Myotonic Dystrophy

- Recently presented data demonstrated sustained functional improvement with DYNE-251 treatment through 18 months - - Data from the fully enrolled DELIVER registrational expansion cohort is planned for late 2025 - April 24, 2025 -- Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage company focused on advancing life-transforming therapeutics for people living with genetically driven neuromuscular diseases, today announced that the European Commission (EC) has granted orphan drug designation for DYNE-251 for the treatment of Duchenne muscular dystrophy (DMD). DYNE-251 is being evaluated in the Phase 1/2 DELIVER global clinical trial in individuals with DMD who are amenable to exon 51 skipping. Long-term clinical data from the ongoing DELIVER trial of DYNE-251 that demonstrated unprecedented and sustained functional improvement at the selected registrational dose were presented in March at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference. Functional assessments in the DELIVER trial include Stride Velocity 95th Centile (SV95C), an objective digital outcome that is accepted as a primary endpoint for DMD clinical trials in Europe. “Our recent long-term DELIVER trial results demonstrated clinically relevant and sustained functional improvement through 18 months, including as assessed by SV95C, which may support a strong rationale for regulatory approval in Europe,” said Doug Kerr, MD, PhD, chief medical officer of Dyne. “We are pleased that the EC has granted orphan drug designation to DYNE-251, reinforcing our belief that our next-generation exon 51 skipping investigational therapy for DMD may be able to bring clinically meaningful functional improvement to those living with this devastating disease. With full enrollment of the registrational expansion cohort in the DELIVER trial complete, we look forward to sharing data from this cohort in late 2025 and the potential to move forward with our first regulatory submissions in early 2026.” The EC grants orphan drug designation to drugs and biologics intended for the treatment, diagnosis or prevention of rare, life-threatening or chronically debilitating diseases or conditions that affect fewer than five in 10,000 people in the European Union (EU). Orphan designation provides companies with certain benefits, including reduced regulatory fees, clinical protocol assistance, research grants and the potential for up to 10 years of market exclusivity in the EU if approved. DYNE-251 was also granted U.S. Food and Drug Administration (FDA) orphan drug and rare pediatric disease designations in March 2023. Key Milestones for the DELIVER Trial Dyne continues to pursue expedited approval pathways globally for DYNE-251 in patients with DMD who are amenable to exon 51 skipping. Dyne has fully enrolled the registrational expansion cohort of 32 patients as part of the DELIVER trial. Data from this cohort are planned for late 2025. Dyne anticipates filing a Biologics License Application (BLA) submission for US accelerated approval in early 2026. DELIVER is a randomized, placebo-controlled, double-blind, Phase 1/2 clinical trial evaluating the safety, tolerability and efficacy of DYNE-251 in patients with Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping. The multiple ascending dose (MAD) portion of the study resulted in the selection of a registrational dose and regimen of 20 mg/kg every four weeks. A registrational expansion cohort to support potential regulatory submissions for expediated approvals, including accelerated approval in the U.S., is fully enrolled. The primary endpoint for this cohort is the change from baseline in dystrophin protein levels as measured by Western blot. For more information on the DELIVER trial, visit clinicaltrials.gov (NCT05524883) and euclinicaltrials.eu (2023-510351-31-00). DYNE-251 is an investigational therapeutic being evaluated in the Phase 1/2 global DELIVER clinical trial for people living with DMD who