10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2023

Commission File Number 001-41374

PEPGEN INC.

(Exact name of Registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (781) 797-0979

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

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common stock, par value $0.0001 per share PEPG Nasdaq Global Select Market

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

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

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

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

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

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

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

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

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

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

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

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

The aggregate market value of the voting and non-voting common equity held by non-affiliates of the Registrant, based on the closing price of the shares of common stock on Nasdaq Global Select Market on June 30, 2023, was $97.7 million. The number of shares of Registrant’s Common Stock outstanding as of March 1, 2024 was 32,354,495.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the registrant’s Definitive Proxy Statement relating to its 2024 Annual Meeting of Stockholders to be filed hereafter are incorporated by reference into Part III of this Annual Report on Form 10-K where indicated.

Auditor Firm Id: 185 Auditor Name: KPMG LLP Auditor Location: Phoenix, AZ, USA

Table of Contents

Page

PART I

Item 1. Business 4

Item 1A. Risk Factors 50

Item 1B. Unresolved Staff Comments 107

Item 1C. Cybersecurity 107

Item 2. Properties 108

Item 3. Legal Proceedings 108

Item 4. Mine Safety Disclosures 108

PART II

Item 6. [Reserved] 109

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 118

Item 8. Financial Statements and Supplementary Data 118

Item 9A. Controls and Procedures 118

Item 9B. Other Information 119

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 119

PART III

Item 10. Directors, Executive Officers and Corporate Governance 120

Item 11. Executive Compensation 120

Item 14. Principal Accounting Fees and Services 120

PART IV

Item 15. Exhibits, Financial Statement Schedules 121

SPECIAL NOTE REGARDING FORWARD LOOKING STATEMENTS

This Annual Report on Form 10-K, or 10-K, contains express or implied forward-looking statements that are based on our management’s belief and assumptions and on information currently available to our management and that are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, or the or the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended, or the Exchange Act. Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to future events or our future operational or financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements in this 10-K include, but are not limited to, statements about:

•

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

•

our ability to efficiently develop our existing product candidates and discover new product candidates;

•

our ability to successfully manufacture our investigational drug substances and drug product for preclinical use, for clinical trials and on a larger scale for commercial use, if our investigational drug candidates are approved;

•

our ability to obtain funding for our operations necessary to complete further development and commercialization of our product candidates;

•

our ability to obtain and maintain regulatory approval of our product candidates;

•

our ability to commercialize our product candidates, if approved;

•

the pricing and reimbursement of our product candidates, if approved;

•

the implementation of our business model, and strategic plans for our business and product candidates;

•

the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates and our technology platform;

•

estimates of our future expenses, revenues, capital requirements, and our needs for additional financing;

•

the size and growth potential of the markets for our product candidates, and our ability to serve those markets;

•

our financial performance;

•

the rate and degree of market acceptance of our product candidates;

•

regulatory developments in the United States, or U.S., and foreign countries;

•

our ability to contract with third-party suppliers and manufacturers and their ability to perform adequately;

•

our ability to produce our products or product candidates with advantages in turnaround times or manufacturing cost;

•

the success of competing therapies that are or may become available;

•

our ability to attract and retain key research and development or management personnel;

•

the impact of laws and regulations;

•

developments relating to our competitors and our industry;

•

the effects of the COVID-19 pandemic, or any future pandemics, including mitigation efforts and economic effects, on any of the foregoing or other aspects of our business operations, including but not limited to our preclinical studies and clinical trials and any future studies or trials; and

•

other risks and uncertainties, including those listed under the caption “Risk Factors.”

In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “should,” “expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue” or the negative of these terms or other comparable terminology. These statements are only predictions, and are subject to change due to known and unknown risks, uncertainties, and other factors, which are, in some cases, beyond our control and which could materially affect results. Factors that

may cause actual results to differ materially from current expectations include, among other things, those listed under the section titled “Risk Factors” and elsewhere in this 10-K. If one or more of these risks or uncertainties occur, or if our underlying assumptions prove to be incorrect, actual events or results may vary significantly from those implied or projected by the forward-looking statements. No forward-looking statement is a guarantee of future performance. Moreover, we operate in an evolving environment. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties. You should read this 10-K and the documents that we reference in this 10-K and have filed with the Securities and Exchange Commission, or the SEC, completely and with the understanding that our actual future results may be materially different from any future results expressed or implied by these forward-looking statements.

The forward-looking statements in this 10-K represent our views as of the date of this 10-K. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should therefore not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this 10-K.

In addition, statements that "we believe" and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this 10-K, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain.

This 10-K also contains estimates, projections and other information concerning our industry, our business and the markets for our programs and product candidates. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances that are assumed in this information. Unless otherwise expressly stated, we obtained this industry, business, market, and other data from our own internal estimates and research as well as from reports, research surveys, studies, and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data and similar sources. While we are not aware of any misstatements regarding any third-party information presented in this 10-K, their estimates, in particular, as they relate to projections, involve numerous assumptions, are subject to risks and uncertainties and are subject to change based on various factors, including those discussed under the section titled “Risk Factors” and elsewhere in this 10-K.

TRADEMARKS

This 10-K contains references to our trademarks and to trademarks belonging to other entities. Solely for convenience, trademarks and trade names referred to, including logos, artwork and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto. We do not intend our use or display of other companies’ trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us by, any other companies.

SUMMARY OF RISK FACTORS

Our business is subject to numerous risks and uncertainties that you should be aware of in evaluating our business. These risks include, but are not limited to, the following:

•

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

•

We will need to raise substantial additional funding. If we are unable to raise capital when needed, we could be forced to delay, scale back, or discontinue our product development programs or future commercialization efforts.

•

We are early in our development efforts. We have only completed a Phase 1 clinical trial for our lead product candidate and initiated a Phase 1 clinical trial of a second product candidate as well as Phase 2 clinical trials ofour lead product candidate, and as a result it will be years before we commercialize a product candidate, if ever. If we are unable to advance our product candidates through preclinical studies and clinical trials, obtain marketing approval and ultimately commercialize them, or experience significant delays in doing so, our business will be materially harmed.

•

Our business is highly dependent on the clinical advancement of our programs and modalities and is especially dependent on the success of our lead product candidates, PGN-EDO51 and PGN-EDODM1. Delay or failure to advance programs or modalities, including PGN-EDO51 and PGN-EDODM1, could adversely impact our business.

•

Preclinical and clinical development involves a lengthy and expensive process with an uncertain outcome, and the results of preclinical and clinical studies, including studies of PGN-EDO51, PGN-EDODM1 and PGN-EDO53, are not necessarily predictive of the results of later preclinical studies and any clinical trials of our product candidates. Our product candidates may not have favorable results in clinical trials, if any, or receive regulatory approval on a timely basis, if at all.

•

Substantial delays in the commencement, enrollment or completion of our clinical trials and advancement of our clinical trials, or failure to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities could prevent us from commercializing product candidates we determine to develop on a timely basis, if at all.

•

We rely, and expect to continue to rely, on third parties to conduct some or all aspects of our product manufacturing, research, preclinical and clinical testing, and these third parties may not perform satisfactorily.

•

We face significant competition, and if our competitors develop technologies or product candidates more rapidly than we do or their technologies or product candidates are more effective or have more favorable safety or tolerability profiles, our business and our ability to develop and successfully commercialize products may be adversely affected.

•

If we are unable to obtain and maintain patent protection for our Enhanced Delivery Oligonucleotide platform, therapeutic development candidates or programs and/or other proprietary technologies we develop, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize products and technology similar or identical to ours, and our ability to successfully commercialize our therapeutic product candidates or programs and other proprietary technologies we may develop may be adversely affected.

•

We expect to expand our headcount to support our development and regulatory capabilities and potentially implement sales, marketing and distribution capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.

•

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

•

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

The summary risk factors described above should be read together with the text of the full risk factors below in the section titled “Risk Factors” in Part I, Item 1.A. and the other information set forth in this 10-K, as well as in other documents that we file with the SEC. The risks summarized above or described in full below are not the only risks that we face. Additional risks and uncertainties not precisely known to us, or that we currently deem to be immaterial, may also materially adversely affect our business, financial condition, results of operations and future growth prospects.

PART I

Item 1. Business.

Overview

PepGen Inc. (also referred to as “PepGen,” “we,” “our” or “us”) is a clinical-stage biotechnology company advancing the next generation of oligonucleotide therapeutics with the goal of transforming the treatment of severe neuromuscular and neurologic diseases. Our proprietary Enhanced Delivery Oligonucleotide, or EDO, platform is founded on over a decade of research and development and leverages cell-penetrating peptides to improve the uptake and activity of conjugated oligonucleotide therapeutics. Our EDO peptides are engineered to optimize tissue penetration, cellular uptake and nuclear delivery, and in preclinical studies we have observed their ability to transport oligonucleotides into a broad range of target tissues, including smooth, skeletal, and cardiac muscle. We have demonstrated robust delivery and activity of oligonucleotides to skeletal muscle in a clinical trial. Furthermore, the high levels of pharmacological activity observed in preclinical and clinical studies support our belief that our EDO platform technology has the potential to deliver therapeutic agents to the nucleus of the target cells. Using these EDO peptides, we are generating a pipeline of oligonucleotide product candidates that target the root cause of serious diseases.

We are initially focused on addressing the underlying cause of Duchenne muscular dystrophy, or DMD, and myotonic dystrophy type 1, or DM1, that have high unmet need. Our current pipeline depicted below consists of two clinical stage programs - PGN-EDO51 for DMD patients who are amenable to exon 51-skipping and PGN-EDODM1 for DM1 patients, and three additional preclinical stage programs. We anticipate expanding this pipeline over time to include other neuromuscular targets as well as potential opportunities in neurologic diseases.

PGN-EDO51

We completed a first-in-human Phase 1 clinical trial in healthy volunteers, or HVs, with our lead product candidate, PGN-EDO51, in the third quarter of 2022. We are developing PGN-EDO51 to treat DMD patients whose mutations are amenable to an exon 51-skipping approach. In the Phase 1 clinical trial in HVs, treatment with PGN-EDO51 resulted in the highest levels of mean exon skippingin humans following a single dose compared to publicly available data for a single dose of other DMD exon 51-skipping approaches that are approved or in clinical development.

Our clinical development program for PGN-EDO51 comprises two parallel Phase 2 studies of PGN-EDO51 in DMD patients whose mutations are amenable to an exon 51-skipping approach. The first study, CONNECT1-EDO51, or CONNECT1, is an ongoing open-label, multiple ascending dose, or MAD, Phase 2 study in boys and young men living with DMD being conducted in Canada. We initiated dosing patients in CONNECT1 in January 2024 and have fully enrolled the first cohort at the 5 mg/kg PGN-EDO51 dose level. We anticipate initial proof-of-concept data, that would include safety, exon skipping and dystrophin production for this cohort in mid-2024.

In February 2024, we received clearance from the Medicines and Healthcare products Regulatory Agency, or MHRA, to initiate the second study, CONNECT2-EDO51, or CONNECT2, a Phase 2, multinational, randomized, double-blind, placebo-controlled MAD study. The results from the initial cohorts of the CONNECT1 study will inform the conduct of the CONNECT2 study, which is designed to support a potential accelerated approval pathway for PGN-EDO51, subject to alignment with regulatory authorities. Building on the high levels of exon skipping of PGN-EDO51 observed in our preclinical studies and Phase 1 trial in HVs, we believe that repeat dosing of PGN-EDO51 may lead to therapeutically relevant accumulation of DMD exon 51-skipped transcript and an

associated increase in dystrophin protein in patients, which may in turn drive meaningful clinical benefit for those who live with this devastating, progressive, life-shortening disease.

PGN-EDODM1

We are also developing PGN-EDODM1 for the treatment of DM1 and are utilizing what we believe to be a unique mechanism of action and a different delivery approach compared to other approaches in more advanced stages of clinical development. The therapeutic oligonucleotide component of PGN-EDODM1 is engineered to bind to the pathogenic cytosine-uracil-guanine, or CUG repeat expansion present in the myotonic dystrophy protein kinase, or DMPK, messenger RNA, or mRNA, of DM1 patients, thus reducing the ability of these expanded trinucleotide repeats to bind and sequester RNA binding proteins including MBNL1, a critical RNA splicing factor. The liberation of MBNL1 in turn leads to the correction of downstream mis-splicing events that drive the pathology of DM1. We believe this approach, which is not designed to knock down or degrade DMPK transcript, has the potential to selectively and directly address the underlying genetic defect central to this disease. In a DM1 mouse model, the HSALR mouse, following single and repeat dosing of PGN-EDODM1 every four weeks, we demonstrated robust correction of mis-splicing and resolution of myotonia.

These preclinical data with PGN-EDODM1 form the basis of our clinical development plan for PGN-EDODM1. In May 2023, we announced that we received a clinical hold notice from the U.S. Food and Drug Administration, or FDA, regarding our investigational new drug, or IND, application to initiate our first in-human Phase 1 FREEDOM-DM1, or FREEDOM, study in DMI patients. In September 2023, we announced that Health Canada had cleared our Clinical Trial Application, or CTA, for the FREEDOM study in Canada. In October 2023, we announced that the FDA lifted the clinical hold on the FREEDOM study, allowing this study to proceed in the U.S. In December 2023, we announced that the MHRA had cleared our CTA for the FREEDOM study in the United Kingdon, or the U.K. FREEDOM is a multinational, randomized, double-blind, placebo-controlled, single ascending dose, or SAD, study, designed to assess PGN-EDODM1's safety, splicing correction, and functional outcome measures in DM1 patients. We expect to report preliminary data from this study in the second half of 2024. In February 2024, we announced that PGN-EDODM1 received Fast Track designation from the FDA for the treatment of DM1. We also expect to open the FREEDOM2-DM1 Phase 2 randomized, double blind, placebo-controlled MAD study in DM1 patients in the second half of 2024.

