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

Karaa A, Bertini E, Carelli V, et al. · Neurology

The largest elamipretide trial missed both primary endpoints. Distance walked at week 24 rose in both arms — 14.1 m on elamipretide and 17.3 m on placebo, a difference of -3.2 m (95% CI -18.7 to 12.3; p=0.69) — and the total fatigue score differed by -0.07 (95% CI -0.10 to 0.26; p=0.37). The paper carries a Class I evidence statement that elamipretide does not improve the 6-minute walk or fatigue at 24 weeks in this disease. Among the 74% of participants with a mitochondrial-DNA alteration, placebo walked 11.0 m further than drug (p=0.21); a post hoc nuclear-DNA subgroup of 29 against 29 favoured elamipretide by 25.2 m (95% CI 3.1 to 47.3; p=0.03) while its fatigue score did not move (0.03, p=0.93). Adverse events were reported by 98.2% on drug against 76.1% on placebo, led by injection-site reactions, and 7.3% against 1.8% discontinued because of them.

Population

218 adults with genetically confirmed primary mitochondrial myopathy, 27 sites

Intervention

Elamipretide 40 mg subcutaneous daily for 24 weeks

Comparator

Placebo

Limitations

The nuclear-DNA subgroup result is post hoc, rests on 58 of 218 participants, and its composition changed after a data-entry error reclassified three participants out of the mitochondrial-DNA group. Both arms improved from baseline on the walk test, so the endpoint carries a large practice or placebo component. Funded by Stealth BioTherapeutics, with investigator conflicts running through most of the author list.