Journal Article

DZNE-2023-00724

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

Karaa, A. ; Bertini, E. ; Carelli, V. ; Cohen, B. H. ; Enns, G. M. ; Falk, M. J. ; Goldstein, A. ; Gorman, G. S. ; Haas, R. ; Hirano, M. ; Klopstock, T.DZNE* ; Koenig, M. K. ; Kornblum, C. ; Lamperti, C. ; Lehman, A. ; Longo, N. ; Molnar, M. J. ; Parikh, S. ; Phan, H. ; Pitceathly, R. D. S. ; Saneto, R. ; Scaglia, F. ; Servidei, S. ; Tarnopolsky, M. ; Toscano, A. ; Van Hove, J. L. K. ; Vissing, J. ; Vockley, J. ; Finman, J. S. ; Brown, D. A. ; Shiffer, J. A. ; Mancuso, M. ; Investigators, M. T. (Collaboration Author)

2023
Ovid [Erscheinungsort nicht ermittelbar]

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Please use a persistent id in citations: doi:10.1212/WNL.0000000000207402

Abstract: 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; 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.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.

Keyword(s): Humans (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Male (MeSH) ; Quality of Life (MeSH) ; Merozoite Surface Protein 1: therapeutic use (MeSH) ; Mitochondrial Myopathies: drug therapy (MeSH) ; Fatigue (MeSH) ; Double-Blind Method (MeSH) ; Treatment Outcome (MeSH) ; arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide ; Merozoite Surface Protein 1

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Contributing Institute(s):

1. Clinical Research (Munich) (AG Höglinger 2 ; Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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