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

Autor: Karaa A; Massachusetts General Hospital, Genetics Division Harvard Medical School Boston, Boston, MA, USA. AKARAA@mgh.harvard.edu., Bertini E; Neuromuscular Unit, Bambino Gesù Ospedale Pediatrico, IRCCS, Rome, Italy., Carelli V; IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Programma Di Neurogenetica, Bologna, Italy.; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Cohen B; Akron Children's Hospital, Rebecca D. Considine Research Institute, Akron, OH, USA., Ennes GM; Stanford University School of Medicine, Stanford, CA, USA., Falk MJ; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Mitochondrial Medicine Frontier Program, Philadelphia, PA, USA., Goldstein A; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Mitochondrial Medicine Frontier Program, Philadelphia, PA, USA., Gorman G; Royal Victoria Infirmary, Newcastle Upon Tyne, England., Haas R; University of California, San Diego, La Jolla, CA, USA., Hirano M; Columbia University Irving Medical Center, New York, NY, USA., Klopstock T; Department of Neurology, LMU Hospital, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität Munich, Munich, Germany.; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Koenig MK; Department of Pediatrics, Division of Child and Adolescent Neurology, Center for the Treatment of Pediatric Neurodegenerative Disease, University of Texas McGovern Medical School, Houston, TX, USA., Kornblum C; Department of Neurology, University Hospital of Bonn, Neuromuscular Diseases Section, Bonn, Germany., Lamperti C; Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Lehman A; Vancouver General Hospital, Vancouver, BC, Canada., Longo N; University of Utah, Salt Lake City, UT, USA., Molnar MJ; Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary., Parikh S; Cleveland Clinic Neurological Institute, Cleveland, OH, USA., Phan H; Rare Disease Research, Atlanta, GA, USA., Pitceathly RDS; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK., Saneto R; Seattle Children's Hospital, Seattle, WA, USA., Scaglia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Texas Children's Hospital, Houston, TX, USA.; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Sha Tin, Hong Kong SAR, China., Servidei S; Fondazione Policlinico Universitario A. Gemelli and Istituto Di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy., Tarnopolsky M; Division of Neuromuscular and Neurometabolic Disorders, McMaster University Children's Hospital, Hamilton, ON, Canada., Toscano A; Department of Clinical and Experimental Medicine, ERN-NMD Center for Neuromuscular Disorders of Messina, University of Messina, Messina, Italy., Van Hove JLK; University of Colorado and Children's Hospital Colorado, Aurora, CO, USA., Vissing J; Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Vockley J; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Finman JS; Jupiter Point Pharma Consulting, LLC, Jupiter, CT, USA., Abbruscato A; Stealth BioTherapeutics, Needham, MA, USA., Brown DA; Stealth BioTherapeutics, Needham, MA, USA., Sullivan A; Stealth BioTherapeutics, Needham, MA, USA., Shiffer JA; Write On Time Medical Communications, LLC, Medford, NJ, USA., Mancuso M; Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Nov 21; Vol. 19 (1), pp. 431. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1186/s13023-024-03421-5
Abstrakt: 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.
Competing Interests: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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