PepGen Inc. (PEPG) Risk Analysis

We have received fast-track designation for PGN-EDODM1 for the treatment of DM1 and may seek fast-track designation for any other product candidates we develop. If a drug is intended for the treatment of a serious or life-threatening condition and nonclinical or clinical data for the drug demonstrates the potential to address an unmet medical need for such a condition, the drug sponsor may apply for fast-track designation. The FDA has broad discretion whether or not to grant this designation, so even if we believe a particular product candidate is eligible for this designation, we cannot assure you that the FDA would decide to grant it for any of our other product candidates. Even with fast-track designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw fast-track designation if it believes that the designation is no longer supported by data from our clinical development program. Fast-track designation alone does not guarantee qualification for the FDA's priority review procedures. We may seek a breakthrough therapy designation for some of our product candidates. A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For drugs that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens. Drugs designated as breakthrough therapies by the FDA may also be eligible for priority review and accelerated approval. Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree and instead determine not to make such designation. In any event, the receipt of a breakthrough therapy designation for a product candidate may not result in a faster development process, review or approval compared to therapies considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of our product candidates qualify as breakthrough therapies, the FDA may later decide that such product candidates no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened. If the FDA determines that a product candidate offers a treatment for a serious or life-threatening condition and, if approved, the product would provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority review. A priority review designation means that the goal for the FDA to review and take action on a marketing application for a new molecular entity is six months, rather than the standard review period of ten months. We may request priority review for our product candidates. The FDA has broad discretion with respect to whether or not to grant priority review status to a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, the FDA may decide not to grant it. Moreover, a priority review designation does not necessarily result in an expedited regulatory review or approval process or necessarily confer any advantage with respect to approval compared to conventional FDA procedures. Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all.

In September 2023, the FDA granted orphan drug designation to PGN-EDODM1 for the treatment of DM1. We may seek orphan drug designation for any other product candidates we develop; however, we may never receive such designations. Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition, defined as a patient population of fewer than 200,000 in the U.S., or a patient population greater than 200,000 in the U.S. where there is no reasonable expectation that the cost of developing the drug will be recovered from sales in the U.S. Orphan drug designation must be requested before submitting an NDA. A similar regulatory scheme governs orphan products in the EU. Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and application fee waivers. After the FDA grants orphan drug designation, the generic identity of the drug and its potential orphan use are disclosed publicly by the FDA. In addition, if a product candidate with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA from approving another marketing application for the same product for the same approved use or indication for seven years. Even if we obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because different products can be approved for the same approved use or indication. In addition, even after an orphan drug is approved, the FDA can subsequently approve the same product for the same approved use or indication if the FDA concludes that the later product is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care. Orphan drug exclusivity may also be lost if the FDA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of the patients with the rare disease or condition. Further, even if we obtain orphan drug designation, we may not be the first to obtain marketing approval for any particular orphan indication due to the uncertainties associated with developing pharmaceutical products. The FDA may further reevaluate the Orphan Drug Act and its regulations and policies. We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business. Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.

Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success particularly with respect to PGN-EDODM1, which is currently our only clinical development program. We may not be able to identify, recruit and enroll a sufficient number of eligible patients, or those with required or desired characteristics, to complete our clinical trials in a timely manner. Patient enrollment and trial completion is affected by factors including: - perceived risks and benefits of novel unproven approaches;- size of the patient population, in particular for rare diseases such as the diseases on which we are initially focused, and process for identifying patients;- design of the trial protocol;- eligibility and exclusion criteria;- perceived risks and benefits of the product candidate under study;- availability of competing therapies and clinical trials;- severity of the disease or disorder under investigation;- proximity and availability of clinical trial sites for prospective patients, including the clearance by FDA of clinical sites in the U.S. for the FREEDOM2 study;- ability to obtain and maintain patient consent;- risk that enrolled patients will drop out before completion of the trial;- ability to recruit clinical trial investigators of appropriate competencies and experience;- patient referral practices of physicians;- ability to monitor patients adequately during and after treatment; and - other factors outside of our control, such as the potential effects of any epidemics, pandemics or health crisis. Our inability to enroll a sufficient number of eligible patients for our clinical trials, including our ongoing FREEDOM2 trial for PGN-EDODM1, would result in significant delays and could require us to abandon one or more clinical trials altogether. Enrollment delays in these clinical trials may result in increased development costs for our product candidates, which would cause the value of our company to decline and limit our ability to obtain additional financing. Furthermore, we rely on and expect to continue to rely on CROs and clinical trial sites to ensure the proper and timely conduct of our clinical trials and we will have limited influence over their performance. Even if we are able to enroll a sufficient number of eligible patients for our clinical trials, we may have difficulty maintaining patients in our clinical trials. Many of the patients who end up receiving placebo may perceive that they are not receiving the product candidate being tested, and they may decide to withdraw from our clinical trials to pursue other alternative therapies rather than continue the trial with the perception that they are receiving placebo. If we have difficulty enrolling or maintaining a sufficient number of patients to conduct our clinical trials, we may need to delay, limit or terminate clinical trials, any of which would harm our business, financial condition, results of operations and prospects.