Additional Development Programs

In addition to these lead clinical stage programs, we are developing EDO candidates for additional DMD sub-populations amenable to skipping of other exons, including exon 53, 45 and 44. We have previously reported robust exon 53-skipping levels following either a single dose or multiple doses in non-human primates, or NHPs, for our PGN-EDO53 program. We anticipate advancing PGN-EDO53, our DMD exon 53-skipping candidate, into CTA and/or IND-enabling preclinical studies in 2024. We have also initiated research efforts for additional indications, including neuromuscular diseases and neurologic disorders.

Our EDO Platform

Background on Oligonucleotide Therapeutics

Oligonucleotide therapeutics consist of small single or double stranded segments of deoxyribonucleic acid, or DNA, or ribonucleic acid, or RNA, molecules that are made up of nucleotides that bind to their targets via complementary Watson-Crick base pairing thereby modulating the expression of their target DNA or RNA sequence, thereby addressing the root cause of many diseases. Upon binding to their target sequence, oligonucleotides can modulate function through the modulation of RNA expression and processing. The mechanisms of action of these medicines include interference with gene expression; degradation of toxic RNA species; alteration of gene translation; interference with interactions between RNA and other nucleic acids or proteins; endogenous human adenosine deaminase acting on RNA, or ADAR; site-directed RNA editing; and modulation of the splicing of transcripts. Each of these approaches can lead to profound biological effects. The development of oligonucleotide therapeutics has enabled the targeting of a diverse set of diseases that have proven difficult to treat through other approaches due to their high degree of specificity to target pathogenic mutations, which is otherwise difficult using conventional drugs.

Oligonucleotide therapeutics have demonstrated clinical benefit and been approved for the treatment of multiple diseases, such as spinal muscular atrophy, DMD, familial hypercholesterolemia and hereditary transthyretin-mediated amyloidosis. These approved drugs span two classes – ASOs, which are short, synthetic, single-stranded oligonucleotides, and small interfering RNAs, or siRNAs, which are double-stranded oligonucleotides. ASOs and siRNAs both bind their target mRNAs or pre-mRNAs but differ in their respective modes of action. ASOs are designed to either (i) degrade target RNA species through an RNAse-H-mediated process, or (ii) modulate RNA-RNA and/or RNA-protein interactions through a steric blocking mechanism. In contrast, siRNAs are designed to silence or knockdown a particular mRNA through the RNA interference, or RNAi, pathway.

ASOs are typically synthetic molecules that may contain modified nucleotide bases, sugars and phosphate linkages designed to overcome the historical limitations of unmodified oligonucleotides, including instability, immunogenicity and a poor pharmacological profile. Many approved oligonucleotides incorporate a modified oligonucleotide backbone in which the phosphate and ribose sugars are replaced by phosphorodiamidate morpholino groups, or PMOs. The resulting PMOs are resistant to multiple hydrolases in serum, while their uncharged nature ensures that they do not interact strongly with proteins in a nonspecific way. PMOs have shown promising results in early-stage preclinical studies and have become marketed products for the treatment of a host of diseases. For example, EXONDYS 51®(eteplirsen), marketed by Sarepta Therapeutics, Inc., or Sarepta, is a PMO that was approved in 2016 for individuals with DMD who are amenable to exon 51-skipping but has left much room for improvement given its relatively low tissue and cell penetration and minimal induction of dystrophin production.

The Challenge of Oligonucleotide Delivery

In order for oligonucleotide therapeutics to exert their intended effect, they must first gain access to the nucleus where mRNAs are synthesized and processed. Historically, the delivery of oligonucleotides to the interior of the cell proved challenging due to their high molecular weight and the lack of a specific mechanism to facilitate their transport across the cell membrane and escape the endosome to enter the cytoplasm and nucleus. Several methods have been developed to increase the cellular uptake of oligonucleotides, the most clinically advanced of which is the covalent attachment of cell-penetrating peptides, or CPPs. CPPs are designed to facilitate the transport of oligonucleotides across the plasma membrane, thus allowing these cargo species to reach their eventual site of action in the nucleus. We believe that these capabilities are critical in enabling oligonucleotides to exert their intended therapeutic effect within the cell. Early research into CPPs showed that simple peptides consisting primarily of multiple arginine residues could increase the cellular uptake of oligonucleotides and increase their activity in modulating RNA splicing. However, a considerable number of these early CPPs were found to be highly toxic in animal models, and in many instances, there existed a direct correlation between toxicity and activity, which limited the clinical translation and development of these first-generation delivery vectors.

Our Approach: A Solution for the Oligonucleotide Delivery Challenge

Our EDO platform is based on novel CPP technology. We engineered our proprietary EDO technology to optimize tissue penetration, cellular uptake and nuclear delivery, which we believe may enhance therapeutic activity and improve the tolerability of oligonucleotide therapeutics. This technology is founded on over a decade of research and development conducted in the academic laboratories of our founders Michael Gait, Ph.D. at the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom, or MRC, and Professor Matthew Wood, M.D., Ph.D. at the University of Oxford, United Kingdom. Drs. Gait and Wood developed a new generation of CPPs focused on oligonucleotide delivery, and optimized these peptides for tissue penetration, cellular uptake and nuclear delivery, along with improved tolerability in animal models.

Our EDO platform peptides possess the following key structural characteristics:

•

Two positively charged, arginine-rich regions, one at the N-terminus and the other at the C-terminus interspersed with non-natural amino acids to confer greater peptide stability;

•

A central core rich in hydrophobic residues that separates the arginine-rich regions and contributes to endosomal escape; and

•

A linear peptide sequence with a length of less than 20 amino acids designed to be non-immunogenic.

Our EDO peptides were developed through an iterative optimization process that selected simultaneously for: biodistribution to key muscle targets, including cardiac tissue; high cellular uptake; endosomal escape, where the therapeutic agent is released from the endosomes, a sub-cellular organelle, in a functional form and delivered to the cell nucleus; and acceptable tolerability. We utilize PMOs in our approach, and these therapeutic cargos are conjugated to one of our optimized, proprietary, novel EDO peptides to generate our lead EDO product candidates - peptide conjugated PMOs, or PPMOs. We intend to continue to build and develop this platform technology to enable us to expand into new therapeutic areas.

We believe that our therapeutic candidates may offer the following advantages with the goal of enabling the safe and efficient delivery of oligonucleotide cargos:

•

Enhanced delivery to skeletal muscle, diaphragm and cardiac muscle. We have observed in preclinical and clinical studies that our peptides delivered their cargo oligonucleotide therapeutics to different muscle tissues, allowing us to address multiple disease pathologies in multi-systemic indications such as DMD and DM1. This differentiating feature of our EDO platform has been observed in mice and NHPs across multiple tissue types, including those critical to neuromuscular indications – skeletal, smooth and cardiac muscle. Furthermore, we believe our EDO peptides support the ability to promote endosomal escape and facilitate the robust delivery of cargo oligonucleotides to the cell nucleus. We have now shown in in vitro and in NHP models that the EDO technology can mediate higher uptake of oligonucleotide in the nucleus.

In vitro, EDO peptide conjugated to a PMO (EDO23) resulted in up to 25-fold higher cellular uptake and nuclear delivery of oligonucleotide into myotubes compared to naked PMO.

In NHPs, EDO peptide conjugated to a PMO (PMO51) led to high levels of oligonucleotide in the muscle nuclei.

In murine myotubes, EDO23 resulted in up to 25-fold higher uptake of EDO23 compared to naked PMO23. In vitro staining image with 10μM conc. of EDO or naked PMO; green= actin, red= EDO or naked PMO and blue= nuclei.

In NHPs, IV dosing of EDO conjugated to PMO51 resulted in 72% of muscle cells with uptake of PMO in the nuclei. RNAScope was performed; red=PMO and blue (DAPI)=nuclei. Cells with PMO signal were quantified; n=3 (± SD)

•

Improved activity in skeletal muscle and tolerable safety profile was observed in a Phase 1 clinical study, in NHPs and in mdx mice, with robust levels of activity observed in skeletal and other muscle types.

In our Phase 1 clinical study of PGN-EDO51 in HVs, we observed the highest levels of mean exon skipping in humans following a single dose when compared to publicly available single dose data for other DMD exon 51-skipping approaches.

In NHPs, a dose of 30 mg/kg of PGN-EDO51 achieved over 70% exon 51 skipping in skeletal muscle, including diaphragm, which we believe is the highest level of exon 51 skipping reported for any approved therapeutic or

known development candidate at tolerable target dose levels based on cross-trial comparison of publicly available data.

In mdx mice, we observed the highest level of dystrophin production following a single dose when compared to “murine analogues” of other clinical-stage DMD therapeutic candidates.

•

Enhanced balance between activity and tolerability, which is designed to afford ourplatform a wider therapeutic index. Our delivery peptides have been specifically engineered to achieve a wider therapeutic index, and we have observed robust activity and an improved tolerability profile in NHPs and humans when compared to data published on previous CPPs.

In a Phase 1 clinical study in HVs, PGN-EDO51, our lead EDO candidate, was found to be generally well-tolerated at therapeutically relevant dose levels. We believe this characteristic is a promising step-change over the narrow therapeutic index observed for previous generations of CPPs.

•

Robust, scalable and cost-efficient manufacturing that does not require cell-based processes. We have developed a modular manufacturing process that is highly scalable, easily characterizable, and utilizes readily available building blocks. This process is fully synthetic in nature and does not rely on microbial fermentation, thus substantially reducing the risk of introducing microbial DNA or protein into our product candidates.

•

Accelerated and efficient development of pipeline therapeutic candidates enabled by use of a single EDO peptide across all our initial programs. We currently utilize the same EDO delivery peptide across all of our programs. We intend to apply our knowledge and learnings from our current lead programs in order to efficiently pursue our future programs, and we will additionally aim to take advantage of economies of scale in our manufacturing processes.

Comparison with Other Oligonucleotide Delivery Technologies in Development

Other CPP-PMO or PPMO Approaches

There are a number of other peptide-mediated approaches that are currently being developed for the delivery of oligonucleotide therapeutics. Of these, we have, through an extensive review of publicly available presentations and patent applications, hypothesized that the most clinically advanced peptide-based delivery approach for oligonucleotides utilizes the cell-penetrating properties of a hexa-arginine sequence with an additional glycine residue. We refer to this CPP as R6G herein and have conducted extensive head-to-head preclinical studies to compare the biodistribution and activity of our model of this moiety with our novel EDO peptides.

We have observed robust in vivo activity of our EDO technology in a number of animal models, with this activity being significantly higher when compared to our model of the competing R6G approach. In one such study, we compared our EDO-conjugated PMO to an R6G peptide which we believe is structurally equivalent to the peptide component of SRP-5051, conjugated to the same murine exon 23-skipping PMO. SRP-5051 is the most clinically advanced peptide-ASO conjugate in development by Sarepta. In this single dose study, we administered 10 mg/kg of PGN-EDO23 or R6G-PMO23 to wild type, or WT mice, intravenously followed by tissue collection one week after dosing. In the biceps, PGN-EDO23 resulted in 51.7% exon skipping versus 0.46% exon skipping with R6G-PMO23 as assessed by RT-PCR, demonstrating that PGN-EDO23 is more potent than R6G-PMO23. In line with high levels of exon skipping in biceps, we observed 62.5% exon skipping in quadriceps with PGN-EDO23 versus 2.0% exon skipping with R6G-PMO23.

Robust exon skipping was observed with single dose of PGN-EDO23 compared to R6G-PMO23 in WT mice. Graph plotted as mean ± SD; n = 5 for each group.

Our EDO technology has shown enhanced delivery of PMO to additional tissues that remain challenging to penetrate with existing technologies. In a repeat-dose preclinical study in WT mice, three 30 mg/kg intravenous doses of our EDO conjugate every

two weeks resulted in exon skipping levels in the heart that were 7-fold higher than those of the R6G conjugate, when measured by RT-PCR seven days after the last dose. We believe the higher level of exon skipping achieved in this study supports the ability of our EDO technology to successfully deliver oligonucleotides to cardiac tissue furthering the potential of EDO technology to address cardio-respiratory failure, the primary cause of death in DMD patients.

Multiple doses of PGN-EDO23 in WT mice led to increased exon skipping in heart compared to R6G-PMO23. Graphs plotted as mean ± SEM; **** denotes extremely significant, p < 0.0001; n = 5 per group for single dose activity, n = 8 per group for repeat dose activity.

Antibody-oligonucleotide Approaches

In addition to the CPP-PMO approaches described above, a number of groups are developing antibody-oligonucleotide conjugates with the aim of enhancing the delivery and activity of their cargo therapeutics. These groups utilize both antigen-binding fragments, or Fabs, and monoclonal antibodies, or mAbs, as delivery vectors, to target specific cell surface receptors. We believe our EDO platform offers significant potential benefits over such approaches, including:

•

More efficient tissue penetration due to the small size of our EDO delivery peptides relative to a mAb or Fab;

•

Superior nuclear delivery with the combination of poly-Arg sequences and hydrophobic core;

•

Limited immunogenicity or risk of complement activation due to the considerably lower protein load associated with our EDO peptides; and

•

A scalable, facile, fully-synthetic manufacturing process with no cell-based steps that is supported by a readily-characterizable drug product.

We believe these benefits support further development and clinical translation of our suite of EDO product candidates and underpin the potential for our robust competitive position in the neuromuscular and neurologic disease space.

