Delandistrogene moxeparvovec

Approximately 25 non-ambulatory participants will receive sirolimus as part of the regimen in Cohort 8 of the ENDEAVOR study, which is expected to begin before the end of the year The enhanced immunosuppressive regimen is designed to mitigate the risk of acute liver injury (ALI) and acute liver failure (ALF) associated with AAV gene therapy Decisions regarding resuming commercial dosing for this population will be made in collaboration with FDA after reviewing study data CAMBRIDGE, Mass. --(BUSINESS WIRE)--Nov. 25, 2025-- Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved dosing in Cohort 8 of ENDEAVOR (Study 9001-103). The purpose of Cohort 8 is to evaluate the use of an enhanced immunosuppressive regimen as part of treatment with ELEVIDYS (delandistrogene moxeparvovec-rokl) for non-ambulant individuals with Duchenne muscular dystrophy. Data from Cohort 8 will be used to determine whether administering sirolimus prior to and after ELEVIDYS infusion can help reduce acute liver injury (ALI), a known risk associated with AAV gene therapy. The cohort will enroll approximately 25 participants in the U.S. who are non-ambulatory. The immunosuppression regimen will include 14 days of peri-infusion sirolimus dosing (prior to ELEVIDYS administration) and will continue for 12 weeks after ELEVIDYS administration. Primary endpoints include incidence of ALI and ELEVIDYS-dystrophin expression at 12 weeks. The approach is based on preclinical data and shaped by real-world clinical experience, including guidance from independent specialists in Duchenne and liver health. “We remain deeply committed to serving all individuals living with Duchenne, including those who have lost the ability to walk. Guided by real-world experience, external clinician expertise, and FDA input, Cohort 8 of the ENDEAVOR study will evaluate integrating sirolimus into our immunosuppression approach, with the goals of mitigating the risk of acute liver injury and restoring access for non-ambulant individuals living with Duchenne,” said Louise Rodino-Klapac , Ph.D., president of research & development and technical operations. “We plan to initiate Cohort 8 by the end of this year and pending enrollment, complete primary endpoint data collection in the second half of 2026.” ELEVIDYS is the only approved gene therapy for Duchenne. To date, ELEVIDYS has been administered to over 1,100 patients globally in clinical and real-world settings. Sarepta continues to work closely with the FDA to ensure that all regulatory decisions are grounded in science and the best interests of patients who face a rare, irreversibly progressive and ultimately fatal disease. ELEVIDYS remains available as appropriate to ambulatory individuals ages 4 and over per an updated label announced earlier this month. About ENDEAVOR (Study 9001-103) Study SRP-9001-103, also known as ENDEAVOR, is an open-label, Phase 1b study assessing the expression and safety of ELEVIDYS (delandistrogene moxeparvovec) in multiple cohorts of male patients with Duchenne. The study has enrolled 55 participants across 7 cohorts, and has dosed younger ambulatory individuals aged 2-7 at time of treatment, and older ambulant individuals and non-ambulant individuals. The primary endpoint in ENDEAVOR is the change from baseline in the quantity of ELEVIDYS micro-dystrophin protein expression measured by western blot at 12 weeks. Secondary outcome measures include change from baseline in micro-dystrophin expression measured by percent