Camp4 Therapeutics Corp

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.

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.

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

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. 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: Potential Treatment 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 treatment of the most prevalent 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, which is then excreted from the body. The inability of the body to properly metabolize ammonia leads to the accumulation of toxic systemic levels in circulation, ultimately resulting in severe health outcomes, such as neurologic disability, seizure and death. UCDs occur across all age groups, from infants to adults, and mild symptoms may go unnoticed until a stressor, such as illness, surgery, protein consumption or environmental stress, overwhelms compensatory functions, resulting in hyperammonemic crisis, or extremely high levels of ammonia. The incidence of UCDs in the United States is estimated to be approximately 1 in 35,000 births, with similar prevalence and incidence estimated for Europe. The most common UCD, accounting for approximately 60% of UCD diagnoses, is ornithine transcarbamylase (“OTC”) deficiency, caused by mutations in the OTC gene. The next two most common genetic subtypes are caused by mutations in the genes coding for the enzymes argininosuccinate lyase (“ASL”), and argininosuccinate synthetase (“ASS1”), deficiencies which affect approximately 16% and 14% 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.

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 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.

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.

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 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 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 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 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 inin vitro andin vivo 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 anin 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

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 15 N-labeled ammonium chloride. Thirty minutes later, blood was drawn to measure total ammonia and 15 N-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

**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.

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

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 15 N-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 15 N-ammonia challenges before dosing on days 8 and 15, and then again on day 22. Total ammonia and 15 N-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%).

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

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

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

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 13 C-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.13 C-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 13 C-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 13 C-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 13 C-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 13 C-sodium acetate, and blood was drawn at eight time points over a four-hour period. The concentration of 13 C-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

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

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 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 neuronsin 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 neuronsin 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 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 neuronsin vitro to link increases in expression to benefits in disease-relevant phenotypes.

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.

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 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 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 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.

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;

•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:

•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.

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 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;

•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.

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.

The FDA may give a priority review designation, such as a rare pediatric disease designation, to drugs that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. A priority review means that the goal for the FDA to review an application is six months, rather than the standard review of ten months under current PDUFA guidelines. Most products that are eligible for Fast Track designation may also be considered appropriate to receive a priority review. In addition, drugs studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval and may be approved on the basis of adequate and well-controlled clinical trials establishing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require a sponsor of a drug receiving accelerated approval to perform adequate and well-controlled post-marketing studies to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical endpoint. Under the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product. In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or publication within 120 days of marketing approval be submitted to the agency for review during the pre-approval review period.

Moreover, a sponsor can request designation of a product candidate as a “breakthrough therapy.” A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Drugs designated as breakthrough therapies are also eligible for accelerated approval. The FDA must take certain actions, such as holding timely meetings and providing advice, intended to expedite the development and review of an application for approval of a breakthrough therapy.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decides that the time period for FDA review or approval will not be shortened. Furthermore, fast-track designation, priority review, accelerated approval, and breakthrough therapy designation do not change the standards for approval and may not ultimately expedite the development or approval process.

Pediatric Information and Pediatric Exclusivity

The Pediatric Research Equity Act (“PREA”) requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, as amended, certain NDAs and NDA supplements must contain data that can be used to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of pediatric data or full or partial waivers. The FDCA requires that a sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan (“PSP”) within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 study. The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any deferral or waiver requests. The FDA and the sponsor must reach an agreement on the PSP. A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation. The FDA is required to send a PREA non-compliance letter to sponsors who have failed to submit pediatric assessments required under PREA, seek or obtain a deferral or deferral extension, or request approval for a required pediatric formulation. The FDA publicly posts such PREA non-compliance letters as well as the sponsor’s response.

A drug can also obtain pediatric market exclusivity in the U.S. Pediatric exclusivity, if granted, adds six months to existing marketing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Marketing Exclusivity

Market exclusivity provisions authorized under the FDCA can delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application (“ANDA”), or an NDA submitted under Section 505(b)(2), or 505(b)(2) NDA, submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all of the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of marketing exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

In addition, pediatric exclusivity and orphan drug exclusivity, as described above, may offer a six-month or seven-year period of exclusivity, respectively, except in certain circumstances.

