Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that
impair mitochondrial oxidative phosphorylation, adversely impacting 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.Following screening, eligible participants
were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day 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- and Clinician-Global Impression of PMM Symptoms.Participants (N=218)
were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women;
94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA)
mutations, 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, mean distance walked on the 6MWT was 336.7±81.2 meters, mean
score for Total Fatigue on the PMMSA was 10.6±2.5, and 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 versus placebo, the difference in the Least Squares Mean (SE)
from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3;
p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26;
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. https://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 6 minute walk test or fatigue at 24 weeks compared to placebo
in patients with primary mitochondrial myopathy.
