from to

Commission file number 001-42365

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CAMP4 Therapeutics Corporation

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(Exact name of registrant as specified in its charter)

One Kendall SquareBuilding 1400 West, 3rd FloorCambridge, Massachusetts 02139

(Address of Principal Executive Offices) (Zip Code)

(617) 651-8867

Registrant’s telephone number, including area code

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 $0.0001 per share CAMP Nasdaq Global 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.

YesoNox

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.

YesoNox

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.

YesxNoo

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).

Yesx No o

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a 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 o Accelerated filer o

Non-accelerated filer x Smaller reporting company x

Emerging growth company x

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 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 Act).

YesoNox

The registrant was not a public company as of the last business day of its most recently completed second fiscal quarter and therefore cannot calculate the aggregate market value of the voting and non-voting common equity held by non-affiliates as of such date.

As of March 13, 2025, there were 20,161,072 shares of the registrant’s common stock, par value $0.0001 per share, outstanding.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s definitive proxy statement for its 2025 annual meeting of stockholders (the “2025 Proxy Statement”) are incorporated by reference into Part III of this Annual Report on Form 10-K. The 2025 Proxy Statement will be filed pursuant to Regulation 14A with the Securities and Exchange Commission not later than 120 days after the registrant’s fiscal year ended December 31, 2024.

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Page

Part I 3

Item 1. Business 7

Item 1A. Risk Factors 47

Item 1B. Unresolved Staff Comments 104

Item 1C. Cybersecurity 104

Item 2. Properties 105

Item 3. Legal Proceedings 105

Item 4. Mine Safety Disclosures 105

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 119

Item 8. Financial Statements 120

Item 9A. Controls and Procedures 146

Item 9B. Other Information 146

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 146

Part III

Item 10. Directors, Executive Officers and Corporate Governance 147

Item 11. Executive Compensation 147

Item 14. Principal Accounting Fees and Services 147

Item 15. Exhibits, Financial Statement Schedules 148

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS AND MARKET AND INDUSTRY DATA

This Annual Report on Form 10-K (“Annual Report”) contains forward-looking statements that involve substantial risks and uncertainties because they relate to events and depend on circumstances that may or may not occur in the future. All statements other than statements of historical fact contained in this Annual Report, including statements regarding our strategy, future operations, future financial position, prospects, plans, objectives of management and expected growth, are forward-looking statements. These statements are based on our current beliefs, expectations and assumptions regarding our intentions, beliefs or current expectations concerning, among other things, the future of our business, future plans and strategies, our operational results and other future conditions. Forward-looking statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.

In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “estimate,” “believe,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions intended to identify statements about the future, although not all forward-looking statements contain these identifying words. These forward-looking statements include, without limitation, statements about the following:

•the initiation, timing, progress, results and costs of our research and development programs and of our current and future preclinical studies and clinical trials of our product candidates, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work, as well as the period during which the results of the trials are expected become available;

•the timing of our planned good laboratory practices toxicology studies and regulatory submissions, initiation of planned clinical trials and timing of expected clinical results for our product candidate CMP-CPS-001, our development candidate CMP-SYNGAP-01, if applicable, and our other future product candidates;

•the timing of any submissions of filings for regulatory approval of, and our ability to obtain and maintain regulatory approvals for, CMP-CPS-001 and any other product candidates;

•our ability to identify patients with the diseases treated by our product candidates, and to enroll patients in trials;

•our expectations regarding the size of the patient populations, market acceptance and opportunity for and clinical utility of our product candidates, if approved for commercial use;

•our reliance on third party manufacturing partners to comply with significant regulations with respect to manufacturing our products;

•our expectations regarding the scope of any approved indication for CMP-CPS-001 or any other product candidate;

•our ability to successfully commercialize our product candidates, if approved;

•our ability to leverage our RAP Platform to identify and develop future product candidates;

•our estimates of our expenses, ongoing losses, future revenue, capital requirements and our need for or ability to obtain additional funding before we can expect to generate any revenue from product sales;

•our ability to establish or maintain strategic collaborations or arrangements, including potential business development opportunities and potential licensing partnerships, and our ability to attract collaborators with development, regulatory and commercialization expertise;

•our ability to identify, recruit and retain key personnel;

•our reliance upon intellectual property licensed from third parties and our ability to obtain such licenses on commercially reasonable terms or at all;

•our ability to protect and enforce our intellectual property position for our product candidates, and the scope of such protection;

•our financial performance;

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•the sufficiency of our existing cash and cash equivalents to fund our future operating expenses and capital expenditure requirements;

•our competitive position and the development of and projections relating to our competitors or our industry;

•our estimates regarding future expenses and needs for additional financing;

•the impact of laws and regulations;

•general economic, industry, geopolitical and market conditions, such as military conflict or war, inflation and financial institution instability, or pandemic or epidemic disease outbreaks, many of which are beyond our control; and

•our expectations regarding the time during which we will be an emerging growth company and smaller reporting company under the Jumpstart Our Business Startups Act of 2012 (the “JOBS Act”).

Although we base these forward-looking statements on assumptions that we believe are reasonable when made, we caution you that forward-looking statements are not guarantees of future performance and that our actual results of operations, financial condition and liquidity, and the development of the industry in which we operate may differ materially from those made in or suggested by the forward-looking statements contained in this Annual Report. In addition, even if our results of operations, financial condition and liquidity, and the development of the industry in which we operate are consistent with the forward-looking statements contained in this Annual Report, those results or developments may not be indicative of results or developments in subsequent periods.

Given these risks and uncertainties, you are cautioned not to place undue reliance on these forward-looking statements. Any forward-looking statement that we make in this Annual Report speaks only as of the date of such statement. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in any forward-looking statements, whether as a result of new information, future events or otherwise. Comparisons of results for current and any prior periods are not intended to express any future trends or indications of future performance, unless specifically expressed as such, and should only be viewed as historical data. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this Annual Report.

Unless otherwise indicated, market and industry data contained in this Annual Report, including potential market opportunities, is based on our management’s estimates and research, as well as industry and general publications and research and studies conducted by third parties. Although we believe that the information from these third-party publications, research and studies included in this Annual Report is reliable, and we are responsible for the accuracy of such information, we have not independently verified the accuracy or completeness of this information. Management’s estimates are derived from publicly available information, their knowledge of our industry and their assumptions based on such information and knowledge, which we believe to be reasonable. This data involves a number of assumptions and limitations and the industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of factors, including those described in Part I, Item 1A. “Risk Factors” in this Annual Report. These and other factors could cause our future performance to differ materially from our assumptions and estimates.

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SUMMARY RISK FACTORS

Our business is subject to a number of risks of which you should be aware before making an investment decision. These risks are discussed more fully in Part I, Item 1A. “Risk Factors” in this Annual Report. These risks include the following:

•We have incurred significant losses since our inception, have no products approved for sale and we expect to incur losses for the foreseeable future;

•We will require substantial additional capital to finance our operations, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce, or terminate our development programs, commercialization efforts or other operations;

•Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates;

•Our independent registered public accounting firm has expressed substantial doubt about our ability to continue as a going concern in its report on our audited financial statements included in this Annual Report;

•We are early in our development efforts. Our product candidates are in varying stages of preclinical and clinical development and we have not completed a clinical trial of any product candidate. As a result, it will be many years before we commercialize a product candidate, if ever. If we are unable to identify and advance product candidates through preclinical studies and clinical trials, obtain marketing approval and ultimately commercialize them, or experience significant delays in doing so, our business will be materially harmed;

•Our business is highly dependent on our lead product candidate, CMP-CPS-001, as our sole clinical-stage program, and we must complete clinical testing before we can seek regulatory approval and begin commercialization of any of our other product candidates. If we are unable to obtain regulatory approval for, and successfully commercialize, CMP-CPS-001, our business may be materially harmed and such failure may affect the viability of our other product candidates;

•Drug development is a lengthy and expensive process, and preclinical and clinical testing is uncertain as to the outcome. We may encounter substantial delays in the commencement, enrollment or completion of our clinical trials and may never advance to clinical trials, or we may fail to demonstrate safety and effectiveness to the satisfaction of applicable regulatory authorities, which could prevent us from advancing or commercializing our product candidates on a timely basis, if at all;

•If any of our current or any future product candidates cause undesirable side effects or have other unexpected adverse properties, such side effects or properties could delay or prevent regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval;

•We face substantial competition, which may result in others discovering, developing or commercializing products before us or more successfully than we do;

•We may enter into collaborations with third parties for the research, development and commercialization of certain of the product candidates we may develop. If any such collaborations are not successful, we may not be able to capitalize on the market potential of those product candidates;

•Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel;

•We may encounter difficulties in managing our growth and expanding our operations successfully;

•We currently depend on third-party suppliers for the manufacture of our product candidates. The loss of these or future third-party suppliers, or their inability to provide us with sufficient supply, could harm our business;

•Our rights to develop and commercialize our product candidates are subject, in part, to the terms and conditions of licenses granted to us by third parties. If we fail to comply with our obligations under these arrangements or otherwise experience disruptions to our business relationships with our current or any future licensors, we could lose such intellectual property rights that are important to our business;

•Third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could harm our business;

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•If we or our licensors are unable to obtain, maintain, enforce and adequately protect our intellectual property rights with respect to our product candidates and technology, or if the scope of any patent or other intellectual property protection obtained is not sufficiently broad, our competitors could develop and commercialize products and technology similar or identical to ours, and our ability to successfully develop and commercialize our product candidates and technology may be adversely affected. Further, we do not currently own or in-license any issued patents directed to the composition of matter, or methods of use, of our product candidates; if we fail to obtain such patents, our competitors may be able to develop, make or market products identical to our product candidates after expiration of any applicable regulatory exclusivities;

•We rely, and intend to continue to rely, on third parties to perform some of our preclinical studies and conduct our clinical trials. If these third parties do not successfully carry out their contractual duties, fail to comply with applicable regulatory requirements, or do not meet expected deadlines, our development programs may be delayed or subject to increased costs or we may be unable to obtain regulatory approval for or commercialize our product candidates;

•Prior to the completion of our initial public offering, there was no public market for our common stock. An active, liquid, and orderly market for our common stock may not develop or be sustained, or we may in the future fail to satisfy the continued listing requirements of Nasdaq; and

•The trading price of the shares of our common stock could be highly volatile, and purchasers of our common stock could incur substantial losses.

If we are unable to adequately address these and other risks we face, our business, results of operations, financial condition and prospects may be harmed.

NOTE REGARDING TRADEMARKS

“CAMP4,” “RAP Platform,” “RNA Actuator” and our other registered or common law trademarks, trade names or service marks appearing in this Annual Report are the property of CAMP4 Therapeutics Corporation and are registered as trademarks in the United States and other countries. This Annual Report also contains references to trademarks belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity.

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PART I

Item 1. Business

Our Company

We are a clinical-stage biopharmaceutical company pioneering the discovery and development of a new class of RNA-based therapeutics with the goal of upregulating gene expression and restoring healthy protein levels to treat a broad range of genetic diseases. Regulatory RNAs (“regRNAs”), play a central role in the regulation of every protein-coding gene by contributing to gene activation and suppression. Our approach is designed to amplify messenger RNA (“mRNA”), expression by harnessing the power of regRNAs that form localized complexes with transcription factors and regulate gene expression. Our proprietary RNA Actuating Platform, or RAP Platform, allows us to rapidly and systematically identify and characterize the active regulatory elements controlling every expressed gene and tens of thousands of druggable enhancer and promoter regRNA sequences that control protein-coding genes. Once a disease-associated target gene is identified, we apply our RAP Platform to identify the controlling regRNA and rapidly generate novel antisense oligonucleotide (“ASO”) candidates, which we also refer to as RNA Actuators. These ASOs are designed to bind to the identified regRNA and amplify the expression of the target gene in a specific and controllable way. We are currently focused on metabolic diseases and diseases of the central nervous system (“CNS”) with validated disease biology, and we believe our RAP Platform allows us to address a broad range of rare and prevalent genetic diseases in which a modest increase in protein expression has the potential to be clinically meaningful.