Our Strategy

Our goal is to become a leading biopharmaceutical company focused on the development and commercialization of oligonucleotide therapies to transform the lives of patients with severe neuromuscular and neurologic diseases. We aim to accomplish this goal by implementing the following strategies:

•

Advance our lead product candidate, PGN-EDO51, through clinical trials and potential regulatory approval. We are developing PGN-EDO51, an EDO peptide conjugated to a PMO therapeutic cargo to treat DMD patients whose mutations are amenable to an exon 51-skipping approach. There is no cure for DMD and approved exon-skipping therapies or advanced stage exon-skipping investigational candidates for patients who are amenable to exon 51 skipping are thought to have limited impact on disease progression due to low levels (<5%) of dystrophin production. In a Phase 1 clinical trial of PGN-EDO51 in HVs, we observed the highest levels of mean exon skipping in humans following a single dose when compared to publicly available single dose data for other exon 51-skipping approaches. We began dosing patients in a Phase 2 clinical trial in January 2024 and have completed enrollment of the first cohort at the 5 mg/kg dose.

•

Advance PGN-EDODM1 through clinical trials and potential regulatory approval. We are developing PGN-EDODM1 (which utilizes the same EDO peptide as PGN-EDO51) conjugated to a PMO therapeutic cargo to treat DM1 patients and have observed robust pharmacological activity in preclinical models with both long and short cytosine-thymine-guanine, or

CTG repeats. We began dosing patients in a Phase 1 clinical trial in December 2023 and announced Fast Track Designation for PGN-EDODM1 in February 2024.

•

Advance and expand our pipeline of oligonucleotide therapeutic candidates for the treatment of additional DMD patient populations. We are expanding our portfolio by pursuing additional programs where our EDO technology could address areas of unmet need. We are employing the same EDO technology used in PGN-EDO51 and PGN-EDODM1 for PGN-EDO53, our exon-skipping product candidate for the treatment of individuals with DMD whose mutations are amenable to treatment with an exon 53-skipping approach. We have observed high levels of exon skipping in NHPs for PGN-EDO53 and we plan to progress this program into IND/CTA enabling studies in 2024.

•

Leverage the full potential of our EDO technology to expand into other neuromuscular and neurological disease areas. Given the potential of the EDO technology to efficiently deliver nucleic acid payloads such as PMOs to skeletal muscle, cardiac tissue and diaphragm, we are looking to develop disease-modifying peptide-conjugated oligonucleotide candidates for the potential treatment of other neuromuscular and neurological indications.

•

Utilize the modular nature of our EDO platform to evaluate new cargos and peptide technologies. We believe that our EDO technology has the potential to facilitate the delivery of multiple classes of nucleic acid payloads, including other oligonucleotide therapeutics, and we intend to expand the scope of the cargos that can be delivered by our EDO platform as part of our ongoing platform development work.

•

Maximize the value of our pipeline and our EDO platform by selectively exploring strategic collaborations. We have a disciplined strategy to maximize the value of our pipeline and currently have worldwide development and commercial rights to all of our product candidates. Given the potential of our EDO platform, we may opportunistically enter into strategic collaborations around certain geographies, targets or programs. We may seek to build such relationships where we believe the resources and expertise of a third-party pharmaceutical or biotechnology company could be beneficial to the development or commercialization of our product candidates or to the expansion of our platform capabilities.

Our Portfolio

We are harnessing the power of our EDO platform to generate a pipeline of oligonucleotide therapeutic candidates. Our EDO conjugates have been engineered to successfully target the root cause of serious diseases while maintaining a tolerability profile that is acceptable for clinical use. We are initially focused on addressing neuromuscular indications and are building a portfolio of therapeutic candidates to address the underlying genetic mutations found in DMD and DM1, with our current pipeline being comprised of five programs, two clinical and three preclinical.

In the future, we anticipate expanding this pipeline to include other neuromuscular targets, along with potential opportunities in neurologic indications, and we will seek to leverage the modular, scalable nature of our EDO technology to support our expansion into these new therapeutic areas. We have worldwide development and commercialization rights to all our programs.

PGN-EDO51

Overview

Our initial product candidate is PGN-EDO51, an EDO peptide conjugated to a PMO, that we are developing for the treatment of DMD patients with mutations amenable to an exon 51-skipping approach. An exon is a segment of a gene that, together with other exons, contains the genetic code that is translated into a protein. Exon skipping is a therapeutic mechanism that enables mutations in the gene to be bypassed, thereby repairing this code or reading frame and enabling production of a truncated, yet functional version of the target protein. PGN-EDO51 is designed to splice out exon 51 and potentially additional exons depending on the mutation of the dystrophin pre-mRNA, resulting in the restoration of the open reading frame of the dystrophin transcript and production of an internally deleted, yet functional dystrophin protein. In a Phase 1 clinical trial of PGN-EDO51 in HVs, we observed the highest levels of mean exon skipping in humans following a single dose in a cross-trial comparison with publicly available Phase 1 HV data following a single dose of vesleteplirsen (SRP-5051 or R6G conjugated exon 51 PMO) and eteplirsen. In NHP studies, at tolerable doses, we have observed what we believe is the highest rate of exon 51 skipping in skeletal muscles, including diaphragm, based on cross-trial comparisons with publicly available data for any approved therapeutic or known developmental candidate for the exon-51 skipping amenable DMD patient population. Furthermore, in head-to-head studies conducted in NHPs, we found that PGN-EDO51 had greater activity than R6G-PMO at the same dose level, a comparator compound which we believe to be structurally equivalent to Sarepta’s SRP-5051, the most clinically advanced PPMO. Our Phase 1 clinical trial also indicated that PGN-EDO51 was generally well-tolerated at pharmacologically relevant dose levels. We opened CONNECT1, an open-label MAD study in DMD patients amenable to an exon 51-skipping approach in Canada and began dosing patients in January 2024. We have fully enrolled the 5 mg/kg dose cohort and expect to report preliminary safety, exon skipping and dystrophin production data from this cohort in mid-2024. In February 2024, we received clearance from the MHRA to initiate CONNECT2 in the U.K. CONNECT2 is a multinational, randomized, placebo-controlled MAD clinical trial designed to potentially support a future accelerated approval pathway, subject to alignment with regulatory authorities.

Disease Background and Prevalence

DMD is a debilitating X-linked recessive, progressive, muscle-wasting disease that predominantly affects boys. It is one of the most prevalent rare genetic diseases globally, with an incidence of up to 1 in 3,500 to 5,000 live male births, and it is invariably fatal by young adulthood. There are up to 15,000 DMD patients in the U.S., approximately 25,000 DMD patients in Europe and approximately 5,000 in Japan. DMD is caused by mutations in the gene encoding dystrophin, a protein necessary for normal muscle function. The primary role of dystrophin is as a shock absorber, and this protein allows muscle cells to retain their structural integrity while under mechanical stress. In the absence of dystrophin, muscle fibers are no longer protected from the mechanical forces of contraction, which leads to cell death, fibrotic tissue formation and muscle degeneration resulting in loss of ambulation.

Early symptoms of disease include difficulty walking or jumping, loss of balance, and increased fatigue when compared to healthy peers. By their mid-teenage years, most DMD patients will need to use a wheelchair on a regular basis. As the disease progresses, life-threatening heart and respiratory conditions become common. Dilated cardiomyopathy – a condition where the cardiac muscle becomes weakened and the chambers of the heart are enlarged – often arises, and heart failure is a leading cause of death in DMD patients. Pulmonary function also becomes progressively impaired as the dystrophic process affects respiratory muscles, including the diaphragm, leading to significant morbidity and mortality. DMD patients ultimately succumb to cardiac and respiratory failure in early adulthood, with a mean lifespan of approximately 25 years. Therefore, the restoration of dystrophin is a compelling therapeutic strategy, and a number of therapeutic modalities have been explored with this goal in mind. However, the nature of the DMD gene, the range of mutations implicated in DMD, and the large size of the dystrophin protein itself provide considerable obstacles to this approach.

The DMD gene, at 2.1 million base pairs and 79 exons, is one of the largest in the human genome. Over 6,000 mutations are known, and the gene has a relatively high natural mutation rate, with approximately 1 in 3 DMD cases arising due to a de novo mutation. There is no one mutation that is highly prevalent, and this factor provides a considerable challenge for therapeutics looking to target the root genetic cause of this debilitating disease.

That said, mutations in the dystrophin gene are not random, with hotspots of mutations existing between exons 45-53 and to a lesser extent between exons 2-20. It is thought that 13% of patients with DMD have mutations that are amenable to treatment with an exon 51-skipping approach, and thus the estimated exon 51 patient population is approximately 2,000 in the U.S., 3,200 in Europe and 700 in Japan.

Breakdown of DMD population by amenability to treatment with exon skipping therapeutics.

Current Approaches and Unmet Needs

There is no cure for DMD and approved exon-skipping therapies or advanced stage exon-skipping investigational candidates for patients who are amenable to exon 51 skipping are thought to have limited impact on disease progression due to low levels (<5%) of dystrophin production. Corticosteroids are the mainstay of pharmacologic treatment for DMD as they have been shown to temporarily improve muscle strength, prolong the period of ambulation and slow the progression of this disease. However, glucocorticoid use is associated with well-known adverse effects, such as weight gain, stunted growth, weakening of bone structure, high blood pressure, diabetes, psychological effects, skin thinning and an increased risk of infection.

Several approaches have been taken to address groups of mutations in the dystrophin gene, one of which is to alter the processing of the dystrophin mRNA. A number of DMD patients suffer from mutations that result in the disruption of the reading frame of the DMD transcript, which in turn leads to an absence of the dystrophin protein. Using an ASO, the mRNA splicing process in the nucleus can be altered to skip over a select exon, allowing the open reading frame to be restored. This exon skipping approach results in the subsequent generation of dystrophin protein isoform which, although internally deleted, retains much of its function and can thus protect muscle tissue against further contraction-induced damage.

Several unconjugated, or “naked” ASOs have been approved to treat DMD, including eteplirsen, marketed as EXONDYS 51 by Sarepta for the treatment of mutations amenable to an exon 51-skipping approach. This drug received accelerated approval from the FDA on the basis of an increase of less than 1% in the expression of dystrophin, with this readout being considered a valid surrogate endpoint under the accelerated approval regulatory pathway. Published observational studies of small numbers of patients on EXONDYS 51 appear to show somewhat slower disease progression than historical controls. However, at this level of dystrophin, this therapeutic has yet to formally establish evidence of clinical benefit through rigorously powered and adequately controlled clinical trials with functional endpoints. EXONDYS 51 has not been approved in Europe, or in Japan on the basis of this minimal degree of dystrophin restoration as a surrogate endpoint.

In addition, several companies are developing gene therapies to treat DMD, including Pfizer Inc. (PF-06939926), which is currently being assessed in a Phase 3 clinical trial, Sarepta (SRP-9001 and Galgt2 gene therapy program), the former of which was approved by the FDA in June 2023 for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene and is marketed as ELEVIDYS. Sarepta has recently filed an efficacy supplement to its biologics license application, or BLA, to expand the indication for ELEVIDYS to encompass “treatment of DMD patients with a confirmed mutation in the DMD gene.” The FDA accepted the filing of the efficacy supplement and has given the application priority review with a review goal date of June 21, 2024. There are additional investigational gene therapy programs in different stages of development to treat DMD. It is important to note that adeno-associated virus, or AAV-based gene replacement approaches deliver a significantly truncated dystrophin (micro-dystrophin) which we believe has the potential to limit the therapeutic efficacy of the approved and clinical stage AAV-based pipeline candidates. In addition, there are gene editing treatments that are in preclinical development. Exon skipping does not face some of the inherent challenges associated with gene therapy modalities, including:

•

Limited packaging size of AAV vectors, resulting in the need to employ truncated ‘micro-dystrophin’ genes with an unclear functional benefit, where >70% of the dystrophin gene is omitted, including regions that correspond to key structural and binding domains;

•

Increased safety concerns with high-dose AAV-based gene therapies (e.g. complement activation);

•

Immunogenicity of AAV, resulting in:

Up to half of all patients possessing antibodies against the most commonly used recombinant AAV vector serotypes, precluding their eligibility for treatment;

Production of anti-AAV antibodies in treated patients, resulting in an inability to re-dose; and

Loss of gene copies over time as patients mature and their cells divide, reducing the durability of therapeutic effect;

•

Complexity and challenges inherent to manufacturing of AAV-based therapies.

We are also aware of several companies targeting non-dystrophin mechanisms for the treatment of DMD, including Edgewise Therapeutics, Inc., or Edgewise, with EDG-5506, a muscle stabilizer that is currently in clinical development.

We believe that an exon skipping approach aimed at producing functional, truncated dystrophin will be a cornerstone approach to effectively treat patients with DMD.

Our Approach

We are developing a portfolio of product candidates for the treatment of DMD in which exon skipping PMOs are conjugated to our EDO peptide in order to enhance their delivery to muscle cells. Our initial product candidate is PGN-EDO51, an investigational EDO peptide-conjugated exon 51-skipping ASO with a proposed mechanism of action we believe to be identical to that of eteplirsen.

PGN-EDO51 is designed to facilitate the skipping of exon 51, allowing the synthesis of a shortened, but functional, dystrophin.

The key differentiator between PGN-EDO51 and other exon 51-skipping approaches is the greater exon skipping activity observed with PGN-EDO51 in HVs and in preclinical models. We believe the higher levels of exon skipping observed with PGN-EDO51 in HVs and in NHPs when compared to publicly available data and head-to-head data, respectively, from other therapies is directly related to the potential of our EDO platform to drive tissue penetration, cellular uptake and nuclear delivery of the PMO cargo therapeutic resulting in exon skipping of the defective dystrophin mRNA.

Our Preclinical Data

We have evaluated the pharmacology of PGN-EDO51 in a number of in vitro and in vivo preclinical studies and have observed robust activity in every model system evaluated. In DMD patient cells, treatment with PGN-EDO51 resulted in high levels of exon 51 skipping and dystrophin production.

