背景:X连锁肌管肌病是一种罕见的,危及生命,先天性肌肉疾病主要在男性中观察到,这是由MTM1中的突变引起的。没有批准治疗这种疾病。我们旨在评估resamirigenebilparvovovec的安全性和有效性,它是传递人MTM1的腺相关病毒载体血清型8。
方法:ASPIRO是一个开放标签,在加拿大七个学术医疗中心进行的剂量递增试验,法国,德国,和美国。我们纳入了5岁以下需要机械呼吸机支持的X连锁肌管肌病男孩。审判最初分为两个部分。第1部分计划为安全性和剂量递增阶段,其中参与者被随机分配(2:1)到第一剂量水平(1·3×1014载体基因组[vg]/kg体重)然后,对于后来的参与者,高剂量(3·5×1014vg/kg体重)的resamirigenebilparvovovec或延迟治疗。第2部分旨在确认第1部分中选择的剂量。Resamirigenebilparvovovec作为单次静脉输注施用。未经治疗的对照组包括参加了一项试验研究(INCEPTUS;NCT02704273)的男孩或未接受任何剂量的延迟治疗队列中的男孩。主要疗效结果是从基线到第24周的每日呼吸机支持时间的变化。在三次意外死亡之后,停止以较高剂量给药,并消除研究设计的两部分特征.由于研究设计在实施过程中发生了变化,分析是在处理后的基础上进行的,被认为是探索性的。所有治疗和对照参与者均纳入安全性分析。该试验已在ClinicalTrials.gov注册,NCT03199469。截至2022年2月28日报告结果。ASPIRO目前暂停,同时对剂量参与者的死亡进行调查。
结果:在2017年8月3日至2021年6月1日之间,对30名参与者进行了资格筛选,其中26人被登记;6人被分配到较低剂量,13到更高的剂量,和七个延迟治疗。在七个延误治疗的孩子中,4人后来接受了更高的剂量(在更高的剂量队列中n=17),一个人接受了较低剂量(低剂量队列中n=7),两个人没有接受剂量,并加入对照组(n=14,包括来自INCEPTUS的12名儿童)。在较低剂量队列中,给药或登记时的中位年龄为12·1个月(IQR10·0-30·9;范围9·5-49·7),31·1个月(16·0-64·7;6·8-72·7)在高剂量队列中,对照组为18·7个月(10·1-31·5;5·9-39·3)。低剂量参与者的中位随访时间为46·1个月(IQR41·0-49·5;范围2·1-54·7),高剂量参与者为27·6个月(24·6-29·1;3·4-41·0),对照参与者为28·3个月(9·7-46·9;5·7-32·7)。在第24周,与对照组相比,低剂量参与者每天呼吸机支持的最小二乘平均小时数减少估计为77·7个百分点(95%CI40·22至115·24),与对照组相比,较高剂量参与者的基线下降幅度为22·8个百分点(6·15~39·37)(p=0·0077).低剂量队列中的一名参与者和高剂量队列中的三名参与者死亡;在死亡时,所有儿童在基因治疗后都有胆汁淤积性肝衰竭(死亡的直接原因是败血症;肝病,严重的免疫功能障碍,和假性败血症;胃肠道出血;和脓毒性休克)。对照组中有3人死亡(出血推测与肝动脉粥样硬化有关;吸入性肺炎和心肺衰竭)。
结论:大多数接受MTM1基因替代疗法的X连锁肌管肌病患儿在呼吸机依赖和运动功能方面有重要改善,超过一半的剂量参与者实现了呼吸机的独立性,一些人实现了独立行走的能力。X连锁肌管肌病潜在肝胆疾病的风险调查,以及在基因替代疗法前监测肝功能的需要,正在进行中。
背景:Astellas基因疗法。
X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.
ASPIRO is an open-label, dose-escalation
trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The
trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in
study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the
study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The
trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.
Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).
Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.
Astellas Gene Therapies.