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Clinical Trial
. 2024 Nov 21;19(1):431.
doi: 10.1186/s13023-024-03421-5.

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

Amel Karaa  1 , Enrico Bertini  2 , Valerio Carelli  3   4 , Bruce Cohen  5 , Gregory M Ennes  6 , Marni J Falk  7 , Amy Goldstein  7 , Gráinne Gorman  8 , Richard Haas  9 , Michio Hirano  10 , Thomas Klopstock  11   12   13 , Mary Kay Koenig  14 , Cornelia Kornblum  15 , Costanza Lamperti  16 , Anna Lehman  17 , Nicola Longo  18 , Maria Judit Molnar  19 , Sumit Parikh  20 , Han Phan  21 , Robert D S Pitceathly  22   23 , Russekk Saneto  24 , Fernando Scaglia  25   26   27 , Serenella Servidei  28 , Mark Tarnopolsky  29 , Antonio Toscano  30 , Johan L K Van Hove  31 , John Vissing  32 , Jerry Vockley  33 , Jeffrey S Finman  34 , Anthony Abbruscato  35 , David A Brown  35 , Alana Sullivan  35 , James A Shiffer  36 , Michelango Mancuso  37 ; MMPOWER-3 Trial Investigators
Affiliations
Clinical Trial

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

Amel Karaa et al. Orphanet J Rare Dis. .

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Classification of evidence: Class I CLINICALTRIALS.

Gov identifier: NCT03323749.

Keywords: Elamipretide; Mitochondria; MtDNA maintenance; MtDNA multiple deletions; PMM; Replisome.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: MMPOWER-3 was conducted in accordance with international ethics guidelines, including the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, ICH GCP guidelines, and all applicable laws and regulations. The trial was approved by institutional review boards, and all subjects provided written informed consent. Consent for publication: Not applicable.

Figures

Fig. 1
Fig. 1
Genotype breakdown of the mtDNA Replisome cohort from MMPOWER-3 (percentage of the cohort [N = 51])
Fig. 2
Fig. 2
6MWT change from baseline (subgroup replisome pathogenic variants and chronic progressive external ophthalmoplegia [CPEO]) phenotype. 6MWT, 6-min Walk Test; CPEO, chronic progressive external ophthalmoplegia; mtDNA, mitochondrial DNA; nDNA, nuclear DNA
Fig. 3
Fig. 3
6MWT Change from baseline in the overall mtDNA population and among the mtDNA subgroups. Other tRNA pathogenic variants, as depicted in the graph on the far right, included those found in the transfer tRNAs that encode for the following amino acids: tyrosine (Y), valine (V), glutamic acid (E), isoleucine (I), serine (S), and threonine (T). ETC, electron transport chain; 6MWT, 6-Minute Walk Test; mtDNA, mitochondrial DNA; tRNA, transfer RNA
Fig. 4
Fig. 4
Effect of low heteroplasmy in MT-TL1 placebo subjects on 6MWT
Fig. 5
Fig. 5
Exposure–response analysis (nDNA cohort at week 24). Change in 6MWT nDNA pathogenic variants as a function of elamipretide steady-state AUC. Placebo subjects are shown with AUC = 0. Symbols indicate sex; colors indicate age bracket. A regression line (and the corresponding P and r values) and a smoother (Loess) are displayed for the elamipretide group. The green smoother excludes values below the limit of quantification
Fig. 6
Fig. 6
Phase 3 trial design of NuPOWER enrolling subjects with replisome-related nDNA pathogenic variants and CPEO10
See this image and copyright information in PMC

References

    1. Mancuso M, McFarland R, Klopstock T, Hirano M, (2017) Consortium on Trial Readiness in Mitochondrial Myopathies. International Workshop: outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16–18 November 2016, Rome, Italy. Neuromuscul Disord; 27(12):1126–37. - PMC - PubMed
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