Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial

This is the MMPOWER-3 trial, the pivotal Phase 3 randomized double-blind placebo-controlled study of elamipretide (SS-31) in primary mitochondrial myopathy and the most consequential single trial of any peptide on this site. Investigators randomized participants 1:1 to subcutaneous elamipretide 40 mg/day or placebo for 24 weeks across 27 clinical research centers in seven countries. The primary endpoints were change in six-minute walk test distance and change in the Primary Mitochondrial Myopathy Symptom Assessment fatigue subscale. The trial did not meet either primary endpoint — both walk-test and fatigue measures were statistically equivalent between elamipretide and placebo arms. The paper provides Class I evidence that elamipretide does not improve these outcomes at 24 weeks in unselected primary mitochondrial myopathy patients. The negative result ended the lead-indication development program for SS-31 in primary mitochondrial myopathy at Stealth BioTherapeutics. A prespecified subgroup of nuclear-DNA mitochondrial disease patients showed apparent response signals that were not the prespecified primary endpoint but informed the subsequent NuPOWER trial design and the parallel Barth syndrome program that did receive FDA approval in September 2025.

The trial population was unselected primary mitochondrial myopathy — a highly heterogeneous group spanning multiple genetic etiologies, fiber-type involvement patterns, and disease severities. The negative result on the prespecified endpoints does not exclude benefit in specific patient subgroups, which is the basis for the NuPOWER follow-up program in the nuclear-DNA mitochondrial disease subset. The 24-week treatment duration is short for a chronic-mitochondrial-disease intervention; whether longer treatment would produce different outcomes is not addressed. The 6MWT is a validated functional endpoint but is influenced by motivation, deconditioning, and pain in ways that may dilute treatment-specific effects. Industry sponsorship by Stealth BioTherapeutics is disclosed; despite the negative outcome being commercially adverse to the sponsor, the trial design and analysis were rigorous and consistent with regulatory expectations. The Class I rating from the journal reflects this. Importantly: a negative trial does not mean the molecule has no biological activity — it means the studied population did not show the expected outcome at the studied dose and duration. Readers extrapolating SS-31 from this trial to cardiac, longevity, or healthy-aging indications are doing so against an unfavorable evidence backdrop, not a favorable one.