Based on our preclinical studies, we believe our lead product candidate, CMP-CPS-001, has the potential to be the first disease-modifying therapy for the treatment of the most prevalent urea cycle disorders (“UCDs”). 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 levels in circulation, ultimately resulting in severe health outcomes, such as neurologic disability, seizure and death. CMP-CPS-001 is designed to improve urea cycle activity by amplifying expression of carbamoyl phosphate synthetase 1 (“CPS1”), an enzyme that catalyzes the first step of the urea cycle, by binding to a CPS1-specific regRNA. Our preclinical studies have demonstrated that modulating the activity of the target regRNA increases expression of the CPS1 gene, resulting in increased CPS1 enzyme levels, which allows for more ammonia to be converted into urea, thereby lowering ammonia levels to normal, healthy ranges. These preclinical studies also demonstrated that CMP-CPS-001 can increase the level of, or upregulate, the production of multiple enzymes responsible for converting ammonia into urea, potentially allowing us to address more than 85% of patients with UCDs, which we refer to as our pan-UCD approach. We are evaluating CMP-CPS-001 in an ongoing Phase 1 clinical trial in healthy volunteers and have completed a planned interim analysis of safety and pharmacokinetic data from all four cohorts of the single ascending dose (“SAD”) portion of the clinical trial, from which no safety trends of concern were observed. We have also completed dosing of the first two cohorts from the multiple ascending dose (“MAD”) portion of the clinical trial, and initiated dosing in the third MAD cohort. We expect to report data from the SAD and MAD portions of the clinical trial, including safety, pharmacokinetic and key pharmacodynamic biomarker data, in the fourth quarter of 2025. We also plan to initiate the expansion of the clinical trial of CMP-CPS-001 in Australia into a Phase 1b clinical trial to enroll female participants who are heterozygous for a mutation of the OTC gene in the second quarter of 2025. In addition, we are leveraging our RAP Platform to advance a preclinical program for the treatment of synaptic Ras GTPase activating protein 1 (“SYNGAP1”)-related disorders. We have nominated a development candidate, CMP-SYNGAP-01, from this program and expect to initiate Good Laboratory Practice (“GLP”) toxicology studies in 2025 to enable the filing of clinical trial applications. In addition, we have initiated a discovery program targeting a regRNA to increase GBA1 gene expression for the treatment of Parkinson’s disease (“PD”) caused by mutations in the GBA1 gene, and plan to initiate discovery programs in other CNS and metabolic indications utilizing our RAP Platform. Finally, we have entered into a strategic research collaboration with BioMarin Pharmaceutical Inc. (“BioMarin”) to advance novel therapeutics that increase protein levels by targeting regRNA sequences for two genetic targets.

The transcription of DNA into mRNA, the molecular template that is then translated into protein, is a complex yet carefully coordinated cellular process involving numerous components. Only a small portion of the DNA in the human genome is transcribed into RNA that codes for proteins. The vast majority of the transcriptome originates from non-coding regions of DNA, a portion of which, referred to as enhancers and promoters, perform a crucial role in determining the specificity, timing and level at which a particular gene is expressed. RegRNAs are non-coding RNAs that are transcribed by these enhancer and promoter DNA regions that form localized complexes with transcription factors to control the expression of protein-coding genes, either increasing or decreasing their expression within natural physiological ranges. The approximately 20,000 genes that code for mRNA in the human genome are controlled by hundreds of thousands of DNA enhancers and their associated regRNAs.

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Deficient protein levels characterize over a thousand diseases. Haploinsufficient diseases are dominantly inherited conditions in which inadequate gene expression is driven by a mutation in a single allele, or gene copy, and results in reductions of protein levels by as much as 50%. Numerous other genetic conditions are caused by recessive mutations that result in diminished gene activity. Data from our preclinical studies and research reports published by third parties demonstrate that increasing expression of disease-associated genes by modest amounts can restore healthy protein levels and provide therapeutic benefit in these disorders. Therefore, modest increases in protein expression have the potential to be clinically meaningful in both haploinsufficient and recessive partial loss-of-function disorders, of which there are more than 1,200. Our RAP Platform has the potential to identify the regRNA associated with all of these diseases, which we believe enables us to design RNA Actuators to address the underlying biology of these diseases. We aim to leverage our RAP Platform to develop product candidates designed to regulate transcription in a gene-specific manner to restore healthy protein levels and remedy these diseases. However, our approach is unproven and may not lead to successful efforts to develop and commercialize our product candidates and to identify and discover additional potential product candidates.

Our RAP Platform

We believe our RAP Platform can unlock the potential of the human genome and have broad applications across a range of rare and prevalent diseases caused by sub-optimal levels of protein expression. Our technology is based upon the pioneering work in transcription regulation conducted by our co-founders, Richard Young, PhD and Leonard Zon, MD. We have built our RAP Platform to identify and characterize every regRNA that controls protein-coding genes and to develop novel ASO-based therapeutics to modulate regRNA activity to increase the expression of protein-coding genes of interest and thereby address the underlying cause of genetic diseases. Based on our proprietary mapping of regRNAs and screening and optimizing of ASOs, we have established a leadership position in regRNA-targeting therapies. Our goal is to be the preeminent company focused on discovering, developing and delivering regRNA-targeting therapeutics to patients. We believe that the ability to upregulate genes selectively through targeting regRNA could provide a new way to treat a wide range of human diseases and has the potential to become a class of new medicines.

At present, very few regRNAs are described in public genomic databases, as they are often expressed at low levels and their importance was not fully understood. Our RAP Platform utilizes next-generation sequencing technologies and custom sequence analyses to map the active regulatory elements controlling every expressed gene. These data empower our proprietary machine learning algorithm, known as EPIC, to identify the specific control elements that regulate any gene of interest in the most specific manner, including elements that may restrict gene expression to a particular cell type. This enables us to identify the exact sites of regRNA synthesis and ultimately map the complete sequence of every candidate regRNA to target for therapeutic gene control. To date, we have mapped multiple cell types in as little as three months, comprising a number of potentially addressable diseases in the liver, CNS, heart, skeletal muscle and immune system. Our in-house development and application of this technology has enabled us to identify tens of thousands of enhancer and promoter regRNA sequences and their key biological properties, resulting in what we believe to be the most robust regRNA dataset available.

We combine our RAP Platform with ASO chemistry that has been utilized and validated in U.S. Food and Drug Administration (“FDA”)-approved products to develop programmable RNA Actuators that are designed to precisely upregulate gene expression at the transcriptional level. Once a target gene is nominated, our RAP Platform rapidly identifies the controlling regRNA sequence, and we perform ASO screens to identify regions where ASO binding results in optimal upregulation of that target gene. Further rational design is applied to the ASOs identified in the screen. Our proprietary technology enables us to design RNA Actuators that optimize for specificity by avoiding binding to regRNAs that act on more than one gene and any other similar sequences found elsewhere in the transcriptome. As a result, our sequence-specific approach enables us to precisely target regRNA transcripts to increase gene expression. Our approach is designed to enable the efficient and systematic creation of RNA Actuators to target regRNAs of interest. Building upon the power of this technology, our RNA Actuators can be programmed to engage regRNA targets, producing tunable increases in protein expression. While other ASOs have received regulatory approval, no regulatory authorities to date have approved ASOs that are directed towards regRNAs and, as a result, there is uncertainty as to the safety and efficacy profile of our product candidates compared to currently approved ASOs.

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The key steps involved in our platform are illustrated below:

Our proprietary RAP Platform

We design RNA Actuators to leverage existing oligonucleotide delivery approaches to enable drug delivery to specific types of tissues throughout the body. We believe our RAP Platform can address any disease where a modest increase in protein expression can be clinically meaningful, including haploinsufficient diseases or recessive loss-of-function diseases. Furthermore, as we continue to map regRNAs and conduct ASO screens in more cell types, the data generated will improve the algorithms we use to identify the candidate regRNAs to specifically control gene expression. We believe the knowledge and learnings from our initial programs will significantly expedite selection of lead candidates and position us to rapidly expand our pipeline.

Our Pipeline

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CMP-CPS-001: Potential Treatment for Urea Cycle Disorders

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 efforts to lower plasma ammonia levels. Reduction in plasma ammonia is achieved through nitrogen scavengers to remove excess nitrogen, along with the dosing of supplemental citrulline. These nitrogen scavenger agents carry an onerous pill regimen and significantly diminish the quality of life for patients. Longer-term maintenance regimens involve strict adherence to a low-protein diet along with the prophylactic use of nitrogen scavenger agents. When necessary, hemodialysis is used to reduce ammonia concentrations. The existing supportive measures are not sufficient, with many patients suffering neurological disability and premature death. Therapies currently in development are targeting only a select subgroup of patients with UCD, which includes those with OTC deficiency and patients 12 years and older. We have designed CMP-CPS-001 to be broadly applicable to UCD patients and to overcome the limitations of the current standard of care as well as programs in development for the treatment of late onset UCDs by using an established ASO modality and convenient once-monthly subcutaneous administration in order to provide UCD patients with the potential for a safe and efficacious treatment option. We are initially targeting our development of CMP-CPS-001 in the most prevalent late-onset patients (those with OTC, ASL and ASS1 deficiencies, which together constitute more than 80% of patients with UCDs) and we may expand into additional groups of patients with less common forms of UCD. The FDA granted Rare Pediatric Disease designation to CMP-CPS-001 for the treatment of UCDs in August 2024 and granted orphan drug designation to CMP-CPS-001 for the treatment of UCDs in September 2024.

CMP-CPS-001 is designed to improve urea cycle activity by amplifying expression of CPS1, a key enzyme that catalyzes the first step of the urea cycle, by binding to a CPS1-specific regRNA. CMP-CPS-001 is a subcutaneously injected ASO conjugated to N-acetylgalactosamine (“GalNAc”), a ligand that enables targeted delivery to the liver, designed to be administered monthly. Increasing CPS1 expression enhances the metabolism of ammonia and upregulates multiple urea cycle enzymes, including OTC, resulting in elevated urea cycle activity. Our RAP Platform enabled us to (i) identify the key enhancer modulating CPS1 expression, (ii) screen ASOs directed to the regRNAs expressed by this enhancer, and (iii) generate a lead RNA Actuator designed to increase CPS1 expression.

Our preclinical studies have demonstrated that modulating the activity of the target regRNA increases expression of the CPS1 gene, resulting in increased CPS1 enzyme levels, which allows for more ammonia to be converted into urea, thereby lowering ammonia levels to normal, healthy ranges. This includes studies in a mouse model where we demonstrate that increasing Cps1 expression can overcome a partial loss of function mutation in the urea cycle enzyme, Otc, and improve ammonia clearance. These preclinical studies also demonstrated that CMP-CPS-001 can upregulate the production of multiple enzymes responsible for converting ammonia into urea, which supports our pan-UCD approach. In non-human primate (“NHP”) studies, the administration of CMP-CPS-001 increased the synthesis of urea, commonly referred to as ureagenesis. In these NHP studies, labeled sodium acetate was used as part of a ureagenesis rate test (“URT”) to measure the metabolic output of the urea cycle. Carbaglu, approved for ultra-rare N-actylgluatamate synthesase (“NAGS”)-deficient patients, utilized the URT in healthy volunteers and showed that minimal increases in ureagenesis translated to substantial ammonia reductions in NAGS-deficient patients. Rates of ureagenesis were found to exceed those achieved by placebo in a statistically significant manner. This assay is also being used in our Phase 1 clinical trial. An increase in the metabolic output of the urea cycle, as indicated by an increase in the amount of labeled sodium acetate metabolized, is expected to

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correlate with an increase in the amount of ammonia metabolized. Although we believe that an increase in ureagenesis in our Phase 1 clinical trial may correspond with clinically meaningful improvements in ammonia metabolism in UCD patients, ureagenesis is not an established clinical endpoint and the URT results obtained in our Phase 1 clinical trial in healthy adult volunteers should not be interpreted as evidence of efficacy of CMP-CPS-001. For a further discussion of our use of this assay, please see Part I, Item 1A., “Risk factors—The outcome of preclinical studies and earlier-stage clinical trials may not be predictive of future results or the success of later preclinical studies and clinical trials,” in this Annual Report.

