RegenXBio (RB0) Risk Analysis

Our main goals continue to include the ability to identify, develop and commercialize product candidates based on our NAV Technology Platform. Research programs to identify new product candidates require substantial technical, financial and human resources. Although certain of our product candidates are currently in research studies or preclinical development, we may fail to identify potential product candidates for clinical development for several reasons. For example, our research may be unsuccessful in identifying potential product candidates or our potential product candidates may be shown to have harmful side effects, may be commercially impracticable to manufacture or may have other characteristics that may make the products unmarketable or unlikely to receive marketing approval. Our spending on current and future research and development programs may not yield any commercially viable products. If we do not accurately evaluate the commercial potential for a particular product candidate, we may relinquish valuable rights to that product candidate through strategic collaboration, licensing or other arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate. Alternatively, we may allocate internal resources to a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement. If any of these events occur, we may be forced to abandon our development efforts with respect to a particular product candidate or fail to develop a potentially successful product candidate, which could materially harm our business, financial condition, results of operations and prospects.

We have concentrated our research and development efforts on our proprietary AAV gene delivery platform (our NAV Technology Platform), and we have granted licenses to certain intellectual property related to our NAV Technology Platform to our NAV Technology Licensees and collaborators. Our future success depends on our and our NAV Technology Licensees' and collaborators' successful development and commercialization of viable gene therapy product candidates. There can be no assurance that we or our NAV Technology Licensees and collaborators will not experience problems or delays in developing current or future product candidates or that such problems or delays will not cause unanticipated costs, or that any such development problems can be solved. We also may experience unanticipated problems or delays in expanding our manufacturing capacity, and this may prevent us from completing our clinical trials, meeting the obligations of our collaborations or commercializing our products on a timely or profitable basis, if at all. For example, we, a partner or another group may uncover one or more previously unknown risks associated with AAV or our NAV Technology Platform, and this may prolong the period of observation required for obtaining regulatory approval, necessitate additional clinical testing or invalidate our NAV Technology. In addition, the clinical trial requirements of the FDA, the EMA and other regulatory authorities and the criteria these regulators use to determine the quality, safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of such product candidates. The regulatory approval process for novel product candidates such as ours can be significantly more expensive and take longer than for product candidates from categories that are better known or that have been studied more extensively. Only a small number of gene therapy products have been approved in the United States, the European Union or elsewhere, including less than ten AAV-based gene therapies approved in the United States as of the end of 2025. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our product candidates in the United States, the European Union or elsewhere, or how long it will take to commercialize our product candidates, if approved. Furthermore, approvals by one regulatory authority may not be indicative of what other regulatory authorities may require for approval, and approvals of ex vivo gene therapy products (such as autologous CAR T-cell therapies) may not be indicative of what may be required for approval of in vivo gene therapy products (such as directly administered AAV-based gene therapies). Regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. Additionally, we may seek regulatory approval in territories outside the United States and the European Union, which may have their own regulatory authorities along with frequently changing requirements or guidelines. The regulatory review committees and advisory groups in the United States, the European Union and elsewhere, and any new guidelines they promulgate, may lengthen the regulatory review process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates, we will be required to consult with these regulatory and advisory groups, and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of certain of our product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate product revenue, and our business, financial condition, results of operations and prospects would be materially harmed.

Gene therapy development has inherent risks. Our lead product candidates in the rare disease space have limited clinical and preclinical results and we may experience unexpected results in the future. We or any of our future development partners will be required to demonstrate through adequate and well-controlled clinical trials that our product candidates containing our proprietary vectors are safe and effective, with a favorable benefit-risk profile, for use in their target indications before we can seek regulatory approvals for their commercial sale. Drug development is a long, expensive and uncertain process, and delay or failure can occur at any stage of development, including after commencement of any of our clinical trials. The results of preclinical studies and early clinical trials are not always predictive of future results. Preclinical studies have experimental and animal model limitations, may not detect or predict human adverse effects, and are not powered to detect rare events. Any product candidate we or any of our future development partners advance into clinical trials, including our lead product candidates, may not have favorable results in later clinical trials, if any, or receive regulatory approval. There is a high failure rate for drugs and biologic products proceeding through clinical trials. Data obtained from preclinical and clinical activities are subject to varying interpretations that may delay, limit or prevent regulatory approval. In addition, we may experience regulatory delays or rejections as a result of many factors, including due to changes in regulatory policy during the period of our product candidate development. Any such delays could materially harm our business, financial condition, results of operations and prospects.

