TY - JOUR

T1 - Efficacy and Safety of Elamipretide in Individuals with Primary Mitochondrial Myopathy

T2 - The MMPOWER-3 Randomized Clinical Trial

AU - Karaa, Amel

AU - Bertini, Enrico

AU - Carelli, Valerio

AU - Cohen, Bruce H.

AU - Enns, Gregory M.

AU - Falk, Marni J.

AU - Goldstein, Amy

AU - Gorman, Gráinne Siobhan

AU - Haas, Richard

AU - Hirano, Michio

AU - Klopstock, Thomas

AU - Koenig, Mary Kay

AU - Kornblum, Cornelia

AU - Lamperti, Costanza

AU - Lehman, Anna

AU - Longo, Nicola

AU - Molnar, Maria Judit

AU - Parikh, Sumit

AU - Phan, Han

AU - Pitceathly, Robert D.S.

AU - Saneto, Russell

AU - Scaglia, Fernando

AU - Servidei, Serenella

AU - Tarnopolsky, Mark

AU - Toscano, Antonio

AU - Van Hove, Johan L. K.

AU - Vissing, John

AU - Vockley, Jerry

AU - Finman, Jeffrey S.

AU - Brown, David A.

AU - Shiffer, James A.

AU - Mancuso, Michelango

N1 - Publisher Copyright: © American Academy of Neurology.

PY - 2023

Y1 - 2023

N2 - Background and ObjectivesPrimary 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.MethodsAfter 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.ResultsParticipants (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.DiscussionSubcutaneous 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 InformationTrial 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 = 2 = 9.Classification of EvidenceThis 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.

AB - Background and ObjectivesPrimary 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.MethodsAfter 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.ResultsParticipants (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.DiscussionSubcutaneous 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 InformationTrial 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 = 2 = 9.Classification of EvidenceThis 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.

U2 - 10.1212/WNL.0000000000207402

DO - 10.1212/WNL.0000000000207402

M3 - Journal article

C2 - 37268435

AN - SCOPUS:85165222625

VL - 101

SP - e238-e252

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 3

ER -