In the mdx mouse, a well-characterized model of DMD, PGN-EDO23, a murine analogue of PGN-EDO51, resulted in high levels of exon skipping and dystrophin production. In the skeletal muscle, a single dose of PGN-EDO23 at 60 mg/kg resulted in 86.3% to 93.1% exon skipping and 90.4% to 99.7% dystrophin restoration. In the diaphragm, this dosing regimen afforded an exon skipping rate of 76.6% and dystrophin restoration levels of 80.6%, while in the heart it resulted in 62.3% exon skipping and 25.7% dystrophin restoration.

Robust dose-dependent increase in exon skipping and dystrophin protein production was observed following a single dose of PGN-EDO23 in mdx mice. Graphs plotted as mean ± SD. Dystrophin protein results are expressed as a percentage of WT dystrophin.

In accordance with the pharmacology, we observed significant reduction in creatine kinase, or CK, which is a critical biomarker of muscle damage, with this enzyme being elevated in DMD patients from birth. In the absence of dystrophin, the structural integrity of the sarcolemma, or muscle cell membrane, is disrupted, leading to the release of CK into the blood. Following intravenous administration of a single, generally well-tolerated dose of 30 mg/kg or 60 mg/kg of PGN-EDO23, we observed normalization of serum CK to WT levels in mdx mice seven days post-dose. The normalization of CK levels observed in this study suggest that PGN-EDO23 may restore muscle cell integrity and prevent further damage in mdx mice under a single dose regimen, and we believe that this outcome supports the potential therapeutic utility of PGN-EDO51 in the treatment of DMD patients.

A single dose of PGN-EDO23, the murine analogue of PGN-EDO51, was observed to normalize creatine kinase, a marker of muscle damage in mdx mice. Graph plotted as mean ± SEM; **** = p ≤ 0.0001, ns = p ≥ 0.05; n = 3 for control groups, n = 5 for treated group.

We subsequently conducted a repeat-dose study where we dosed mdx mice with 30 mg/kg of PGN-EDO23 every four weeks, with up to four doses, with tissue collection and analysis four weeks following the final dose. In the biceps, the level of exon skipping was observed to be 91.5% after four doses when measured by RT-PCR, a value that was 1.7 times higher than that observed following a single dose (52.5%). Dystrophin production was measured by western blot and was observed to reach a level of 82.2% in the same tissue after four doses in comparison to a level of 22.5% obtained after a single dose. We believe this marked increase of 3.7 times between the level of dystrophin obtained following one dose, and the level obtained following four doses supports the clinical

potential of a once-every-four-week dosing regimen for PGN-EDO51 and serves to highlight our belief that dystrophin production is likely to increase with subsequent doses in DMD patients.

Robust exon skipping and dystrophin restoration was observed with repeat dosing of PGN-EDO23 in mdx mice. Graph plotted as mean ± SD; n = 4-5 for each group; grey band represents dystrophin LLOQ (2.5%).

In addition, in this repeat dosing study in mdx mice, dystrophin protein localization and the percent dystrophin positive fibers, or PDPF, were evaluated by immunofluorescence microscopy. Importantly, this orthogonal assessment of dystrophin demonstrated that dystrophin protein was uniformly distributed across the skeletal muscle sarcolemma and found 97.1% of biceps muscle fibers were dystrophin positive following four doses of PGN-EDO23 administered once every four weeks, which was close to WT dystrophin levels (>99%).

Dystrophin levels and distribution in skeletal muscle with repeat dosing of PGN-EDO23 in mdx mice. Dystrophin protein evaluation by western blot and immunofluorescence (IF). Graph is presented as mean ± SD; n = 4-5 per cohort; grey band is dystrophin LLOQ (2.5%).

We have also conducted a number of studies in NHPs and have observed the robust in vivo activity of PGN-EDO51 in this higher order animal model. There is complete homology of the oligonucleotide binding site between the DMD gene in humans and the

DMD gene in NHPs for an exon 51-skipping therapeutic, thus allowing the activity of our clinical candidate to be assessed in this species.

We observed that seven days following a single dose of PGN-EDO51 in NHPs, high rates of exon 51 skipping were observed in the tibialis anterior, or TA, diaphragm and heart. In the TA, diaphragm and heart, exon skipping levels of 57.6%, 70.7% and 18.6%, respectively, were observed by RT-PCR following single doses of 20mg/kg.

Single doses of PGN-EDO51 led to high rates of exon 51 skipping in a preclinical NHP study. Graph plotted as mean ± SEM; n = 2 per group.

In order to benchmark the ability of our lead EDO peptide to improve the tissue penetration, cellular uptake and nuclear delivery of oligonucleotide therapeutics, we carried out a study comparing our EDO-conjugated PMO to an R6G peptide conjugated to the same PMO. We have conducted a considerable number of benchmarking studies of PGN-EDO51 against this conjugate, and we believe, based on publicly available information, that R6G-PMO is structurally equivalent to SRP-5051, Sarepta’s CPP-PMO product candidate that is currently in clinical development for the treatment of DMD patients who are amenable to an exon 51-skipping approach. In this preclinical study, NHPs were dosed intravenously with either PGN-EDO51, R6G-PMO or a saline control three times with an interval of two weeks between doses. Biopsies of the biceps and quadriceps were collected seven days after the first and second dose, and tissues were harvested seven days after the final dose.

Through RT-PCR analysis of key skeletal muscles collected by biopsy seven days after the first dose, we observed markedly higher exon skipping levels for PGN-EDO51 when compared to R6G-PMO. At 30 mg/kg, a single dose of PGN-EDO51 afforded an

exon 51-skipping level of 43.6% in the biceps, which was eight times higher than the level of 5.5% observed for R6G-PMO. In the quadriceps, this differential was 10 times, with 44.9% exon 51 skipping observed for PGN-EDO51, and just 4.5% for R6G-PMO.

Single dose administration of PGN-EDO51 in NHPs yielded considerably higher exon skipping levels than R6G-PMO. Graph plotted as mean ± SD; n = 3 per group; study was not powered for statistical significance.

Following three bi-weekly doses of 30 mg/kg, we observed robust exon skipping activity for PGN-EDO51, with levels of greater than 70% obtained in key skeletal muscles following analysis by RT-PCR seven days after the final dose. In biceps, an exon 51 skipping level of 77.5% was obtained; and in quadriceps, 73.4%. We observed exon 51 skipping levels of over 20% in the left ventricle for PGN-EDO51, and 75.9% in the diaphragm, and we believe that these results highlight the potential of our lead candidate to address the key cardio-respiratory morbidities affecting multiple organs observed in DMD.

Repeat dose administration of PGN-EDO51 in NHPs yielded high exon skipping rates in the key skeletal muscles, including the diaphragm, and in the cardiac left ventricle. Graph plotted as mean ± SD; n = 3 per group; study was not powered for statistical significance.

In order to understand the potential accumulation of exon 51-skipped transcripts under a four-weekly, or Q4W, repeat dose regimen, we assessed NHP tissue samples of the biceps collected seven days following a single administration of PGN-EDO51, and compared these with samples of the biceps collected seven days following four administrations of PGN-EDO51 once every four weeks. The levels of exon 51 skipping of the DMD transcript were assayed via a droplet digital PCR, or ddPCR, protocol. The results obtained showed a robust accumulation in the levels of the exon 51-skipped transcript between one dose and four doses. Following four doses of 20 and 30 mg/kg, exon 51 skipping levels were 34.9% and 37.6%, respectively, which were 14 times and 3.4 times higher than for a single dose. We believe this accumulative effect suggests that the activity of PGN-EDO51 is likely to increase with

chronic dosing in DMD patients, which we believe further supports the clinical potential of our lead candidate in this devastating disease. Our ongoing CONNECT1 study will determine the level of exon skipping and dystrophin production in biceps in DMD patients following four monthly doses of PGN-EDO51.

Exon skipped transcripts in the biceps accumulated under a preclinical repeat-dose regimen of PGN-EDO51 when assessed by ddPCR. Graph plotted as mean ± SD; n = 3-8 per group; study was not powered for statistical significance.

In conclusion, we demonstrated 14 times higher levels of exon 51 skipping in NHPs following four doses of PGN-EDO51 compared to a single dose. This 14-fold increase in exon-skipped transcript can be ascribed to the accumulation of PGN-EDO51 oligonucleotide in the muscle and the accumulation of exon 51-skipped transcript with repeat dosing shown in NHP studies. In HVs, following a single 10 mg/kg dose of PGN-EDO51, we observed 1.4% exon skipping 28 days following dosing, and similar to our observations in NHPs, we anticipate seeing meaningfully higher levels of exon 51-skipped transcript following four doses. Higher levels of exon-skipped transcript have been shown to produce higher levels of dystrophin in mdx mice and in DMD patients.

PGN-EDO51 was generally well-tolerated in single-dose, 28-day Good Laboratory Practice, or GLP, toxicity studies in mice and NHPs; no treatment-related mortality and no serious adverse events were observed through the therapeutic dose range. There were no adverse microscopic observations and no adverse impacts on clinical chemistry markers at clinically relevant dose levels.

An in vitro T cell stimulation assay conducted with peripheral blood mononuclear cells from healthy donors indicated that PGN-EDO51 has a very low immunotoxicity risk. This is further supported by data showing that the pharmacokinetic, or PK, profile of PGN-EDO51 was similar following the first and third dose, suggesting no significant neutralizing anti-drug antibody responses were present after a three-dose regimen in NHPs.

We have also conducted several repeat dose NHP studies to assess the safety and tolerability of PGN-EDO51. In one such study, we administered 11 doses of PGN-EDO51 intravenously to NHPs at 45 mg/kg over 60 minutes every 28 days over 39 weeks, and serum chemistry markers were assessed. Following the first administration, an elevation in serum creatinine was observed at day two; this elevation was completely resolved by day eight. Importantly, there were no adverse findings in the kidney even after 11 doses and there were no notable hematologic, cardiovascular or hepatic effects in this study. Additionally, following subsequent administrations, the day two elevations seen after the first dose were of lower magnitude. We believe these data support an acceptable tolerability profile for the ongoing CONNECT1 and planned CONNECT2 clinical studies since the planned therapeutic dose, as described below, is significantly under 45 mg/kg.

In NHPs, an amelioration of elevations in serum creatinine was observed with repeat dosing of PGN-EDO51 at 45 mg/kg. Graph plotted as mean ± SD; n = 12; grey bar shows normal range.* Samples were not collected for these time points. PD= Pre-dose

Clinical Development

Phase 1 HV Study

In 2022, we completed a first-in-human, Phase 1, single-center, randomized, double-blind, placebo-controlled, SAD clinical trial to assess the target engagement (exon skipping), pharmacokinetics (oligonucleotide tissue concentration), safety and tolerability of PGN-EDO51 administered intravenously to 32 healthy adult male volunteers. Following administration, safety data were evaluated by a safety review committee prior to progressing to the next dose level. Volunteers were dosed with either 1, 5, 10 or 15 mg/kg of PGN-EDO51 or placebo. Oligonucleotide tissue concentration and exon skipping were assessed from needle biopsies of biceps muscle taken on Days 10 and 28, with the latter being measured by a ddPCR assay.

A dose dependent increase in mean exon skipping was observed in biceps, with the levels obtained being the highest observed in humans following a single dose, based on cross-trial comparisons with publicly available data for other exon 51-skipping approaches.

•

In the 10 mg/kg dose cohort, PGN-EDO51 exhibited mean exon skipping of 1.4% in biceps biopsies taken at Day 28 (n=6).

•

In the 15 mg/kg dose cohort, PGN-EDO51 exhibited mean exon skipping of 2.0% in biceps biopsies taken at Day 28 (n=6).

We observed the highest levels of mean exon skipping in humans following a single dose based on cross-trial comparisons with publicly available data for other exon 51-skipping approaches. Data is shown as mean ± SD; n = 6 for PGN-EDO51 (n = 5 for D10 at 15 mg/kg), n = 8 for placebo. Asterisks indicate values that were under the lower level of quantification.

A dose-dependent increase in PGN-EDO51 tissue concentration was observed in biceps, with the levels obtained being the highest observed in humans for a DMD therapeutic following a single dose, based on cross-trial comparisons with publicly available data for other exon 51 skipping approaches.

•

In the 10 mg/kg dose cohort, PGN-EDO51 exhibited mean oligonucleotide tissue concentrations of 11 nM in biceps biopsies taken at Day 28 (n=6).

•

In the 15 mg/kg dose cohort, PGN-EDO51 exhibited mean oligonucleotide tissue concentrations of 50 nM in biceps biopsies taken at Day 28 (n=6).

High, persistent tissue concentrations of oligonucleotide were observed. Data is shown as mean ± SD; n = 6 for PGN-EDO51 (n = 5 for D10 at 15 mg/kg), n = 8 for placebo. Asterixis indicate values that were under the lower level of quantification.

In summary, we have demonstrated six times higher exon skipping after a single 10 mg/kg dose of PGN-EDO51 compared to SRP-5051 dosed at 20 mg/kg, based on cross-trial comparison of publicly available data from a Phase 1 HV study following a single dose of SRP-5051. We believe that the exon skipping data obtained from HVs in this clinical trial indicate the potential for clinically meaningful accumulation of exon 51-skipped transcripts and dystrophin in patient tissue with repeated doses of PGN-EDO51. Accumulation of exon skipped transcripts is further supported by the preclinical data from NHPs that demonstrated repeat dosing of PGN-EDO51 at 20 mg/kg resulted in 14 times greater exon skipping compared to a single dose. Thus, based on these data, we anticipate that the exon skipping rates afforded by PGN-EDO51 when administered to patients have the potential to exceed the rates observed when administered to HVs.