Patent Term Restoration and Extension

Depending upon the timing, duration and specifics of FDA approval of our product candidates, some of a sponsor’s U.S. patents may be eligible for limited patent term extension (“PTE”) under the Hatch-Waxman Amendments. As compensation for patent term lost during product development and the FDA regulatory review process, the Hatch-Waxman Amendments permit a patent restoration term, which is limited to a maximum of five years, or less if the extended patent term would exceed 14 years after the date of the regulatory approval of the product. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA, less any time the sponsor did not act with due diligence during the period and the approval of that application less any time the sponsor did not act with due diligence during the period. Only one patent applicable to an approved drug or drug product is eligible for the extension, only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended, and the application for the extension must be submitted prior to the expiration of the patent. Moreover, a given patent may only extended once based on a single product. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, we may intend to apply for restoration of a patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA. However, we may not receive an extension if we fail to exercise due diligence during the testing phase or regulatory review process, fail to apply within applicable deadlines, fail to apply prior to expiration of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. There can be no assurance that we will benefit from any PTE or favorable adjustment to the term of any of our patents.

Regulation Outside of the United States

In addition to regulations in the United States, we are subject to a variety of regulations in other jurisdictions governing clinical studies, commercial sales, and distribution of our products. Most countries outside of the United States require that clinical trial applications be submitted to and approved by the local regulatory authority for each clinical study.

Government Regulation in the European Union

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

The assessment of applications for clinical trials is divided into two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation). Part I is assessed by a coordinated review by the competent authorities of all European Union Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned) of a draft report prepared by a Reference Member State. Part II is assessed separately by each Member State concerned. The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the Member State concerned, however overall related timelines are defined by the Clinical Trials Regulation. The new Clinical Trials Regulation also provides for simplified reporting procedures for clinical trial sponsors.

In addition, whether or not we obtain FDA approval for a product, we must obtain approval of a product by the comparable regulatory authorities of countries outside the United States before we can commence marketing of the product in those countries. The approval process and requirements vary from country to country, so the number and type of nonclinical, clinical, and manufacturing studies needed may differ, and the time may be longer or shorter than that required for FDA approval.

To obtain regulatory approval of our medicinal products under the European Union regulatory system, we are required to submit a marketing authorization application (“MAA”) to be assessed in the centralized procedure. The centralized procedure allows applicants to obtain a marketing authorization (“MA”) that is valid throughout the European Union, and the additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway) (“EEA”). It is compulsory for medicinal products manufactured using biotechnological processes, orphan medicinal products, advanced therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and human products containing a new active substance which is not authorized in the European Union and which is intended for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, auto-immune and other immune dysfunctions, viral diseases or diabetes. The centralized procedure is optional for any other products containing new active substances not authorized in the European Union or for products which constitute a significant therapeutic, scientific, or technical innovation or for which a centralized authorization is in the interests of patients at European Union level. When a company wishes to place on the market a medicinal product that is eligible for the centralized procedure, it sends an application directly to the EMA, to be assessed by the Committee for Medicinal Products for Human Use (“CHMP”). The CHMP is responsible for conducting the assessment of whether a medicine meets the required quality, safety, and efficacy requirements, and whether the product has a positive risk/benefit profile. The procedure results in a European Commission decision, which is valid in all European Union Member States. The centralized procedure is as follows: full copies of the MAA are sent to a rapporteur and a co-rapporteur designated by the competent EMA scientific committee. They coordinate the EMA’s scientific assessment of the medicinal product and prepare draft reports. Once the draft reports are prepared (other experts might be called upon for this purpose), they are sent to the CHMP, whose comments or objections are communicated to the applicant. The rapporteur is therefore the privileged interlocutor of the applicant and continues to play this role, even after the MA has been granted.