We are evaluating CMP-CPS-001 in a randomized, double-blind and placebo-controlled Phase 1 clinical trial to evaluate safety, tolerability and pharmacokinetics in healthy volunteers in Australia, and have completed a planned interim analysis of safety and pharmacokinetic data from all four cohorts of the SAD portion of the clinical trial, from which no safety trends of concern were observed. We have also completed dosing of the first two cohorts from the MAD portion of the clinical trial, and initiated dosing in the third MAD cohort. We expect to report data from the SAD and MAD portions of the clinical trial, including safety, pharmacokinetic and key pharmacodynamic biomarker data, in the fourth quarter of 2025. In addition, we plan to initiate the expansion of the clinical trial of CMP-CPS-001 in Australia into a Phase 1b clinical trial to enroll female OTC heterozygotes in the second quarter of 2025.

CMP-SYNGAP: Program for the Treatment of SYNGAP1-related Disorders

Our initial CNS development program, CMP-SYNGAP, aims to address the underlying cause of SYNGAP1-related disorders. SYNGAP1-related disorders are a group of neurodevelopmental conditions caused by pathogenic variants in the SYNGAP1 gene leading to a haploinsufficient state that reduces SYNGAP protein levels by as much as 50%. SYNGAP plays a critical role in the development of cognition and proper synaptic function. Epilepsy is a common characteristic of these disorders and nearly all patients present with some degree of developmental delay and cognitive impairment. Patient estimates for SYNGAP1-related disorders vary significantly, with incidence estimates ranging from one to 40 in 100,000 individuals. While we believe that SYNGAP1-related disorders remain underdiagnosed, we estimate that there are approximately 10,000 individuals living with these disorders in the United States. SYNGAP1-related disorders are reported to represent 0.5% to 1.0% of all intellectual disability cases, making them among the most common causes of intellectual disability in patients with epilepsy, and indicating that the patient population may be significantly larger than incidence estimates suggest.

There are no FDA-approved, disease-modifying therapies for SYNGAP1-related disorders. There is also no definitive treatment protocol, which is dependent on seizure type and severity and other neurological characteristics. Treatment is often limited to supportive physical, occupational and speech therapy. A combination of non-specific anti-seizure medications may be prescribed to treat seizures, though SYNGAP1-related disorders have proven difficult to control with available therapeutics. As many as 50% of patients do not adequately respond to medication, in which case implantable devices, such as those for vagus nerve stimulation, may offer incremental therapeutic benefit.

We are advancing our CMP-SYNGAP program to address the significant unmet need for these patients by targeting the direct cause of SYNGAP1-related disorders, haploinsufficiency, which we believe is amenable to targeting through regRNAs. Our CMP-SYNGAP program is a novel approach that targets the SYNGAP1 gene at the transcriptional level to restore SYNGAP function and improve symptoms, by utilizing an intrathecally delivered ASO. We have identified specific regRNA sequences involved in SYNGAP1 transcription and utilized our RAP Platform to generate ASOs that function to increase SYNGAP1 transcription. Upregulation of SYNGAP1 gene expression may increase SYNGAP protein levels in amounts sufficient to yield therapeutic benefit. Our preclinical studies demonstrated a dose-dependent increase in SYNGAP1 mRNA levels accompanied by a reduction in SYNGAP1 expression. We have nominated a development candidate, CMP-SYNGAP-01, from this program and expect to initiate GLP toxicology studies in 2025 to enable the filing of a clinical trial application.

Program for the Treatment of GBA1-related Parkinson’s Disease

We have initiated a discovery program focused on increasing GBA1 gene expression as a potential treatment for PD. Approximately 5-15% of PD patients harbor GBA1 mutations, which reduce glucocerebrosidase enzyme (“GCase”) activity by approximately 50%, leading to toxic substance buildup in the brain and accelerating disease progression. GCase and α-synuclein, the hallmark protein of PD, create a feedback loop that accelerates neurodegeneration. We plan to explore the potential of increasing GBA1 expression both in patients with GBA1 haploinsufficiency and in a broader subset of PD patients. Using our RAP Platform, we have identified ASOs that target the regRNAs controlling the expression of GBA1 and that have been observed to increase GBA1 expression in in vitro studies. We are continuing to advance our GBA1 discovery program with the objective of selecting a development candidate to progress into preclinical development.

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The Role of RegRNA in Controlling Transcription

The transcription of DNA into mRNA, the molecular template that is then translated into protein, is a complex yet carefully coordinated biological process involving numerous components. Only a small portion of the DNA encodes for proteins. Much of the remaining DNA comprises regions, known as promoters and enhancers, that control gene expression. The approximately 20,000 genes which code for mRNA in the human genome are controlled by hundreds of thousands of these elements and their associated regRNAs. The promoter region of the gene is located immediately before the DNA sequence encoding for an mRNA. Promoters bind transcription factors, coactivators and RNA polymerase leading to transcription initiation. Enhancers bind transcriptional regulatory proteins and interact with promoters to determine the specificity, timing and level at which a particular gene is expressed.

More than a decade ago, it was discovered that all active gene regulatory elements are also transcribed. These non-coding RNA transcripts generated by both enhancer and promoter DNA regions are defined as regRNAs. Recently, it was discovered that regRNAs play a central role in the formation of localized molecular complexes with transcriptional activators and suppressors, which function to control mRNA transcription. As shown in the illustration below, promoters and enhancers are brought into close proximity when a gene is being actively transcribed. RegRNAs generated from these regulatory elements remain closely associated with the complex that forms at the enhancer-promoter interface. Thus, regRNAs act in a gene-specific manner, only influencing the expression of the gene near the sites where they arise.

Interactions between enhancer and promoter DNA regions are critical regulators of gene expression

Deficient protein levels characterize over a thousand human diseases. Haploinsufficient diseases are dominantly inherited conditions in which inadequate gene expression, driven by a mutation in a single allele, or gene copy, results in reductions of protein levels by as much as 50%. Data from our preclinical studies and research reports published by third parties demonstrates that increasing expression of disease-associated genes by modest amounts can restore healthy protein levels and provide therapeutic benefit in these disorders. In addition to haploinsufficiencies, numerous other genetic conditions are characterized by a loss of protein function. These include recessive loss-of-function diseases caused by mutations in both alleles that reduce, but do not completely abolish, protein function. Similar to haploinsufficiencies, our preclinical studies and research conducted by third parties shows that even modest increases in expression of these partially active proteins can be therapeutically beneficial.

The figures below illustrate the concept that modest increases in protein expression can lead to clinically meaningful therapeutic benefits in both haploinsufficient and recessive partial loss-of-function disorders, of which there are more than 1,200. Our RAP Platform has the potential to identify the regRNA associated with all of these diseases, which we believe enables us to design RNA Actuators to address the underlying biology of these diseases. The image on the left illustrates that, with respect to haploinsufficient diseases, it is anticipated that an increase in functional protein levels, even below those expressed in the wild-type phenotype, would be clinically meaningful. The image on the right illustrates that, with respect to partial loss-of-function disorders, the increase of protein expression, even where the protein continues to be mutated, may be sufficient to achieve a clinically meaningful result for affected patients. We are leveraging proprietary insights into the regulatory activities of regRNAs generated internally using our proprietary RAP Platform to pioneer the development of novel therapeutics designed to achieve this objective.

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Gene expression increases have the potential to reduce or eliminate disease related to haploinsufficiency and loss of function disorders

Our RAP Platform

The evolving view of gene regulation now recognizes RNA as a key regulator of transcription. We were founded on the pioneering work in transcription regulation conducted by our co-founders, Richard Young, PhD and Leonard Zon, MD. We believe our RAP Platform can unlock the potential of the human genome and have broad applications across a range of rare and prevalent diseases caused by sub-optimal levels of protein expression. We have built our proprietary RAP Platform to discover the regRNAs that control protein-coding genes and develop novel ASO-based therapeutics to modulate regRNA activity to increase the expression of protein-coding genes of interest and thereby address the underlying cause of genetic diseases. Based on our proprietary mapping of regRNAs and screening and optimizing of ASOs, we have established a leadership position in regRNA-targeting therapies. Our goal is to be the preeminent company focused on discovering, developing and delivering regRNA-targeting therapeutics to patients. We believe that the ability to upregulate genes selectively through targeting regRNA could provide a new way to treat a wide range of human diseases and has the potential to become a new class of medicines.

Our proprietary RAP Platform is built to map every regRNA for the tunable amplification of gene expression. Only a few regRNAs are described in public genomic databases, as they are often expressed at low levels and their importance was not fully understood. Our RAP Platform utilizes next-generation sequencing technologies and custom sequence analyses to map the active regulatory elements controlling every expressed gene. Further distinguishing the robust capabilities of RAP Platform is our ability to use primary human cell lines, rather than immortalized cultured cells, to preserve the functional integrity of specific cell types. To date, we have mapped multiple cell types in as little as three months, comprising a number of potentially addressable diseases in the liver, CNS, heart, skeletal muscle and immune system. We have demonstrated that we can identify regRNA-targeting ASOs that increase specific gene expression in those tissues. These data are analyzed with our proprietary machine learning algorithms to select candidate regRNA targets that regulate transcription in a gene-specific manner to increase protein production within a physiological range. Our in-house development and application of this technology has enabled us to identify tens of thousands of regRNA sequences and their key physiological properties resulting in what we believe to be the most robust regRNA dataset available. Moreover, we believe the ability of our RAP Platform to select the most likely regRNAs controlling a given gene from the large number of candidates is a key advantage of our technology, and represents a significant barrier to others seeking to develop this approach.

Our approach is designed to enable the efficient and systematic creation of RNA Actuators to target regRNAs of interest. Building upon the power of this technology, our RNA Actuators can be programmed to engage regRNA targets and induce tunable increases in protein expression. As we continue to map regRNAs and conduct ASO screens in more cell types, the data generated will improve the algorithms we use to identify the candidate regRNAs to specifically control gene expression. Thus, we believe the knowledge and learnings from our initial programs will significantly expedite selection of lead candidates and position us to rapidly expand our pipeline.

We combine our proprietary RAP Platform with validated ASO chemistry to develop programmable RNA Actuators that are designed to precisely upregulate gene expression at the transcriptional level. An ASO construct is a single-stranded, chemically modified, nucleic-acid sequence that binds to a target regRNA sequence and modulates its activity. ASOs block or remove key interactions and lead to both increased mRNA and protein expression. Once a target

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gene is selected, our RAP Platform rapidly identifies the controlling regRNA, and we perform ASO screens to identify regions where ASO binding results in optimal upregulation of that target gene. Further rational design is applied to lead sequences utilizing established approaches to optimize ASOs. Our RAP Platform enables us to design RNA Actuators that potentially optimize for specificity by avoiding the potential of binding to similar sequences found elsewhere in the transcriptome which may result in deleterious side effects. As a result, our sequence-specific approach enables us to precisely target regRNA transcripts to increase gene expression.

Our use of validated ASO chemistry to generate potential therapeutic candidates provides us the flexibility to screen using a range of target sequences and to design and synthesize multiple ASO construct variations that integrate a range of chemical modifications and tissue-targeting delivery vehicles intended to optimize therapeutic potency and target specificity.

We design RNA Actuators to leverage existing oligonucleotide delivery approaches to enable drug delivery to specific types of tissues throughout the body. Our metabolic programs utilize subcutaneous administration of GalNAc-conjugated ASOs for efficient liver delivery. Our CNS program utilizes intrathecal delivery of an unconjugated ASO which provides sufficient distribution in the CNS. Our RAP Platform has the potential to address any disease where increasing protein expression can be clinically meaningful, including haploinsufficient diseases or recessive loss-of-function diseases, by returning protein levels to a normal physiological range. Furthermore, given the versatility of our platform, we believe the knowledge and learnings from our initial programs will expedite selection of lead candidates and position us to rapidly expand our pipeline.