The Phase 1 trial met its primary endpoint, providing evidence that PGN-EDO51 was generally well tolerated at clinically relevant doses. By way of example, at a dose of 10 mg/kg:

•

All participants completed the study with no discontinuations;

•

All related treatment-emergent adverse events, or TEAEs, including transient, reversible changes in kidney biomarkers, were assessed as mild and resolved without any intervention;

•

Serum cystatin C, the recommended biomarker to assess renal function in DMD, did not change; and

•

There was no evidence of hypomagnesemia.

At 15 mg/kg there was one non-life threatening serious adverse event, or SAE, related to changes in kidney biomarkers that were transient and reversible. This HV was admitted to the hospital for less than 24 hours, received hydration and then was re-admitted to the Phase 1 unit and completed the study. There were no clinical symptoms of acute kidney injury in any of the subjects.

Based on the tissue concentration and exon skipping observed in this Phase 1 study, alongside PK and pharmacodynamic, or PD, prediction models informed by preclinical data from mdx mice and NHPs, we are expecting our target therapeutic dose in CONNECT1 and CONNECT2 studies to be lower than 15 mg/kg and at these doses, we expect a favorable safety profile. Additionally, in support of the expected tolerability profile for PGN-EDO51, as mentioned above, we have demonstrated in NHPs that 11 doses of PGN-EDO51 administered intravenously at 45 mg/kg every 28 days resulted in elevation in serum creatinine at day two post dose, but this elevation was completely resolved by day eight. At target therapeutic doses in our CONNECT1 study and CONNECT2 study, we may see changes in kidney biomarkers at 10 mg/kg or higher doses but expect these will be transient and reversible.

We also observed transient mild (Grade 1) hypomagnesemia in one participant and moderate (Grade 2) hypomagnesemia in one participant at the 15 mg/kg dose that did not require any intervention. We note that ≥ Grade 3 hypomagnesemia was a SAE observed with repeat dosing of SRP-5051 at the 20 mg/kg and 30 mg/kg doses in the MOMENTUM study and that Sarepta amended the protocol to include magnesium supplementation in the pivotal Phase 2 MOMENTUM, Part B study. The Phase 2 MOMENTUM Part A and Part B safety and tolerability data shows that the severity of hypomagnesemia is dose dependent. Based on the safety and tolerability data of PGN-EDO51 to date, and the expected higher potency of PGN-EDO51 compared to SRP-5051, we believe PGN-EDO51 has the potential for a wider therapeutic index enabling desirable efficacy at a lower dose without ≥ Grade 3 hypomagnesemia and without the need for prophylactic magnesium supplementation. It is possible that we may observe mild tomoderate hypomagnesemia following repeat-dose administration of PGN-EDO51 in our clinical trials, and we are carefully monitoring serum magnesium levels in our ongoing CONNECT1 clinical trial.

Under the Phase 1 protocol for PGN-EDO51, any non-life-threatening SAE was considered a dose-limiting toxicity, or DLT, however the study was not halted by the safety review committee, nor was it put on hold by Health Canada. In light of higher than anticipated oligonucleotide levels and exon skipping levels in muscle observed at 5 mg/kg and 10 mg/kg, we determined that further dose escalation in the Phase 1 study was not necessary.

TEAEs were mild and resolved without intervention at clinically relevant doses. Asterisk denotes that no Grade 4 or 5 TEAEs were recorded.

CONNECT1 and CONNECT2 Phase 2 MAD Studies

The results from our Phase 1 HV clinical trial, together with the experience and expertise of our clinical development team and scientific advisory board, as well as learnings from previous clinical studies conducted in exon 51 skipping-amenable DMD patients,

have guided the design, parameters and objectives of our planned Phase 2 clinical trials of PGN-EDO51 in DMD patients amenable to an exon 51-skipping approach.

The Phase 2 clinical development plan for PGN-EDO51 consists of two studies conducted in parallel; a smaller open label MAD study, CONNECT1, is being conducted in Canada. A larger, multinational, randomized, double-blind placebo-controlled MAD study, CONNECT2, was recently authorized by the MHRA for initiation in the U.K. In the CONNECT1 study, participants will be administered PGN-EDO51 once every four weeks at 5 mg/kg, 10 mg/kg or potentially a higher dose (if needed) for 12 weeks. Dose escalation is based on data review by the data safety monitoring board, or DSMB. We will conduct muscle biopsies at baseline and week 13. In addition to assessing safety and tolerability, we are measuring exon skipping and dystrophin expression in CONNECT1. We began dosing patients in our CONNECT1 study in early 2024 and have fully enrolled the 5 mg/kg dose cohort. We anticipate reporting preliminary data from this cohort in mid-2024, including safety, exon skipping and dystrophin production.

As noted above, in February 2024, we received clearance from the MHRA to initiate CONNECT2 in the U.K. The CONNECT2 will enroll approximately 20 ambulatory and non-ambulatory boys and young men living with DMD amenable to exon 51-skipping, who are at least six years of age. Participants will receive seven doses of either PGN-EDO51 or placebo at approximately four-week intervals for 24 weeks. The starting dose will escalate from 5 mg/kg to 10 mg/kg, and potentially higher (if needed); the same dose levels are being evaluated in the CONNECT1 trial. Dose escalation will be determined based on data review by the DSMB. We will conduct muscle biopsies at baseline and at week 25. We will assess safety, tolerability, exon skipping, dystrophin production and functional outcome measures in this study.

We believe that this clinical development plan may enable us to pursue an accelerated approval pathway for PGN-EDO51 with the FDA. In the DMD space, the FDA has approved four drugs under the accelerated approval pathway since 2016. If we receive positive results from our Phase 2 trials for PGN-EDO51 that show an acceptable emerging safety profile; a clinically meaningful increase in dystrophin levels, a surrogate endpoint in the biceps of DMD patients; and robust exon skipping levels in the same tissue; we intend to pursue discussions with the FDA for a potential accelerated approval pathway.

PGN-EDODM1

Overview

We are developing PGN-EDODM1, an EDO peptide-conjugated PMO, for the treatment of DM1, a debilitating genetic disease with no approved therapies. PGN-EDODM1 leverages the same EDO peptide as PGN-EDO51 to deliver a PMO into muscle cells that binds to the pathogenic CUG trinucleotide repeat expansion present in the DMPK mRNA, thus reducing the ability of these trinucleotide repeats to sequester RNA binding proteins like MBNL1, a critical RNA processing protein. This approach, which is not designed to knock down DMPK, directly addresses the underlying genetic defect of this disease, and we have observed robust levels of activity in preclinical models with both long and short CTG repeats. In DM1 patient cells, we observed that treatment with PGN-EDODM1 led to a reduction in toxic nuclear foci, and liberated bound MBNL1 which mediated robust correction of mis-splicing. In preclinical studies in the mouse HSALR DM1 model, a single dose of PGN-EDODM1 was observed to correct the molecular and functional deficits, including correcting >65% of transcript mis-splicing events and reversing >70% of myotonia. Multiple monthly doses of PGN-EDODM1 corrected 99% of transcript mis-splicing and myotonia. This correction of mis-splicing following a single dose of PGN-EDODM1 was observed to persist for up to six months. Furthermore, the muscle concentrations of PGN-EDODM1 oligonucleotide that mediated these effects in the HSALR mouse model were similar to those observed 28 days following a single dose of 10 mg/kg of PGN-EDO51 in human muscle in our Phase 1 HV clinical trial. Given the molecular overlaps of PGN-EDO51 and PGN-EDODM1, we believe this supports the potential of a single 10 mg/kg dose of PGN-EDODM1 to achieve therapeutic muscle levels of oligonucleotide in DM1 patients.

We opened our FREEDOM Phase 1, randomized, placebo-controlled SAD clinical trial of PGN-EDODM1 in DM1 patients in the second half of 2023 in Canada, followed by the U.S. and U.K. and began dosing patients in December 2023. We expect to report preliminary data from this study, including safety, splicing correction and functional outcome measures in the second half of 2024. We also expect to open the FREEDOM2-DM1 Phase 2 randomized, double blind, placebo-controlled MAD study in DM1 patients in the second half of 2024.

Disease Background and Prevalence

DM1 is a monogenic, autosomal dominant, progressive disorder that primarily affects skeletal, cardiac and smooth muscles, with central nervous system, or CNS, symptoms also being evident. Globally, the prevalence of DM1 is estimated to be 1 in 8,000 people, with approximately 40,000 patients in the U.S., 75,000 patients in Europe and 15,000 patients in Japan. However, under- and misdiagnosis is believed to be widespread, and genetic screening studies for DMPK triplet repeats have suggested that the prevalence of DM1 may be as high as 1 in 2,100 people.

DM1 patients can suffer from various manifestations of disease including myotonia, or a temporary rigidity due to the inability to relax muscles, muscle weakness, cardiac abnormalities, respiratory problems, fatigue, gastrointestinal complications, early cataracts, and cognitive and behavioral impairments. For patients with more severe forms of DM1, life expectancy is reduced due to increased mortality rates resulting from pulmonary and cardiac complications.

The broad spectrum of pathologies associated with DM1 arise due to genetic changes in the DMPK gene. Specifically, DM1 is caused by an expansion in the number of CTG triplet repeats that are present in the non-coding region of the DMPK gene, and following transcription this mutant DMPK gene yields an mRNA product with an expanded CUG repeat region. Healthy,

asymptomatic individuals possess between 5 and 37 such repeats, but in DM1 patients the number of repeats can be in the thousands. These highly repetitive sequences form stable hairpin structures in the nucleus of cells and sequester critical RNA splicing proteins, such as MBNL1, leading to the formation of nuclear foci. The sequestration of MBNL1 prevents this key protein from performing its normal function of processing RNA molecules before they are exported from the nucleus, leading to downstream mis-splicing events in a number of other transcripts. The mis-splicing of these transcripts results in the dysregulation of a broad set of downstream proteins, which in turn leads to in the multi-systemic pathologies that are associated with DM1, which include:

•

Musculoskeletal: Myotonia (a temporary inability to relax a muscle after contraction), muscle weakness & wasting.

•

Cardiac: Conduction defects.

•

Respiratory: Breathing difficulties, sleep apnea.

•

Gastrointestinal: Dysphagia (difficulty swallowing), constipation, Irritable Bowel Syndrome.

•

CNS: Cognitive impairments, behavioral / psychologic disorders, excessive daytime sleepiness.

•

Vision: Early-onset cataracts, retinal damage.

•

Endocrine: Thyroid dysfunction, diabetes.

•

Other pathologies: Skin, immune system and reproductive pathologies, increased cancer risk.

There is a general correlation between the number of CTG repeats in the aberrant DMPK gene and the severity of disease. Individuals with 50 to 150 repeats are prone to development of mild myotonia and cataracts, but typically have a normal lifespan. Individuals with up to approximately 1,000 repeats typically have muscle weakness and cardiac arrhythmia, with an average lifespan of 48 to 55 years. The most serious cases of DM1 are generally observed in individuals with more than 1,000 repeats, and these patients are likely to also suffer from respiratory defects and intellectual disability, with a shortened lifespan of approximately 45 years. Genetic anticipation is also observed, whereby the age of onset decreases in subsequent generations due to expansion of the CTG repeat between generations.

Current Approaches and Limitations

There are no approved therapies to treat DM1, with current standards of care being medicines that are used off-label for symptom management. Previously, a phosphorothioate ASO designed to cause degradation of the DMPK transcript was clinically assessed as a therapeutic for DM1. However, this therapeutic approach was restricted by the inefficiency of ASO delivery into target tissues and cells, thus limiting the effective clinical translation of this product candidate.

There are several clinical-stage approaches leveraging antibody-oligonucleotide conjugate, or AOC, technologies, that are currently in development for the treatment of DM1. These approaches utilize mAbs and Fabs that target the transferrin receptor 1, or TfR1, in order to deliver cargo oligonucleotides that are designed to knockdown or degrade DMPK. Such knockdown or degradation approaches cannot differentiate between expanded and non-expanded transcripts. In contrast to knockdown or degradation of overall DMPK levels, our approach is more targeted as PGN-EDODM1 is designed to disrupt the binding of MBNL1to the DMPK transcript. This approach maintains overall DMPK levels and thereby averts any potential for haploinsufficiency, a condition where a copy of the gene is deleted or mutated and the remaining copy is unable to produce sufficient protein for normal function. Furthermore, the correlation between the level of DMPK knockdown and the level of splicing correction required for therapeutic benefit is currently unclear, a consideration that may confound clinical development of these approaches. Therefore, we believe that PGN-EDODM1 is differentiated relative to the DMPK knockdown approaches in development for DM1 given its mechanism of action that is intended to bind DMPK, allowing release of MBNL1 to restore splicing and downstream functional effects. In addition, in preclinical studies, the EDO platform has shown successful delivery of therapeutic PMOs to the nucleus, which we believe is critical to drive the anticipated therapeutic benefit of PGN-EDODM1.

We are also aware of VX-670, another cell-penetrating peptide approach conjugated to a PMO that is designed to block the CUG repeats in the DMPK transcript that has recently entered clinical development for the treatment of DM1.

Our Approach

Our product candidate for the treatment of DM1, PGN-EDODM1, consists of our lead EDO CPP conjugated to an ASO that binds to the pathogenic CUG repeat expansion in the DMPK mRNA. We are employing the same EDO peptide in PGN-EDO51 and PGN-EDODM1. PGN-EDODM1 is designed to directly address the deleterious effects of genetic alteration in DM1, specifically the sequestration of MBNL1 due to the high number of CUG repeat expansion in the DMPK transcript.

We believe that this innovative therapeutic approach has considerable advantages over oligonucleotide modalities that rely on knockdown or degradation of the DMPK transcript. PGN-EDODM1 disrupts the binding between the CUG repeat expansion and MBNL1, an approach which we believe will allow the DMPK transcript to continue performing its normal function within the cell,

while also liberating MBNL1 to correct downstream mis-splicing events. We believe that this therapeutic strategy positions us to potentially provide clinically meaningful benefits for DM1 patients while mitigating the risk of potential deleterious outcomes.