During the clinical development process, we will need to identify success criteria and endpoints for our clinical trials such that the FDA will be able to subsequently evaluate the clinical efficacy and safety profile of our product candidates. As we are developing novel treatments for diseases in which there is little clinical experience with new endpoints and methodologies, there is heightened risk that the FDA, the EMA or other regulatory bodies may not consider the clinical trial endpoints that we select to directly reflect how a treatment impacts a disease. In addition, we may not successfully achieve the statistical criteria to reflect what is clinically meaningful, or the resulting clinical data and results may be difficult to analyze. For example, even if we do achieve the pre-specified criteria, we may produce results that are unpredictable or inconsistent with the results of the non-primary endpoints or other relevant data. Further, we may be required to produce more data, including enhanced functional data, increased number of patients and/or data from untreated control arm patients to achieve FDA support. The FDA also weighs the benefits of a product against its risks, and the FDA may view the efficacy results in the context of safety as not being supportive of regulatory approval. The EMA and other regulatory authorities in the European Union and other countries may make similar comments with respect to these endpoints and data, which may jeopardize or preclude our ability to obtain regulatory approvals in the European Union and other jurisdictions.

While we believe our product candidates should be applicable for the treatment of patients with certain conditions, the results from our preclinical and planned clinical trials may not support as broad of a marketing approval as we seek. This could result in significant cost increases and substantial delays in obtaining, or never obtaining, marketing approval for our product candidates to treat patients. In addition, even if we obtain regulatory approval for our product candidates, we may be required by the FDA, the EMA or other regulatory bodies to conduct additional clinical trials to support approval of our product candidates for patients diagnosed with different mutations of the respective diseases to which our product candidates relate. In addition, we may be approved only for severe forms of a disease or condition. The inability to market our product candidates to treat patients for the intended indications would materially harm our business, financial condition, results of operations and prospects.

Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate their safety and efficacy. Clinical testing is expensive, time-consuming and uncertain as to outcome. A failure of one or more clinical trials can occur at any stage of testing. Events that may prevent successful or timely commencement and completion of preclinical and clinical development include: - delays in reaching a consensus with or changing requirements by 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 independent Ethics Committee approval at each clinical trial site;- delays in recruiting and enrolling suitable subjects to participate in our clinical trials, due to factors such as the size of the trial or subject population, process for identifying subjects, design or expansion of protocols, eligibility and exclusive criteria, perceived risks and benefits of the relevant product candidate or gene therapy generally, availability of competing therapies and trials, severity of the disease under investigation, need and length of time required to discontinue other potential therapies, availability of genetic testing, availability and proximity of trial sites for prospective subjects, ability to obtain subject consent and referral practices of physicians;- imposition of a clinical hold by regulatory authorities in trials in addition to RGX-121 and RGX-111;- failure by us, any CROs we engage or any other third parties to adhere to clinical trial requirements;- failure to perform in accordance with GCP, or applicable regulatory guidelines in the European Union and other countries;- 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;- delays in having subjects complete participation in a trial or return for post-treatment follow-up;- clinical trial sites or subjects 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 in trials of the same class of agents conducted by other sponsors; or - changes in regulatory requirements and guidance that require amending or submitting new clinical protocols. Any inability to successfully complete research studies and preclinical and clinical development 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, if approved, or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates, if approved, and may harm our business, financial condition, results of operations and prospects. Furthermore, unpredictability in the regulatory environment and the regulatory requirements to obtain approval of our product candidates may adversely impact our ability to raise the capital needed to finance our operations.

In January of this year the FDA placed a clinical hold on the investigational new drug application(s) ("IND") for RGX-111 and RGX-121, which was later identified as a partial clinical hold in FDA letters received February of this year. The clinical holds preclude the recruitment of new patients in the ongoing studies and any new dosing of any study subject pending our submission of additional information requested by the FDA. Under the clinical holds, certain aspects of the clinical investigation may continue including limited enrollment and continued monitoring. The FDA indicated that the clinical holds were imposed due to an unreasonable and significant risk of human illness or injury and the need for additional information to assess those risks to subjects. We are working to address the FDA's requests and intend to submit a complete response as soon as practicable. However, we cannot predict the timing or outcome of FDA's review or the steps that may be required to lift the clinical holds on either RGX-111 or RGX-121. FDA will require additional information regarding safety assessment related to malignancy risk, longer-term follow up data and cross-program safety assessment. Our responses to the clinical hold deficiencies could be time-consuming and costly and may not ultimately satisfy FDA. The holds have already paused screening, enrollment, dosing and other study activities and may adversely impact investigator engagement, site readiness, patient retention and our relationships with regulators, partners and patient communities. If the holds are not lifted in a timely manner, or at all, or if additional safety signals emerge, our ability to resume development, obtain regulatory approvals and ultimately commercialize RGX-111 and/or RGX-121 could be materially impaired, which would adversely impact our business, financial condition, results of operations and prospects.