The rapporteur and co-rapporteur then assess the applicant’s replies, submit them for discussion to the CHMP, and taking into account the conclusions of this debate, prepare a final assessment report. Once the evaluation is completed, the CHMP gives a favorable or unfavorable opinion as to whether to grant the authorization. When the opinion is favorable, it shall include the draft summary of product characteristics (“SmPC”), the package leaflet, and the texts proposed for the various packaging materials. The time limit for the evaluation procedure is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP). The EMA then has 15 days to forward its opinion to the European Commission, which will make a binding decision on the grant of an MA within 67 days of the receipt of the CHMP opinion.

There are two other procedures in the European Union for the grant of an MA in multiple European Union Member States. The decentralized procedure provides for approval by one or more other (“Concerned Member States”) of an assessment of an application performed by one Member State, known as the Reference Member State. Under this procedure, an applicant submits an application, or dossier, and related materials including a draft SmPC, and draft labeling and package leaflet, to the Reference Member State and Concerned Member States. The Reference Member State prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application. Within 90 days of receiving the Reference Member State’s assessment report, each Concerned Member State must decide whether to approve the assessment report and related materials. If a Member State cannot approve the assessment report and related materials on the grounds of potential serious risk to the public health, the disputed points may eventually be referred to the European Commission, whose decision is binding on all Member States. Where a product has already been authorized for marketing in a European Union Member State, this national MA can be recognized in other Member States through the mutual recognition procedure.

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

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

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

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

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

A pediatric investigation plan (“PIP”) in the European Union is aimed at ensuring that the necessary data are obtained to support the authorization of a medicine for children, through studies in children. All applications for MAs for new medicines have to include the results of studies as described in an agreed PIP, unless the medicine is exempt because of a deferral or waiver. This requirement also applies when an MA holder wants to add a new indication, pharmaceutical form, or route of administration for a medicine that is already authorized and covered by intellectual property rights. Several rewards and incentives for the development of pediatric medicines for children are available in the European Union. Medicines authorized across the European Union with the results of studies from a PIP included in the product information are eligible for an extension of their supplementary protection certificate (“SPC”) by six months (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to two years before the SPC expires). This is the case even when the studies’ results are negative. For orphan medicinal products, the incentive is an additional two years of market exclusivity. Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines. Medicines developed specifically for children that are already authorized but are not protected by a patent or supplementary protection certificate are eligible for a pediatric-use MA (“PUMA”). If a PUMA is granted, the product will benefit from ten years of market protection as an incentive.

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

The aforementioned European Union rules are generally applicable in the EEA. The United Kingdom left the European Union on January 31, 2020, and the United Kingdom and the European Union have concluded a trade and cooperation agreement (“TCA”), which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of United Kingdom and European Union pharmaceutical regulations. At present, Great Britain has implemented European Union legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended). Except in respect of the new European Union Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with current European Union medicines regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the European Union and the TCA does not provide for mutual recognition of United

Kingdom and European Union pharmaceutical legislation. However, notwithstanding that there is no wholesale recognition of European Union pharmaceutical legislation under the TCA, under a new framework mentioned below which will be put in place by the Medicines and Healthcare products Regulatory Agency (“MHRA”), the United Kingdom’s medicines regulator, from January 1, 2024, the MHRA has stated that it will take into account decisions on the approval of MAs from the EMA (and certain other regulators) when considering an application for a Great Britain MA.

On February 27, 2023, the United Kingdom government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework.” This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the United Kingdom. In particular, the MHRA will be responsible for approving all medicinal products destined for the United Kingdom market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland. A single United Kingdom-wide MA will be granted by the MHRA for all medicinal products to be sold in the United Kingdom, enabling products to be sold in a single pack and under a single authorization throughout the United Kingdom. The Windsor Framework was approved by the European Union-United Kingdom Joint Committee on March 24, 2023, so the United Kingdom government and the European Union will enact legislative measures to bring it into law.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, an accelerated assessment procedure and new routes of evaluation for novel products and biotechnological products. All existing European Union MAs for centrally authorized products were automatically converted (grandfathered) into United Kingdom MAs free of charge on January 1, 2021. For a period of three years from January 1, 2021, the MHRA may rely on a decision taken by the European Commission on the approval of a new MA in the centralized procedure, in order to more quickly grant a new Great Britain MA. A separate application will, however, still be required. On January 24, 2023, the MHRA announced that a new international recognition framework will be put in place from January 1, 2024, which will have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new Great Britain MA.