PGN-EDODM1 is designed to bind to the CUG repeats in DMPK RNA and liberate MBNL1 to restore physiological splicing, in contrast to modalities that indiscriminately target both normal and pathogenic DMPK for degradation.

Preclinical Data

In an in vitro study utilizing DM1 patient cells with approximately 2,600 CTG repeats in the DMPK gene, we observed a robust reduction in nuclear foci, liberation of MBNL1 from foci and the correction of downstream transcript mis-splicing pathologies. In this study, immortalized myoblasts from a DM1 patient were differentiated for four days, and then treated for 24 hours with PGN-EDODM1 at a range of concentrations from 0 μM to 20 μM. Myoblasts from a healthy individual were utilized as a control, and the unconjugated PMO was also assessed at a concentration of 20 μM in this study in order to demonstrate the critical role that our EDO platform plays in driving efficient cell uptake of this therapeutic cargo.

A characteristic feature of DM1 is the accumulation of nuclear foci, or myonuclear aggregates of DMPK mRNA bearing the pathogenic CUG repeat expansion. These foci sequester MBNL1, a critical modulator of transcript splicing, and thus play a key role in the downstream spliceopathies that are observed in this multi-systemic disorder. We assessed the impact of PGN-EDODM1 treatment on the presence of nuclear foci in DM1 cells through visualization with fluorescence in situ hybridization, or FISH, and immunofluorescence co-staining, and we observed that treatment led to a robust reduction of 54% in the number of these toxic aggregates. In contrast, treatment with the unconjugated PMO cargo did not yield a reduction in nuclear foci, an observation which we

believe supports the potential utility of our EDO platform in driving the successful delivery of therapeutic agents to their nuclear site of action.

In a preclinical study conducted in DM1 patient cells, PGN-EDODM1 treatment supported the reduction of pathogenic nuclear foci in a dose-dependent fashion. Graph plotted as mean ± SD; n = 3-4 per group.

In this same in vitro study, we also assessed the impact of PGN-EDODM1 treatment on the sequestration of MBNL1. Following treatment and visualization, we observed a reduction in the amount of foci-bound MBNL1, indicating that that this critical splicing factor is liberated upon treatment with our DM1 product candidate. We believe these results provide additional support for the proposed mechanism of action of PGN-EDODM1, suggesting that – once delivered to the cell nucleus – our therapeutic cargo may

bind to the CUG repeat expansion present in the DMPK transcript, resulting in a reduction in the number of nuclear foci and the liberation of MBNL1.

PGN-EDODM1 treatment resulted in the liberation of MBNL1 from DPMKfoci.

Treatment of DM1 patient cells with PGN-EDODM1 led to robust correction of downstream mis-spliced transcripts associated with key disease pathologies in a dose-dependent fashion. At the highest dose assessed, 20 μM, PGN-EDODM1 treatment resulted in robust mis-splicing correction, resulting in exon inclusion or exclusion rates of approximately 70% of healthy control levels in these transcripts. This observation supports our therapeutic hypothesis that treatment with PGN-EDODM1 may restore the altered global spliceopathy profiles seen in DM1 patients, thus ameliorating the key pathologies that are the hallmark of this devastating disease.

In an in vitro study, PGN-EDODM1 treatment resulted in correction of mis-splicing pathologies to around 70% of healthy control levels. Graph plotted as mean ± SD; n = 5 per group.

Building on the encouraging positive data from our in vitro studies, we utilized the HSALR mouse model of DM1 to assess the activity of PGN-EDODM1. This transgenic mouse model contains between 220 and 250 CTG trinucleotide repeats in the inserted

human skeletal actin, or HSA, gene, and exhibits molecular and functional pathologies that are very similar to those seen in human DM1 patients. The CUG repeat expansion present in the HSALR mouse model, and the subsequent sequestration of MBNL1, leads to downstream defects in the normal mRNA splicing patterns for a number of transcripts, resulting in aberrant inclusions or exclusions of exons.

Sequestration of MBNL1 in the HSALR mouse model causes mis-splicing of multiple RNAs including Clcn1 and Atp2a1, both of which are involved in the regulation of muscle movement. This mis-splicing causes the mice to exhibit myotonia, effectively recapitulating the classic symptom of disease that is observed in DM1 patients. Mis-splicing of Atp2a1 manifests as a lack of exon 22 inclusion in the Atp2a1 mRNA when compared to wild-type splicing patterns, while mis-splicing of Clcn1 manifests as an increase in exon 7a inclusion in the Clcn1 mRNA when compared to wild-type splicing patterns. Following a single intravenous administration of PGN-EDODM1, we observed dose-dependent normalization of the splicing of these genes in the quadriceps and gastrocnemius muscles two weeks after dosing. At a dose of 30 mg/kg, we achieved 91% correction of Atp2a1 mis-splicing and 68% correction of Clcn1 mis-splicing, highlighting the potential of our product candidate to address such downstream pathologies.

PGN-EDODM1 led to a dose-dependent normalization of the splicing of Atp2a1 and Clcn1 transcripts in preclinical study in quadriceps muscles in HSALR mice. Graph plotted as mean ± SEM; n = 8 for PGN-EDODM1 group, n = 16 for HSALR saline control, n = 8 for WT saline control; **** = p≤0.0001.

Consistent with the reversal of mis-splicing events, treatment with a single dose of PGN-EDODM1 also led to a complete reversal of myotonia phenotype in HSALR mice as assessed by electromyography, with a dose of 30 mg/kg showing complete normalization two weeks after administration. In observational studies we noted quantitative amelioration of myotonia, where treated mice were able to ambulate normally following the inducement of this functional phenotype of disease by hindlimb pinching. In

contrast, untreated HSALR mice were unable to efficiently use their hind legs and dragged them behind following the same myotonic inducement event.

PGN-EDODM1 led to a complete amelioration of myotonia in a preclinical study after a single administration. Graph plotted as min to max; n = 8 for PGN-EDODM1 group, n = 16 for HSALR saline control, n = 8 for WT saline control; *** = p≤0.001.

Furthermore, the pharmacologic effects of PGN-EDODM1 were observed to be highly durable. In a duration of effect study, again in the HSALR mouse model, amelioration of the pathogenic splicing patterns of the Atp2a1 and Clcn1 transcripts in the gastrocnemius and quadriceps persisted for at least 24 weeks following a single 30 mg/kg intravenous administration of PGN-EDODM1.

PGN-EDODM1 led to durable improvements in mRNA splicing through 24 weeks post-dose in the HSALR mouse model. Graph plotted as mean ±SEM; n = 7 for 0 timepoint, 8 for 2- and 12-week timepoints; 5 for 24-week timepoint.

In another study in the HSALR mouse model, multiple doses of PGN-EDODM1 at 30 mg/kg given once every four weeks were evaluated. While a single dose corrected 68% of transcript mis-splicing and 76% of myotonia, as measured using the pinch test, four repeat doses produced 99% correction of mis-splicing and 99% correction of the myotonia.

PGN-EDODM1 led to a normalization of splicing and near complete correction of myotonia in a repeat dosing preclinical study in skeletal muscles in HSALR mice. Mis-splicing analysis considers multiple transcripts. Graph is presented as mean ± SD; n = 8-12 per cohort per transcript. Myotonia pinch test was performed four weeks post-final dose. Grade 3 = Clear sign of myotonia strong AND reproducible, Grade 2 = Clear sign of myotonia, strong OR reproducible, Grade 1 = Clear sign of myotonia but non reproducible, Grade 0 = No sign of myotonia. Graph is presented as mean ± SD; n = 12-43 per cohort.

In order to understand the PK/PD relationship for PGN-EDODM1 to inform the clinical development strategy for PGN-EDODM1, we also quantified the concentration of PGN-EDODM1 in the muscle tissue in HSALR mouse model. Following PGN-EDODM1 administration in HSALR mice, we observed mean tissue concentrations of 6 nM at 28 days post single dose and 13 nM at 28 days post four doses. Furthermore, the clinical PK/PD relationship for PGN-EDO51 demonstrated that PGN-EDO51 at 10 mg/kg resulted in exon skipping activity in HVs while achieving muscle PMO concentration in the range of concentration similar to PGN-EDODM1 in HSAlr mice, as indicated below. Therefore, given that the EDO delivery peptide is identical for both programs and

based on PGN-EDODM1 HSALR mouse PK/PD relationship and PGN-EDO51 human PK/PD relationship, we believe that PGN-EDODM1 has the potential to demonstrate improvement in splicing with a single dose in our ongoing FREEDOM trial.

Tissue concentrations of PGN-EDODM1 28 days post dose in HSALR mice and tissue concentrations of PGN-EDO51 28 days post single dose (as shown in Phase 1 HV study results included above). Graph plotted as mean ± SEM; n = 8 for PGN-EDODM1 group, n = 8 for WT saline control; n = 6 for PGN-EDO51 data.

In summary, based on our preclinical data from the HSALR mouse model along with the expected PK/PD relationship from PGN-EDO51, we have designed a clinical development plan that we believe has the potential to translate the robust impact of PGN-EDODM1 on splicing and functional outcomes observed in the HSALR mouse model to patients.

Unlike several other approaches currently in clinical development, PGN-EDODM1’s mechanism of action does not target DMPK transcript for degradation. In both DM1 patient cells and in NHPs, mean DMPK transcript levels remained unchanged relative to an untreated control following exposure to PGN-EDODM1.

To elaborate on these studies, in an in vitro study, immortalized myoblasts from a DM1 patient with 2,600 CTG repeats were differentiated for four days to myotubes and treated for 24 hours with PGN-EDODM1 at a range of concentrations between 1 and 20 μM. DMPK transcript levels were evaluated by qPCR and normalized to ribosomal protein P0, orRPLP0. In NHPs, three doses of 10, 30 or 60 mg/kg of PGN-EDODM1 were administered every two weeks. One week following the final dose, DMPK transcript levels were evaluated by RT-PCR and normalized to RPLP0. Mean DMPK transcript levels remained unchanged relative to an untreated control following exposure to PGN-EDODM1.

No significant changes in mean DMPK transcript levels were observed in DM1 patient cells or in NHPs. Graphs plotted as mean ± SEM; n = 4 for patient cell data, n = 3-4 for NHP data.

Thus, we believe this unique mechanism of action design may offer a potential safety benefit, as we believe such an approach does not carry the risk of possible DMPK haploinsufficiency.

We have completed a number of GLP studies that support a generally well-tolerated safety profile for PGN-EDODM1. In a four dose, 12-week sub-chronic toxicology study in NHPs, PGN-EDODM1 was observed to be generally well-tolerated through 60 mg/kg. While we observed transient increases in serum creatinine that resolve within a week post dose, importantly, we did not see any adverse findings in the kidney through 60 mg/kg. Furthermore, there were no noteworthy hematologic, cardiovascular or hepatic effects observed.

PGN-EDODM1 administration in NHPs led to a transient increase in serum creatinine followed by reduction in serum creatinine to baseline levels by day 8. NHPs were dosed intravenously four times once every 28 days at 60 mg/kg over 60 min (n=6 males; n=6 females). Data shown as mean ± SD.

We believe that the totality of the data obtained from the safety/toxicology studies that have enabled IND/CTA filings highlight a potentially favorable safety profile for PGN-EDODM1.

In summary, based on PGN-EDODM1’s improvement of mis-splicing and myotonia in HSALR mouse model, the favorable safety profile observed in toxicology studies, and the ability of the EDO technology to achieve pharmacologically active levels of

PMO in skeletal muscle, as seen in the PGN-EDO51 Phase 1 HV data, we believe that PGN-EDODM1 has the potential to be a meaningful therapy for patients with DM1.

Clinical Development

We are currently enrolling patients with DM1 in the FREEDOM study, a randomized, double-blind placebo-controlled Phase 1 study. In this study, we intend to enroll approximately 24 adult patients with DM1 in multiple geographies including the U.S., U.K. and Canada, to evaluate the safety and tolerability of PGN-EDODM1. Per the protocol, PGN-EDODM1 will be administered at the starting dose of 5 mg/kg and subsequently at 10 mg/kg and 20 mg/kg. Dose escalation to the higher dose will be determined based upon evaluation of safety data from the prior dose cohort(s). We will conduct muscle biopsies at baseline, at day 28 and at week 16. In addition to safety and tolerability, we plan to assess oligonucleotide muscle concentrations, splicing correction and functional outcome measures at day 28 and at week 16 following a single dose of PGN-EDODM1. We anticipate reporting preliminary data, including safety, correction of splicing and functional outcome measures, in the second half of 2024.

The safety data from the initial cohorts of the FREEDOM trial will inform the design of the planned FREEDOM2-DM1 trial, which will be a Phase 2 randomized, double blind, placebo-controlled MAD study in DM1 patients, which we anticipate opening in the second half of 2024.

Based on preclinical data, emerging safety profile and translatability of our EDO platform from preclinical species to humans as observed with PGN-EDO51, we believe that PGN-EDODM1 has the potential to be disease-modifying and could improve outcomes for patients living with DM1. Notably, the FDA has recently granted Fast Track designation to PGN-EDODM1.

PGN-EDO53

Overview

We are also developing EDO therapeutics for additional DMD patient population, including PGN-EDO53, for patients who are amenable to exon 53 skipping, representing approximately 8% of DMD patients. PGN-EDO53 utilizes the same EDO CPP as our exon 51-skipping product candidate, PGN-EDO51, which we believe will allow us to leverage our drug development experience in DMD to rapidly drive this candidate to the clinic. In a NHP study of PGN-EDO53, we observed single-dose exon skipping levels that were almost seven times higher than those observed for R6G-PMO53, a relevant comparator peptide-PMO conjugate approach. We intend to progress the selected candidate for PGN-EDO53 into IND/CTA enabling studies in 2024.