We conducted our first clinical trial in Canada, and we intend to continue to conduct one or more of our subsequent clinical trials for our product candidates outside the U.S., including our FREEDOM and FREEDOM2 clinical trials, each of which has or will have sites in multiple countries outside of the U.S. Currently, there are no U.S. sites opened in the FREEDOM2 due to the partial clinical hold of the FREEDOM2 trial in the U.S . Although the FDA may accept data from clinical trials conducted outside the U.S., acceptance of this data is subject to certain conditions imposed by the FDA. Where data from foreign clinical trials are intended to serve as the basis for marketing approval in the U.S., the FDA will not approve the application on the basis of foreign data alone unless those data are applicable to the U.S. population and U.S. medical practice; the studies were performed by clinical investigators of recognized competence; and the data are considered valid without the need for an on-site inspection by the FDA or, if the FDA considers such an inspection to be necessary, the FDA is able to validate the data through an on-site inspection or other appropriate means. For studies that are conducted only at sites outside of the U.S. and not subject to an IND, the FDA generally does not provide advance comment on the clinical protocols for the studies, and therefore there is an additional potential risk that the FDA could determine that the study design or protocol for a non-U.S. clinical trial was inadequate, and require us to conduct additional clinical trials. In addition, even where the foreign study data are not intended to serve as the sole basis for approval, the FDA will not accept the data as support for an application for marketing approval unless the study is well-designed and well-conducted in accordance with GCP and the FDA is able to validate the data from the study through an onsite inspection if deemed necessary. Many foreign regulatory authorities have similar approval requirements. There can be no assurance the FDA will accept data from clinical trials conducted outside of the U.S. If the FDA does not accept data from our clinical trials of our product candidates, we would likely need to conduct additional clinical trials, which would be costly and time consuming and delay or permanently halt our development of our product candidates. Additionally, recent policy proposals in the U.S., if enacted in the future, may make acceptance by the FDA or inclusion in a marketing application of foreign data more difficult or costly. Conducting clinical trials outside the U.S. also exposes us to additional risks, including risks associated with: - additional foreign regulatory requirements;- foreign exchange fluctuations;- compliance with foreign manufacturing, customs, shipment and storage requirements;- cultural differences in medical practice and clinical research;- geopolitical risks; and - diminished protection of intellectual property in some countries.

We have no products approved for commercial sale and have not generated any revenue from product sales. Our ability to generate revenue from product sales and achieve profitability will depend on our ability, alone or with collaborators, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, PGN-EDODM1, our lead product candidate, and any future product candidates we may develop. As a result, we currently intend to devote a substantial portion of our resources and business efforts to the continued clinical development of PGN-EDODM1. The success of PGN-EDODM1, and any future product candidates we may develop, will depend on several factors, including the following: - the successful completion of clinical trials of PGN-EDODM1 on a timely basis, including our ongoing FREEDOM2 clinical trial and any subsequent studies that may be required;- successful outcome of discussions with the U.S. Food and Drug Administration, or the FDA, relating to the partial clinical hold placed on the FREEDOM2 study;- the frequency and severity of any adverse events, or AEs, observed in PGN-EDODM1 clinical trials;- maintaining and establishing relationships with contract research organizations, or CROs, and clinical trial sites for the clinical development of PGN-EDODM1 in the United States and internationally;- the successful conduct and completion of clinical trials in compliance with applicable Good Clinical Practice, or GCP, and Good Laboratory Practice, or GLP, requirements;- demonstration of efficacy, safety and tolerability profiles that are acceptable to the U.S. Food and Drug Administration, or the FDA, the European Medicines Agency, or the EMA, or other comparable foreign regulatory authorities for marketing approval;- the timely receipt of marketing approvals from applicable regulatory authorities;- the scope and extent of any post-marketing approval commitments that may be required by regulatory authorities;- the maintenance of existing, or establishment of new, supply arrangements with third-party suppliers and manufacturers to support the clinical development of PGN-EDODM1;- the maintenance of existing, or establishment of new, scalable commercial manufacturing arrangements with third-party manufacturers to produce finished product suitable for commercial sale, if PGN-EDODM1 is approved;- commercial acceptance by patients, physicians and the broader medical community;- our ability to obtain coverage and adequate reimbursement from third-party payors, and patients' willingness to pay out-of-pocket in the absence of such coverage;- our ability to compete effectively with other therapies, including those that may be further advanced in clinical development;- our ability to negotiate favorable terms in any collaboration, licensing or other strategic arrangements and perform our obligations under such arrangements; and - our ability to maintain, protect, enforce and defend our intellectual property portfolio in the United States and internationally. We do not have complete control over many of these factors, including aspects of clinical development and the regulatory review process, the actions of regulatory authorities, potential challenges to our intellectual property rights, and the manufacturing, commercialization and distribution activities of third-party collaborators, if any. If we are not successful in addressing one or more of these factors in a timely manner or at all, we could experience significant delays or be unable to successfully commercialize PGN-EDODM1, which would materially harm our business, financial condition and prospects. If we do not receive marketing approval for PGN-EDODM1, we may not be able to continue our operations.

