Despite Failure to Meet End Points, Results of Elamipretide Offer Further Insight on Primary Mitochondrial Myopathy


In one of the first phase 3 trials of primary mitochondrial myopathy, elamipretide failed to meet its primary end points; however, a subgroup of patients with nuclear DNA defects saw improvement in 6-minute walk test, raising further questions.

Amel Karaa, MD, director of the Mitochondrial Disease Program at Massachusetts General Hospital

Amel Karaa, MD

Recently published findings from the phase 3, randomized, placebo-controlled MMPOWER-3 study (NCT03323749) showed that subcutaneous elamipretide (Stealth BioTherapeutics) failed to distinguish itself from placebo in the treatment of primary mitochondrial myopathy (PMM). All told, the study did not meet its primary end points assessing changes in the 6-minute walk test (6MWT) and Total Fatigue Score (TFS) on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA).

Published in Neurology, the trial double-blind study included 218 individuals, most of which had mitochondrial DNA (mtDNA) mutations (n = 162; 74%), with the remaining having nuclear DNA (nDNA) defects. Between those who received elamipretide and placebo, investigators observed least square mean (LSM) differences of –3.2 (95% CI, –18.7 to 12.3; P = .69) meters on distance walked on the 6MWT and –0.07 (95% CI, –0.10 to 0.26; P = .37) points on PMMSA TFS after 24 weeks of treatment.

Led by Amel Karaa, MD, director of the Mitochondrial Disease Program at Massachusetts General Hospital, the study randomly assigned patients 1:1 to either 24 weeks of elamipretide 40 mg/day or placebo subcutaneously. Elamipretide, a water-soluble, aromatic-cationic mitochondria-targeting tetrapeptide, is an investigational agent in development for various mitochondrial diseases. The agent’s clinical development program included MMPOWER-1 and MMPOWER-2 (NCT02805790), whereby treatment with elamipretide demonstrated meaningful improvements in patient-reported outcomes for individuals with confirmed PMM.

In MMPOWER-3, the mean age was 44.9 years with participants mostly being White (94%) and female (64.2%). Of those included, 205 (94%) completed the double-blind period of the study, with a similar percentage of participants for each treatment group completing (elamipretide: n = 102 [93.6%]; placebo: n = 103 [94.5%]). From baseline to week 24, elamipretide-treated patients reported LSM change of –1.13 (±0.22) on the PMMSA TFS compared with 1.05 (±0.22) for those on placebo.

"The MMPOWER clinical development program was the most advanced and complete in PMM and provided significant lessons regarding study design and patient enrollment parameters," the study authors concluded. "MMPOWER-3 was the first trial that progressed into phase 3 to assess a therapy for participants with PMM. Although the primary end points, were not met for the overall population, the observation of the improvement in the 6MWT in the nDNA subgroup is encouraging and hypothesis generating."

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In such subgroup analyses, those with nDNA mutations receiving elamipretide demonstrated an LSM change of 25.5 (±8.0) meters in distance walked compared with 0.3 (±7.7) meters for those on placebo, a 25.2-meter difference between the groups (95% CI, 3.1-47.3; P = .03). The opposite was observed in the mtDNA group, as those on elamipretide showed changes of 14.0 (±6.1) meters vs 25.0 (±6.1) meters for those on placebo, equating to an –11.0 meter between-group difference favoring placebo (95% CI, –28.1 to 6.1; P = .21). Of note, no major statistically significant differences in PMMSA TFS were found in the subgroup analyses of genetic mutation.

Elamipretide continued to show a safe and tolerable profile, as the most commonly reported adverse events (AEs) were injection site reactions. Investigators observed a low percentage of serious AEs for participants in the elamipretide (4.6%) and placebo (2.8%) groups, and were not deemed to be treatment-related. The incidence of AEs leading to discontinuation was greater in the elamipretide group (7.3% vs 1.8%), and no participants had an AE with an outcome of death or hospitalization.

Near the conclusions, the investigators provided some "lessons learned" from the trial, the first of which stated that a better understanding of the natural history of PMM will help in future studies. In addition, they wrote that "there is a clear need to further study meaningful endpoints in this patient population. Fatigue has been identified as the primary issue from which this patient population suffers, identifying a definitive focal point to be addressed in future therapeutic trials. Refining the sensitivity of the PMMSA fatigue scores in PMD and PMM further to capture signals is tantamount for future studies to address data gaps."

The third lesson was from the basket design of MMPOWER-3, which pooled both nDNA and mtDNA participants. Because of the subgroup findings on 6MWT, investigators claimed that the trial design introduced insurmountable heterogeneity. “It has been shown that substantial efficiencies are possible in basket trial design only if the investigational drug works in most or all baskets in the clinical study, with losses of power and statistical significance if the investigational drug only works in a single basket,” Karaa et al wrote.

1. Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitrochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. Published June 2, 2023. doi:10.1212/WNL.00000000000207402
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