Our Programs

We are leveraging our RAP Platform to advance a pipeline of programs currently focused on metabolic and CNS disorders with validated disease biology and attractive potential market opportunities due to the significant unmet need of affected patients. Our lead product candidates and programs include: (i) a product candidate currently in a Phase 1 clinical trial, CMP-CPS-001, for the treatment of UCDs, (ii) a development candidate, CMP-SYNGAP-01, for the treatment of SYNGAP1-related disorders, for which we expect to initiate GLP toxicology studies in 2025 to enable the filing of a clinical trial application, and (iii) a discovery program targeting a regRNA to increase GBA1 gene expression for the treatment of PD caused by mutations in the GBA1 gene. We have also entered into a strategic research collaboration with BioMarin to advance novel therapeutics that increase protein levels by targeting regRNA sequences for two genetic targets. We retain exclusive, worldwide development and commercialization rights to all of our current product candidates and preclinical programs other than pursuant to our research collaboration with BioMarin.

CMP-CPS-001: Our Lead Product Candidate for Urea Cycle Disorders

Based on our preclinical studies, we believe our lead product candidate, CMP-CPS-001, has the potential to be the first disease-modifying therapy for the most prevalent UCDs, and is designed to improve urea cycle activity by amplifying expression of CPS1 by binding to a CPS1-specific regRNA. CMP-CPS-001 is a subcutaneously injected ASO conjugated to GalNAc and designed to be administered monthly. Our preclinical studies have demonstrated that modulating the activity of the target regRNA increases expression of the CPS1 gene, resulting in increased CPS1 enzyme levels, which allows for more ammonia to be converted into urea, thereby lowering ammonia levels to normal, healthy ranges. Our preclinical studies have also demonstrated that CMP-CPS-001 can upregulate the production of multiple enzymes responsible for converting ammonia into urea, potentially allowing us to address more than 85% of patients with UCDs. We are evaluating CMP-CPS-001 in an ongoing Phase 1 clinical trial in healthy volunteers, and have completed a planned interim analysis of safety and pharmacokinetic data from all four cohorts of the SAD portion of the clinical trial, from which no safety trends of concern were observed. We have also completed dosing of the first two cohorts from the MAD portion of the clinical trial, and initiated dosing in the third MAD cohort. We expect to report data from the SAD and MAD portion of the clinical trial, including safety, pharmacokinetic and key pharmacodynamic biomarker data, in the fourth quarter of 2025. In addition, we plan to initiate the expansion of the clinical trial of CMP-CPS-001 in Australia into a Phase 1b clinical trial to enroll female OTC heterozygotes in the second quarter of 2025.

The FDA granted Rare Pediatric Disease designation to CMP-CPS-001 for the treatment of UCDs in August 2024 and granted orphan drug designation to CMP-CPS-001 for the treatment of UCDs in September 2024.

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, which is then excreted from the body. The urea cycle is the key metabolic pathway for removing excess ammonia, a waste by-product of protein metabolism, and toxic—particularly to the central nervous system—from the body. In the liver, nitrogen containing ammonia is converted to urea, which is nontoxic, water-soluble and easily excreted from the body through the kidneys as a component of urine. The

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inability of the body to properly metabolize ammonia leads to toxic systemic levels in circulation, ultimately resulting in severe health outcomes, such as neurologic disability, seizure and death.

Six enzymes are involved in conversion of ammonia to urea including CPS1, NAGS, OTC, ASS1, ASL, and arginase 1 (“ARG1”). In addition, two transporter proteins, ORNT1 and Citrin, play critical roles in the proper functioning of the urea cycle. A genetic aberration, which results in deficiency or reduced function, in any one of these enzymes or transporter proteins results in a UCD and a buildup of ammonia. A schematic representation of the urea cycle is presented below.

The urea cycle converts ammonia into urea

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, generally resulting in hyperammonemic crisis. The incidence of UCDs in the United States is estimated to be approximately 1 in 35,000 births, with similar prevalence and incidence rates estimated for Europe. The onset and severity of UCDs is highly variable, with severity correlating with the degree of impairment of the conversion of ammonia to urea and inversely with the amount of residual enzyme function. An estimated 10% of patients with UCDs present as neonatal onset, with severe symptom onset presenting before the first month of life, with enzyme levels less than 5% of normal. In neonatal onset UCD, ammonia concentrations in the blood rise rapidly, with the clinical consequences of the disease often presenting within a week of birth. A liver transplant is typically required by six months of age. Patients with late onset forms of the disease may present as severe with numerous neuropsychological complications including development delays, learning and intellectual disabilities, attention deficit hyperactivity disorder and executive function deficit. Moreover, recurrent hyperammonemic crises are common despite existing supportive management, and acute life-threatening episodes can occur at any age, regardless of disease severity at initial presentation.

The most common UCD, accounting for approximately 60% of UCD diagnoses, is OTC deficiency, caused by mutations in the OTC gene. Unlike other UCDs, which are autosomal recessive disorders, OTC enzyme deficiency is an X-chromosome linked disorder. As such, particularly severe cases of the disorder are more prevalent in males, since males only have a single copy of the X chromosome. The incidence of OTC deficiency in the United States is estimated to be 1 in 56,500 births. The next two most common genetic subtypes are caused by mutations in the genes coding for the enzymes ASS1 and ASL, deficiencies which affect approximately 14% and 16% of UCD patients, respectively. The prevalence of UCDs is estimated to be approximately 3,700 patients in the United States, of which we estimate 90% are late onset, defined as having severe symptom onset after one month of life, and 96% of these late onset patients have enzyme deficiencies we believe we can address.

In addition, we estimate that more than 1,200 female OTC heterozygotes, who have inherited one copy of a gene with OTC-related changes, experience potentially addressable UCD symptoms. While males with OTC deficiency almost always experience symptoms, the severity and presence of symptoms in female heterozygotes can vary. Research now

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shows that many of these women face chronic, under-recognized symptoms and serious health risks, including the danger of hyperammonemic crises triggered by stress, illness, pregnancy, or surgery.

UCD patient population by deficiency

Current Treatments for Urea Cycle Disorders and Their Limitations

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, but not eliminate hyperammonemic crises. Current protocols for patients involve efforts to lower plasma ammonia levels. Reduction in plasma ammonia is achieved through nitrogen scavengers to remove excess nitrogen, along with the dosing of supplemental citrulline. When necessary, hemodialysis is used to reduce ammonia concentrations.

Longer-term maintenance regimens involve strict adherence to a low-protein diet along with the prophylactic use of nitrogen scavenger agents that carry an onerous pill regimen and significantly diminish the quality of life for patients. The objective of maintenance therapy is to minimize nitrogen intake while facilitating its removal through alternate pathways. The existing supportive measures are not sufficient, with many patients suffering neurological disability and premature death. A liver transplant, which is usually limited to early onset patients, is intended to prevent further hyperammonemic crises and neuropsychological deterioration and is the only curative treatment, but is available to fewer than 10% of patients.

In addition to approved maintenance therapies, we are aware of several other product candidates in development for the treatment of only a portion of UCDs. These candidates are administered through infusion as they utilize lipid nanoparticle (“LNP”) or adeno-associated virus-based (“AAV-based”) approaches that target correcting the under-expression of OTC only. Despite the therapeutic potential of these technologies, there is little published clinical data to date on these programs and some have been hampered by delays. Furthermore, the AAV-based gene therapy approach has an irreversible mechanism of action and is designed to only address OTC deficiency in patients 12 years or older. This could limit initial clinical utility of these AAV-based therapeutics to a small patient pool. Like all AAV-based therapeutics, these product candidates are not able to be redosed due to immunogenicity, potentially limiting their long-term utility. Additionally, there is potential for efficacy waning as liver cells turn over, leaving additional need for other therapeutics to be used in patients where the effects of gene therapy diminish. While LNPs can be redosed, they face the challenge of potential toxicity associated with repeated administration.

Our Solution for UCDs: CMP-CPS-001

Our lead product candidate, CMP-CPS-001, is a potentially disease-modifying therapy designed to amplify expression of CPS1, an enzyme that catalyzes the first step of the urea cycle, by binding to a CPS1-specific regRNA. In our preclinical studies, we have demonstrated that modulating the activity of this regRNA increases expression of the CPS1 gene, causing increased CPS1 enzyme levels, which allows for more ammonia to be converted into urea, thereby

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lowering ammonia levels to normal, healthy ranges. Our preclinical studies have also demonstrated that CMP-CPS-001 can upregulate the production of multiple enzymes responsible for converting ammonia into urea, potentially allowing us to address more than 85% of patients with UCDs. This includes the OTC deficient patient population as well as ASS1 and ASL, and others, with the exception of CPS1 and NAGS deficiencies.

Our RAP Platform enabled us to (i) identify the key enhancer modulating CPS1 expression, (ii) screen ASOs directed to the regRNAs expressed by this enhancer, and (iii) generate a RNA Actuator designed to increase CPS1 expression. We commenced work on the program, identified the CPS1 regulatory RNA target and identified the lead ASO sequence for CMP-CPS-001 in 2021.

We have demonstrated the controllability of our RNA Actuators in in vitro and invivo studies. The figures below illustrate the concentration-dependent increase in CPS1 mRNA achieved by the lead regRNA-targeting ASO in healthy human donor hepatocytes in an in vitro study. This ASO, designated “CMP-CPS-001 Analog,” has the same sequence and chemical modifications as CMP-CPS-001, but lacks a GalNAc conjugate, which is not necessary for in vitro delivery. In this study, both healthy human donor hepatocytes and OTC mutant hepatocytes were treated with a range of concentrations of the CMP-CPS-001 Analog and CPS1 mRNA levels were measured and normalized to untreated cells. As depicted in the figures below, the results of this study show that the ASO elevated expression of CPS1 in a concentration-dependent manner in both wild-type and OTC mutant human hepatocytes. The GalNAc-conjugated version of the CMP-CPS-001 Analog is our lead product candidate, CMP-CPS-001.

Concentration-dependent increase in CPS1 mRNA

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Error bars represent standard error of the mean; UTC denotes untreated control; NTC denotes non-targeting control.

Our Preclinical Studies

Our Preclinical Evaluation of CPS1 Upregulation in a Mouse Otc Deficiency Model

The Otcspf-ash mouse is an established animal model of OTC deficiency which carries an Otc mutation that reduces Otc expression to less than 10% of wild-type levels. Following an acute ammonia challenge, these mice displayed elevated plasma ammonia levels as compared to wild-type mice. We used this model for proof of concept that elevating the expression of CPS1 can overcome a deficiency in OTC, the enzyme most commonly mutated in UCDs. We applied our RAP Platform to identify a surrogate ASO targeting mouse Cps1 regRNA in order to conduct studies in this model.

In the first study, adult Otcspf-ash mice were administered eight doses (on days 1, 3, 5, 9, 11, 13, 15 and 17) of the ASO specifically engineered to target mouse Cps1 regRNA, at three different dose levels (8.33 (N=4), 16.6 (N=4) and 33.3 mg/kg (N=3)). A control group received placebo (phosphate-buffered saline (“PBS”)). Two days after the last dose, the mice were challenged with an injection of 15N-labeled ammonium chloride. Thirty minutes later, blood was drawn to

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measure total ammonia and 15N-urea levels. Statistical significance between groups was determined using appropriate statistical tests including two-way ANOVA and p-values reported. P-values (or probability values) are used to determine if the outcome of an experiment is statistically significant. A low p-value means that there is a very low likelihood that a given outcome was a result of a random occurrence. A high p-value means that assuming the null hypothesis is true, this outcome was very likely due to random occurrence. Generally, a p-value of less than 0.05 (or 5% odds of the event being random) is regarded as statistically significant. In our preclinical studies, p-values of <0.05 were considered statistically significant. In some cases, we identified directional trends in effects that did not meet statistical significance due to limited group sizes, small effect size, and variability. As is depicted in the graph below, treatment of these Otc-deficient mice with the mouse surrogate tool ASO led to a dose-dependent decrease in ammonia, including a 48% decrease at the highest dose level (p<.01), along with a trend toward increased urea synthesis, including a 20% increase at the highest dose level) compared to mice treated with PBS. This demonstrates that upregulation of Cps1 can improve ammonia metabolism in the context of a pathogenic mutation in the downstream Otc gene, and that the reduction in toxic ammonia is greater than the increase in urea.