We are early in our development efforts and have invested our research efforts to date in developing our EDO platform. Until May 2025, we had two product candidates in clinical trials -PGN-EDODM1 for DM1 and PGN-EDO51 for DMD. We have since voluntarily discontinued development of PGN-EDO51 and have substantially completed the wind-down of DMD-related research and development activities. We initiated a Phase 1 clinical trial, designated FREEDOM, for our product candidate, PGN-EDODM1, in December 2023 which was completed earlier this year. We are also conducting a Phase 2 clinical trial, FREEDOM2, in Canada, the U.K, South Korea, Australia and New Zealand, which has concluded dosing of the?5 mg/kg cohort with seven of eight patients having completed dosing in the 10 mg/kg cohort. We are primarily focusing our efforts on the clinical development of PGN-EDODM1 and, accordingly, have not completed IND- or CTA-enabling activities for any other product candidates or advanced any additional product candidates into clinical trials. Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful clinical development and eventual commercialization of our product candidates, which may never occur. We currently generate no revenue from sales of any product, and we may never be able to develop or commercialize a marketable product. Commencing clinical trials in the U.S. is subject to authorization by the FDA of an IND and finalizing the trial design based on discussions with the FDA and other regulatory authorities. In the event that the FDA requires us to complete additional preclinical studies, or we are required to satisfy other FDA or other regulator requests prior to commencing clinical trials, the start of our clinical trials may be delayed. For instance, in May 2023, we announced that FDA had placed a clinical hold on our planned Phase 1 FREEDOM clinical trial of PGN-EDODM1 in the U.S. We submitted a response to the FDA and in October 2023, we announced that the FDA had lifted the clinical hold, allowing us to initiate FREEDOM in the U.S. However, in March 2026, we announced that we received notice of a partial clinical hold from the FDA based on previously submitted preclinical pharmacology and toxicology studies and we continue to work with the FDA to address questions raised by the FDA as quickly as possible. We may not be able to resolve the issues related to such partial clinical hold in a timely manner, or at all, which may negatively impact the PGN-EDODM1 program, including the FREEDOM2 enrollment timelines. Furthermore, in the future, the FDA or other regulatory authorities could disagree that we have satisfied their requirements to commence any clinical trial, including our FREEDOM2 study of PGN-EDODM1, or disagree with or change their position on the acceptability of our trial design or the clinical endpoints selected, which may require us to complete additional preclinical studies or clinical trials or impose stricter approval conditions than we currently expect. There are equivalent processes and risks applicable to CTAs in other countries, including Canada and countries in Europe. Moreover, regulatory authorities in other countries could request that we pause dosing or further enrollment in one or more of our ongoing studies based in whole or in part on a clinical hold or partial clinical hold in the U.S. Commercialization of our product candidates will require preclinical and clinical development; regulatory approval; manufacturing supply, capacity and expertise; a commercial organization; and significant marketing efforts. The success of our current and future product candidates will depend on many factors, including the following: - timely and successful completion of preclinical studies, including toxicology studies, biodistribution studies and minimally efficacious dose studies in animals, where applicable;- regulatory clearance to initiate clinical trials under INDs, CTAs or comparable foreign applications that allow commencement of our planned clinical trials or future clinical trials for our product candidates;- successful initiation, enrollment and completion of clinical trials, including under the FDA's Good Clinical Practice, or GCP, Good Laboratory Practice, and any additional regulatory requirements from foreign regulatory authorities;- positive results from our clinical trials that support a finding of safety and effectiveness and an acceptable risk-benefit profile in the intended populations to the satisfaction of the applicable regulatory authorities;- receipt of marketing approvals from applicable regulatory authorities, including the completion of any required post-marketing studies or trials;- establishment of arrangements through our own facilities or with third-party manufacturers for clinical supply and, where applicable, commercial manufacturing capabilities;- establishment, maintenance, defense and enforcement of patent, trademark, trade secret and other intellectual property protection or regulatory exclusivity for our product candidates;- commercial launch of our product candidates, if approved, whether alone or in collaboration with others;- acceptance of the benefits and use of our product candidates, including method of administration, if and when approved, by patients, the medical community and third-party payors;- effective competition with other therapies;- maintenance of a continued acceptable safety, tolerability and efficacy profile of our product candidates following marketing approval, including acceptable results from any post-approval studies or clinical trials agreed to by us or required by FDA or other regulatory authorities; and - establishment and maintenance of healthcare coverage and adequate reimbursement by payors. Many of these factors are beyond our control and if we do not succeed in one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize any product candidates, which would materially harm our business. If we are unable to advance our product candidates to clinical development or successfully complete clinical trials, obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

