From the Massachusetts General Hospital (A.K.), Harvard Medical School Boston; Neuromuscular Unit (E.B.), Bambino Gesù Ospedale Pediatrico, IRCCS, Rome; IRCCS Istituto delle Scienze Neurologiche di Bologna (V.C.), Programma di Neurogenetica; Department of Biomedical and Neuromotor Sciences (V.C.), University of Bologna, Italy; Rebecca D. Considine Research Institute (B.H.C.), Akron Children's Hospital, OH; Stanford University School of Medicine (G.M.E.), CA; Mitochondrial Medicine Frontier Program (M.J.F., A.G.), Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; Royal Victoria Infirmary (G.S.G.), Newcastle upon Tyne, United Kingdom; University of California (R.H.), San Diego, La Jolla; Columbia University Irving Medical Center (M.H.), New York; Friedrich-Baur-Institute (T.K.), Department of Neurology, LMU Hospital, Ludwig Maximilian University of Munich; German Center for Neurodegenerative Diseases (DZNE); Munich Cluster for Systems Neurology (SyNergy), Germany; Department of Pediatrics (M.K.K.), University of Texas McGovern Medical School, Houston; Department of Neurology, Neuromuscular Diseases Section (C.K.), University Hospital of Bonn, Germany; Fondazione IRCCS Istituto Neurologico Carlo Besta (C.L.), Milano, Italy; Vancouver General Hospital (A.L.), British Columbia, Canada; University of Utah (N.L.), Salt Lake City; Institute of Genomic Medicine and Rare Disorders (M.J.M.), Semmelweis University, Budapest, Hungary; Cleveland Clinic Neurological Institute (S.P.), OH; Rare Disease Research (H.P.), Atlanta, GA; Department of Neuromuscular Diseases (R.D.S.P.), UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom; Seattle Children's Hospital (R.S.), WA; Baylor College of Medicine (F.S.), Houston, TX; Texas Children's Hospital (F.S.); Joint BCM-CUHK Center of Medical Genetics (F.S.), Hong Kong SAR; Fondazione Policlinico Universitario A. Gemelli and Istituto di Neurologia (S.S.), Università Cattolica del Sacro Cuore, Rome, Italy; McMaster University Medical Center (M.T.), Hamilton, Ontario, Canada; Neurology and Neuromuscular Unit (A.T.), Department of Clinical and Experimental Medicine, University of Messina, Italy; University of Colorado and Children's Hospital Colorado (J.L.K.V.H.), Aurora; Copenhagen Neuromuscular Center (John Vissing), Rigshospitalet University of Copenhagen, Denmark; Children's Hospital of Pittsburgh (Jerry Vockley), University of Pittsburgh School of Medicine, PA; Jupiter Point Pharma Consulting (J.S.F.), LLC; Stealth BioTherapeutics (D.A.B.)Write On Time Medical Communications (J.A.S.), LLC; and Department of Clinical and Experimental Medicine (M.M.), Neurological Institute, University of Pisa, Italy.
Neurology. 2023 Jul 18;101(3):e238-e252. doi: 10.1212/WNL.0000000000207402. Epub 2023 Jun 2.
Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.
After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms.
Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.
Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.
Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017.
gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9.
This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
原发性线粒体肌病（PMM）是一组遗传疾病，这些疾病损害了线粒体氧化磷酸化，从而对身体机能、运动能力和生活质量（QoL）产生不利影响。目前的 PMM 护理标准针对的是症状，临床影响有限，构成了重大的治疗需求未得到满足。我们报告了 MMPOWER-3 的数据，这是一项关键性的、3 期、随机、双盲、安慰剂对照的临床试验，评估了在经过基因确认的 PMM 患者中，elamipretide 的疗效和安全性。
筛选后，符合条件的参与者以 1:1 的比例随机接受为期 24 周的 40mg/d elamipretide 或安慰剂皮下注射。主要疗效终点包括从基线到第 24 周的 6 分钟步行试验（6MWT）和原发性线粒体肌病症状评估（PMMSA）总疲劳的变化。次要终点包括 PMMSA 中最令人困扰的症状评分、NeuroQoL 疲劳简短量表评分以及患者整体印象和临床医生对 PMM 症状的整体印象。
共有 218 名参与者被随机分配（n = 109 名 elamipretide；n = 109 名安慰剂）。参与者的平均年龄为 45.6 岁（64%为女性；94%为白人）。大多数参与者（n = 162 [74%]）有线粒体 DNA（mtDNA）改变，其余参与者有核 DNA（nDNA）缺陷。在筛选时，PMMSA 上最常见的令人困扰的 PMM 症状是活动时疲劳（28.9%）。在基线时，6MWT 的平均步行距离为 336.7 ± 81.2 米，PMMSA 的总疲劳评分平均为 10.6 ± 2.5，Neuro-QoL 疲劳简短量表的 T 评分平均为 54.7 ± 7.5。该研究未达到评估 6MWT 和 PMMSA 总疲劳评分变化的主要终点。与接受 elamipretide 的参与者和接受安慰剂的参与者相比，6MWT 行走距离的最小二乘均值（SE）从基线到第 24 周的差异为-3.2（95%CI-18.7 至 12.3； = 0.69）米，在 PMMSA 上，总疲劳评分差异为-0.07（95%CI-0.10 至 0.26； = 0.37）。Elamipretide 治疗耐受性良好，大多数不良事件为轻度至中度严重程度。
皮下注射 elamipretide 治疗不能改善 PMM 患者的 6MWT 和 PMMSA TFS 结果。然而，这项 3 期研究表明，皮下注射 elamipretide 是可以耐受的。
该试验已在 clinicaltrials.gov 上注册，临床试验标识符：NCT03323749；于 2017 年 10 月 12 日提交；首位患者于 2017 年 10 月 9 日入组。
gov/ct2/show/NCT03323749？term = elamipretide&draw = 2&rank = 9。
这项研究提供了 1 级证据，表明与安慰剂相比，在原发性线粒体肌病患者中，elamipretide 在 24 周时不能改善 6MWT 或疲劳。
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