If the results of our planned clinical trials are inconclusive or if there are safety concerns or serious adverse events associated with our product candidates, we may: - receive a clinical hold for a particular product candidate, in addition to RGX-111 and RGX-121, which, if not lifted, could require that we discontinue development of a product candidate;- be required to conduct additional studies or clinical trials with respect to a product candidate or for a potential indication, which may result in additional significant expense and delays in seeking regulatory approval;- be delayed in obtaining regulatory approval for our 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 or other requirements;- have regulatory authorities withdraw, vary or suspend their approval of the product or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation;- be subject to the addition of labeling statements, such as warnings or contraindications;- be sued; or - experience damage to our reputation.

There have been several significant adverse side effects in gene therapy treatments in the past, including reported cases of leukemia in trials using lentivirus vectors and death seen in trials sponsored by other companies using adenovirus vectors and AAV vectors, including NAV vectors. Gene therapy is still a relatively new approach to disease treatment and additional adverse side effects could be identified. Any such adverse safety events in our programs or in AAV gene therapy programs conducted by other companies may negatively impact the regulatory environment, public perception, and financing conditions for AAV-based therapies, which could significantly increase our associated expenses and negatively impact our ability to raise additional capital. There also is the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biologic activity of the genetic material or other components of products used to carry the genetic material. Possible adverse side effects that could occur with treatment with gene therapy products include an immunologic reaction early after administration which could substantially limit the effectiveness of the treatment. In previous clinical trials involving AAV vectors for gene therapy, some subjects experienced the development of a T-cell response, whereby after the vector is within the target cell, the subject's immune response system triggers the removal of transduced cells by activated T-cells. Approved labels for certain gene therapies state that AAV vector DNA can integrate into the host genome at low frequency and that such integration may carry a theoretical risk of malignancy, including hepatocellular carcinoma. Furthermore, in clinical trials sponsored by other companies involving AAV vectors administered intravitreally for the treatment of retinal conditions, serious adverse reactions, such as panuveitis and loss of vision, have occurred. In addition to side effects caused by product candidates, the administration process or related procedures also can cause adverse side effects. If any such adverse events occur in our or third-party trials, our clinical trials could be suspended or terminated. Additionally, if clinically meaningful AAV integration events or an increased incidence of cancer were observed in our studies or in the broader gene therapy field, the FDA or other regulatory authorities could impose additional requirements, place our clinical trials on hold, restrict dosing or patient populations, require enhanced warnings or other labeling limitations, or delay or deny approval of our product candidates. In the RGX-121 CRL, FDA noted that we should include a safety post marketing requirement in the resubmission. As a result of these concerns, we may decide, or the FDA, the European Commission, the EMA or other regulatory authorities could order us, to halt, delay or amend preclinical development or clinical development of our product candidates or we may be unable to receive regulatory approval of our product candidates for any or all targeted indications. Even if we are able to demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the trial. Moreover, if we elect, or are required, to delay, suspend or terminate any clinical trial of any of our product candidates, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these occurrences may harm our ability to develop other product candidates and may harm our business, financial condition and prospects significantly. Additionally, if any of our product candidates receives marketing approval, the FDA could require us to adopt a Risk Evaluation and Mitigation Strategy (REMS) and other regulatory authorities could impose other specific obligations as a condition of approval to ensure that the benefits of our product candidates outweigh their risks, which could delay approval of our product candidates. A REMS may include, among other things, a medication guide outlining the risks of the product for distribution to patients; a communication plan to health care practitioners or patients; and elements to assure safe use, which can severely restrict the distribution of a product by, for example, requiring that health care providers receive particular training and obtain special certification prior to prescribing and dispensing the product, limiting the healthcare settings in which the product may be dispensed and subjecting patients to monitoring and enrollment in a registry. If the FDA requires us to adopt a REMS program for our products and we are unable to comply with its requirements, the FDA may deem our products to be misbranded and we may be subject to civil money penalties. The European Commission, the EMA and other regulatory authorities may, following grant of marketing authorization in their territory, impose similar obligations. Any of these events could prevent us from achieving or maintaining market acceptance of our NAV Technology Platform and our product candidates and could materially harm our business, prospects, financial condition and results of operations.