FDA Lifts Hold on Audentes’ Trial of X-Linked Myotubular Myopathy Drug

FDA暂停X-连锁肌管肌病药物的临床试验

2020-12-29 06:32:04 BioSpace

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Sarah Silbiger/Getty Images The U.S. Food and Drug Administration (FDA) has lifted a clinical hold on Audentes Therapeutics’ ASPIRO trial studying the AT132 as a potential treatment for X-linked myotubular myopathy (XLMTM), a rare neuromuscular disease. The agency placed the hold on the Astellas company’s trial after two patients died in the trial. “We are grateful for the efforts of our team and investigators who have worked tirelessly to answer the FDA’s questions and we now look forward to resuming this study,” according to a statement made by Natalie Holles, the President and Chief Executive Officer of Audentes Therapeutics. “We want to again extend our deepest sympathies to patients’ families impacted by the events earlier this year. We are deeply committed to the continued safe development of AT132 for the families and patients living with XLMTM, a disease with no existing treatments.” XLMTM, a life-threatening neuromuscular disease, includes hallmark symptoms such as muscle weakness, respiratory failure and early death. The associated rate of mortality is approximately 50% in the first 18 months of life, and this increases to an additional 25% by the age of 10 years in those who survive past infancy. The genetic disease is caused by a MTM1 gene mutation. Approximately 1 in 40,000 to 50,000 newborn males are diagnosed with the disease. In addition, the majority of patients with XLMTM need ventilator support, and most patients also require for nutritional support via a gastrostomy tube. There is currently a significant unmet need for effective XLMTM treatments that not only reduce the burden of the disease’s symptoms, but that also prolong life. Audentes Therapeutics hopes AT132, an AAV8 vector consisting of a functional copy of the MTM1 gene, may be the answer to this unmet treatment need. In May, Audentes Therapeutics said that a patient in the ASPIRO trial who received a high dose of AT132 died from sepsis. Additionally, another two patients who received high doses of the experimental drug also had serious side effects during treatment, and one of these two patients later experienced progressive liver dysfunction. The patient who had liver dysfunction later died because of a bacterial infection, in addition to sepsis. In August, the company said another death was caused by gastrointestinal bleeding. But despite these deaths, the FDA says the study can continue following a comprehensive review of the events. The ASPIRO trial, a two-part, open-label ascending dose study, is currently examining the safety and preliminary efficacy of AT132 in children with XLMTM younger than five years old. The study, which builds on previous studies supporting the drug’s safety, includes adverse events and certain laboratory measures and assessments of neuromuscular and respiratory function as primary endpoints. Additional secondary endpoints include disease burden and health-related quality-of-life as well as muscle tissue histology and biomarkers. Audentes Therapeutics says it is currently “working to complete all clinical and regulatory activities necessary to resume dosing” and also “plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132.” Most Read Today
Sarah Silbiger/Getty图片 美国食品和药物管理局(FDA)已经解除了Audentes TherapeuticsAspiro试验的临床搁置,该试验研究了AT132作为一种罕见的神经肌肉疾病X连锁肌管性肌病(XLMTM)的潜在治疗方法。在Astellas公司的试验中有两名病人死亡后,该机构暂停了试验。 Audentes Therapeutics公司总裁兼首席执行官娜塔莉·霍尔斯在一份声明中表示,我们非常感谢我们的团队和调查人员的努力,他们不知疲倦地回答了FDA的问题,我们现在期待着恢复这项研究。我们想再次向受今年早些时候事件影响的病人及其家属表达我们最深切的同情。我们坚定地致力于为XLMTM的家庭和患者继续安全开发AT132,XLMTM是一种目前尚无治疗方法的疾病。 XLMTM是一种危及生命的神经肌肉疾病,包括肌肉无力,呼吸衰竭和早死等标志性症状。在出生后的头18个月内,相关的死亡率约为50%,而在婴儿期后存活的人中,这一比率在10岁时增加到额外的25%。这种遗传病是由MTM1基因突变引起的。大约每40 000至50 000名新生儿中就有1人被诊断患有此病。 此外,大多数XLMTM患者需要呼吸机支持,大多数患者还需要通过胃造瘘管进行营养支持。目前,对有效的XLMTM治疗的需求仍未得到满足,不仅能减轻疾病症状的负担,而且还能延长生命。Audentes Therapeutics希望AT132,一种由MTM1基因的功能拷贝组成的AAV8载体,可以解决这一未满足的治疗需求。 5月,Audentes Therapeutics公司表示,阿司匹罗试验中一名接受高剂量AT132的患者死于败血症。此外,另外两名接受高剂量实验药物的患者在治疗过程中也出现了严重的副作用,其中一名患者后来出现了进行性肝功能障碍。这位肝功能不全的病人后来死于细菌感染和败血症。8月份,该公司表示,另一起死亡事件是由肠胃出血引起的。 但是,尽管有这些死亡病例,FDA表示,在对这些事件进行全面回顾之后,这项研究可以继续下去。阿司匹罗试验是一项由两部分组成的,开放标记的递增剂量研究,目前正在检查AT132在小于5岁的XLMTM患儿中的安全性和初步疗效。这项研究建立在先前支持该药物安全性的研究基础之上,包括不良事件和某些实验室测量以及神经肌肉和呼吸功能的评估作为主要终点。其他次要终点包括疾病负担和健康相关的生活质量,以及肌肉组织,组织学和生物标志物。 Audentes Therapeutics表示,它目前正在努力完成恢复给药所需的所有临床和监管活动,并计划在将来与监管机构就AT132的全球注册申请进行讨论。 今天阅读最多的

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