dystrophin positive fibers at 12 weeks. About ELEVIDYS (delandistrogene moxeparvovec-rokl) ELEVIDYS (delandistrogene moxeparvovec-rokl) is a single-dose, adeno-associated virus (AAV)-based gene transfer therapy for intravenous infusion designed to address the underlying genetic cause of Duchenne muscular dystrophy – mutations or changes in the DMD gene that result in the lack of dystrophin protein – through the delivery of a transgene that codes for the targeted production of ELEVIDYS micro-dystrophin in skeletal muscle. ELEVIDYS is indicated for the treatment of ambulatory patients 4 years of age and older with Duchenne muscular dystrophy (DMD) who have a confirmed mutation in the DMD gene. Limitations of Use ELEVIDYS is not recommended in patients with: Preexisting liver impairment (defined as gamma-glutamyl transferase [GGT] > 2 x upper limit of normal or total bilirubin > the upper limit of normal not due to Gilbert’s syndrome) or active hepatic viral infection due to the high risk of acute serious liver injury and acute liver failure. Recent vaccination (within 4 weeks of treatment) due to immunogenicity and potential safety concerns. Active or recent (within 4 weeks) infections due to safety concerns. IMPORTANT SAFETY INFORMATION BOXED WARNING: Acute Serious Liver Injury and Acute Liver Failure Acute serious liver injury, including life-threatening and fatal acute liver failure, has occurred. Patients with preexisting liver impairment may be at higher risk. Prior to infusion, assess liver function by clinical examination and laboratory testing. Administer systemic corticosteroids before and after ELEVIDYS infusion. Continue to monitor liver function weekly for the first 3 months after infusion and continue until results are unremarkable. Instruct patients to maintain proximity to an appropriate healthcare facility, as determined by the healthcare provider, for at least 2 months following ELEVIDYS infusion. Obtain prompt consultation with a specialist (e.g., gastroenterologist or hepatologist) if acute serious liver injury or impending acute liver failure is suspected. CONTRAINDICATION: ELEVIDYS is contraindicated in patients with any deletion in exon 8 and/or exon 9, including a deletion of any portion or the entirety of these exons, in the DMD gene. WARNINGS AND PRECAUTIONS: Acute Serious Liver Injury and Acute Liver Failure See Boxed Warning. Acute serious liver injury marked by elevations of liver enzymes (e.g., GGT, ALT) and total bilirubin and acute liver failure has occurred with ELEVIDYS. Onset of the liver injury typically begins within 8 weeks of ELEVIDYS administration. In non-ambulatory patients treated with ELEVIDYS, acute liver failure with fatal outcome has occurred in the clinical and post-marketing settings. Life-threatening mesenteric vein thrombosis, complicated by bowel ischemia and necrosis, and portal hypertension have been reported following acute liver injury associated with ELEVIDYS in a non-ambulatory patient. Patients with preexisting liver impairment, chronic hepatic condition, or acute liver disease (e.g., acute hepatic viral infection) may be at higher risk of acute serious liver injury or acute liver failure. Postpone ELEVIDYS administration in patients with acute liver disease until resolved or controlled. Systemic corticosteroid treatment is recommended for patients before and after ELEVIDYS infusion. Adjust corticosteroid regimen when indicated. Serious Infections Increased susceptibility to serious infections may occur due to