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

Government Regulation in Australia

Our Phase 1 clinical trial for CMP-CPS-001 is being conducted in Australia. The Therapeutic Goods Administration (“TGA”) and the National Health and Medical Research Council (“NHMRC”) set the GCP requirements for clinical research in Australia.

Compliance with the regulations, standards and codes set by the TGA and NHMRC is mandatory. Under the Therapeutic Goods Act 1989 (Cth) and the Therapeutic Goods Regulations 1990 (Cth), it is a condition (amongst other conditions) of all clinical trials involving investigational medicinal products to comply with the National Statement on Ethical Conduct in Research Involving Humans, published by the NHMRC (the National Statement), and the Guideline for Good Clinical Practice published by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH Guidelines”). The ICH Guidelines have been adopted in Australia, and must be complied with across all fields of clinical research involving therapeutic goods, including those related to pharmaceutical quality, nonclinical and clinical data requirements and trial designs. The basic requirements for preclinical data to support a first-in-human trial under ICH Guidelines are applicable in Australia. Requirements related to adverse event reporting in Australia are generally similar to those required in other major jurisdictions, although reporting timeframes may differ to other jurisdictions.

Clinical trials conducted using “unapproved therapeutic goods” in Australia, being those which have not yet been evaluated by the TGA for quality, safety and efficacy (and including unapproved indications of therapeutic goods which have otherwise been approved for use in Australia) must occur pursuant to either the Clinical Trial Notification Scheme (“CTN Scheme”) or the Clinical Trial Approval Scheme (“CTA Scheme”). In each case, the trial is supervised by a Human Research Ethics Committee (“HREC”), an independent review committee constituted in accordance with the National Statement that ensures the protection of rights, safety and well-being of human subjects involved in a clinical trial. A HREC reviews, approves and provides continuing oversight of trial protocols (including any amendments), methods and materials intended to be used in obtaining and documenting informed consent of the clinical trial subjects.

The CTN Scheme broadly involves:

•submission to a HREC, of all material relating to the proposed clinical trial, including the trial protocol;

•the HREC reviews the scientific validity of the trial design, the balance of risk versus harm of the therapeutic good, the ethical acceptability of the trial process, and approves the trial protocol. The HREC is also responsible for monitoring the conduct of the trial;

•the institution or organization at which the trial will be conducted, referred to as the “Approving Authority,” giving final approval for the conduct of the trial at the site, in terms no less restrictive to those advised by the HREC; and

•the investigator submitting a ‘Notification of Intent to Conduct a Clinical Trial’ form (“CTN Form”) to the TGA. The CTN form must be signed by the sponsor, the principal investigator, the chairman of the HREC and a person responsible from the Approving Authority. The TGA does not review any data relating to the clinical trial however CTN trials cannot commence until the trial has been notified to the TGA.

Under the CTA Scheme:

•a sponsor submits an application to conduct a clinical trial to the TGA for evaluation and comment;

•a sponsor must forward any comments made by the TGA Delegate to the HREC(s) at the sites where the trial will be conducted;

•the HREC is responsible for considering the scientific and ethical issues of the proposed trial protocol.

A sponsor cannot commence a trial under the CTA Scheme until written advice has been received from the TGA regarding the application and approval for the conduct of the trial has been obtained from an ethics committee and the institution at which the trial will be conducted.

Approval for inclusion in the Australian Register of Therapeutic Goods (“ARTG”), is required before a therapeutic good (including pharmaceutical product) may be marketed (or supplied, imported, exported or manufactured) in Australia. Exceptions apply to therapeutic goods/pharmaceutical products that are supplied, imported, and exported to and from Australia for the purposes of a clinical trial, on the basis that certain conditions are met (e.g., the trial is conducted in accordance with the CTN or CTA scheme).

