As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant
benefit of elamipretide treatment in a genotypically diverse population of adults
with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects
with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide
experienced an improvement in the six-minute walk test (6MWT), while the cohort of
subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus
placebo. These published findings prompted additional genotype-specific post hoc analyses
of the MMPOWER-3 trial. Here, we present these analyses to further investigate the
findings and to seek trends and commonalities among those subjects who responded to
treatment, to build a more precise Phase 3 trial design for further investigation
in likely responders.Subjects with mtDNA pathogenic variants or single large-scale
mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA
cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants.
Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA
maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA
replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant,
in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6
m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome
variants showed a significant change in the elamipretide group subjects who had chronic
progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus - 8.0 ± 10.7 m for
the placebo group; p = 0.0024). Pharmacokinetic (exposure-response) analyses in the
nDNA cohort showed a weak positive correlation between plasma elamipretide concentration
and 6MWT improvement.Post hoc analyses indicated that elamipretide had a beneficial
effect in PMM patients with mtDNA replisome disorders, underscoring the importance
of considering specific genetic subtypes in PMM clinical trials. These data serve
as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been
designed as described in this paper to determine the efficacy of elamipretide in patients
with mtDNA maintenance-related disorders.Class I CLINICALTRIALS.NCT03323749.