The success of our business depends upon our ability to identify, develop and commercialize products based on our proprietary EDO platform. Our current product candidates that have been developed through our EDO platform are peptide-conjugated oligonucleotides designed to have a disease-modifying impact on degenerative neuromuscular diseases. Our lead product candidate is currently in clinical-stage development, while other past product candidate programs were in the research or preclinical stage of development. Thus, our approach to treating muscle disease is unproven; for example past efficacy and safety results observed in the PGN-EDODM1 program may not result in a favorable safety profile or efficacy results as future clinical studies readout. In the future, our research programs may fail to identify potential product candidates for clinical development for a number of reasons. Our research methodology may be unsuccessful in identifying potential product candidates and our potential product candidates may be shown to have harmful side effects in preclinical in vitro experiments or in vivo animal model studies, or in future clinical studies. In addition, our potential product candidates may not show promising signals of therapeutic effect in such experiments or studies, as was the case with PGN-EDO51, or they may have other characteristics that may make the product candidates impractical to manufacture, unmarketable or unlikely to receive marketing approval. Further, because all of our development programs are based on our EDO platform, adverse developments with respect to one of our programs may have a significant adverse impact on the actual or perceived likelihood of success and value of our other programs. In addition, we may be negatively impacted by the decision of other companies to discontinue development of products using technology similar to our technology. For example, during 2024, Sarepta Therapeutics, Inc., or Sarepta, announced that it was discontinuing its SRP-5051 peptide-linked phosphorodiamidate morpholino, or PMO, development program, based on the risk-benefit of the program, including some patients experiencing hypomagnesemia even after treatment with SRP-5051 was discontinued, feedback from the FDA, and the evolving therapeutic landscape for DMD. We advanced two product candidates, PGN-EDO51 and PGN-EDODM1, into the clinic, and completed a Phase 1 trial of PGN-EDO51 in healthy volunteers. However, the positive results we observed in our preclinical studies and in the completed Phase 1 trial of PGN-EDO51 were not repeated at the same level in our CONNECT1 Phase 2 clinical trial, and we decided to discontinue development of PGN-EDO51. Accordingly, the results observed in our preclinical and Phase 1 clinical studies of PGN-EDODM1 may not be repeated in our ongoing Phase 2 clinical study. For instance, although we were encouraged by the trends observed in initial splicing and functional outcome data in the FREEDOM study, in the multi-dose 5 mg/kg cohort of the FREEDOM2 study, the splicing correction results were 7.3% versus 12.7% in the 5 mg/kg cohort of the single dose phase 1 FREEDOM study. Moreover, regulatory authorities may disagree with the interpretation of data from our trials. Although we are continuing to focus the majority of our efforts on the advancement of our program in DM1, our EDO platform may fail to yield additional product candidates for clinical development for a number of reasons, including those discussed in these risk factors. In addition: - we may not be able to assemble sufficient resources to acquire or discover product candidates;- competitors may develop alternatives that render our potential product candidates obsolete or less attractive;- potential product candidates we develop may be covered by third parties' patents or other intellectual property rights;- potential product candidates may, on further study, be shown to have harmful side effects, toxicities or other characteristics that indicate that they are unlikely to be products that will receive marketing approval and achieve market acceptance;- potential product candidates may not be effective in treating their targeted diseases or disorders;- the market for a potential product candidate may change so that the continued development of that product candidate is no longer reasonable;- a potential product candidate may not be capable of being produced in commercial quantities at an acceptable cost, or at all; or - the regulatory pathway for a potential product candidate may be too complex and difficult to navigate successfully or economically. If we are unable to identify and discover suitable product candidates for clinical development, this would adversely impact our business strategy and our financial position and share price and could potentially cause us to cease operations.