Targeting Cps1 regRNA with an ASO leads to decreased ammonia levels and increased urea production

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**denotes p<.01; OtcD denotes Otc deficiency; PBS denotes phosphate-buffered saline; Error bars represent standard error of the mean.

A second Otcspf-ash mouse study was conducted to investigate the onset and duration of the pharmacodynamic effect of elevating Cps1 expression in the context of Otc deficiency. In this study, mice were administered three dose levels of ASO totaling 10, 30 and 90 mg/kg split over three days (days 1, 3 and 5). Control animals received placebo. Ammonia challenges were administered to cohorts of animals prior to dosing and at weekly intervals beginning three days after the final dose for a total of eight weeks. Blood was drawn 30 minutes post-challenge and total ammonia levels were measured. As shown in the figure below, the onset of effect was dose-dependent with ammonia levels reduced to within the range of wild-type animals (“WT Range”) by 3, 10 and 22 days post-dose for each of the high, mid and low dose groups, respectively. Ammonia levels approach baseline levels by 5 to 6 weeks post-dose, demonstrating a durable, greater than one month, pharmacodynamic effect. In addition, the impact of ASO treatment on Cps1 mRNA was assessed, and demonstrated a peak increase of approximately 71% for the high-dose group at day 15 that returned to baseline by day 29. The mid-dose group exhibited an approximately 27% increase in Cps1 mRNA along with prominent reductions in ammonia. The low-dose group exhibited minimal impact on Cps1 mRNA at the timepoints tested, had slower onset of ammonia reduction but still exhibited an overall effect. These data demonstrate that significant reductions of ammonia result from modest effects on transcription and associated increased flux through the urea cycle.

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Targeting Cps1 regRNA with an ASO leads to sustained decrease in ammonia levels

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Error bars represent standard error of the mean; PBS denotes phosphate-buffered saline.

Our Preclinical Evaluation of CMP-CPS-001 in Mice with Humanized Livers

The above studies were conducted using a mouse surrogate ASO that targets mouse Cps1 regRNA. To assess the impact on ureagenesis of CMP-CPS-001 in vivo we utilized mice whose livers had been repopulated with hepatocytes from a healthy human donor. These humanized-liver mice were given a 15N-ammonia challenge on day 1, then administered four doses of 25 mg/kg CMP-CPS-001 on days 8, 12, 15 and 19. In addition to day 1, the mice received 15N-ammonia challenges before dosing on days 8 and 15, and then again on day 22. Total ammonia and 15N-urea were measured at each of these time points. Consistent with the studies using Otcspf-ash mice involving the mouse surrogate ASO above, the results of this assessment, which are illustrated in the figure below, also demonstrated that CMP-CPS-001 targeting the Cps1 regRNA produced a statistically significant decrease in ammonia levels (approximately 71% on day 22, p<.05) along with increased ureagenesis (approximately 31% on day 22, p<0.01). Similar to the Otc-deficient mouse study, this study in wild-type humanized liver mice demonstrated that large decreases in ammonia (approximately 71%) are associated with more modest increases in urea (approximately 31%).

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CMP-CPS-001 produced statistically significant changes in levels of ammonia and ureagenesis in wild-type humanized mice compared to placebo treated mice at day 22

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Error bars represent standard error of the mean; * denotes p<.05; ** denotes p<.01.

On day 22, animals were sacrificed and livers collected to measure expression levels of CPS1 and other urea cycle enzymes. As shown in the figure below, treatment with CMP-CPS-001 resulted in a directional, though not statistically significant, increase in the expression of CPS1 by approximately 20%, with a similar increase in OTC. In addition, similar elevations of two other urea cycle enzymes (ASL and ARG1) were observed. This demonstrates that an increase in the expression of CPS1 can enhance enzymatic activity at multiple stages of the urea cycle, supporting development of CMP-CPS-001 as a potential therapeutic for urea cycle disorders in addition to OTC deficiency. The results of our studies of UCD-relevant mRNA transcription across multiple urea cycle enzymes is presented below.

CMP-CPS-001 increases transcription of mRNA of multiple urea cycle enzymes

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Error bars represent standard error of the mean; PBS denotes phosphate-buffered saline.

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An ammonia challenge cannot be utilized in a clinical trial due to safety concerns, as ammonia is an extremely toxic molecule. Instead, the metabolic output of the urea cycle can be assessed by using a URT in which subjects are administered 13C-sodium acetate. Sodium acetate is a salt that is commonly found in food sources and, like ammonia, the carbon is metabolized through the urea cycle and excreted in the urine. 13C-sodium acetate, a labeled isotope of sodium acetate, is ingested by participants as part of the URT to measure the overall activity of the urea cycle, and blood is drawn at multiple time points to measure the amount of 13C-urea that is generated. This measure of ureagenesis represents a clinically meaningful signal of the metabolic output of the urea cycle. An increase in the metabolic output of the urea cycle, as indicated by an increase in the amount of 13C-sodium acetate metabolized, is expected to correlate with an increase in the amount of ammonia metabolized. The rate of ureagenesis is inversely related to the severity of UCD. Studies have shown that while baseline plasma urea levels of asymptomatic carriers of these disorders are indistinguishable from those of healthy volunteers, baseline plasma urea levels among symptomatic patients are significantly lower. Notably, the measurement of ureagenesis in prior clinical trials of therapeutics designed to treat patients with OTC deficiency has been demonstrated to translate well to clinical response. Although preclinical studies suggest increases in urea are less pronounced than decreases in ammonia, we believe ureagenesis is a reliable indicator of therapeutic efficacy. Thus, we have incorporated this assay in ongoing assessments of CMP-CPS-001 in our healthy volunteer Phase 1 clinical trial. Based on our preclinical studies we believe small increases (approximately 20%) in ureagenesis may ultimately translate to meaningful clinical activity in patients in subsequent trials. It is possible that we may observe smaller increases in healthy volunteers, as their ureagenesis rates are operating at full capacity, underrepresenting the potential efficacy when tested in patients with low ureagenesis rates. However, it is possible that an increase in 13C-sodium acetate metabolism, as measured by the URT, will not correlate to an increase in ammonia metabolism and that variability in the results of the assay could render interpretation difficult. For a further discussion of our use of this assay, please see Part I, Item 1A., “Risk factors—The outcome of preclinical studies and earlier-stage clinical trials may not be predictive of future results or the success of later preclinical studies and clinical trials” in this Annual Report.

Our Preclinical Evaluation of CMP-CPS-001 in Non-Human Primates

The effect of increased CPS1 production on ureagenesis was also studied in wild-type cynomolgus monkeys. These NHPs were administered two doses of 5 mg/kg CMP-CPS-001, 30 days apart, with urea production measured one week after the second dose. To measure ureagenesis, animals were administered 13C-sodium acetate, and blood was drawn at eight time points over a four-hour period. The concentration of 13C-urea was measured utilizing a URT. As shown below, CMP-CPS-001 treatment increased ureagenesis by 40% compared to those animals administered the placebo (p<0.05 at 180 minutes; p<0.01 at 240 minutes). As in the humanized mouse study, this study shows that CMP-CPS-001 can increase activity of the urea cycle in wild-type animals. Moreover, the NHP study measured ureagenesis with the same assay being employed in the ongoing Phase 1 clinical trial in healthy volunteers, supporting this approach to measure a pharmacodynamic effect in humans.

CMP-CPS-001 increased ureagenesis compared to placebo in wild-type NHPs

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Error bars represent standard error of the mean; PBS denotes phosphate-buffered saline; * denotes p<.05; ** denotes p<.01.

Preclinical Safety Evaluations

CMP-CPS-001 was evaluated in three-month GLP toxicity studies of both mice and NHPs. Animals were dosed subcutaneously, once monthly for three months. In both species, CMP-CPS-001 was generally well tolerated with all clinical observations considered non-adverse due to low severity and lack of clinical correlates. No observable adverse effects were noted at 12.5 mg/kg and 50 mg/kg dosing, the highest dose levels tested in mice and NHPs respectively. Drug metabolism and pharmacokinetic evaluations reflected findings consistent with the drug class.

Our Ongoing Phase 1 Clinical Trial

CMP-CPS-001 is currently being evaluated in an approximately 96-person randomized, double-blind, and placebo-controlled Phase 1 clinical trial to evaluate safety, tolerability as well as pharmacokinetics and pharmacodynamics in healthy volunteers in Australia, where we are able to benefit from certain cost-effective tax incentives provided by the Australian government. CMP-CPS-001 is being administered by subcutaneous injection on a monthly basis. Primary endpoints of this trial include safety and tolerability and a secondary endpoint is to assess change in ureagenesis using the same URT utilized in our NHP study. Inclusion of the URT assessment is designed to enable the establishment of URT methodology that can be used to optimize the design of future registrational studies in patients with UCDs as well as enable a reference range of normal ureagenesis rates as both a tool for studies in patients with UCDs and as support for our engagement with regulators.

The SAD portion of the trial was segregated into four cohorts of 10-12 subjects each. Nine subjects in each cohort received CMP-CPS-001 with the additional three subjects receiving placebo. We dosed the first participant in this Phase 1 SAD clinical trial in March 2024. Dosing levels began at 0.2 mg/kg in the first cohort and, per the clinical trial design, increased with each successive cohort unless a maximum tolerated dose was reached, with dose escalation between cohorts only after a two-week safety review committee confirmation of safety and tolerability. In the absence of any concerning safety trends observed in the first two SAD cohorts, the trial was designed to then initiate an evaluation of CMP-CPS-001 in four MAD cohorts of 12 subjects each, staggered concurrently to the latter SAD cohorts. As was the design for the SAD portion of the Phase 1 clinical trial, the active therapeutic candidate to placebo participant ratio in each cohort of the MAD portion of the Phase 1 clinical trial is 3:1. Initial dosing levels and dose ranges for the MAD portion of the Phase 1 clinical trial were determined based on observations from the SAD trial portion. Dose escalation occurred after a 59-day safety review committee confirmation for the MAD portion of the Phase 1 clinical trial.

Phase 1 clinical trial design

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Phase 1 Clinical Trial Data-SAD Cohorts 1 Through 4

We have completed a planned interim analysis of safety and pharmacokinetic data from all four SAD cohorts of the trial in 48 healthy volunteer participants. No safety trends of concern were observed, no treatment-related serious adverse events occurred, and CMP-CPS-001 appeared to be well tolerated, with no indication of a maximum tolerated dose at the tested dose levels. All treatment emergent adverse events (“TEAEs”) were Grade 1 (mild) or Grade 2 (moderate), and the two most common TEAEs across all cohorts were headache (six participants) and nausea (four participants). Pharmacokinetic data similarly was observed to be consistent with expectations, demonstrating a dose-dependent increase in exposure with clear separation between groups.

Anticipated Milestones

Dosing has been completed in the first two MAD cohorts, and we have initiated dosing of the third MAD cohort. We expect to report data from the SAD and MAD portions of the clinical trial, including safety, pharmacokinetic and key pharmacodynamic biomarker data, in the fourth quarter of 2025. We also plan to initiate the expansion of the trial of CMP-CPS-001 in Australia into a Phase 1b clinical trial to enroll female OTC heterozygotes in the second quarter of 2025. In addition, we intend to submit a clinical trial application in Europe and to open an additional European clinical trial site, pending regulatory clearance of the clinical trial application.

