Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial.

Karaa A, Bertini E, Carelli V, Cohen B, Ennes GM, Falk MJ, Goldstein A, Gorman G, Haas R, Hirano M, Klopstock T, Koenig MK and 22 more

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Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Abbruscato A, Brown DA, Sullivan A, Shiffer JA, Mancuso M

Orphanet journal of rare diseases21 Nov 2024Cited by 11 (Europe PMC)

PMID39574155PMCIDPMC11583740DOI10.1186/s13023-024-03421-5PepBankPUB-39574155

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Summary

BackgroundAs 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.ResultsSubjects 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.ConclusionsPost 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.Classification of evidenceClass I CLINICALTRIALS.Gov identifierNCT03323749.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

3 results from studies that gave the peptide. 3 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with primary mitochondrial myopathy and mtDNA replisome variants, 6MWT improvement with elamipretide versus placebo trended toward significance but was not significant (post hoc).
In plain wordsIn adults with a type of mitochondrial muscle disease, walking distance rose more with elamipretide than placebo, but the difference was not clearly significant.
Peptide
Elamipretide (SS-31)
Outcome
No significant change6MWT change in mtDNA replisome cohort
Study
n: not reported in source
Comparator
Placebo
Outcome group
Exercise and physical function · Musculoskeletal
Studied dose
Dose not stated
Measurements
6MWT change
25.2 m
elamipretide, mtDNA replisome cohort
6MWT change
2 m
placebo, mtDNA replisome cohort
Source sentences
Summary
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).
Show in the study text Report a problemFND-3957415501
02HumanRandomized controlled trialEfficacy outcome
In adults with primary mitochondrial myopathy, replisome variants and CPEO, 6MWT distance at week 24 changed significantly more with elamipretide than with placebo (post hoc).
In plain wordsIn adults with this mitochondrial muscle disease and eye-muscle weakness (CPEO), walking distance improved more with elamipretide than with placebo.
Peptide
Elamipretide (SS-31)
Outcome
Increase6MWT change at week 24 in replisome variants with CPEO
Study
n: not reported in source
Comparator
Placebo
Outcome group
Exercise and physical function · Musculoskeletal
Studied dose
Dose not stated
Measurements
6MWT change
37.3 m
elamipretide, replisome variants with CPEO, week 24
6MWT change
−8 m
placebo, replisome variants with CPEO, week 24
Source sentences
Summary
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).
Show in the study text Report a problemFND-3957415502
03HumanRandomized controlled trialPharmacokinetics
In the nDNA cohort, exposure-response analysis showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement.
In plain wordsIn adults with this disease, higher blood levels of elamipretide were weakly linked to larger gains in walking distance.
Peptide
Elamipretide (SS-31)
Outcome
Not applicableExposure-response: plasma elamipretide concentration vs 6MWT improvement
Study
n: not reported in source
Outcome group
Pharmacokinetics · Pharmacology
Studied dose
Dose not stated
Source sentences
Summary
Pharmacokinetic (exposure-response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement.
Show in the study text Report a problemFND-3957415503

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Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 stopped early · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

TerminatedPhase 3Results postedNCT03323749

A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension

Stealth BioTherapeutics Inc.n = 2189 Oct 2017 to 10 Feb 2020

Primary Mitochondrial Myopathy

Trial page ClinicalTrials.govUpdated 24 Jan 2022

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
9 Oct 2026, 18:17 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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