concomitant administration of corticosteroid regimen and additional immunosuppressants, and ELEVIDYS. Serious respiratory infections, including with fatal outcomes, have occurred in patients taking immunosuppressant corticosteroids required for ELEVIDYS administration. Monitor patients for signs and symptoms of infection before and after ELEVIDYS administration and treat appropriately. Administer immunizations according to best clinical practices and immunization guidelines prior to initiation of the corticosteroid regimen required before ELEVIDYS infusion. Avoid administration of ELEVIDYS to patients with active infections. Myocarditis Acute, serious, life-threatening myocarditis and troponin-I elevations have been observed within 24 hours to more than 1 year following ELEVIDYS infusion. If a patient experiences myocarditis, those with pre-existing left ventricle ejection fraction (LVEF) impairment may be at higher risk of adverse outcomes. Monitor troponin-I before ELEVIDYS infusion and weekly for the first month following infusion and continue monitoring if clinically indicated, until results return to near baseline levels or stabilize. More frequent monitoring may be warranted in the presence of cardiac symptoms, such as chest pain or shortness of breath. Advise patients to contact a physician immediately if they experience cardiac symptoms. Infusion-related Reactions Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred during or up to several hours following ELEVIDYS administration. Closely monitor patients during and for at least 3 hours after the end of infusion. If symptoms of infusion-related reactions occur, slow or stop the infusion and give appropriate treatment. Once symptoms resolve, the infusion may be restarted at a lower rate. ELEVIDYS should be administered in a setting where treatment for infusion-related reactions is immediately available. Discontinue infusion for anaphylaxis. Immune-mediated Myositis Immune-mediated myositis, including serious and life-threatening events, has occurred approximately 1 month following ELEVIDYS infusion. Signs and symptoms include severe muscle weakness, including dysphagia, dyspnea, dysphonia, and hypophonia. Severe to life-threatening immune-mediated myositis has been reported in patients with deletions including portions of exons 1-17 and/or exons 59-71 of the DMD gene. Regardless of genetic mutation, advise patients to contact a physician immediately if they experience any unexplained increased muscle pain, tenderness, or weakness, including dysphagia, dyspnea, dysphonia, or hypophonia, as these may be symptoms of myositis. Consider additional immunomodulatory treatment based on patient’s clinical presentation and medical history if these symptoms occur. Preexisting Immunity against AAVrh74 In AAV-vector based gene therapies, preexisting anti-AAV antibodies may impede transgene expression at desired therapeutic levels. Following treatment with ELEVIDYS, all patients developed anti-AAVrh74 antibodies. Perform baseline testing for the presence of anti-AAVrh74 total binding antibodies prior to ELEVIDYS administration. ELEVIDYS administration is not recommended in patients with elevated anti-AAVrh74 total binding antibody titers ≥1:400. ADVERSE REACTIONS The most common adverse reactions (incidence ≥5%) reported in clinical studies were vomiting, nausea, liver injury, pyrexia, thrombocytopenia, and troponin-I increased. Report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Sarepta Therapeutics at 1-888-SAREPTA (1-888-727-3782). Please see the full Prescribing Information for ELEVIDYS, including Boxed Warning and Medication Guide. About Sarepta Therapeutics Sarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. We hold a leadership position in Duchenne muscular dystrophy (Duchenne) and are building a robust portfolio of programs across muscle, central nervous system, and cardiac diseases. For more information, please visit www.sarepta.com or follow us on LinkedIn, X, Instagram and Facebook. Forward-Looking Statements This statement contains “forward-looking statements.” Any statements that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “believe,” “anticipate,” “plan,” “expect,” “will,” “may,” “intend,” “prepare,” “look,” “potential,” “possible” and similar expressions are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements relating to our future operations, ELEVIDYS, planned clinical trials and the timing of such trials, the potential benefits of an enhanced immunosuppression regimen, and ongoing interactions with FDA related to ELEVIDYS. Actual results could materially differ from those stated or implied by these forward-looking statements as a result of such risks and uncertainties. Known risk factors include the following: different methodologies, assumptions and applications we use to assess particular safety or efficacy parameters may yield different statistical results, and even if we believe the data collected from clinical trials are positive, the results of future research may not be consistent with past positive results, or may fail to meet regulatory approval requirements for the safety and efficacy of our products; our products or product candidates may be perceived as insufficiently effective, unsafe or may result in unforeseen adverse events; our products or product candidates may cause undesirable side effects that result in significant negative consequences following any marketing approval; we may not be able to comply with all FDA requests in a timely manner or at all; the possible impact of regulations and regulatory decisions by the FDA and other regulatory agencies on our business; and those risks identified under the heading “Risk Factors” in our most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company, which you are encouraged to review. Any of the foregoing risks could materially and adversely affect the Company’s business, results of operations and the trading price of Sarepta’s common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained herein. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof, except as required by law. Internet Posting of Information We routinely post information that may be important to investors in the 'For Investors' section of our website at www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us. View source version on businesswire.com: https://www.businesswire.com/news/home/20251125916203/en/ Investor Contacts: Ian Estepan , 617-274-4052 iestepan@sarepta.com Ryan Wong , 617-800-4112 rwong@sarepta.com Media Contacts: Tracy Sorrentino , 617-301-8566 tsorrentino@sarepta.com Kara Hoeger , 617-710-3898 khoeger@sarepta.com Source: Sarepta Therapeutics, Inc.

