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000272991 1001_ $$00000-0001-5781-9824$$aKaraa, Amel$$b0
000272991 245__ $$aGenotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial.
000272991 260__ $$aLondon$$bBioMed Central$$c2024
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000272991 520__ $$aAs 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.
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000272991 650_7 $$2Other$$aElamipretide
000272991 650_7 $$2Other$$aMitochondria
000272991 650_7 $$2Other$$aMtDNA maintenance
000272991 650_7 $$2Other$$aMtDNA multiple deletions
000272991 650_7 $$2Other$$aPMM
000272991 650_7 $$2Other$$aReplisome
000272991 650_7 $$2NLM Chemicals$$aarginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
000272991 650_7 $$2NLM Chemicals$$aDNA, Mitochondrial
000272991 650_7 $$2NLM Chemicals$$aOligopeptides
000272991 650_2 $$2MeSH$$aHumans
000272991 650_2 $$2MeSH$$aMale
000272991 650_2 $$2MeSH$$aFemale
000272991 650_2 $$2MeSH$$aDNA, Mitochondrial: genetics
000272991 650_2 $$2MeSH$$aMitochondrial Myopathies: drug therapy
000272991 650_2 $$2MeSH$$aMitochondrial Myopathies: genetics
000272991 650_2 $$2MeSH$$aGenotype
000272991 650_2 $$2MeSH$$aAdult
000272991 650_2 $$2MeSH$$aMiddle Aged
000272991 650_2 $$2MeSH$$aOligopeptides: therapeutic use
000272991 7001_ $$aBertini, Enrico$$b1
000272991 7001_ $$aCarelli, Valerio$$b2
000272991 7001_ $$aCohen, Bruce$$b3
000272991 7001_ $$aEnnes, Gregory M$$b4
000272991 7001_ $$aFalk, Marni J$$b5
000272991 7001_ $$aGoldstein, Amy$$b6
000272991 7001_ $$aGorman, Gráinne$$b7
000272991 7001_ $$aHaas, Richard$$b8
000272991 7001_ $$aHirano, Michio$$b9
000272991 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b10$$udzne
000272991 7001_ $$aKoenig, Mary Kay$$b11
000272991 7001_ $$aKornblum, Cornelia$$b12
000272991 7001_ $$aLamperti, Costanza$$b13
000272991 7001_ $$aLehman, Anna$$b14
000272991 7001_ $$aLongo, Nicola$$b15
000272991 7001_ $$aMolnar, Maria Judit$$b16
000272991 7001_ $$aParikh, Sumit$$b17
000272991 7001_ $$aPhan, Han$$b18
000272991 7001_ $$aPitceathly, Robert D S$$b19
000272991 7001_ $$aSaneto, Russekk$$b20
000272991 7001_ $$aScaglia, Fernando$$b21
000272991 7001_ $$aServidei, Serenella$$b22
000272991 7001_ $$aTarnopolsky, Mark$$b23
000272991 7001_ $$aToscano, Antonio$$b24
000272991 7001_ $$aVan Hove, Johan L K$$b25
000272991 7001_ $$aVissing, John$$b26
000272991 7001_ $$aVockley, Jerry$$b27
000272991 7001_ $$aFinman, Jeffrey S$$b28
000272991 7001_ $$aAbbruscato, Anthony$$b29
000272991 7001_ $$aBrown, David A$$b30
000272991 7001_ $$aSullivan, Alana$$b31
000272991 7001_ $$aShiffer, James A$$b32
000272991 7001_ $$aMancuso, Michelango$$b33
000272991 7001_ $$aInvestigators, MMPOWER-3 Trial$$b34$$eCollaboration Author
000272991 773__ $$0PERI:(DE-600)2225857-7$$a10.1186/s13023-024-03421-5$$gVol. 19, no. 1, p. 431$$n1$$p431$$tOrphanet journal of rare diseases$$v19$$x1750-1172$$y2024
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