The risk of failure in developing product candidates is high. It is impossible to predict when or if any product candidate would prove effective or safe in humans or will receive regulatory approval. Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinical development, obtain regulatory clearance to commence clinical trials, and then conduct extensive clinical trials to demonstrate the safety and efficacy of product candidates in humans. To date, we have completed a Phase 1 clinical trial for PGN-EDODM1, and are conducting a Phase 2 clinical trial for PGN-EDODM1. Clinical trials may fail to demonstrate that our product candidates are safe for humans and effective for indicated uses, and earlier results, both preclinical and clinical, may not be indicative of future clinical trial results. For example, in the case of PGN-EDO51, our product candidate for DMD, based on the levels of dystrophin protein measured in the 10 mg/kg cohort of CONNECT1,despite a favorable emerging safety profile, we decided to voluntarily discontinue development of PGN-EDO51 and have substantially completed the wind-down of DMD-related research and development activities, including our research efforts in DMD relating to exons 44, 45 and 53. Even if our clinical trials are successful, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance, varying interpretations of clinical data or changes in regulatory review for each submitted product application may cause delays in the approval or rejection of an application. Before we can commence clinical trials for a product candidate, we must complete extensive preclinical testing and studies that support clearance of our INDs, CTAs and other similar regulatory filings. We cannot be certain if the outcome of our preclinical studies and clinical trials will ultimately support further development of our product candidates, as was the case with PGN-EDO51 or future programs, or future regulatory approval and commercialization. Although we have completed a Phase 1 trial and are conducting a Phase 2 clinical trial of our second candidate, PGN-EDODM1, we cannot be certain of the outcome of our preclinical testing, and clinical studies for PGN-EDODM1 or any of our other product candidates and cannot predict whether the FDA, or comparable foreign regulatory authorities will accept our proposed clinical program for PGN-EDODM1, or whether the outcome of our preclinical testing and clinical studies will ultimately support the further development of PGN-EODM1 or any other product candidates we may develop. Conducting preclinical testing is a lengthy, time-consuming and expensive process. The length of time may vary substantially according to the type, complexity and novelty of the program, and often can be several years or more per program. In addition, the progress and timing of our preclinical studies, including pharmacology and toxicology studies, may be impacted by the limited supply of NHPs needed for such studies. As a result, we cannot be sure that we will be able to submit INDs, CTAs and other similar regulatory filings for our programs on the timelines we expect, if at all, and we cannot be sure that submission of such regulatory filings will result in the FDA, competent authorities of the EU member states, or comparable foreign regulatory authorities allowing clinical trials to begin, including in the case of our FREEDOM2 clinical study for PGN-EDODM1. For example, in March 2026, we announced that we received notice of a partial clinical hold from the FDA based on previously submitted preclinical pharmacology and toxicology studies. We are committed to working with the FDA to address their questions; however, we may not be able to resolve the issues related to such partial clinical hold in a timely manner, or at all, which may negatively impact the PGN-EDODM1 program, including the FREEDOM2 enrollment timelines. Furthermore, 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. Furthermore, product candidates are subject to continued preclinical safety studies, which may be conducted concurrently with our clinical testing. The outcomes of these safety studies may delay the launch of, or enrollment in clinical trials and could impact our ability to continue to conduct our clinical trials. Clinical testing is expensive, is difficult to design and implement, can take many years to complete and is uncertain as to outcome. We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, or at all. A failure of one or more clinical trials can occur at any stage of testing, which may result from a multitude of factors, including, but not limited to, flaws in trial design, dose selection issues, patient enrollment criteria and failure to demonstrate favorable safety or efficacy traits. Other events that may prevent successful or timely completion of clinical development include: - delays in reaching a consensus with regulatory authorities on trial design;- delays in reaching agreement on acceptable terms with prospective CROs and clinical trial sites;- delays in opening clinical trial sites or obtaining required institutional review board, or IRB, or independent ethics committee approval, or the equivalent review groups for sites outside the U.S., at each clinical trial site;- failure of the FDA to remove the partial clinical hold on PGN-EDODM1 or the imposition of further clinical holds by regulatory authorities as a result of a serious adverse events, manufacturing concerns, or after an inspection of our clinical trial operations or trial sites;- negative or inconclusive results observed in clinical trials, including failure to demonstrate statistical significance, which could lead us, or cause regulators to require us, to conduct additional clinical trials or abandon product development programs;- failure by us, any CROs we engage or any other third parties to adhere to clinical trial requirements;- failure to perform in accordance with the FDA's GCPs or those of other regulatory authorities;- failure by physicians to adhere to delivery protocols leading to variable results;- delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical sites, including delays by third parties with