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Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized
Amel Karaa1, Enrico Bertini2, Valerio Carelli2
1From 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. akaraa@mgh.harvard.edu.
Background And Objectives:
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.
Methods:
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.
Results:
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; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.
Discussion:
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 Registration Information:
Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017.
Clinicaltrials:
gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9.
Classification Of Evidence:
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.
Insights
Elamipretide did not improve the 6-minute walk test or fatigue in primary mitochondrial myopathy patients. The phase-3 trial found elamipretide to be well-tolerated, indicating a need for new therapeutic strategies.
Area of Science:
- Mitochondrial Medicine
- Clinical Pharmacology
- Genetics
Background:
- Primary mitochondrial myopathies (PMMs) are genetic disorders impacting mitochondrial function, leading to reduced exercise capacity and quality of life.
- Current treatments for PMMs are largely symptomatic and offer limited clinical benefit, highlighting a significant unmet medical need.
- Elamipretide, a drug targeting mitochondrial function, was investigated for its efficacy and safety in PMM patients.
Purpose of the Study:
- To evaluate the efficacy and safety of elamipretide in individuals with genetically confirmed primary mitochondrial myopathies.
- To assess the impact of elamipretide on physical function (6-minute walk test) and fatigue levels (Primary Mitochondrial Myopathy Symptom Assessment).
Main Methods:
- A pivotal, phase-3, randomized, double-blind, placebo-controlled trial (MMPOWER-3) involving 218 participants with PMM.
- Participants received either 40 mg/d subcutaneous elamipretide or placebo for 24 weeks.
- Primary endpoints included changes in the 6-minute walk test distance and total fatigue score on the PMMSA.
Main Results:
- The study did not meet its primary endpoints; elamipretide showed no significant improvement in the 6-minute walk test or total fatigue score compared to placebo.
- The difference in 6-minute walk test distance was -3.2 meters (p=0.69) and in PMMSA total fatigue score was -0.07 (p=0.37).
- Elamipretide was well-tolerated, with adverse events generally being mild to moderate in severity.
Conclusions:
- Subcutaneous elamipretide did not demonstrate efficacy in improving the 6-minute walk test or fatigue in patients with primary mitochondrial myopathy.
- Despite not meeting primary efficacy endpoints, elamipretide was found to be safe and well-tolerated in this patient population.
- Further research into novel therapeutic strategies for PMMs is warranted given the limited clinical impact of current treatments.
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