are amenable to exon 51 skipping. DYNE-251 consists of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a fragment antibody (Fab) that binds to the transferrin receptor 1 (TfR1), which is highly expressed on muscle. It is designed to enable targeted muscle tissue delivery and promote exon skipping in the nucleus, allowing muscle cells to create internally shortened, near full-length dystrophin protein, with the goal of stopping or reversing disease progression. DYNE-251 has been granted fast track, orphan drug and rare pediatric disease designations by the U.S. Food and Drug Administration for the treatment of DMD mutations amenable to exon 51 skipping. In addition to DYNE-251, Dyne is building a global DMD franchise and has preclinical programs targeting other exons, including 53, 45 and 44. DMD is a rare disease caused by mutations in the gene that encodes for dystrophin, a protein critical for the normal function of muscle cells. These mutations, the majority of which are deletions, result in the lack of dystrophin protein and progressive loss of muscle function. DMD occurs primarily in males and affects an estimated 12,000 to 15,000 individuals in the U.S. and 25,000 in Europe. Loss of strength and function typically first appears in pre-school age boys and worsens as they age. As the disease progresses, the severity of damage to skeletal and cardiac muscle often results in patients experiencing total loss of ambulation by their early teenage years and includes worsening cardiac and respiratory symptoms and loss of upper body function by the later teens. There is no cure for DMD, and currently approved therapies provide limited benefit. Dyne Therapeutics is discovering and advancing innovative life-transforming therapeutics for people living with genetically driven neuromuscular diseases. Leveraging the modularity of its FORCE™ platform, Dyne is developing targeted therapeutics that deliver to muscle and the central nervous system (CNS). Dyne has a broad pipeline for neuromuscular diseases, including clinical programs for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy (DMD), and preclinical programs for facioscapulohumeral muscular dystrophy (FSHD) and Pompe disease. 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随着抗体药物偶联物（ADCs）的迅速发展，目前已有12种ADC获得FDA批准，另有超过280种不同的ADC处于临床开发阶段。尽管在ADC药物的研发上取得了一定的成功，但仍然存在重大挑战。特别是，将临床前研究结果转化为临床应用仍然十分困难。这是因为许多ADC常与血液学毒性相关，这种毒性可能是由于ADC直接杀伤造血细胞，或由在身体其他部位释放的载荷间接引起的。因此，开发能够预测临床结果的体外检测方法成为ADC药物向临床转化的不可或缺的条件。近日的AACR大会上，Zymeworks公布开发了一种可能会改善ADC的开发，并指导选择最优的连接子和载荷的体外预测血液学毒性的方法。图1. 骨髓来源的造血干细胞/祖细胞在正常分化为谱系特异性细胞及其相关血液学毒性过程中的细胞层级结构示意图。研究方法Zymeworks测试了不同的抗体药物偶联物（ADC）载荷（exatecan、DXd、SN-38、ZD06519、DM1、DM4、MMAE、MMAF），以了解游离载荷本身对非靶向毒性的影响。通过将靶向抗体和非靶向抗体与一种共同的hemiasterlin微管抑制剂偶联，同时改变可被蛋白酶切割的连接子，生成了不同的ADC，以评估连接子对靶向和非靶向细胞毒性在体外的影响。并且在最后，Zymeworks测试了两种具有相同药物-连接子的临床验证的ADC，以评估抗体在ADC非靶向毒性中的影响。图2. 抗体药物偶联物（ADC）的示意图，使用这些ADC进行了克隆形成、可切割性、细胞毒性以及/或体外稳定性检测。Telisotuzumab和Palivizumab ADC的药物抗体比（DAR）为4（±0.2），而Trastuzumab和Patritumab ADC的DAR分别为7.8和7.7。人源克隆形成细胞（CFC）检测能够预测某些与抗体药物偶联物（ADCs）相关的临床毒性。Zymeworks从骨髓中分离出健康的CD34⁺造血干细胞，并与多种细胞因子共同培养，以诱导其分化为红系（BFU-E）、髓系（CFUGM）或巨核系（CFU-Mk）祖细胞，随后用不同浓度的抗体药物偶联物（ADC）、载荷或仅用制剂缓冲液（溶剂对照）进行处理。孵育后，计数克隆数量，并通过比较处理组与溶剂对照组的克隆数量，确定克隆抑制百分比。图3. 克隆形成细胞（CFC）检测流程的示意图。载荷——ADC载荷对人类红系、髓系和巨核系祖细胞具有不同的固有细胞毒性。图4. 在克隆形成细胞（CFC）检测中（如图3所示），游离拓扑异构酶1抑制剂（TOPO1i）和微管抑制剂（MTI）载荷的体外细胞毒性。上图的结果显示，Exatecan在CFC检测中表现出比其他TOPO1i载荷更高的细胞毒性。类似地，对于MTI载荷，DM4和MMAE显示出最高的细胞毒性，其次是DM1和MMAF。连接子——比较具有相同抗体和载荷但不同连接子的非靶向ADC，突出了连接子对非靶向毒性的潜在影响。表1. 不同ADC在克隆形成细胞（CFC）检测中的细胞毒性（EC₅₀，单位为nM，检测方法如图3所示）。抗体——比较具有相同载荷和连接子但不同抗体的ADC，突出了抗体对非靶向毒性的潜在贡献。图5. 克隆形成细胞（CFC）检测（如图3所示）。图中显示，Patritumab deruxtecan（HER3-DXd）表现出比Trastuzumab deruxtecan（T-DXd）更高的细胞毒性，这与在临床环境中接受HER3-DXd治疗的患者相比接受T-DXd治疗的患者出现更高发生率的血液学毒性的观察结果一致（参考文献1、2）。体外连接子切割和细胞毒性检测揭示了不同的载荷释放动力学。不同的连接子在溶酶体检测中以不同的速率释放载荷，如下图所示。图6. 通过将相应的测试样品（1-3 μM）加入到人溶酶体提取液中，测量了来自抗体药物偶联物（ADCs）的释放载荷。释放的载荷通过液相色谱-质谱（LC-MS）进行测定。P.L.Salomon等人（参考文献3）也报告了在生化检测中连接子切割速率与体外细胞毒性之间存在显著的不一致性。对带有不同连接子的cMet和palivizumab的半花碱类抗体药物偶联物（ADCs）的体外评估突出了靶向依赖性细胞毒性以及某些连接子的不稳定性。