whom we have contracted to perform certain of those functions;- failure of our third-party contractors to comply with regulatory requirements or to meet their contractual obligations to us in a timely manner, or at all;- inability to recruit patients to participate in a clinical trial, including as a result of competition with other pharmaceutical and biotechnology companies and the patient population size for our product candidates;- delays in having patients complete participation in a clinical trial or return for post-treatment follow-up;- clinical trial sites or patients dropping out of a trial;- selection of clinical endpoints that require prolonged periods of clinical observation or analysis of the resulting data;- occurrence of serious adverse events associated with the product candidate that are viewed to outweigh its potential benefits;- occurrence of serious adverse events associated with a product candidate in development by another company, which are viewed to outweigh its potential benefits, and which may negatively impact the perception of our product due to a similarity in technology or approach;- changes in regulatory requirements and guidance that require amending or submitting new clinical protocols;- changes in the legal or regulatory regimes domestically or internationally related to patient rights and privacy;- lack of adequate funding to continue the clinical trial; or - lack of diminished revenue potential of the program(s) due to competition. Clinical trials must be conducted in accordance with the FDA and other applicable regulatory authorities' legal requirements, regulations or guidelines, and are subject to oversight by these governmental agencies and IRBs or ethics committees at the medical institutions where the clinical trials are conducted. We could encounter delays if a clinical trial is suspended or terminated by us, by the data safety monitoring board for such trial or by the FDA or any other regulatory authority, or if the IRBs of the institutions in which such trials are being conducted suspend or terminate the participation of their clinical investigators and sites subject to their review. Such authorities may suspend or terminate a clinical trial due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product candidate, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial. In addition, disruptions caused by the effects of any epidemics or pandemics may increase the likelihood that we encounter such difficulties or delays in initiating, enrolling, conducting or completing our planned and ongoing clinical trials. Moreover, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services. Under certain circumstances, we may be required to report some of these relationships to the FDA or comparable foreign regulatory authorities. The FDA or comparable foreign regulatory authority may conclude that a financial relationship between us and a principal investigator has created a conflict of interest or otherwise affected interpretation of the trial. The FDA or comparable foreign regulatory authority may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized. This could result in a delay in approval, or rejection, of our marketing applications by the FDA or comparable foreign regulatory authority, as the case may be, and may ultimately lead to the denial of marketing approval of our product candidates. Any inability to successfully complete preclinical studies and clinical trials, including in the case of the PGN-EDO51 program, could result in additional costs to us or impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our product candidates, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business, financial condition, results of operations and prospects. Further, conducting clinical trials in foreign countries, as we plan to continue to do for our product candidates, including PGN-EDODM1, presents additional risks that may delay completion of our clinical trials. These risks include the failure of enrolled patients in foreign countries to adhere to clinical protocol as a result of differences in healthcare services or cultural customs, managing additional administrative burdens associated with foreign regulatory schemes, as well as political and economic risks relevant to such foreign countries. Additionally, if the results of clinical trials are inconclusive or if there are safety concerns or serious adverse events associated with our product candidates, we may: - be delayed in obtaining marketing approval for product candidates, if at all;- obtain approval for indications or patient populations that are not as broad as intended or desired;- obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;- be subject to changes in the way the product is administered;- be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;- have regulatory authorities withdraw, or suspend, their approval of the product or impose restrictions on its distribution in the form of a Risk Evaluation and Mitigation Strategy, or REMS;- be subject to the addition of labeling statements, such as warnings or contraindications;- be sued; or - experience damage to our reputation. In particular, each of the conditions for which we plan to develop or are developing product candidates is a rare genetic disease with limited patient pools from which to draw for clinical trials. Further, because it can be difficult to diagnose these diseases in the absence of a genetic screen, we may have difficulty finding patients who are eligible to participate in our studies. The eligibility criteria of our clinical trials will further limit the pool of available study participants. Additionally, the process of finding and diagnosing patients may prove costly. The treating physicians in our clinical trials may also use their medical discretion in advising patients enrolled in our clinical trials to withdraw from our studies or to try alternative therapies. Finally, we must compete with other companies with either approved therapies or investigational therapies in development for the conditions which we are developing product candidates for, which may further limit the pool of potential patients.

