DYNE-251

▎药明康德内容团队编辑 Dyne Therapeutics今天公布其进行中的1/2期试验DELIVER的最新临床数据。该试验检视其在研抗体偶联寡核苷酸疗法DYNE-251在适合进行外显子51跳跃治疗的杜氏肌营养不良（DMD）患者中的疗效与安全性。根据新闻稿，在接受DYNE-251治疗后，多个队列患者的抗肌萎缩蛋白表达达到前所未有的水平，且患者的临床功能获得改善。基于这些积极数据和与监管单位讨论的结果，Dyne正在准备启动DELIVER试验中的注册性队列。 DELIVER是一项包括24周多剂量递增（MAD）随机安慰剂对照期、24周开放标签延长期和96周长期延长期的试验。该试验招募年龄在4至16岁之间，且适合进行外显子51跳跃治疗DMD患者。主要终点是安全性、耐受性和抗肌萎缩蛋白水平相对于基线的变化。次要终点包括患者的肌肉功能、外显子跳跃和药代动力学。 这次公布的结果包括20 mg/kg队列中8名男性患者的6个月生物标志物和临床功能数据，这些患者随机接受每4周一次的DYNE-251或安慰剂治疗，以及10 mg/kg队列中6名受试者的12个月临床功能数据。DYNE-251在两个队列中均表现出剂量依赖性的外显子跳跃和抗肌萎缩蛋白表达，以及多个临床功能终点的改善。主要发现包括： ▲Dyne管线图（图片来源：Dyne Therapeutics公司官网）  抗肌萎缩蛋白表达提升：DYNE-251组患者显示出高度的抗肌萎缩蛋白表达。接受20 mg/kg剂量治疗患者的平均绝对抗肌萎缩蛋白表达为正常值的3.71%（未根据肌肉含量进行调整），比接受每周一次标准治疗的临床试验中所报告的0.3%高出10倍以上。当根据肌肉含量进行调整时，DYNE-251治疗组的平均绝对抗肌萎缩蛋白表达量达到8.72%。 患者的临床功能改善：接受20 mg/kg和10 mg/kg剂量治疗的患者在多个临床功能终点均有显著改善，包括北极星步行评估（NSAA）、步速95百分位数（SV95C）、10米步行/跑步时间（10-MWR）、从地面起身的时间。在试验6个月到12个月期间，10 mg/kg组患者在所有的指标中均显示出持续改善。 SV95C是一项衡量患者在日常环境中行走能力的数字化的客观指标，已获批准作为欧洲杜氏肌营养不良症临床试验的主要终点。在DELIVER试验中，10 mg/kg和20 mg/kg剂量组患者的SV95C变化与基线相比具有临床意义上的改善。 良好的安全性和耐受性：安全性和耐受性的数据包含参与该试验的54名受试者。结果显示，DYNE-251表现出良好的安全性，大多数治疗相关的不良事件均为轻度或中度。 DYNE-251由磷酸二氨基甲酰吗啉寡核苷酸（PMO）与靶向转铁蛋白受体1（TfR1）的抗体片段（Fab）偶联而成，TfR1在肌肉组织中高度表达。该疗法旨在实现靶向肌肉组织递送，促进核内外显子跳跃，从而使肌肉细胞生成截短但功能正常的抗肌萎缩蛋白，目标是停止或逆转疾病的进展。DYNE-251已被美国FDA授予快速通道、孤儿药和罕见儿科疾病认定，用于治疗适合使用外显子51跳跃治疗DMD患者。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Dyne Therapeutics Announces New Clinical Data from Phase 1/2 DELIVER Trial of DYNE-251 in Duchenne Muscular Dystrophy Demonstrating Unprecedented Dystrophin Expression and Functional Improvement in Multiple Cohorts. Retrieved September 3, 2024 from https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-new-clinical-data-phase-12-deliver 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Dyne Therapeutics’ new data on its experimental Duchenne muscular dystrophy drug is being overshadowed by the departure of several top executives. The biotech announced Tuesday that its chief operating officer, chief business officer and chief medical officer are all leaving, nearly six months after new CEO John Cox stepped into the role. Dyne’s shares $DYN fell 30% Tuesday morning, just weeks after reaching an all-time high. In an interview with Endpoints News , CEO John Cox described the executive changes as “a natural transition as we move Dyne into the next phase of its growth.” Cox joined Dyne in March, replacing Joshua Brumm, who had been CEO since 2019. The muscle disease company had been riding high on compelling clinical results from its experimental therapies for myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy. Tuesday’s update on its Duchenne treatment, known as DYNE-251, built on previous results reported in May from the Phase 1/2 study. The treatment is an “exon skipping” drug developed for Duchenne muscular dystrophy patients with certain mutations amenable to exon 51 skipping. In eight male patients who received 20 mg/kg once a month, Dyne said mean absolute dystrophin expression was 3.71% of normal, which it added was “more than 10-fold higher than the 0.3% reported in a clinical trial of the weekly standard of care, eteplirsen,” Sarepta’s approved exon 51-skipping drug that’s marketed as Exondys 51 in the US. Dyne also said there were “meaningful improvements in multiple functional endpoints,” including on a common measure used for DMD called the North Star Ambulatory Assessment, in both the 10 mg/kg and 20 mg/kg groups. Dyne “could have two superior assets for DM1 and DMD Exon 51” programs, Jefferies analyst Andrew Tsai wrote in a note, adding that Dyne could have a $2 billion to $3 billion opportunity with the two drugs. Two patients who received a higher dose of 40 mg/kg experienced serious adverse events potentially related to Dyne’s treatment. One patient experienced acute kidney injury and thrombocytopenia, or low platelet counts, while the other experienced pancytopenia, or low counts of both red and white blood cells. Dyne said in the footnotes of its presentation Tuesday that 14 patients who started the study at the 40 mg/kg dose are now being dosed at 20 mg/kg “following evaluation of the safety profile at 40 mg/kg.” “You can anticipate that we would move rapidly with the 20 mg [dose]. I think that’s a reasonable expectation,” Cox said. Tsai wrote that with the 20 mg/kg dose compared to lower doses, the results “are not necessarily translating to a clean dose-response on dystrophin and functional benefits,” which suggests that the drug’s effect is plateauing, but he noted that “the efficacy data at 10-20 mg/kg thus far (including dystrophin production) still seems stronger than eteplirsen.” But the surprise management overhaul appears to have startled investors. CMO Wildon Farwell will be replaced by Doug Kerr, a venture partner at Atlas Venture and formerly a key leader at Biogen behind Spinraza, the first treatment approved for spinal muscular atrophy. Farwell will stay through the end of the year. COO Susanna High and CBO Jonathan McNeill “have decided to step down from their roles to pursue other opportunities,” according to the press release. Cox affirmed all three had made the choice to leave, and said they had “accomplished what they have wanted to accomplish.” Dyne is bringing in Johanna Friedl-Naderer as chief commercial officer and Lucia Celona as chief human resources officer. Dyne is expected to provide an update on its regulatory plans for both this program and its DM1 program by the end of the year. It’s also planning to share additional clinical data on its DM1 program by the end of the year.