Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy
Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH
Neurology (2018) · n=36
Across 36 adults with genetically confirmed primary mitochondrial myopathy, the highest-dose elamipretide arm walked 64.5 metres farther on the six-minute walk test at day 5 versus 20.4 metres on placebo — the positive Phase 2 signal that motivated the larger MMPOWER-3 trial that ultimately failed.
This 2018 Neurology paper is the Phase 1/2 dose-escalation trial that produced the positive efficacy signal for elamipretide in primary mitochondrial myopathy and motivated the larger Phase 3 MMPOWER-3 trial (Karaa 2023) that ultimately failed. The investigators enrolled 36 adults with genetically confirmed primary mitochondrial myopathy across multiple US centres and randomized them to one of three intravenous elamipretide doses (0.01, 0.10, 0.25 mg/kg/h) or placebo administered as a 2-hour infusion for 5 consecutive days. The primary efficacy endpoint was the six-minute walk test (6MWT) at day 5. The highest-dose group walked a mean 64.5 metres farther at day 5 versus 20.4 metres in the placebo arm (p = 0.053 on the unadjusted comparison, p = 0.0297 on the adjusted analysis showing 51.2-metre improvement at the highest dose). The dose-dependent 6MWT improvement across the three active arms reached statistical significance (p = 0.014). Adverse events were dose-related but manageable, with no serious safety concerns reported. The trial established the 40 mg subcutaneous daily dose carried forward into MMPOWER-2 (an open-label-followed-by-blinded crossover extension) and MMPOWER-3 (the 24-week double-blind placebo-controlled Phase 3 trial).
This is a 36-patient Phase 1/2 trial with a short (5-day) intervention period — the effect sizes reported are exploratory rather than definitive, and the wide confidence intervals around the small-cohort comparisons should be read carefully. The p = 0.053 statistic on the primary unadjusted comparison is just outside conventional significance; the adjusted-analysis p = 0.0297 reaches significance but the multiple-comparison structure of the analysis means readers should not over-weight the result. The 5-day treatment period does not address chronic-dosing efficacy, durability, or the time required for clinical-functional change in a chronic mitochondrial disease. Most importantly, the larger Phase 3 MMPOWER-3 trial that this paper motivated — same 6MWT endpoint, longer (24-week) treatment, larger cohort — did not reproduce the dose-escalation findings in its prespecified primary analysis. The most defensible reading of this paper today is that it produced a real but modest acute-treatment-period signal that did not translate to the chronic-dosing setting at the population the Phase 3 trial enrolled. Industry sponsorship by Stealth BioTherapeutics is disclosed.
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