% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Karaa:272991,
      author       = {Karaa, Amel and Bertini, Enrico and Carelli, Valerio and
                      Cohen, Bruce and Ennes, Gregory M and Falk, Marni J and
                      Goldstein, Amy and Gorman, Gráinne and Haas, Richard and
                      Hirano, Michio and Klopstock, Thomas and Koenig, Mary Kay
                      and Kornblum, Cornelia and Lamperti, Costanza and Lehman,
                      Anna and Longo, Nicola and Molnar, Maria Judit and Parikh,
                      Sumit and Phan, Han and Pitceathly, Robert D S and Saneto,
                      Russekk and Scaglia, Fernando and Servidei, Serenella and
                      Tarnopolsky, Mark and Toscano, Antonio and Van Hove, Johan L
                      K and Vissing, John and Vockley, Jerry and Finman, Jeffrey S
                      and Abbruscato, Anthony and Brown, David A and Sullivan,
                      Alana and Shiffer, James A and Mancuso, Michelango},
      collaboration = {Investigators, MMPOWER-3 Trial},
      title        = {{G}enotype-specific effects of elamipretide in patients
                      with primary mitochondrial myopathy: a post hoc analysis of
                      the {MMPOWER}-3 trial.},
      journal      = {Orphanet journal of rare diseases},
      volume       = {19},
      number       = {1},
      issn         = {1750-1172},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2024-01365},
      pages        = {431},
      year         = {2024},
      abstract     = {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.},
      keywords     = {Humans / Male / Female / DNA, Mitochondrial: genetics /
                      Mitochondrial Myopathies: drug therapy / Mitochondrial
                      Myopathies: genetics / Genotype / Adult / Middle Aged /
                      Oligopeptides: therapeutic use / Elamipretide (Other) /
                      Mitochondria (Other) / MtDNA maintenance (Other) / MtDNA
                      multiple deletions (Other) / PMM (Other) / Replisome (Other)
                      / arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide (NLM
                      Chemicals) / DNA, Mitochondrial (NLM Chemicals) /
                      Oligopeptides (NLM Chemicals)},
      cin          = {Clinical Research (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1111015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11583740},
      pubmed       = {pmid:39574155},
      doi          = {10.1186/s13023-024-03421-5},
      url          = {https://pub.dzne.de/record/272991},
}