Planned Clinical Trials

Assuming the successful completion of our ongoing clinical trial and regulatory feedback from regulatory agencies, we plan to utilize a stepwise development approach in which we would initiate one or more 52-week Phase 2/3 clinical trials involving CMP-CPS-001, with the potential for an open-label extension. We anticipate the first of these two Phase 2/3 clinical trials to enroll patients in the first years of life and older who have been diagnosed with an OTC deficiency to be randomized to either our active therapeutic candidate or to placebo. We currently expect that the Phase 2/3 clinical trial would initially start with adults in the United States, and step down by age segment into patients in the first years of life and older as required by regulators. Pediatric dosing timelines, levels, and schedule may differ between U.S. and ex-U.S. regulators. Key endpoints are likely to include responder analysis defined as a reduction and/or maintenance in ammonia levels compared to baseline, diet liberalization, nitrogen scavenger reduction, and increase in ureagenesis, along with a maintenance of no or a decrease in clinical episodes during the treatment period. Assuming a positive assessment of the OTC trial results during the interim analysis, we envision initiating a second Phase 2/3 clinical trial expanding enrollment to include ASS1 and ASL deficient patient populations.

CMP-SYNGAP for SYNGAP1-Related Disorders

Our initial CNS development program, CMP-SYNGAP, aims to address the underlying cause of SYNGAP1-related disorders. CMP-SYNGAP utilizes a novel approach that targets the SYNGAP1 gene at the transcriptional level designed to restore SYNGAP function. We are advancing our CMP-SYNGAP program to address the significant unmet need for these patients by targeting the direct cause of SYNGAP1-related disorders, haploinsufficiency, which we believe is amenable to treatment by targeting SYNGAP1 regRNAs. Based on compelling data across our preclinical studies, including recent primate studies, we have nominated a development candidate, CMP-SYNGAP-01, from this program, and expect to initiate GLP toxicology studies in 2025 to enable the filing of a clinical trial application.

SYNGAP1-Related Disorders

SYNGAP plays a critical role in the development of cognition and proper synaptic function, enabling synaptic plasticity and axon formation through signal attenuation. SYNGAP1-related disorders are a group of neurodevelopmental conditions caused by pathogenic variants in the SYNGAP1 gene leading to a haploinsufficient state that reduces SYNGAP protein levels by as much as 50%. A majority of these SYNGAP1 pathogenic variants, or mutations, are mutations that result in truncation of the protein or destruction of the RNA by nonsense-mediated decay, ultimately resulting in lower protein levels and haploinsufficiency. These disorders can manifest with a variety of symptoms that can include developmental delays, movement disorders and features of autism spectrum disorder. Epilepsy is a common feature of SYNGAP1-related disorders, with seizures usually beginning in early childhood. Nearly all children have some degree of developmental delay and cognitive impairment, though disease symptoms and their severity vary widely. SYNGAP1-related disorders are autosomal dominant with clinical disease presentation if either of the two alleles have a mutation. In most cases the pathogenic variant occurs spontaneously and is not inherited. Patient estimates for SYNGAP1-related disorders vary significantly, with incidence estimates ranging from one to 40 in 100,000 individuals. While we believe that SYNGAP1-related disorders remain underdiagnosed, we estimate that there are approximately 10,000 individuals living

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with these disorders in the United States. The disorders are reported to represent 0.5% to 1.0% of all intellectual disability cases, making them among the most common causes of intellectual disability in patients with epilepsy, and indicating that the patient population may be significantly larger than incidence estimates suggest.

Current Treatments and Their Limitations

There is currently no FDA-approved treatment, disease-modifying or otherwise, for SYNGAP1-related disorders. There is also no definitive treatment protocol, which is dependent on seizure type and severity and other neurological characteristics of the disease. Treatment is often limited to supportive physical, occupational and speech therapy. A combination of anti-seizure medications may be prescribed to treat seizures, though SYNGAP1-related disorders have proven difficult to control with available therapeutics. As many as 50% of patients do not adequately respond to medication in which case implantable devices, such as those for vagus nerve stimulation, may offer incremental therapeutic benefit.

Our Solution

Our CMP-SYNGAP program is a novel approach that targets the SYNGAP1 gene at the transcriptional level to restore SYNGAP function and improve symptoms. We are advancing our CMP-SYNGAP program to address the significant unmet need for these patients by targeting the direct cause of SYNGAP1-related disorders, haploinsufficiency, which we believe is amenable to targeting through regRNAs. As haploinsufficiency characterizes SYNGAP1-related disorders, upregulation of SYNGAP1 gene expression may enable an increase in protein levels which may yield therapeutic benefit, including potential improvements to memory and incidence of seizures. Our CMP-SYNGAP program utilizes an intrathecally delivered ASO for the treatment of SYNGAP1-related disorders. We have identified specific regRNA sequences involved in SYNGAP1 transcription and have leveraged our RAP Platform to generate ASOs that function to increase SYNGAP1 transcription.

Our Preclinical Studies

We are currently pursuing parallel workstreams to identify both tool ASOs for mouse proof-of-concept studies, as well as human-specific ASOs as drug candidates to assess the clinical effect of ASOs on SYNGAP1 levels in both patient-derived neurons and mice expressing human SYNGAP1.

Lead human-specific ASOs have been identified that increase SYNGAP1 mRNA in human neurons in vitro as shown in the figure below (left). In addition, a mouse tool ASO was administered by intracerebroventricular injection to neonatal mice with the goal of confirming an ability to increase Syngap1 expression. Assessment of brain tissue revealed a dose-dependent increase in Syngap1 mRNA levels three weeks post-dose. These findings are presented in the graph below (right). Future studies will evaluate the impact of increased Syngap1 expression on functional deficits caused by haploinsufficiency.

Dose-dependent increase in Syngap1 mRNA in the brains of mice

As part of our assessment of lead human-specific ASOs in human neurons in vitro, we have confirmed that SYNGAP1 patient-derived induced pluripotent stem cell (“iPSC”) neurons exhibit one-half as much SYNGAP1 mRNA as those derived from a familial control iPSC neurons. Two representative lead ASOs demonstrated robust target engagement

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where they increased SYNGAP1 mRNA at least two-fold in both control and mutant neurons, where SYNGAP1 mRNA levels were fully restored to wild-type levels. We are continuing to explore electrophysiological and biochemical phenotypes in iPSC neurons in vitro to link increases in expression to benefits in disease-relevant phenotypes.

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Error bars represent standard deviation of fold change increase in SYNGAP1 mRNA levels; NTC denotes non-targeting control. ASO-7 and ASO-9 denote two lead candidate ASOs of our CMP-SYNGAP program.

Dose-dependent increase in SYNGAP1 protein in the brains of humanized mice

As part of our evaluation of CMP-SYNGAP-01 in a humanized SYNGAP1 mouse model, we assessed its ability to increase SYNGAP1 protein levels following intracerebroventricular injection. The study demonstrated a dose-dependent increase in SYNGAP1 protein across multiple brain regions, with levels rising up to approximately 1.7-fold compared to control. These findings support the potential of CMP-SYNGAP-01 to enhance SYNGAP1 expression, and we continue to investigate the downstream functional benefits associated with this increase.

We have nominated CMP-SYNGAP-01 as our development candidate from this program and expect to initiate GLP toxicology studies in 2025 to enable the filing of a clinical trial application.

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Program for the Treatment of GBA1-related Parkinson’s Disease

We have initiated a new discovery program focused on increasing the expression of the GBA1 gene as a potential treatment for PD. Approximately 5-15% of PD patients harbor mutations in the GBA1 gene, which encodes GCase. We estimate that there are approximately 100,000 PD patients with GBA1 mutations in the United States, representing a meaningful portion of the overall PD community.

GBA1 mutations have been shown to lead to a reduction in GCase activity of approximately 50%, which contributes to the pathological accumulation of toxic substances in the brain, exacerbating disease progression and symptoms. GCase and α-synuclein, the hallmark protein of PD, are part of a positive feedback loop in the brain that accelerates neurodegeneration. Notably, GCase activity is also reduced in sporadic forms of Parkinson’s disease, and we plan to explore the therapeutic potential of increasing GBA1 expression both in patients with GBA1 haploinsufficiency and in a broader subset of PD patients.

Using our RAP Platform, we have identified specific ASOs that target the regRNAs controlling the expression of GBA1. These ASOs have been observed to increase GBA1 expression in in vitro studies. We are continuing to advance our GBA1 discovery program with the objective of selecting a development candidate to progress into preclinical development. We believe that future clinical development of this program will be enabled by established biomarkers and assessment tools commonly used in PD research.

Manufacturing Strategy

We do not own or operate, and currently have no plans to establish, any manufacturing facilities. We rely on third- party contract manufacturers for the manufacture of our product candidate for our clinical trials, and, if we receive marketing approval, we will rely on such third parties for commercial manufacture. In addition, we rely on third parties to package, label, store and distribute our product candidates, and we intend to rely on third parties for our commercial products if marketing approval is obtained. We expect this strategy will enable us to maintain a more efficient infrastructure, avoiding dependence on our own manufacturing facility and equipment, while simultaneously enabling us to focus our expertise on the clinical development and future commercialization of our products. Chemistry, Manufacturing and Controls (“CMC”) is a critical element of the drug development process and involves the various procedures used to assess the physical and chemical characteristics of drug products, to ensure their quality and consistency throughout manufacture. CMC increases in complexity as the development process matures.

License and Collaboration Agreements

Whitehead Institute Patent License Agreement

In October 2019, we and the Whitehead Institute for Biomedical Research (the “Whitehead Institute”) entered into a patent license agreement (as amended in December 2021 and November 2023, the “Whitehead Agreement”) pursuant to which we received a worldwide, royalty-bearing, sublicensable license under certain patent rights owned or controlled by the Whitehead Institute to develop, make, have made, use, sell, offer to sell, lease and import products, and to perform and have performed licensed processes, in each case, in the fields of human and animal therapeutics and diagnostics. The license granted under the Whitehead Agreement included an exclusive license to certain patent rights generally related to, among other things, methods of modulating gene expression using oligonucleotides, and a co-exclusive license to certain patent rights generally relating to, among other things, methods of modulating gene expression by targeting certain genomic sequences.

Under the Whitehead Agreement, the Whitehead Institute retains the right to practice the licensed patent rights for research, teaching, and other educational purposes, including use in third-party sponsored research, and to grant non-exclusive licenses to other nonprofit and academic institutes solely for non-commercial research, teaching, and other educational purposes. The license granted to us under the Whitehead Agreement is also subject to certain rights held by the U.S. government under applicable law with respect to inventions that arose from federal research funding. In addition, the license is subject to a certain non-exclusive license for internal research purposes only that the Whitehead Institute granted to a certain third party, and to certain preexisting rights held by a certain third party who is a party to a certain sponsored research agreement (“SRA”) with the Whitehead Institute. Under the SRA, the Whitehead Institute covenanted not to sue said third party if certain inventions arising under the SRA, or SRA inventions, are dominated by the licensed patent rights and we are thereby excluded from asserting certain patent rights licensed from the Whitehead Institute that cover the SRA inventions against said third party.

We are obligated to use certain efforts to develop one or more products or licensed processes and commercialize the products or licensed processes in a major market. Furthermore, beginning five years from the effective date and subject

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to certain terms and conditions, the Whitehead Agreement requires us to negotiate and potentially issue mandatory sublicenses to a third party under the exclusively licensed patent rights to make, have made, use, sell, offer to sell, or import a product or process that is not directly competitive with a licensed product or licensed process then offered for sale or in bona fide research or development by or on behalf of us.

Under the terms of the Whitehead Agreement, we paid to the Whitehead Institute an upfront license issuance fees of $0.1 million and de minimis additional fees in connection with each of the December 2021 and November 2023 amendments to the agreement that were recorded as research and development expense in our consolidated statement of operations and comprehensive loss. We are also obligated to make annual license maintenance fees under the agreement, pursuant to which we have paid an aggregate of $0.3 million through December 31, 2024. In addition, we are obligated to pay certain filing, prosecution and maintenance fees with respect to certain patent rights licensed to us under the agreement, pursuant to which we have paid an aggregate of $0.3 million through December 31, 2024. We are obligated to pay potential development milestone payments of up to an aggregate of $1.9 million under the terms of the agreement upon the achievement of certain specified contingent events, pursuant to which we have paid an aggregate of $0.2 million through December 31, 2024. In addition, if we successfully commercialize a product under the Whitehead Agreement, then we will be required to pay the Whitehead Institute tiered royalties at percentage rates ranging from less than one percent to the mid-single digits of net sales or of running royalties of net sales, subject to specified reductions, until either the last-to-expire valid claim of a Whitehead Institute patent covering the product or seven years after the first commercial sale, in each case on a product-by-product and country-by-country basis.