We are in the early stages of our programs and have completed a Phase 1 clinical trial and are conducting a Phase 2 clinical trial for our PGN-EDODM1 product candidate. We reported data from three cohorts of our Phase 1 trial, and from one cohort of our Phase 2 trial of PGN-EDODM1, but we have not completed IND- or CTA-enabling activities or advanced any other product candidates (except PGN-EDO51) into clinical development. As a result, our belief in the capabilities of our platform is based on early research, preclinical studies, and early data from our early-stage studies and clinical trials. However, the results of preclinical studies may not be predictive of the results of later preclinical studies or clinical trials, and the results of any early-stage clinical trials may not be predictive of the results of later clinical trials. For example, since PGN-EDO51 did not achieve target dystrophin levels in the CONNECT1 trial, we made the decision to discontinue development of our DMD programs. We have reported single-dose data for all of the planned cohorts (5,10 and 15 mg/kg) in the Phase 1 FREEDOM study. While we observed robust dose-dependent mean splicing correction at the 5, 10 and 15 mg/kg dose level in the FREEDOM study, we observed limited change in functional outcomes in all cohorts of the Phase 1 FREEDOM study after a single dose as well as in the lowest dose (5 mg/kg) of the multi-dose Phase 2 FREEDOM2 study. We believe robust splicing correction with PGN-EDODM1 has the potential to lead to meaningful functional improvements with repeat dosing over time, but this may not be the case. If we do not see functional improvements in the higher dose cohorts of the FREEDOM2 study, we may have to consider alternate dosing, lengthening the exposure to the drug candidate or increasing the number of patients in certain cohorts to properly assess optimal efficacy. Any such changes to our development strategy or a determination in the future that PGN-EDODM1 may not yield sufficient functional improvement would harm our business, financial condition, results of operations and prospects. Additionally, our planned clinical trials may utilize an "open-label" trial design. An "open-label" clinical trial is one where both the patient and investigator know whether the patient is receiving the investigational product candidate or either an existing approved drug or placebo. Most typically, open-label clinical trials test only the investigational product candidate and sometimes may do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. Open-label clinical trials may be subject to a "patient bias" where patients perceive their symptoms to have improved merely due to their awareness of receiving an experimental treatment. In addition, open-label clinical trials may be subject to an "investigator bias" where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge. The results from an open-label trial may not be predictive of future clinical trial results with any of our product candidates when studied in a controlled environment with a placebo or active control.

From time to time, we may publicly disclose preliminary or topline data from our preclinical studies and clinical trials, which is based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial. The topline or preliminary results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated. Topline data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, topline data and preliminary results should be viewed with caution until the final data are available. For example, based on preclinical, HV and early data in patients, we believed that with a longer treatment period and higher doses of PGN-EDO51, we could expect to see higher levels of exon skipped transcript potentially resulting in significant increases in dystrophin in our CONNECT1 Phase 2 trial. However, the data from the 10 mg/kg cohort of CONNECT1 demonstrated that PGN-EDO51 did not achieve target dystrophin levels, and we made the decision to discontinue development of our DMD programs. Additionally, although we were encouraged by the trends observed in initial splicing and functional outcome data in the FREEDOM study, in the multi-dose 5 mg/kg cohort of the FREEDOM2 study, the splicing correction results were 7.3% versus 12.7% in the 5 mg/kg cohort of the single dose phase 1 FREEDOM study. From time to time, we may also disclose interim data from our preclinical studies and clinical trials. Interim data from clinical trials that we may complete are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available or as patients from our clinical trials continue other treatments for their disease. Adverse differences between preliminary or interim data and final data could significantly harm our business prospects. Further, disclosure of interim data could result in volatility in the price of our common stock. Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the value of the particular program, the approvability or commercialization of the particular product candidate or product and our company in general. In addition, the information we choose to publicly disclose regarding a particular study or clinical trial is based on what is typically extensive information, and you or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure. If the interim, topline, or preliminary data that we report differ from actual results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability to obtain approval for, and commercialize, our product candidates may be harmed, which could harm our business, operating results, prospects or financial condition.