表2. 靶向ADC与非靶向ADC的体外细胞毒性及培养基中稳定性比较。对于细胞毒性检测，癌细胞用测试样品的梯度稀释液处理，并在标准培养条件下孵育4天。处理后，通过ATP定量荧光试剂测定细胞活性。对于ADC在生长培养基中的稳定性检测，将EBC-1癌细胞在标准培养条件下培养4天后，收集培养基（RPMI 1640培养基，添加10%胎牛血清），随后通过离心去除细胞和杂质。ADC在生长培养基中以1.4 μM的浓度孵育4天，并通过质谱法测定载荷释放量（占理论值的百分比）。结论能够预测临床毒性特征非常重要，这一特征在很大程度上取决于载荷类别以及抗体药物偶联物（ADC）的关键属性。临床前研究结果难以有效预测ADC的临床毒性，导致ADC设计需要在患者中进行经验性测试。使用原代骨髓细胞的克隆形成细胞（CFC）检测可用于评估ADC及其载荷对血液祖细胞系的毒性。将ADC的临床毒性与体外CFC检测结果进行比较表明，CFC检测能够有效重现特定的临床观察结果，使其成为ADC筛选的有价值工具。由于ADC在人体内的复杂代谢过程，预测ADC的临床毒性特征仍然是一个复杂的挑战。简单了解--ZymeworksZymeworks是一家全球性的生物技术公司，致力于开发用于治疗难治性疾病的新型多功能治疗药物，包括癌症、炎症和自身免疫性疾病。Zymeworks正凭借其在抗体药物偶联物和多特异性抗体治疗药物领域的经验和能力，快速推进丰富的产品管线，覆盖多个具有重大未满足医疗需求的适应症中的新型靶点。除了拥有完全自主的管线外，Zymeworks还拥有Azymetric™技术平台，通过与全球生物制药公司的战略合作伙伴关系，在产品开发中得到了进一步的利用和临床验证。参考文献1. I. E. Krop et al. J. Clin. Oncol. 2023, 41, 5550-55602. S. Modi et al. N. Engl. J. Med. 2020, 382, 610-6213. P. L. Salomon et al. Pharmaceutics 2019, 16, 4817-4825基础知识点供给站：Exatecan（依喜替康）：一种DNA拓扑异构酶I抑制剂（Topoisomerase I inhibitor），通过抑制拓扑异构酶I的活性，干扰癌细胞的DNA复制和修复过程，从而发挥抗癌作用。主要用于癌症治疗研究，包括结直肠癌、肺癌、乳腺癌等。它可以单独使用，也可以与其他药物（如氟尿嘧啶类药物）联合使用，能够显著延长患者的生存期，提高生活质量。DM4：一种细胞毒性美登素类药物，是美登素（maytansine）的结构类似物，含有巯基（-SH）。它通过抑制微管蛋白聚合和微管组装，增强微管的不稳定性，从而有效抑制微管动力学，导致有丝分裂阻滞和细胞凋亡。主要用于制备抗体药物偶联物（ADC），通过二硫键将美登素与抗体连接起来，用于癌症的靶向治疗。MMAE（Monomethyl auristatin E）：一种合成的微管蛋白抑制剂，属于奥瑞他汀类药物。它通过与微管蛋白结合，阻止微管的聚合，从而抑制细胞的有丝分裂，导致细胞周期阻滞和细胞凋亡。广泛用于抗体药物偶联物（ADC）的开发，作为载荷部分，通过抗体将药物精准递送到癌细胞中，发挥高效的细胞毒性作用。DM1（Mertansine）：一种美登素类药物，是一种强效的微管蛋白抑制剂。它通过与微管蛋白结合，抑制微管的动态性，从而阻止细胞的有丝分裂。DM1是最早用于抗体药物偶联物（ADC）的载荷之一，例如在T-DM1（Ado-trastuzumab emtansine）中，DM1通过连接子与抗体结合，用于治疗HER2阳性乳腺癌。欢迎感兴趣的朋友进群讨论，群二维码如下：推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。原创内容未经授权，禁止转载至其他平台。有问题可发邮件至yong_wang@pku.edu.cn获取更多信息。©2021 医药速览 保留所有权利往期链接“小小疫苗”养成记 | 医药公司管线盘点 人人学懂免疫学| 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普|医药前沿笔记PROTAC技术| 抗体药物| 抗体药物偶联-ADC核酸疫苗 | CAR技术| 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群请扫描上方二维码，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送①点击标题下方“医药速览”  ②至右上角“...”  ③点击“设为星标

Vertex is pulling back on its genetic medicine research, ending all work related to adeno-associated viruses, or AAVs — the viral vectors commonly used to deliver gene therapies into the body, the company confirmed to Endpoints News . The cuts impact Vertex’s collaborations with at least two biotech startups: the AAV design company Affinia Therapeutics and tRNA therapy company Tevard Biosciences, which uses AAVs. It also calls into question Vertex’s work on CRISPR therapies for genetic muscle diseases. Several bigger pharmaceutical companies, including Biogen , Pfizer , Roche and Takeda , have cut or pared back on AAV gene therapy research in recent years. And several gene therapy biotech companies have trimmed their pipelines and staff as private and public investors sour on the field. This change of fortune was seemingly unimaginable a few years ago. AAV technology ushered in a new era of gene therapy investment and led to several commercial products for diseases, including Roche’s Luxturna for childhood blindness, Sarepta Therapeutics’ Elevidys for Duchenne muscular dystrophy, and Novartis’ Zolgensma for an otherwise fatal neurodegenerative condition in infants. But a panoply of challenges — including costly manufacturing, multimillion-dollar drug prices, slow progress in improving targeted delivery and lingering safety issues — has raised questions about the future of AAV medicines. Vertex did not have any AAV gene therapies in clinical development, despite work on the technology stretching back to at least 2019 when it acquired Exonics Therapeutics for its early-stage CRISPR therapies for two muscle diseases: Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). Exonics relied on AAV vectors to deliver its therapies to muscles. Vertex has shared few updates on the program since its acquisition. The approach was essentially a permanent version of the commercial exon-skipping therapies for DMD, meaning it wouldn’t fully restore the dystrophin