Current Approaches and Unmet Needs

Two unconjugated ASOs leveraging PMO chemistry have been approved for the treatment of individuals with DMD who are amenable to an exon 53-skipping approach – golodirsen, marketed as VYONDYS 53® by Sarepta and viltolarsen, marketed as VILTEPSO® by NS Pharma, Inc. in the U.S.. These drugs were approved in the U.S. through the accelerated approval regulatory pathway based on an increased expression of dystrophin, which is considered to be a surrogate endpoint for this indication. Both golodirsen and viltolarsen have yet to establish a clinical benefit for DMD patients through a confirmatory trial.

Our Approach for Preclinical Development

We are developing PGN-EDO53, a peptide-conjugated ASO designed to skip exon 53 of the dystrophin transcript in DMD patients who are amenable to such a therapeutic approach. We have completed a preclinical in vitro screen of a number of candidate ASO sequences utilizing the established PMO chemistry. We synthesized several exon 53-skipping PMOs conjugated to our lead EDO peptide and assessed the activity of these in human-derived myoblasts carrying mutations that are amenable to treatment with an exon 53-skipping approach. Based on the data obtained from this in vitro screen, we have subsequently assessed several development candidates in a repeat-dose NHP study, where these PPMOs were assessed alongside a relevant comparator, R6G-PMO53. Three doses of each PPMO were administered intravenously over 60 minutes every four weeks, with biopsies of the biceps collected five to seven days after the first and second administrations, and terminal samples collected seven days after the final dose. Exon 53 skipping was assessed by RT-PCR.

Notably, the single-dose exon skipping levels of 36.4% obtained for the selected PGN-EDO53 candidate were almost seven times higher than those observed for the R6G-PMO53 comparator at 5.4%. Furthermore, exon 53 skipped transcripts accumulated with repeat dosing of PGN-EDO53. Following the third and final dose of PGN-EDO53, mean exon skipping levels were observed to be 57.2%, a level that was nearly three times higher than the mean exon skipping levels of 20.8% that were observed for the R6G-PMO53 comparator. We believe that this accumulation in skipped transcript is indicative of the potential of the EDO platform to drive

clinically meaningful levels of exon skipping, and ultimately dystrophin production, in DMD patients. We are initiating IND/CTA enabling studies for PGN-EDO53 in 2024.

Treatment with PGN-EDO53 afforded single-dose exon skipping levels almost seven times higher than for a comparator PPMO. Graphs plotted as mean ± SD; n = 3 per group; study was not powered for statistical significance.

Expanding the Application and Scope of Our EDO Platform

New Indications with PMO Therapeutics

In the future, we intend to apply our deep understanding of our EDO platform and PMO therapeutics to the development of additional product candidates in other indications. Based on extensive preclinical data we have generated, we believe that the ability of our EDO peptides to deliver exon skipping and RNA blocking therapeutics to muscle cells and other target tissues positions us to develop additional product candidates in other neuromuscular indications as well as in potentially neurologic indications.

New Cargos

We believe that our EDO technology has the potential to facilitate the delivery of multiple types of oligonucleotide therapeutics. To date, our efforts have primarily focused on the delivery of PMOs, but we also intend to pursue the expansion of our cargo scope to other nucleic acid species.

New Peptide Technologies

We intend to further establish our expertise and competitive position in the field of oligonucleotide delivery through the ongoing research and development of new peptides. In connection with these efforts, we intend to leverage our deep expertise in this field to design new peptides that target specific tissue types, and to seek to further optimize the tissue and cellular delivery of our EDO platform.

Manufacturing

Our manufacturing process is modular in nature. The peptide and oligonucleotide components are assembled using readily available building blocks and are subsequently conjugated using well-established methodologies. This process is fully synthetic and does not rely on microbial fermentation, thus substantially reducing the risk of introducing microbial DNA or protein into our product candidates. Furthermore, our manufacturing process is highly scalable and easily characterizable – attributes that we intend to leverage to support the rapid development and clinical translation of our EDO conjugate therapeutics. We have produced, manufactured and released multiple batches under current Good Manufacturing Practice, or cGMP, and have successfully utilized this material in a Phase 1 clinical trial.

We do not own or operate manufacturing facilities, and currently rely on third-party contract development manufacturing organizations, or CDMOs, and suppliers for the cell-penetrating peptide, linker and oligonucleotide components that comprise our EDOs, and for the conjugation of our product candidates as well as for the manufacturing of the finished dosage form (sterile injectable drug product). We anticipate that we will continue to utilize third-party CDMOs and suppliers to support our ongoing and

future preclinical, clinical and commercial activities, and our intention is to build this network of organizations as we scale our manufacturing requirements. Long-term, we may also decide to establish internal manufacturing of our drugs or selected intermediates.

We believe that there are multiple sources for all raw materials employed in the manufacturing of our EDO therapeutics, and we believe that several CDMOs are able to assemble either the peptide intermediate, the linker, and the oligonucleotide as well as the final API.

There are extensive regulations that govern the manufacturing of biopharmaceutical products, and the third-party manufacturing organizations we work with are required to adhere to these regulations. Our CDMOs are required to manufacture our product candidates under cGMP requirements, alongside other applicable laws and regulations.

Competition

The biopharmaceutical industry is characterized by the rapid evolution and development of new technologies, leading to an environment that is intensely competitive in nature and thus supports the robust protection and defense of intellectual property. Any EDO product candidates that we successfully develop and commercialize will compete both with existing therapeutics, and with new approaches that may arise in the future. While we believe that our unique EDO platform and extensive expertise in oligonucleotide delivery may provide us with a differentiated position in the neuromuscular and neurologic spaces, such competing technologies may arise from many different sources, including large biopharmaceutical organizations, specialty pharmaceutical and biotechnology companies, academic institutions, government agencies, and public and private research organizations.

We expect to face competition from existing products and product candidates in development for each of our programs. Currently, patients with DMD are treated with corticosteroids to manage the inflammatory component of the disease. EMFLAZA (deflazacort) is an FDA-approved corticosteroid marketed by PTC Therapeutics, Inc., or PTC. Individuals with DMD also use prednisone or prednisolone off-label. In addition, there are several FDA-approved exon skipping drugs: EXONDYS 51 and VYONDYS 53, which are naked PMOs approved for the treatment of DMD patients amenable to exon 51 and exon 53 skipping, respectively, marketed by Sarepta; and VILTEPSO, a naked PMO approved for the treatment of DMD patients amenable to exon 53 skipping, which is marketed in the U.S. by NS Pharma, Inc. Companies focused on developing treatments for DMD that target increased dystrophin expression, as our DMD program does, include Sarepta with SRP-5051, a peptide-linked PMO currently being evaluated in a Phase 2b clinical trial for patients amenable to exon 51 skipping, Dyne Therapeutics, Inc., or Dyne, with DYNE-251, an antibody-conjugated PMO that targets exon 51 skipping in a Phase 1/2 clinical trial; BioMarin Pharmaceutical Inc., or BioMarin, with BMN-351,a phosphorothioate oligonucleotide that targets exon 51 skipping currently in preclinical development; and Wave Life Sciences Ltd., or Wave, with WVE-N531, a stereopure oligonucleotide in a Phase 1/2 clinical trial for patients amenable to exon 53 skipping.

In addition, several companies are developing gene therapies to treat DMD. These include Sarepta’s ELEVIDYS (SRP-9001) which was approved in June 2023 for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene. In an interim readout of a recent Phase 3 EMBARK trial, which is still ongoing, patients with DMD between ages 4 through 7 years treated with ELEVIDYS did not show statistically significant benefit on the North Star Ambulatory Assessment, which was the primary endpoint. ELEVIDYS showed statistically significant results on all key pre-specified secondary endpoints, time to rise and 10-meter walk/run test. Based on the interim read out from EMBARK, Sarepta has filed an efficacy supplement to its BLA to encompass “treatment of DMD patients with a confirmed mutation in the DMD gene.” The FDA accepted the filing of the efficacy supplement and has given the application priority review with a review goal date of June 21, 2024. In addition, several other companies are developing investigational gene therapies to treat DMD, including Pfizer Inc.’s PF-06939926, fordadistrogene movaparvovec, which is currently being assessed in a Phase 3 clinical trial, and Sarepta’s Galgt2 gene therapy program, Solid Biosciences Inc.’s SGT-003 and REGENXBIO Inc.’s RGX-202, currently in clinical development. Gene editing treatments that are in preclinical development are also being pursued by Vertex Pharmaceuticals, Inc., or Vertex, and Sarepta.

We are also aware of several companies targeting non-dystrophin mechanisms for the treatment of DMD, including Edgewise with EDG-5506, a muscle stabilizer that is currently in clinical development and givinostat, a histone deacetylase, or HDAC, inhibitor, that reduces fibrosis in patients with DMD and is currently under review by the FDA and EMA.

For DM1, there are currently no approved therapies to treat the underlying cause of the disease. Product candidates currently in clinical development to treat DM1 include several approaches that target DMPK RNA. These include AOC 1001, an antibody linked siRNA in Phase 1/2 clinical development with a global Phase 3 study planned for initiation in the second quarter of 2024 by Avidity Biosciences, Inc., or Avidity; DYNE-101, an antibody conjugated antisense oligonucleotide in clinical development by Dyne; and VX-670, a peptide conjugated PMO in Phase 1 by Entrada Therapeutics, Inc., or Entrada, and Vertex. There are additional approaches under development such as ATX-01, a micro RNA that modulates the expression of MBNL1 by Arthex Biotech S.L. that recently received IND clearance. Another small molecule, tideglusib, which is a GSK3-ß inhibitor is in clinical development by AMO Pharma Ltd. for the congenital phenotype of DM1, recently failed to meet primary endpoint in a pivotal study.

Several gene editing treatments are in preclinical development by Vertex; an artificial site-specific RNA endonuclease gene therapy is being developed by Enzerna Biosciences Inc., or Enzerna; Design Therapeutics, Inc. is developing an approach to prevent formation of CUG hairpins; Expansion Therapeutics, Inc. is developing an approach utilizing the interaction of small molecules with RNA in preclinical development; and therapeutics based on biomolecular condensate biology are in preclinical development by Dewpoint Therapeutics, Inc., or Dewpoint, and Pfizer.

We will also compete more generally with other companies developing alternative scientific and technological approaches, including companies working to develop conjugates with oligonucleotides for extra-hepatic delivery, including Alnylam Pharmaceuticals, Inc., or Alnylam, Aro Biotherapeutics Co., or Aro, Arrowhead Pharmaceuticals, Inc., or Arrowhead, Avidity, Dicerna Pharmaceuticals, Inc. (acquired by Novo Nordisk), or Dicerna, Dyne, Entrada, Ionis Pharmaceuticals, Inc., or Ionis. NeuBase Therapeutics, Inc., or NeuBase, PYC Therapeutics Limited, or PYC, and Sarepta, as well as gene therapy and gene editing approaches.

Many of the companies which we compete with or may compete with in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Accordingly, our competitors may be more successful than us in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining approval for treatments and achieving widespread market acceptance, rendering our treatments obsolete or non-competitive.

Additionally, mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

If we successfully obtain approval for any product candidate, we will face competition based on many different factors, including the safety and effectiveness of our products, the ease with which our products can be administered and the extent to which patients accept relatively new routes of administration, the timing and scope of regulatory approvals for these products, the availability and cost of manufacturing, marketing and sales capabilities, price, reimbursement coverage and patent position. Competing products could present superior treatment alternatives, including by being more effective, safer, more convenient, less expensive or marketed and sold more effectively than any of our products, if approved. Competitive products or technological approaches may make any products we develop, or our EDO platform, obsolete or noncompetitive before we recover the expense of developing and commercializing our product candidates. If we are unable to compete effectively, our opportunity to generate revenue from the sale of our products, if approved, could be adversely affected.

Sales and Marketing

We currently do not have a commercial infrastructure in any geography. As we progress our programs through development, we may build a commercial infrastructure in the U.S. and selected other territories to support the commercialization of each of our product candidates when we believe a regulatory approval in a particular territory is likely. We intend to conduct market research in connection with designing our commercialization strategy for each of our product candidates, which strategy may depend on the size and geographic dispersion of the target patient population and the characteristics of the prescribing audience for our products, if approved. For example, with respect to certain of our product candidates that target diseases with a limited patient population, a concentrated prescribing audience and a small number of key opinion leaders who influence the treatments prescribed for the relevant patient population, we may address each such market using our own targeted, specialty sales and marketing organization supported by internal sales personnel, an internal marketing group and distribution support. For other product candidates, we may establish a larger and more dispersed sales force, or seek strategic collaborations to support our commercialization efforts.

We intend to evaluate our commercialization strategy as we advance each product candidate through clinical development. In any core markets outside of the U.S. that we may identify, where appropriate, we may utilize strategic partners, distributors or contract sales forces to expand the commercial availability of our product candidates.

Material Contracts

License of Technology Agreement with Oxford University Innovation Limited and Medical Research Council as Part of United Kingdom Research and Innovation

On March 26, 2018, we, through our wholly-owned subsidiary PepGen Limited, entered into a license agreement, or the OUI/MRC License, with Oxford University Innovation Limited, or OUI, and MRC. We amended the OUI/MRC License on December 21, 2018, and subsequently amended and restated it on November 23, 2020.

Pursuant to the OUI/MRC License, we obtained from OUI and MRC an exclusive, royalty-bearing, sublicensable with consent (through one tier) license under certain patent rights, or the OUI/MRC Patents, and data, or the OUI/MRC Licensed Technology, and a nonexclusive, royalty-bearing, sublicensable (through one tier) license under certain know-how, or the OUI/MRC Know-How, for certain biological and chemical compounds, including compounds that comprise amino acids and/or nucleic acids relating to our EDO peptides, proprietary linkers and the resulting EDO conjugates. The Licensed Technology is incorporated in our product candidates PGN-EDO51, PGN-EDODM1, PGN-EDO53, PGN-EDO45 and PGN-EDO44, and will likely be utilized in future discovery programs. Under such licenses, we have the right to make, have made, import, use, sell, offer for sale, market, research, develop, trial, register, modify, enhance, improve, manufacture, have manufactured, hold, keep, formulate, optimize, have used, export, transfer, distribute, promote, have sold, dispose of, offer to dispose of or otherwise exploit in all fields of use on a worldwide basis any products or services that incorporate or otherwise utilize the OUI/MRC Licensed Technology or, in each such case, an OUI/MRC Licensed Product. We granted OUI, and those persons who at any time work or have worked on the OUI/MRC Licensed Technology and OUI/MRC Know-How, and MRC an irrevocable, perpetual, royalty-free, sublicensable license under the OUI/MRC Licensed Technology and OUI/MRC Know-How to use the OUI/MRC Licensed Technology and OUI/MRC Know-How for non-commercial

clinical, research, teaching, publication, or other scholarly purposes, or Non-Commercial Purposes. MRC also retained the right to grant sublicenses under our rights in the OUI/MRC Licensed Technology and OUI/MRC Know-How for Non-Commercial Purposes to any person at MRC or any academic or not-for-profit institutions who have worked or collaborated on, or otherwise funded, the OUI/MRC Licensed Technology or OUI/MRC Know-How. Further, OUI, MRC and the Chancellor, Masters and Scholars of the University of Oxford retained the right to freely use, publish (subject to certain obligations) or grant licenses under the OUI/MRC Know-How.

The OUI/MRC License requires us to use commercially reasonable efforts to exploit the OUI/MRC Licensed Technology and to achieve certain development milestones in accordance with a development plan and commercialize the OUI/MRC Licensed Products.

In consideration for the rights conveyed by OUI and MRC under the OUI/MRC License, we were obligated to pay, and have paid, to OUI certain up-front fees in an aggregate amount of approximately £80,000 in connection with the execution of each of the original OUI/MRC License and the amended and restated OUI/MRC License. In addition, we are obligated to pay to OUI sub-single to low, single-digit percentage royalties, or the Royalty Rate, on net sales of any OUI/MRC Licensed Products in excess of a threshold amount between £20 million and £30 million that are commercialized by us. The royalty rate for a given OUI/MRC Licensed Product will decrease a certain percentage following expiration or revocation of the last valid claim of the OUI/MRC Patents covering such OUI/MRC Licensed Product and where there is a product sold by a third party that competes with such OUI/MRC Licensed Product on a country-by-country basis. If we receive any non-royalty payments and royalties in connection with sublicenses or other contracts relating to the OUI/MRC Licensed Technology or OUI/MRC Know-How, we are obligated to pay to OUI, in each instance, a sublicense fee that is from mid-single digit to mid teen percentage depending on the license year in which we execute the sublicense or contract. We are also required to pay certain milestone payments to OUI upon the achievement by us or our sublicensees of specified commercial milestones in an aggregate amount of £100,000 for each OUI/MRC Licensed Product and specified patent procurement milestones in an aggregate amount of £10,000.

Upon completion of our initial public offering, or IPO, in May 2022, we paid an exit fee of $1.4 million to OUI during the second quarter of 2022.

Unless earlier terminated, the OUI/MRC License will terminate in its entirety upon the later of (a) the date on which all patents and patent applications licensed to us under the OUI/MRC License have been abandoned or allowed to lapse or expired or been rejected or revoked without a right of further appeal in a relevant country or territory or (b) March 26, 2038. The last-to-expire licensed patent under the OUI/MRC License is set to expire on February 11, 2042. We may terminate the OUI/MRC License in its entirety at any time for convenience upon providing OUI and MRC with written notice. Either party may terminate the OUI/MRC License in its entirety for the other party’s uncured material breach after an opportunity for the other party to cure such material breach. OUI and MRC may terminate the OUI/MRC License for our (a) insolvency or if we challenge the validity of the licensed patents, (b) breach our obligation to develop and exploit the technology in accordance with the development plan and subsequent failure to take remedial action reasonably requested by OUI and/or MRC or (c) failure to pay the Exit Fee or Exit Buy Out Fee. If the OUI/MRC License is terminated by either party for any reason, the OUI/MRC Licenses will terminate and all rights thereunder will revert to OUI and MRC, respectively.

Intellectual Property

We seek to protect the intellectual property, or IP, and proprietary technology that we consider important to our business, including by pursuing patent applications that cover our product candidates and methods of using the same, as well as any other relevant inventions and improvements that are considered commercially important to the development of our business. We likewise seek to protect the IP to which we obtain rights through licenses and sublicenses (e.g., from universities and research institutions) and work collaboratively with our licensors to ensure (and if possible be the driver of) patent prosecution and protection. We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our proprietary and IP positions. Our commercial success depends, in part, on our ability to obtain, maintain, enforce and protect our intellectual property and other proprietary rights for the technology, inventions and improvements we consider important to our business, and to defend any patents we may own or in-license in the future, prevent others from infringing any patents we may own or in-license in the future, preserve the confidentiality of our trade secrets, and operate without infringing, misappropriating or otherwise violating the valid and enforceable patents and proprietary rights of third parties.

As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position(s) for our product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, our pending patent applications, and any patent applications that we may in the future file or license from third parties, may not result in the issuance of patents and any issued patents we may obtain do not guarantee us the right to protect our technology in relation to the commercialization of our products. We also cannot predict the breadth of claims that may be allowed or enforced in any patents we may own or in-license in the future. Notwithstanding the scope of the patent protection available to us, a competitor could develop competitive products that are not covered by our intellectual property, and we may be unable to stop such competitor from commercializing such products.

Any issued patents that we may own or in-license in the future may be challenged, invalidated, circumvented or have the scope of their claims narrowed. Because patent applications can take many years to issue, there may be applications unknown to us, which applications may later result in issued patents that our existing or future products or technologies may be alleged to infringe. Additionally, we cannot be certain of the priority of inventions covered by pending third-party patent applications. If third parties prepare and file patent applications in the U.S. that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings in the U.S. Patent and Trademark Office, or USPTO, to determine priority of invention, which is highly unpredictable and which could result in substantial costs, even if the eventual outcome is favorable to us. We are aware of

certain patents in the U.S. and other jurisdictions owned by third parties that claim subject matter that relates to our product candidates and the EDO platform. In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any patent covering a certain product may expire or remain in force for only a short period following commercialization, thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide.

The term of individual patents depends upon the date of filing of the patent application, the date of patent issuance and the legal term of patents in the countries in which they are obtained. In most countries, including the U.S., the patent term is 20 years from the earliest filing date of a non-provisional patent application. In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent or may be shortened if a patent is terminally disclaimed over an earlier expiring patent.

The term of a patent claiming a new drug product may also be eligible for a limited patent term extension when FDA approval is granted, provided statutory and regulatory requirements are met. The restoration period granted on a patent covering a product is typically one-half the time between the effective date of a clinical investigation involving human beings is begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date. The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval. Only one patent applicable to an approved product is eligible for the extension, and only those claims covering the approved product, a method for using it, or a method for manufacturing it may be extended. Additionally, the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals. The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA. In the future, if our product candidates receive approval by the FDA, we expect to apply for patent term extensions on any issued patents covering those products, depending upon the length of the clinical studies for each product and other factors.

There can be no assurance that our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustments to the terms of any patents we may own or in-license in the future. In addition, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent. Patent term may be inadequate to protect our competitive position on our products for an adequate amount of time.

In the future, we may need to engage in litigation to enforce patents issued or licensed to us, to protect our trade secrets or know-how or to defend against claims of infringement of the rights of others. Litigation could be costly and could divert our attention from other functions and responsibilities. Furthermore, even if our patents are found to be valid and infringed, a court may refuse to grant injunctive relief against the infringer and instead grant us monetary damages and/or ongoing royalties. Such monetary compensation may be insufficient to adequately offset the damage to our business caused by the infringer’s competition in the market. Adverse determinations in litigation could subject us to significant liabilities to third parties, could require us to seek licenses from third parties and pay significant royalties to such third parties and could prevent us from manufacturing, selling or using our product or techniques, any of which could severely harm our business.

As of December 31, 2023, we owned two pending U.S. patent applications and one pending Patent Cooperation Treaty, or PCT, international application, and exclusively licensed one issued patent (a European patent validated in France, Germany, Italy, Spain, and Great Britain) and 74 pending patent applications under our OUI/MRC License. For more information regarding our OUI/MRC License, see the section titled “Business—Material Contracts—License of Technology Agreement with Oxford University Innovation Limited and Medical Research Council as Part of United Kingdom Research and Innovation.”

The issued patent and patent applications that cover our product candidates and technology, as of December 31, 2023, include:

•

With respect to PGN-EDO51, we owned applications pending in the U.S., Europe and Japan that cover methods of use and exclusively licensed 47 pending patent applications under the OUI/MRC License that cover compositions of matter and methods of use, including applications in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, South Korea, Mexico, the Russian Federation, Saudi Arabia, and the U.S. Any patents issuing from the patent applications would have expiration dates ranging from 2039 to 2042, without accounting for any available patent term adjustments or extensions.

•

With respect to PGN-EDODM1, we owned applications pending in the U.S., Canada, China, Europe and Japan that cover methods of use and exclusively licensed 45 pending patent applications under the OUI/MRC License that cover compositions of matter and methods of use, including applications in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, South Korea, Mexico, the Russian Federation, Saudi Arabia, and the U.S. Any patents issuing from the patent applications would have expiration dates ranging from 2039 to 2042, without accounting for any available patent term adjustments or extensions.

•

With respect to PGN-EDO53, PGN-EDO45 and PGN-EDO44, we exclusively licensed 30 pending patent applications under the OUI/MRC License that cover compositions of matter and methods of use, including applications in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, South Korea, Mexico, the Russian Federation, Saudi Arabia, and the U.S. Any patents issuing from these patent applications would expire in 2039, without accounting for any available patent term adjustments or extensions.

•

With respect to our EDO platform, we owned one pending PCT international patent application and exclusively licensed one issued European patent and 41 pending patent applications under the OUI/MRC License that cover compositions of matter and methods of use, including applications in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, India, Japan, South Korea, Mexico, the Russian Federation, Saudi Arabia, and the U.S. The issued European patent is expected to expire in 2035, without accounting for any available patent term adjustments or extensions. The issued European patent was validated in France, Germany, Italy, Spain, and Great Britain, and it relates to certain compositions of matter and uses that may be utilized during future platform development activities. Any patents issuing from the patent applications would have expiration dates ranging from 2035 to 2043, without accounting for any available patent term adjustments or extensions.

Government Regulation

The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those we are developing. These agencies and other federal, state and local entities regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of drugs.

U.S. Government Regulation of Drug Products

In the U.S., the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending New Drug Applications, or NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

The process required by the FDA before a drug may be marketed in the U.S. generally involves the following:

•

Completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s GLP regulations;

•

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

•

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

•

Performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practices, or GCP, requirements to establish the safety and efficacy of the proposed drug product for each proposed indication;

•

Submission to the FDA of an NDA after completion of all pivotal trials, together with the payment of application user fees, as applicable;

•

A determination by the FDA within 60 days of its receipt of an NDA to accept the marketing application for review;

•

Satisfactory completion of an FDA advisory committee review, if applicable;

•

Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;

•

Satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; and

•

FDA review and approval of the NDA.

Preclinical Studies

Before testing any drug product candidate, including our product candidates, in humans, the product candidate must undergo rigorous preclinical testing. Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as in vitro and animal studies to assess potential safety and efficacy. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies.

Prior to beginning the first clinical trial with a product candidate in the U.S., we must submit an IND to the FDA. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data and any available clinical data or literature and plans for clinical studies, among other things, to the FDA as part of an IND. An IND is a request for authorization from the FDA to administer an investigational product to humans and must become effective before human clinical trials may begin. Some preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue even after

the IND is submitted. An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the clinical trial on 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 not result in the FDA allowing clinical trials to initiate. For example, in May 2023, we announced that we received a clinical hold notice from the FDA regarding our IND application to initiate our Phase 1 FREEDOM study, and in June 2023, we provided an update on our plans with respect to this program. In October 2023, we announced that the FDA lifted the clinical hold on our Phase 1 FREEDOM study, allowing this study to proceed in the U.S.

Clinical Trials

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it is initiated at that institution. An IRB is charged with protecting the welfare and rights of trial 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 must review and approve the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completion.

Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a DSMB, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their www.clinicaltrials.gov website. Information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial. Although sponsors are obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for some time. Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

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

•

Phase 1: The drug is initially introduced into healthy human subjects or patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.

•

Phase 2: The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

•

Phase 3: The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval on an NDA.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if SAEs occur. Written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human subjects and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.

NDA Submission and FDA Review and Approval

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are

submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, 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 effectiveness of the investigational drug product for the proposed indication to the satisfaction of the FDA. In most cases, the submission of an NDA is subject to a substantial application user fee; a waiver of such fees may be obtained under certain limited circumstances.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective 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.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA, for a new molecular entity to review and act on the submission, and six months from the filing date of a new molecular entity NDA with priority review. Accordingly, this review process typically takes 12 months and eight months, respectively from the date the NDA is submitted to the FDA. 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. The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective 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.

PEPG US Equity

PEPG · 10-K · period ended 2023-12-31

Item 1. Business.

PEPG US Equity☆

PEPG · 10-K · period ended 2023-12-31

Item 1. Business.

PEPG US Equity