Undesirable side effects caused by PGN-EDODM1, or future product candidates, could cause us or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other regulatory authorities. For instance, in March 2026, we announced that we received notice of a partial clinical hold from the FDA based on previously submitted preclinical pharmacology and toxicology studies. Although other oligonucleotide therapeutics have received regulatory approval, ours is a novel approach to oligonucleotide therapy. As a result, there is uncertainty as to the safety profile of our product candidates compared to more well-established classes of therapies, or oligonucleotide therapeutics on their own. Moreover, there have been only a limited number of clinical trials involving the use of peptide conjugated oligonucleotide therapeutics or our proprietary technology used in our EDO platform. For example, following the recent unblinding of the single-ascending dose portion of the FREEDOM trial, analysis of a kidney safety composite measure biomarker was conducted, and, at the 10 and 15 mg/kg dose levels, transient biomarkers associated with tubular insult were noted, as well as the observation of a DLT being identified at the 15 mg/kg dose level. Furthermore, we continue to observe transient increases in albuminuria in certain patients. Although these laboratory findings resolved without medical treatment or intervention and were not associated with clinical symptoms, the clinical significance of these findings is not yet fully understood. As we continue dose escalation and multi-dose administration in the FREEDOM2 study, with seven of eight patients having completed dosing doses in the 10 mg/kg cohort, we are monitoring safety results, including continuing to note transient increases in certain kidney function biomarkers, with a goal of determining the optimal dose in multi-dose cohorts in future clinical studies. Accordingly, we may observe additional renal effects, including more pronounced or persistent laboratory abnormalities, clinically symptomatic renal events, or other safety signals as the study continues. Given the stage of clinical development of PGN-EDODM1, there can be no assurance that PGN-EDODM1 will not cause undesirable side effects in patients with further dosing and dose escalation, including, for example, safety events similar to those observed in our studies with PGN-EDO51. If such events occur, we may be required to modify, suspend, or terminate clinical trials, reduce dosing, implement additional monitoring, or conduct additional preclinical studies, which could delay development, increase costs, or adversely affect the commercial prospects of PGN-EDODM1. Additionally, in our Phase 1 and Phase 2 clinical trials of PGN-EDO51, we observed mild, transient, reversible changes in kidney biomarkers that resolved without intervention in all but one participant who experienced a non-life threatening serious adverse event and transient mild to moderate hypomagnesemia that resolved without intervention or with low-dose oral magnesium supplementation. One participant experienced a reduction of his estimated glomerular filtration rate, or eGFR, that a subsequent nuclear scan indicated?was in the normal range. There were no treatment-related SAEs, and all treatment-related adverse events were mild. Despite what we believed to be a favorable emerging safety profile for PGN-EDO51, in May 2025, following a review of the dystrophin data from the 10 mg/kg cohort, we made the voluntary decision to cease development of PGN-EDO51. We may also observe additional safety or tolerability issues in ongoing or future clinical trials as we test our product candidates in larger populations, over longer durations, or with different dosing regimens. Historically, many third-party product candidates that initially showed promise in early-stage testing were later found to cause side effects that prevented further clinical development. It is possible that, if the use of our product candidates becomes more widespread following any regulatory approval, illnesses, injuries, discomforts and other adverse events that were observed in earlier trials, as well as conditions that did not occur or went undetected in previous trials, will be reported by patients. If such side effects become known later in development or upon approval, if any, such findings may harm our business, financial condition, results of operations and prospects significantly. In addition, if our product candidates receive marketing approval, and we or others later identify undesirable side effects caused by treatment with such drug, a number of potentially significant negative consequences could result, including: - regulatory authorities may suspend, limit or withdraw approvals of such product, or seek an injunction against its manufacture or distribution;- we may be required to recall a product or change the way the drug is administered to patients;- regulatory authorities may require additional warnings in the labeling, such as a contraindication or a boxed warning, or issue safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product;- we may be required to change the way the product is administered or conduct additional clinical trials or post-approval studies;- we may be required to implement a REMS, or create a medication guide outlining the risks of such side effects for distribution to patients;- additional restrictions may be imposed on the marketing or promotion of the particular product or the manufacturing processes for the product or any component thereof;- we may be subject to fines, injunctions or the imposition of criminal penalties;- we could be sued and held liable for harm caused to patients;- the drug could become less competitive; and - our reputation may suffer. Any of these events could prevent us from achieving or maintaining market acceptance of our lead product candidate or our other product candidates, if approved, and could significantly harm our business, financial condition, results of operations and prospects.