Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial
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...
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2024-11-01
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| author | Amel Karaa Enrico Bertini Valerio Carelli Bruce Cohen Gregory M. Ennes Marni J. Falk Amy Goldstein Gráinne Gorman Richard Haas Michio Hirano Thomas Klopstock Mary Kay Koenig Cornelia Kornblum Costanza Lamperti Anna Lehman Nicola Longo Maria Judit Molnar Sumit Parikh Han Phan Robert D. S. Pitceathly Russekk Saneto Fernando Scaglia Serenella Servidei Mark Tarnopolsky Antonio Toscano Johan L. K. Van Hove John Vissing Jerry Vockley Jeffrey S. Finman Anthony Abbruscato David A. Brown Alana Sullivan James A. Shiffer Michelango Mancuso on behalf of the MMPOWER-3 Trial Investigators |
| author_facet | Amel Karaa Enrico Bertini Valerio Carelli Bruce Cohen Gregory M. Ennes Marni J. Falk Amy Goldstein Gráinne Gorman Richard Haas Michio Hirano Thomas Klopstock Mary Kay Koenig Cornelia Kornblum Costanza Lamperti Anna Lehman Nicola Longo Maria Judit Molnar Sumit Parikh Han Phan Robert D. S. Pitceathly Russekk Saneto Fernando Scaglia Serenella Servidei Mark Tarnopolsky Antonio Toscano Johan L. K. Van Hove John Vissing Jerry Vockley Jeffrey S. Finman Anthony Abbruscato David A. Brown Alana Sullivan James A. Shiffer Michelango Mancuso on behalf of the MMPOWER-3 Trial Investigators |
| author_sort | Amel Karaa |
| collection | DOAJ |
| description | 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 |
| format | Article |
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| institution | OA Journals |
| issn | 1750-1172 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-9ee65de424ba47d7a85aadc248d7ce122025-08-20T02:33:31ZengBMCOrphanet Journal of Rare Diseases1750-11722024-11-0119111210.1186/s13023-024-03421-5Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trialAmel Karaa0Enrico Bertini1Valerio Carelli2Bruce Cohen3Gregory M. Ennes4Marni J. Falk5Amy Goldstein6Gráinne Gorman7Richard Haas8Michio Hirano9Thomas Klopstock10Mary Kay Koenig11Cornelia Kornblum12Costanza Lamperti13Anna Lehman14Nicola Longo15Maria Judit Molnar16Sumit Parikh17Han Phan18Robert D. S. Pitceathly19Russekk Saneto20Fernando Scaglia21Serenella Servidei22Mark Tarnopolsky23Antonio Toscano24Johan L. K. Van Hove25John Vissing26Jerry Vockley27Jeffrey S. Finman28Anthony Abbruscato29David A. Brown30Alana Sullivan31James A. Shiffer32Michelango Mancuso33on behalf of the MMPOWER-3 Trial Investigators Massachusetts General Hospital, Genetics Division Harvard Medical School BostonNeuromuscular Unit, Bambino Gesù Ospedale Pediatrico, IRCCSIRCCS Istituto Delle Scienze Neurologiche Di Bologna, Programma Di NeurogeneticaAkron Children’s Hospital, Rebecca D. Considine Research InstituteStanford University School of MedicineDivision of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Mitochondrial Medicine Frontier ProgramDivision of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Mitochondrial Medicine Frontier ProgramRoyal Victoria InfirmaryUniversity of CaliforniaColumbia University Irving Medical CenterDepartment of Neurology, LMU Hospital, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität MunichDepartment of Pediatrics, Division of Child and Adolescent Neurology, Center for the Treatment of Pediatric Neurodegenerative Disease, University of Texas McGovern Medical SchoolDepartment of Neurology, University Hospital of Bonn, Neuromuscular Diseases SectionFondazione IRCCS Istituto Neurologico Carlo BestaVancouver General HospitalUniversity of UtahInstitute of Genomic Medicine and Rare Disorders, Semmelweis UniversityCleveland Clinic Neurological InstituteRare Disease ResearchDepartment of Neuromuscular Diseases, UCL Queen Square Institute of NeurologySeattle Children’s HospitalDepartment of Molecular and Human Genetics, Baylor College of MedicineFondazione Policlinico Universitario A. Gemelli and Istituto Di Neurologia, Università Cattolica del Sacro CuoreDivision of Neuromuscular and Neurometabolic Disorders, McMaster University Children’s HospitalDepartment of Clinical and Experimental Medicine, ERN-NMD Center for Neuromuscular Disorders of Messina, University of MessinaUniversity of Colorado and Children’s Hospital ColoradoCopenhagen Neuromuscular Center, Rigshospitalet, University of CopenhagenChildren’s Hospital of Pittsburgh, University of Pittsburgh School of MedicineJupiter Point Pharma Consulting, LLCStealth BioTherapeuticsStealth BioTherapeuticsStealth BioTherapeuticsWrite On Time Medical Communications, LLCDepartment of Clinical and Experimental Medicine, Neurological Institute, University of PisaAbstract 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 NCT03323749https://doi.org/10.1186/s13023-024-03421-5ElamipretidePMMReplisomeMitochondriaMtDNA maintenanceMtDNA multiple deletions |
| spellingShingle | Amel Karaa Enrico Bertini Valerio Carelli Bruce Cohen Gregory M. Ennes Marni J. Falk Amy Goldstein Gráinne Gorman Richard Haas Michio Hirano Thomas Klopstock Mary Kay Koenig Cornelia Kornblum Costanza Lamperti Anna Lehman Nicola Longo Maria Judit Molnar Sumit Parikh Han Phan Robert D. S. Pitceathly Russekk Saneto Fernando Scaglia Serenella Servidei Mark Tarnopolsky Antonio Toscano Johan L. K. Van Hove John Vissing Jerry Vockley Jeffrey S. Finman Anthony Abbruscato David A. Brown Alana Sullivan James A. Shiffer Michelango Mancuso on behalf of the MMPOWER-3 Trial Investigators Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial Orphanet Journal of Rare Diseases Elamipretide PMM Replisome Mitochondria MtDNA maintenance MtDNA multiple deletions |
| title | Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial |
| title_full | Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial |
| title_fullStr | Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial |
| title_full_unstemmed | Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial |
| title_short | Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial |
| title_sort | genotype specific effects of elamipretide in patients with primary mitochondrial myopathy a post hoc analysis of the mmpower 3 trial |
| topic | Elamipretide PMM Replisome Mitochondria MtDNA maintenance MtDNA multiple deletions |
| url | https://doi.org/10.1186/s13023-024-03421-5 |
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