Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy.
Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy.
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DOI：
10.1212/wnl.0000000000005255
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发表时间：
2018-04-03
期刊：
影响因子：
9.9
通讯作者：
Cohen BH
中科院分区：
文献类型：
--
作者：
Karaa A;Haas R;Goldstein A;Vockley J;Weaver WD;Cohen BH
为了评估依拉米pretide的安全性和有效性，依拉米pretide是一种芳香阳离子四肽，可以很容易地穿透细胞膜，并短暂地定位于线粒体内膜，在那里它与心磷脂结合，用于原发性线粒体肌病（PMM）的成人。一项研究MTP-131治疗线粒体肌病（MMPOWER）的安全性、耐受性和有效性的研究是一项I/II期多中心、随机、双盲、安慰剂对照试验，在36名遗传证实的PMM患者中进行了依拉米pretide试验。参与者随机接受静脉注射埃拉米普利肽（0.01、0.1和0.25 mg/kg/h或安慰剂，按剂量递增顺序持续2小时）。主要疗效指标是治疗5天后6分钟步行测试（6MWT）中步行距离的变化。其他疗效测量包括心肺运动测试参数的变化、参与者报告的症状、血清和尿液生物标志物的变化。安全性、耐受性和药代动力学也被测量。接受最高剂量埃拉米普肽的参与者在第5天平均行走了64.5米，而安慰剂组的变化为20.4米（p = 0.053）。此外，依拉米普肽治疗后，6MWT行走距离呈剂量依赖性增加（p = 0.014）。在一个对可能影响反应的其他协变量进行校正的模型中，最高剂量埃拉米普肽的校正变化为51.2 vs安慰剂组的3.0 m （p = 0.0297）。在其他疗效和安全性终点上没有观察到显著差异。治疗5天后，埃拉米普肽增加了PMM患者的运动表现，但没有增加安全性问题。这些发现，以及其他功能和患者报告的措施，仍需在更大规模的试验中进行测试，并进行更长的治疗期，以发现受这种疾病影响的个体的其他潜在治疗益处。该试验提供了一级证据，证明对于PMM患者，埃拉米普肽改善了在6MWT上行走的距离。
To assess the safety and efficacy of elamipretide, an aromatic-cationic tetrapeptide that readily penetrates cell membranes and transiently localizes to the inner mitochondrial membrane where it associates with cardiolipin, in adults with primary mitochondrial myopathy (PMM). A Study Investigating the Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy (MMPOWER) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial of elamipretide in 36 participants with genetically confirmed PMM. Participants were randomized to intravenous elamipretide (0.01, 0.1, and 0.25 mg/kg/h or placebo for 2 hours in a dose-escalating sequence). The primary efficacy measure was the change in distance walked in the 6-minute walk test (6MWT) after 5 days of treatment. Other efficacy measures included changes in cardiopulmonary exercise testing parameters, in participant-reported symptoms, and in serum and urinary biomarkers. Safety, tolerability, and pharmacokinetics were also measured. Participants who received the highest dose of elamipretide walked a mean of 64.5 m farther at day 5 compared to a change of 20.4 m in the placebo group (p = 0.053). In addition, there was a dose-dependent increase in distance walked on the 6MWT with elamipretide treatment (p = 0.014). In a model that adjusted for additional covariates possibly affecting response, the adjusted change for the highest dose of elamipretide was 51.2 vs 3.0 m in the placebo group (p = 0.0297). No significant differences were observed in other efficacy and safety endpoints. Elamipretide increased exercise performance after 5 days of treatment in patients with PMM without increased safety concerns. These findings, as well as additional functional and patient-reported measures, remain to be tested in larger trials with longer treatment periods to detect other potential therapeutic benefits in individuals affected by this condition. This trial provides Class I evidence that for patients with PMM, elamipretide improved the distance walked on the 6MWT.