The expected termination of the royalty obligations will depend on factors such as the availability and application of patent term extensions for the licensed patents in the licensed territory. The Whitehead Agreement will remain in effect until voluntarily terminated by the company and may be earlier terminated by the Whitehead Institute if the company fails to pay any amounts due under the agreement or materially breaches the agreement and fails to cure such breach. The last to expire patent, if issued, under the Whitehead Agreement, is expected to expire in 2043.

Competition

The biotechnology and pharmaceutical industries have made substantial investments in recent years into the rapid development of novel treatments for metabolic and CNS-related diseases and disorders.

We face substantial competition from multiple sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies and public and private research institutions. Our competitors compete with us on the level of the technologies employed, or on the level of development of product candidates. In addition, many small biotechnology companies have formed collaborations with large, established companies to (i) obtain support for their research, development and commercialization of products or (ii) combine several treatment approaches to develop longer lasting or more efficacious treatments that may potentially directly compete with our current or future product candidates. We anticipate that we will continue to face increasing competition as new therapies and combinations thereof, technologies, and data emerge within the field of antisense oligonucleotide therapeutics and, furthermore, within the treatment of metabolic and CNS-related diseases and disorders.

In addition to the current standard-of-care treatments to address the diseases we are targeting in therapeutic development programs, numerous commercial and academic preclinical studies and clinical trials are being undertaken by a large number of parties to assess novel technologies and product candidates.

For the broad treatment of patients with UCDs, we will compete with Amgen Inc., who has commercialized Ravicti, a nitrogen scavenger. Other therapeutics in development are focused on patients with OTC deficiency only, where we will potentially compete with Ultragenyx Pharmaceutical Inc., Arcturus Therapeutics Holdings Inc., and iECURE, Inc. (“iECURE”), among others, assuming they are successful in clinical development. Ultragenyx Pharmaceutical Inc. is developing its potential therapy in OTC patients aged 12 and older; and iECURE is initially targeting neonatal patients only. Companies that compete with us directly on the level of the development of product candidates targeting SYNGAP1-related disorders include Stoke Therapeutics, Inc. and Praxis Precision Medicines, Inc., along with other companies with programs currently in discovery stages of development, such as Tevard Biosciences, Inc., Regel Therapeutics, Inc., and Quiver Bioscience Inc. For the treatment of GBA1 Parkinson’s Disease, we will potentially compete with Gain Therapeutics, Inc., Vanqua Bio, Inc., BIAL-Portela & Ca., S.A., and Prevail Therapeutics Inc. (a subsidiary of Eli Lilly and Company), assuming they are successful in clinical development, along with other companies with programs currently in preclinical stages of development. Companies engaged in the commercialization and development of antisense oligonucleotides as therapeutics include Alnylam Pharmaceuticals, Inc. and Ionis Pharmaceuticals Inc.

Many of our competitors, either alone or in combination with their respective strategic partners, have significantly greater financial resources and expertise in research and development, manufacturing, the regulatory approval process, and

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marketing than we do. Mergers and acquisition activity in the pharmaceutical, biopharmaceutical and biotechnology sector is likely to result in greater resource concentration among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through sizeable collaborative arrangements with established companies. These competitors also compete with us in recruiting and retain qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Our commercial opportunity could be reduced or eliminated if one or more of our competitors develop and commercialize products that are safer, more effective, better tolerated, or of greater convenience or economic benefit than our proposed product offering. Our competitors also may be in a position to obtain FDA or other regulatory approval for their products more rapidly, resulting in a stronger or dominant 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 product safety, efficacy, convenience and treatment cost.

Intellectual Property

We believe that our intellectual property estate is a strategic asset that has the potential to provide us with a competitive advantage. We strive to protect and enhance the proprietary technology, inventions and improvements that we believe are important to our business, including pursuing, maintaining and defending patent rights, whether developed internally or licensed from third parties. We also rely on trade secrets and know-how relating to our proprietary technology and product candidates, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary and intellectual property position. We additionally may rely on data exclusivity, market exclusivity and patent term extensions, when available, and plan to seek and rely on regulatory protection afforded through orphan drug designations. Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for our technology, inventions, and improvements; to preserve the confidentiality of our trade secrets; to defend and enforce our proprietary rights, including our patents; and to operate without infringing on the valid and enforceable patents and other proprietary rights of third parties.

Our wholly owned and in-licensed patent portfolio includes patent rights covering various aspects of our RAP Platform and current product candidates, and certain legacy programs the company is no longer pursuing. As of December 31, 2024, our patent portfolio consists of 25 patent families, including two owned U.S. issued patents, 16 in-licensed U.S. issued patents, 24 in-licensed foreign issued patents, 25 owned or in-licensed U.S. pending patent applications (including provisional patent applications), 51 owned or in-licensed foreign pending patent applications, and three owned or in-licensed pending Patent Cooperation Treaty applications (“PCT applications”) that have not entered national phase. Our objective is to continue to expand our patent portfolio to protect our technology, inventions, improvements and current and future product candidates. Examples of the product candidates and technology areas covered by our intellectual property portfolio are described below.

Program-related Intellectual Property

The program-related patent rights in our patent portfolio provide coverage for product candidates designed to address certain diseases and disorders. The program-related patent applications for our lead programs include those described below. Each of the program-related patent applications described below is wholly owned by us.

CMP-CPS-001 Program

Our lead product candidate, CMP-CPS-001, is designed to amplify CPS1 expression. As of December 31, 2024, we owned two U.S. non-provisional patent applications and 15 foreign patent applications in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore and South Africa relating to compositions of matter, including CMP-CPS-001, designed to amplify CPS1 expression, and methods of treating UCDs. Each of these patent applications are national or regional phase applications based on a PCT application filed in December 2022, and claiming priority to two separate U.S. provisional patent applications, the earliest of which was filed in December 2021. We expect patents issuing from or claiming priority to these patent applications, if any, to expire in 2042, excluding any patent term adjustments or extensions.

CMP-SYNGAP Program

Our CMP-SYNGAP program aims to amplify SYNGAP1 expression. As of December 31, 2024, we owned one pending PCT application filed in December 2023, which claims priority to a U.S. provisional patent application filed in December 2022, as well as two pending U.S. provisional patent applications filed in June 2024, each relating to

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compositions of matter, including ASOs designed to amplify SYNGAP1 expression, and methods of treating SYNGAP1-related disorders. We expect patents claiming priority to these patent applications, if any, to expire between 2043 and 2045, excluding any patent term adjustments or extensions.

In addition to our programs listed above, we also have patent applications relating to ASO compositions directed to regRNAs involved in the transcription of additional gene targets and their use for treating additional diseases or disorders that may benefit from upregulation of gene expression. As of December 31, 2024 we owned one U.S. non-provisional patent application and ten foreign patent applications in Australia, Canada, China, Europe, Hong Kong, Israel, India, Japan and Mexico relating to compositions and methods for treating UCDs. Each of these patent applications are national or regional phase applications based on a PCT application filed in September 2022, which claims priority to two separate provisional U.S. patent applications, the earliest of which was filed in September 2021. We expect patents issuing from or claiming priority from these pending patent applications, if any, to expire in 2042, excluding any patent term adjustments or extensions. As of December 31, 2024, we owned one U.S. non-provisional patent application and six foreign patent applications in Australia, Canada, Europe, Israel, Japan, and Mexico relating to compositions and methods for treating several diseases and disorders including frontotemporal dementia. Each of these pending patent applications are national or regional phase applications based on a PCT application filed in June 2023, claiming priority to three separate U.S. provisional patent applications, the earliest of which was filed in June 2022. We expect patents issuing from or claiming priority from these pending patent applications, if any, to expire in 2043, excluding any patent term adjustments or extensions. As of December 31, 2024, we owned one PCT application filed in November 2023, claiming priority to a U.S. provisional patent application filed in November 2022, which relates to compositions and methods for treating cholestatic liver disease. We expect patents claiming priority from this pending application, if any, to expire in 2043, excluding any patent term adjustments or extensions.

Platform-related Intellectual Property

In addition to the program-related intellectual property, our intellectual property portfolio includes know-how and patent applications directed to our RAP Platform and other technologies developed internally or in-licensed from the Whitehead Institute. Exemplary platform technologies that are subject to such patent applications include methods of modulating gene expression using oligonucleotides, methods for characterizing enhancer-promoter pairs, and methods for modulating condensate-dependent transcription. These platform technologies, and our intellectual property portfolio related thereto, relate broadly to our existing product candidates and those we may develop in the future.

We continually assess and refine our intellectual property strategy as we develop new product candidates and technologies. To that end, we expect to file additional patent applications in support of current and new product candidates as well as new technologies.

Our ability to stop third parties from making, using, selling, marketing, offering to sell, importing, and commercializing our product candidates and technology is dependent upon the extent to which we have rights under valid and enforceable patents and other intellectual property rights that cover our product candidates and technology. We cannot predict whether or when our owned or licensed pending and future patent applications will result in the issuance of patents, nor can we predict whether any patents that may be granted to us in the future will be commercially useful in protecting our product candidates and technology.

The terms of individual patents depend 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 patent term is 20 years from the earliest date of filing a non-provisional patent application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office (“USPTO”) in granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.

In the United States, the term of a patent that covers an FDA-approved drug may be eligible for a patent term extension under the Hatch-Waxman Act as compensation for the loss of patent term during the FDA regulatory review process. The period of extension may be up to five years beyond the expiration of the patent, but cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension may be extended, and a given patent may only be extended once. Similar provisions are available in Europe and in certain other jurisdictions to extend the term of a patent that covers an approved drug. If our product candidates receive approval, we intend to apply for patent term extensions, if available, to extend the term of patents that cover the approved product candidates. We also intend to seek patent term extensions in any jurisdiction where they are available, however there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment that such extensions should be granted, and if granted, the length of such extensions.

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In addition to patent protection, we also rely on know-how and trade secret protection for our proprietary information to develop and maintain our proprietary and intellectual property position. However, trade secrets can be difficult to protect. Although we take steps to protect our proprietary information, including entering into agreements with our employees, corporate collaborators, external scientific collaborators, contract manufacturers, consultants, advisors, and other third parties, such individuals may breach such agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. In addition, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our proprietary information. As a result, we may be unable to meaningfully protect our know-how, trade secrets and proprietary information.

Government Regulation in the United States

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, testing, manufacture, pricing, reimbursement, sales, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting and import and export of drugs. We, along with our contract manufacturers (“CMOs”), contract research organizations CROs, and third-party vendors, will be required to satisfy these requirements in each of the countries in which we wish to conduct studies or seek approval of our product candidates. The process of obtaining marketing approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources. The regulatory requirements applicable to drug development, approval, and marketing are subject to change, and regulations and administrative guidance often are revised or reinterpreted by the agencies in ways that may have a significant impact on our business. We cannot predict whether legislative changes will be enacted or if regulatory authorities’ guidance or interpretations will change.

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”), as amended, and its implementing regulations. Drugs are also subject to other federal, state and local statutes and regulations. FDA clearance of an Investigational New Drug (“IND”) application must be obtained before commencing clinical testing of a new drug in the U.S. FDA approval also must generally be obtained before a drug may be legally marketed in the United States.

Failure to comply with applicable regulatory requirements at any time during the product development, approval, or post-approval processes, could result in delays in the conduct of clinical trials or regulatory review and approval, as well as 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, issuance of clinical holds for planned or ongoing studies, suspension or revocation of existing product approvals, issuance of warning or untitled letters, adverse publicity, product withdrawals or recalls, marketing restrictions, product seizures, total or partial suspensions of manufacturing or distribution, import detentions or refusals, injunctions, fines, government investigations, civil penalties or criminal prosecution.