protein that’s broken in people with the disease. A Chinese biotech called HuidaGene has developed a similar CRISPR therapy and has already treated two boys, Endpoints reported last month . The first patient had modest improvement in his walking ability three months after the treatment. It is unknown why Vertex’s own CRISPR therapy has seemingly lagged behind. It is possible that the company is holding out for a more curative approach. It may also have been spooked by multiple deaths in people who received the high doses of AAV needed to reach the body’s many muscles, including two from Pfizer’s experimental therapy , one from Sarepta’s approved drug and one from a custom CRISPR therapy . Heather Nichols, a spokesperson for Vertex, confirmed that the company has discontinued its AAV work, but in an email said that the company’s “commitment to cell and genetic therapies remains strong” and that other investments in DMD and DM1 continue. The company declined to provide further comment on its AAV cuts or make an executive available for an interview. The need for better AAVs, ones that could deliver more of the therapy at lower doses, has been clear for years. Vertex struck a partnership with Affinia in 2020 worth up to $1.6 billion for access to the startup’s viral vectors designed to better target the muscles for treating DMD and DM1 and target the lungs to treat cystic fibrosis, the disease responsible for most of the company’s $11 billion revenue last year. Affinia CEO Rick Modi told Endpoints in an email that his company regained the rights to its muscle-targeting viruses from Vertex in March. He said the earlier work on cystic fibrosis ended in 2022 and rights to those programs were returned then. The startup is currently focused on finishing preclinical studies and designing a clinical trial for its lead candidate, for a heart condition called BAG3 dilated cardiomyopathy. Modi said that Affinia received “the maximum amount of milestone payments” for the research phase of its DMD and DM1 collaboration with Vertex, but he wouldn’t specify the amount. He added that Affinia is looking to license its newly-regained muscle capsids to other companies. Vertex’s step back from AAVs also impacts Tevard Biosciences. The small startup, which is housed in Eli Lilly’s genetics-focused research center that opened in Boston last summer, struck a four-year partnership with Vertex in February 2023 to develop a new class of genetic medicines known as tRNA therapies. In nature, tRNA molecules are part of the machinery that cells use to translate genetic code into proteins. Tevard is one of a few companies developing synthetic versions of these molecules to help skip over genetic mutations that prevent cells from making fully functional proteins. Tevard believes its approach could help restore the vital dystrophin protein missing from the muscles of the 15% of people with DMD whose disease is caused by so-called nonsense mutations. While some companies are trying to package tRNA therapies in lipid nanoparticles, those delivery vessels are not readily taken up by the body’s many muscles, so Tevard planned to use AAVs to deliver its treatment. “We were doing great. The collaboration was going great. But in December, we were informed that they were realigning priorities, and multiple programs were being terminated, including this one,” Tevard CEO Daniel Fischer told Endpoints in an interview. “Two weeks ago, we got the rights back to this program.” Other tRNA companies have also struggled, including HC Bioscience, which shut down in March after “challenges in targeted delivery,” Endpoints previously reported . Fischer said the fate of the DMD program will depend on whether Tevard can find another drugmaker to partner with or raise enough money to move it forward on its own. The company is planning to present data showing that the DMD therapy works in mice at the upcoming American Society of Gene & Cell Therapy meeting later this month.