Once a sponsor decides to register a therapeutic good/pharmaceutical product in Australia, in order to obtain registration of the product on the ARTG, it is required that (amongst others):

•the sponsor submits appropriate documentation, including the outcomes of clinical trials and studies, to allow the TGA to assess the quality, safety and efficacy of the therapeutic product/pharmaceutical product; and

•the sponsor submits evidence which demonstrates that the manufacture of the therapeutic product/pharmaceutical product complies with the applicable GMP requirements.

The TGA has the ultimate discretion to decide whether to include the therapeutic product/pharmaceutical product in the ARTG.

Healthcare Laws and Regulations in the United States

Sales of our product candidates, if approved, or any other future product candidate, will be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments in which we might conduct our business. The healthcare laws and regulations that may affect our ability to operate include the following:

•The federal Anti-Kickback Statute (“AKS”), which makes it illegal for any person or entity to knowingly and willfully, directly or indirectly, solicit, receive, offer, or pay any remuneration that is in exchange for or to induce the referral of business, including the purchase, order, lease of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as Medicare or Medicaid. The term “remuneration” has been broadly interpreted to include anything of value. Liability may be established without proving actual knowledge of the statute or specific intent to violate it;

•Federal false claims, and false statement laws, including the federal civil False Claims Act (“FCA”), which prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, for payment to, or approval by, federal programs, including Medicare and Medicaid, claims for items or services, including drugs and biologics, that are false or fraudulent. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims; the FCA also permits a private individual acting as whistleblower to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery;

•The Civil Monetary Penalties Law, which covers a variety of conduct, often violations under other laws, and includes penalties for violating the AKS violations, causing the submission of false claims, and offering or transfer of remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state healthcare program;

•The Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 and their implementing regulations, imposes criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors or making any false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services;

•HIPAA also imposes obligations related to the privacy, security, and transmission of individually identifiable health information that apply to many healthcare providers, physicians, and third-party payors with whom we interact;

•Federal consumer protection and unfair competition laws broadly regulate marketplace activities and activities that potentially harm consumers;

•Federal government price reporting laws, which require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under governmental healthcare programs;

•The federal Physician Payments Sunshine Act which requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services (“CMS”) information related to payments or other transfers of value made to “physicians” (which has the same meaning as under Section 1861(r) of the Social Security Act, which generally includes doctors of medicine, osteopathy, dentists, podiatrists, optometrists and chiropractors who are legally authorized to practice by a state) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Beginning in 2022, applicable manufacturers are also required to report such information regarding payments and transfers of value provided during the previous year to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified nurse anesthetists and certified nurse-midwives; and

•The Foreign Corrupt Practices Act (“FCPA”), which prohibits U.S. businesses and their representatives from offering to pay, paying, promising to pay or authorizing the payment of money or anything of value to a foreign official in order to influence any act or decision of the foreign official in his or her official capacity or to secure any other improper advantage in order to obtain or retain business. The scope of the FCPA includes interactions with certain healthcare professionals in many countries.

Many states have similar laws and regulations, such as anti-kickback and false claims laws, that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Additionally, we may be subject to state laws that require pharmaceutical companies to comply with the federal government’s and/or pharmaceutical industry’s voluntary compliance guidelines, state laws that require drug and biologics manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, as well as state and foreign laws governing the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA. The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform. Additionally, to the extent that our product is sold in a foreign country, we may be subject to similar foreign laws.

Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws in the future. If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to, on a corporate or individual basis, penalties, including civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, the exclusion from participation in federal and state healthcare programs and even imprisonment, any of which could materially adversely affect our ability to operate our business and our financial results. In addition, the cost of implementing sufficient systems, controls, and processes to ensure compliance with all of the aforementioned laws could be significant. Any action for violation of these laws, even if successfully defended, could cause us to incur significant legal expenses and divert management’s attention from the operation of the company’s business. If any of the physicians or other healthcare providers or entities with whom we expect to do business is found not to be in compliance with applicable laws, that person or entity may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

It is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent inappropriate conduct may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations. Efforts to ensure that our business arrangements will comply with applicable healthcare laws may involve substantial costs. It is possible that governmental and enforcement authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations. If any such actions are instituted against us and we are not successful in defending ourselves or asserting our rights those actions, our business may be impaired.