U.S. Development Process

The process for seeking approval to market and distribute a new drug in the United States generally involves the following:

•completion of nonclinical laboratory tests and animal studies according to GLP requirements and applicable requirements for the humane use of laboratory animals or other regulations;

•completion of the manufacture, under current Good Manufacturing Practices (“cGMPs”), 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 application, which must become effective before human clinical trials may begin;

•approval by an institutional review board (“IRB”) reviewing each clinical site before each clinical trial may be initiated;

•performance of adequate and well-controlled human clinical trials according to Good Clinical Practices (“GCPs”), and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the drug for its intended use;

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•preparation and submission to the FDA of a New Drug Application (“NDA”) requesting marketing approval for one or more proposed indications, including submission of detailed information on the chemistry, manufacture and quality controls of the product in clinical development and proposed labeling;

•satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the drug will be produced, including those of third parties, to assess compliance with cGMP requirements;

•potential FDA audit of the nonclinical and clinical study sites that generated the data in support of the NDA to assess compliance with GLP and GCP and the integrity of clinical data in support of the NDA;

•payment of user fees under the Prescription Drug User Fee Act (“PDUFA”), unless exempted;

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

•compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy (“REMS”), and the potential requirement to conduct post approval studies.

Before testing any drug in humans, the product candidate enters the preclinical testing stage. Nonclinical tests include laboratory evaluations of drug 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 nonclinical studies is subject to federal and state regulation, including GLPs. The clinical study sponsor must submit the results of the nonclinical tests, together with manufacturing information, analytical data, any available clinical data or literature, and a proposed clinical protocol, to the FDA as part of the IND. Some nonclinical testing typically continues after the IND is submitted.

An IND is an exemption from the FDCA that allows an unapproved product to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational product to humans. The IND must become effective before clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions about the product or conduct of the proposed clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks. If the FDA raises concerns or questions either during the initial 30-day period, or at any time during the IND review process, it may choose to impose a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may or may not result in FDA authorization to begin a clinical trial, or to begin a clinical trial on the terms originally specified by the sponsor in the IND. A separate submission to an existing IND must also be made for each successive clinical trial conducted, and the FDA must grant permission, either explicitly or implicitly by not objecting, before each clinical trial can begin.

Clinical trials may involve the administration of the drug product candidate to healthy volunteers or subjects under the supervision of qualified investigators. Clinical trials involving some products for certain diseases, including some rare diseases may begin with testing in patients with the disease. 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 to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and any amendments to the protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research subjects or his or her legal representative provide informed consent. Further, each clinical trial must be reviewed and approved by an independent IRB, at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of study participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

Some clinical trials also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or data monitoring committee. This group may recommend continuation of the trial as planned, changes in trial conduct, or cessation of the trial at designated check points based on certain data from the trial to which only the group has access.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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•Phase 1. The drug is initially introduced into healthy human subjects and tested for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics. In the case of some products for rare diseases, the initial human testing is often conducted in patients.

•Phase 2. The drug is evaluated in a limited patient population to identify possible adverse effects and safety risks, preliminarily evaluate the efficacy of the product for specific targeted diseases, and determine dosage tolerance, optimal dosage, and dosing schedule. Multiple Phase 2 clinical trials may be conducted by the sponsor to obtain information prior to beginning larger and more costly Phase 3 clinical trials.

•Phase 3. Phase 3 clinical trials typically proceed if the Phase 2 clinical trials demonstrate that a dose range of the product candidate is potentially effective and has an acceptable safety profile. Phase 3 clinical trials are generally undertaken within an expanded patient population to further evaluate dosage, provide substantial evidence of clinical efficacy and further test for safety, in a diverse patient population at multiple, geographically dispersed clinical trial sites. A well-controlled, statistically robust Phase 3 trial may be designed to deliver the data that regulatory authorities will use to decide whether or not to approve, and, if approved, how to appropriately label a product candidate.

In some cases, the FDA may approve an NDA for a product but require the sponsor to conduct additional clinical trials to further assess the product’s safety and effectiveness after approval. Such post-approval trials are typically referred to as Phase 4 clinical trials. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and to document a clinical benefit for products approved under accelerated approval regulations. The failure to exercise due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.

During all phases of clinical development, the FDA requires extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of serious suspected adverse reactions over those listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for such reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within 7 calendar days after the sponsor’s initial receipt of the information. Phase 1, Phase 2, and Phase 3 clinical trials may not be completed successfully within any specified period, if at all. At any time while clinical trials are ongoing under the IND, the FDA may impose a partial or complete clinical hold. Clinical holds may be imposed when there is concern for patient safety, and may be a result of new data, findings, or developments in clinical, nonclinical, and/or chemistry, manufacturing and controls or where there is non-compliance with regulatory requirements. If the FDA imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements and either the IRB or the data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development.

Concurrent with clinical trials, companies must 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.

There are also various laws and regulations regarding laboratory practices, the experimental use of animals, and the use and disposal of hazardous or potentially hazardous substances in connection with the research. In each of these areas, the FDA and other regulatory authorities have broad regulatory and enforcement powers, including the ability to levy fines and civil penalties, suspend or delay issuance of approvals, seize or recall products, and withdraw approvals.

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Information about certain clinical trials must be submitted within specific timeframes for public dissemination on the clinicaltrials.gov website. Sponsors or distributors of investigational products for the diagnosis, monitoring, or treatment of one or more serious diseases or conditions must also have a publicly available policy on evaluating and responding to requests for expanded access requests.

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. When a foreign clinical trial is conducted under an IND, all FDA IND requirements must be met unless waived. 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 conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary. The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data. They further help ensure that non-IND foreign trials are conducted in a manner comparable to that required for clinical trials in the United States.

U.S. Review and Approval Processes

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 package 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 product to the satisfaction of the FDA. FDA must generally approve an NDA before a drug may be marketed in the United States.

The FDA reviews all submitted NDAs 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 drug is safe and effective for the indications sought and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity. The FDA likely will reanalyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the review process. Under the goals and polices agreed to by the FDA under PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of an NDA and respond to the applicant, and six months from the filing date of an 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. Each NDA must be accompanied by a substantial PDUFA user fee, which FDA adjusts 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.

The FDA may refer an application for a novel drug or drug that presents difficult questions of safety and efficacy 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 generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical or preclinical testing in order for the FDA to reconsider the application. The NDA sponsor will have one year to submit to the FDA

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information that represents a complete response to the deficiencies described in the letter. The FDA will then re-review the application, taking into consideration the response and determine whether the application meets the 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 drug with specific prescribing information for specific indications.

Even if the FDA approves a product, it may limit the approved indications for use of the product and require that contraindications, warnings or precautions be included in the product labeling. Additionally, the FDA may require post-approval studies, including Phase 4 clinical trials, to further assess a drug’s efficacy or safety after approval. The agency may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS. A REMS can include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk-minimization tools, 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.

Post-approval Requirements

Maintaining substantial compliance with applicable federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources. Rigorous and extensive FDA regulation of drugs continues after approval, particularly with respect to cGMP. If we obtain regulatory approval for any of our products, we will be required to comply with all post-approval regulatory requirements as well as any specific post-approval requirements that the FDA have imposed as part of the approval process. We will be required to report certain adverse reactions and production problems to the FDA, provide updated safety and efficacy information, and comply with requirements concerning advertising and promotional labeling requirements and record-keeping requirements. Further, if there are any modifications to the drug, including changes in indications, labeling or manufacturing processes or facilities, we may be required to submit and obtain FDA approval of a new NDA or NDA supplement, which may require the generation of additional data or the conduct of additional preclinical studies and clinical trials. Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

We will rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of any products that we may commercialize. Manufacturers of our products are required to comply with applicable requirements in the cGMP regulations, including quality control and quality assurance and maintenance of records and documentation.

Manufacturing facilities are required to register their establishments with the FDA and certain state agencies and are subject to periodic inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements. Failure to comply with statutory and regulatory requirements may result in the issuance of an FDA Form 483 notice of inspectional observations, untitled letter, warning letter, or suspension of manufacturing or other legal or regulatory action, such as product seizures, injunctions, civil penalties or criminal prosecution. Additionally, defects in manufacturing of commercial products can result in product recalls.

Systems need to be put in place to record and evaluate adverse events reported by health care providers and patients and to assess product complaints. 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:

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

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

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

•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;

•injunctions or the imposition of civil or criminal penalties; and

•consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs; or mandated modification of promotional materials and labeling and issuance of corrective information.

The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities and promotional activities involving the internet and social media. Promotional claims about a drug’s safety or effectiveness are prohibited before the drug is approved. After approval, a drug product generally may not be promoted for uses or patient populations that are not approved by the FDA, as reflected in the product’s prescribing information (known as “off-label” use). In the United States, healthcare professionals are generally permitted to prescribe drugs for such off-label uses because the FDA does not regulate the practice of medicine. However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use.

If a company, including any agent of the company or anyone speaking on behalf of the company, is found to have promoted off-label uses, the company may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the DOJ, or the Office of the Inspector General of the Department of Health and Human Services (“HHS”), as well as state authorities. This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.

Orphan Drug Designation

Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation (“ODD”) to a drug intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug available in the United States for this type of disease or condition will be recovered from sales of the product. ODD must be requested before submitting a marketing application. After the FDA grants ODD, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. ODD does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has ODD receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances, such as not being able to supply the product for patients or showing clinical superiority to the product with orphan exclusivity.

Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. Orphan product exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease. If a drug designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity.

The FDA has historically taken the position that the scope of orphan exclusivity aligns with the approved indication or use of a product, rather than the disease or condition for which the product received orphan designation. However, in Catalyst Pharms., Inc. v. Becerra, 14 F.4th 1299 (11th Cir. 2021), the court disagreed with this position, holding that orphan-drug exclusivity blocked the FDA’s approval of the same drug for all uses or indications within the same orphan-designated disease. On January 24, 2023, the FDA published a notice in the Federal Register to clarify that the FDA intends to continue to apply its longstanding interpretation of the regulations to all matters outside of the scope of the Catalyst order and will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved. It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

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Rare Pediatric Disease Priority Review Voucher Program

Under the Rare Pediatric Disease Priority Review Voucher program, the FDA may award a priority review voucher to the sponsor of an approved marketing application for a drug that is for the prevention or treatment of a rare pediatric disease. The sponsor can use the voucher to obtain priority review for a subsequent human drug or biologic application. The sponsor can also transfer or sell the voucher to another company.

To be eligible for a rare pediatric disease priority review voucher, the NDA must be for a drug that prevents or treats a “rare pediatric disease” defined to mean a serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States, or affects 200,000 or more individuals in the United States but for which there is no reasonable expectation that the cost of developing the drug will be recovered from sales of the drug in the United States. Additionally, the NDA must be deemed eligible for priority review, rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population, not seek approval for a different adult indication in the original rare pediatric disease product application and be for a drug that does not include a previously approved active ingredient. A sponsor may request rare pediatric disease designation from the FDA prior to the submission of the NDA; however rare pediatric disease designation does not guarantee that a sponsor will receive a priority review voucher upon approval of the NDA.

The Rare Pediatric Disease Priority Review Voucher program was originally set to expire in October 2020 but was extended for an additional six years. Under the current statutory sunset provisions, the FDA may only award a rare pediatric disease priority review voucher if a sponsor has received rare pediatric disease designation for the drug before December 20, 2024, and the NDA for the product is approved before September 30, 2026. After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers, unless the program is extended.

Expedited Review and Approval Programs

The FDA has various programs, including Fast Track designation, priority review, accelerated approval, and breakthrough therapy designation, that are intended to expedite or simplify the process for the development and FDA review of drugs that are intended for the treatment of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs. The purpose of these programs is to provide important new drugs to patients earlier than under standard FDA review procedures. To be eligible for a Fast Track designation, the FDA must determine, based on the request of a sponsor, that a drug is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need. The FDA will determine that a product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety factors. In addition to other benefits, such as the ability to have greater interactions with the FDA, the FDA may initiate review of sections of a Fast Track BLA before the application is complete, a process known as rolling review.

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CAMP · 10-K · period ended 2024-12-31

Item 1. Business

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