您好，我是大兵（尹相兵），是一名DMD孩子家长，也是专家型DMD家庭倡导者， 见字如面。 我们正在研究 ELEVIDYS（delandistrogene moxeparvovec-rokl）基因疗法的 NSAA 评分、肌酸激酶 (CK) 和肌营养不良蛋白水平，该疗法尚未获得欧洲药品管理局的批准。 接受 ELEVIDYS（delandistrogene moxeparvovec-rokl）治疗的 DMD 儿童肌酸激酶 (CK) 水平下降多少、NSAA 评分和正常肌营养不良蛋白水平上升多少，仍然是一个令人好奇的问题。ELEVIDYS 是由 Sarepta Therapeutics 开发的用于治疗杜氏肌营养不良症的世界上最昂贵的疗法之一。. ELEVIDYS（delandistrogene moxeparvovec-rokl）由Sarepta Therapeutics公司研发，是一种一次性AAV（腺相关病毒）基因疗法，于2023年6月在美国获批用于治疗4-5岁可独立行走的儿童DMD患者，之后适应症范围扩大。 它的设计目的是将编码微型肌营养不良蛋白（约138 kDa，而正常的肌营养不良蛋白约为427 kDa）的基因导入肌肉细胞。 杜氏肌营养不良症 (DMD) 中，肌营养不良蛋白的缺失或严重缺乏会导致肌肉细胞损伤；随着肌纤维的退化，肌酸激酶 (CK) 等标志物水平升高。因此，杜氏肌营养不良症中考虑的两种替代生物标志物是： CK水平，作为肌肉损伤/渗漏入血的标志物 肌肉组织中肌营养不良蛋白（或在本例中为微型肌营养不良蛋白）的表达水平关于 Elevidys 基因治疗中肌酸激酶 (CK)、肌营养不良蛋白水平和 NSAA 评分的核心问题：接受 ELEVIDYS 治疗的 DMD 儿童患者，CK 水平下降多少？肌营养不良蛋白/微型肌营养不良蛋白上升多少？接受 Elevidys 治疗的儿童体内的微型肌营养不良蛋白发生率占正常肌营养不良发生率的百分比是多少？这个发生率是否足够？levidys 产生多少微型肌营养不良蛋白？ 根据Elevidys官方网站公布的信息，在所有临床试验中，受试者在接受3个月治疗后平均产生了34%至51%的ELEVIDYS微型肌营养不良蛋白。但该网站并未具体说明这一数量相当于多少正常肌营养不良蛋白。 看看Vyondys 53外显子跳跃疗法中肌营养不良蛋白的增加情况。接受 Elevidys 治疗的儿童的 NSAA 评分提高了多少？什么是北极星动态评估（NSAA）？ 总分0-34分，分数越高表示功能水平越高。该评估包括两项计时测试：定时起立测试（RFF）和10米定时步行/跑步测试（10MWR）。该评估方法已通过验证，并广泛应用于临床试验和临床实践中。 根据 Elevidys 官方网站公布的信息，接受基因治疗的儿童在 34 分制 NSAA 测试中得分提高了 2.6 分，而未接受基因治疗的儿童得分提高了 1.9 分。. 这意味着未接受 Elevidys 基因治疗的儿童也出现了病情改善。 根据EMA报告，此次涨幅仅为0.65个百分点。 接受 Elevidys 治疗的儿童的病情改善程度如何？ 接受 ELEVIDYS 治疗的患者在一年后（平均而言）从地上站起来的速度比接受安慰剂（未服用 ELEVIDYS）的患者快 0.64 秒。  接受 ELEVIDYS 治疗的患者在一年后（平均而言）步行/跑步 10 米的速度比接受安慰剂（未服用 ELEVIDYS）的患者快 0.42 秒 我们目前对微型肌营养不良蛋白增加的了解 根据批准摘要，FDA 研究发现，ELEVIDYS 可增加接受治疗患者骨骼肌中微型肌营养不良蛋白的表达。 一篇综述文章（预印本）指出：“经过 48 周的治疗，患者在蛋白质印迹分析中显示出平均微型肌营养不良蛋白表达量约为 28 %。” 关于EMBARK研究的公告指出：‘在第一部分接受治疗的患者中，给药后64周采集的活检样本显示，与第12周的活检样本相比，ELEVIDYS微型肌营养不良蛋白的表达持续稳定，这通过蛋白质印迹法检测得出，并为观察到的功能性结果提供了生物学支持。’然而，该公告并未披露微型肌营养不良蛋白的产量及其随时间推移的维持情况。  因此，一项可用的数据是，在治疗组（该小型研究）中，大约 48 周时，TP146T 表达量相对于正常水平（通过蛋白质印迹法检测）约为 28%。然而： 在该测量中，“100%”的含义（正常健康的肌营养不良蛋白水平）并不总是很清楚。. 在更大规模的试验中，功能改善（运动终点）并未达到主要终点。 因此，虽然微型肌营养不良蛋白水平确实会增加，但具体幅度各不相同，长期持久性仍在研究中，转化为临床益处仍不确定。关于CK降低，我们目前尚不清楚的是哪些方面。 在我们查阅的公开监管文件和出版物中，没有明确公布的、可靠的数据表明，患有杜氏肌营养不良症 (DMD) 的儿童在接受 ELEVIDYS 治疗后，肌酸激酶 (CK) 水平会下降多少。要点： FDA 扩展批准声明中提到，在考虑的所有证据中，包括“肌酸激酶水平的改善”等终点指标。  然而，我们在同行评审的文献中（至少在可访问的来源中）没有找到诸如“CK 平均在 Y 周/月内下降 X%”之类的已发表数据。 许多结果仍属于探索性或次要终点；EMBARK 研究的主要功能终点（NSAA）在 52 周时未达到统计学意义（差异约为 0.65 分）。 因此，虽然有迹象表明 CK 水平可能会下降，但下降的程度（例如，百分比减少、绝对单位）在多项大型研究中尚未得到公开的充分描述（或者至少还没有以易于获取的形式发表）。数据缺口为何如此重要 肌酸激酶 (CK) 是杜氏肌营养不良症 (DMD) 中广泛使用的生物标志物，用于追踪肌肉损伤/渗漏情况。CK 水平显著下降可能提示持续性肌肉损伤有所减轻。 肌营养不良蛋白（或微型肌营养不良蛋白）的表达是一种机制标志：表明该疗法正在发挥其设计的作用。 但即使微型肌营养不良蛋白增加而 CK 减少，关键问题仍然存在： 这是否能转化为有意义的功能/运动方面的益处、更长的行走时间、更高的生活质量？ 大型三期临床试验未能达到其主要运动终点，这一事实令人担忧：蛋白质表达增加并不一定能保证功能显著改善。  监管机构，例如欧洲药品管理局（EMA），则持更为怀疑的态度：EMA 的人用药品委员会（CHMP）建议在 2025 年 7 月不授予 Elevidys 上市许可，理由是尽管该药物能产生微型肌营养不良蛋白，但其功能获益不足。 这对儿童/家庭和临床医生意味着什么 如果您是正在考虑使用 ELEVIDYS 的家庭或临床医生，那么您应该了解，微型肌营养不良蛋白的表达确实会增加（例如，在一项研究中，~28%），但长期实际使用中能否转化为清晰、有意义的功能性获益仍有待验证。 由于 CK 降低的数值没有明确定义/没有一致公布，因此不应假设 CK 会下降特定的百分比；监测 CK 仍然是研究/临床随访的一部分，但应该降低预期。 参与或进行后续/确认性试验（如 EMBARK）以及监测肌肉生物标志物（肌营养不良蛋白表达、CK）和功能终点（行走、计时测试、呼吸/心脏状态）仍然至关重要。 由于基因疗法是一次性的，而且非常昂贵（据讨论报道，初始定价在数百万美元范围内），并且存在已知的安全风险（例如肝损伤），因此必须权衡已知和未知因素。关于杜氏肌营养不良症溶酶体损伤的新研究 尽管基因疗法（delandistrogene moxeparvovec）已获得美国食品药品监督管理局（FDA）批准（FDA）用于门诊患者，但患者的功能改善程度并未达到临床前预期。这种有限的临床获益可能归因于多种因素，包括缺乏全长肌营养不良蛋白中存在的某些功能域。因此，基因转移可能无法逆转肌肉中的所有病理机制。识别基因疗法无法纠正的特定病理机制，并探索针对这些机制的联合疗法，至关重要。结论 使用 ELEVIDYS 治疗会导致肌肉中微型肌营养不良蛋白表达增加（在一项研究中，数值约为 ~28%）。 CK 降低的程度尚未得到充分宣传，也没有在同行评审的大规模研究中得到充分描述——因此，它仍然是一个“令人好奇的问题”。 长期功能获益仍有待验证，这意味着生物标志物的改善（肌营养不良蛋白升高，CK 可能降低）令人鼓舞，但还不能最终保证运动结果的改善。 随着来自验证性试验和真实世界注册研究的更多数据的出现，我们预计会看到 CK 降低、持续存在的肌营养不良蛋白/微型肌营养不良蛋白以及与运动功能的相关性的更详细的数据——这将有助于家庭和临床医生做出更明智的决定。 DMD口服激素标准剂量计算器上线！让足量的关心陪伴孩子每一天！ 恳切的希望，所有的CDMD(China DMD)家友们，一起努力好好学习专业知识，用知识武装头脑，成为 ⌈专家型DMD家庭⌋ ，为了DMD孩子们的明天，全力去推动 ⌈未来五年，药物可及所有DMD患者⌋。为了成为 ⌈专家型DMD家庭⌋ ，恳请CDMD家友们可以关注公众号后回复：DMD 打开链接登录网盘后，即可领取完整版资料 《DMD患者读本》和《DMD家庭与教育者手册》 【CDMD家友会】公众号分享最新的国内外DMD药物研发信息和临床招募信息，已经在【CDMD患者互助(一)群 或 (二）群或（三）群 或（四）群 或（五）群 或（六）群】就不要加入啦，请扫二维码加入【CDMD患者互助(七)群】啦！