Pharmaceutical Coverage, Pricing and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we obtain regulatory approval. In the United States and foreign markets, sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on the extent to which third-party payors provide coverage, and establish adequate reimbursement levels for such drug products. In the United States, third-party payors include federal and state healthcare programs, private managed care organizations, private health insurers and other organizations.

In the United States, no uniform policy of coverage and reimbursement for products exists among third-party payors. One payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product. Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical drug products and medical services, in addition to questioning their safety and efficacy. As a result, obtaining coverage and reimbursement approval of a product from these payors can be a time-consuming and costly process that could require us to provide each payor supporting scientific, supporting scientific, clinical and cost-effectiveness data for the use of our products on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained. We may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals. Nonetheless, our product candidates may not be considered medically necessary or cost-effective. In the United States, the principal decisions about reimbursement for new medicines are typically made by CMS. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree. Such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication.

Further, the process for determining whether a third-party payor will provide coverage for a drug product may be separate from the process for setting the price of a drug product or for establishing the reimbursement rate that such a payor will pay for the drug product. A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Even if we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability or may require co-payments that patients find unacceptably high. There is significant uncertainty related to insurance coverage and reimbursement of newly approved products. It is difficult to predict at this time what third-party payors will decide with respect to the coverage and reimbursement for our product candidates.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and impacted by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States. In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely.

The marketability of any product candidates for which we receive regulatory approval for commercial sale may suffer if third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care in the United States has increased and could increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Healthcare Reform

The United States and many foreign jurisdictions have enacted or proposed legislative and regulatory changes affecting the healthcare system. The U.S. government, state legislatures and foreign governments also have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement, and requirements for substitution of generic products for branded prescription drugs and biologics. In recent years, Congress has considered reductions in Medicare reimbursement levels for drugs and biologics administered by physicians. CMS, the agency that administers the Medicare and Medicaid programs, also has authority to revise reimbursement rates and to implement coverage restrictions for some drugs and biologics. Cost reduction initiatives and changes in coverage implemented through legislation or regulation could decrease utilization of and reimbursement for any approved products. While Medicare regulations apply only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates. Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payors.

By way of example, the U.S. and state governments continue to propose and pass legislation designed to reduce the cost of healthcare. In March 2010, the U.S. Congress enacted the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act (the “Affordable Care Act”), which, among other things, includes changes to the coverage and payments for products under government healthcare programs. profitability of drug products through increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and, annual fees based on pharmaceutical companies’ share of sales to federal health care programs. Current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price for any approved products. Since the enactment of the Affordable Care Act, there have been, and continue to be, numerous judicial, administrative, executive, and legislative challenges to certain aspects of the Affordable Care Act, and there could be additional amendments to the Affordable Care Act in the future. It is unclear whether the Affordable Care Act will be overturned, repealed, replaced, or further amended. We cannot predict what affect further changes to the Affordable Care Act would have on our business.

Additionally, there have been several U.S. congressional inquiries and proposed federal and proposed and enacted state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient support programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. Due to increasing political pressure and governmental budget constraints, we expect these mechanisms to remain robust, potentially even be strengthened, and to have a continued negative influence on the prices we may be able charge for our products, if approved, in the future. For example, the Inflation Reduction Act of 2022 (the “IRA”), signed into law on August 16, 2022, includes several provisions that may impact the pharmaceutical industry to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries, impose new manufacturer financial liability on all drugs in Medicare Part D, allow the U.S. government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

The IRA mandates that eligible Medicare Part B and Part D drugs participate in what the statute calls the Drug Price Negotiation Program (the “Program”). This Program will seek to lower the prices of certain Medicare Part B and Part D drugs without competition via government negotiation, starting in 2026. Through this Program, the HHS Secretary must (1) publish a list of selected drugs, (2) enter into agreements with manufacturers of those drugs, (3) negotiate and, where applicable, renegotiate “maximum fair prices,” for selected drugs that will apply to Medicare Parts B and D, and (4) monitor and enforce compliance, including through new civil monetary penalties and excise taxes. Each year, starting in 2026, a new cohort of Medicare-covered drugs (“Selected Drugs”) will be subject to a negotiated price. Specifically, the HHS Secretary must select for negotiation 10 Part D drugs for the initial 2026 price applicability year, 15 Part D drugs for 2027, 15 Part B or Part D drugs for 2028, and 20 Part B or Part D drugs for 2029 and each subsequent year. These negotiation-eligible drugs must be selected from the 50 Part B drugs and 50 Part D drugs with the highest Medicare program expenditures over the preceding 12-month period. A negotiation-eligible drug means a single source pharmaceutical product that is either (1) an FDA-approved drug for which at least seven years have elapsed since the date of its approval and for which there is no generic on the market, or (2) an FDA-licensed biologic for which at least 11 years have elapsed since licensure and for which there is no biosimilar on the market. On August 29, 2023, the U.S. government released the list of the first 10 Selected Drugs to be subject to the Program. On January 17, 2025, the U.S. government released the list next 15 Selected Drugs to be subject to the Program. Following the publication of the Selected Drugs, significant uncertainty remains regarding the ultimate impact of the Program on the pharmaceutical and biotech industries. The IRA is broadly impacting regulatory and corporate strategy for biotechnology and pharmaceutical firms of all sizes.

Companies have or are planning to review and adjust their economic projections for pipeline assets, particularly for drugs with the potential to become Selected Drugs. The IRA continues to face legal challenges from industry stakeholders and advocacy groups, as well as political opposition from certain lawmakers in Congress. These efforts in the courts and Congress may influence the future of the Program, though a full repeal is unlikely. With the transition to a new Congress and the Trump administration, changes to certain provisions and U.S. federal government guidance are possible, potentially altering the Program’s implementation and impact.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, and marketing cost disclosure and transparency measures, and in some cases, designed to encourage importation from other countries and bulk purchasing. As of December 31, 2024, at least 24 U.S. states have passed legislation intended to impact pricing or requiring manufacturers to report price increases to states, with eight of these states also allowing for drug affordability (i.e., price control) review boards. The disclosure requirements vary by state. Many states require multiple types of reporting, including for new drug applications, new drug launches, prior notice of price increases, and quarterly or annual reporting. Further, states may seek approval from the HHS Secretary to establish a Canadian drug importation program. Seven U.S. states (Colorado, Florida, Maine, New Hampshire, New Mexico, Texas and Vermont) have enacted laws authorizing the establishment of such a program. However, the HHS Secretary must approve each state importation plan before it can be implemented. As of December 31, 2024, Florida is the only state to receive FDA approval for a state importation plan, which is not yet implemented. Drug importation could lower manufacturer revenue or otherwise have a chilling effect on incentives to pursue research and development of new or improved versions of drugs.

We expect that additional federal, state, and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for our products, once approved, or additional pricing pressures. We cannot predict the ultimate content, timing or effect of any healthcare reform legislation or the impact of potential legislation on us. We also cannot predict changes resulting from the 2024 U.S. election and resulting changes in HHS leadership, including potential changes that might impact the pharmaceutical and biotech industry.

Employees and Human Capital Resources

As of December 31, 2024, we had 55 employees, all of whom were full-time and 41 of whom were engaged in research and development activities. Twenty-two of our employees hold PhD or MD degrees. All laboratory personnel and our administrative team are based in and around Boston, Massachusetts. None of our employees are represented by a labor union or covered under a collective bargaining agreement. We consider our relationship with our employees to be good.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants. The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Corporate Information

We were originally incorporated under the laws of the State of Delaware in 2015 under the name Marauder Therapeutics, Inc. and began operations in 2016. We changed our name to CAMP4 Therapeutics Corporation in March 2018. Our principal executive offices are located at One Kendall Square, Building 1400 West, 3rd Floor, Cambridge, Massachusetts 02139 and our telephone number is (617) 651-8867. Our website address is www.camp4tx.com. The information contained on, or accessible through, our website is not incorporated by reference into this Annual Report. We have included our website in this Annual Report solely as an inactive textual reference.

We will make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (the “SEC”). The SEC maintains an Internet site (http://www.sec.gov) containing reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC.