Evidence map›Paper›PMID 39574155›Full record

Trial reportOrphanet journal of rare diseases2024

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

Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano and 25 more

Registry-linked trialAbstract readRandomized Controlled TrialClinical Trial, Phase III
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Orphanet journal of rare diseases, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03323749 (A Phase 3 Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects With Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension), which is not on this map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT03323749 phase3terminatednot on this map

A Phase 3 Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects With Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension

TypeinterventionalSponsorStealth BioTherapeutics Inc.Ran2017 to 2020Enrolled218ConditionsPrimary Mitochondrial MyopathyArmselamipretide, placebo comparator, elamipretide open label treatment
3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

35 authors.

Amel KaraaMassachusetts General Hospital, Genetics Division Harvard Medical School Boston, Boston, MA, USA. AKARAA@mgh.harvard.edu.ORCID 0000-0001-5781-9824
Enrico BertiniNeuromuscular Unit, Bambino Gesù Ospedale Pediatrico, IRCCS, Rome, Italy.
Valerio CarelliIRCCS Istituto Delle Scienze Neurologiche Di Bologna, Programma Di Neurogenetica, Bologna, Italy.
Bruce CohenAkron Children's Hospital, Rebecca D. Considine Research Institute, Akron, OH, USA.
Gregory M EnnesStanford University School of Medicine, Stanford, CA, USA.
Marni J FalkDivision 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.
Amy GoldsteinDivision 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.
Gráinne GormanRoyal Victoria Infirmary, Newcastle Upon Tyne, England.
Richard HaasUniversity of California, San Diego, La Jolla, CA, USA.
Michio HiranoColumbia University Irving Medical Center, New York, NY, USA.
Thomas KlopstockDepartment of Neurology, LMU Hospital, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität Munich, Munich, Germany.
Mary Kay KoenigDepartment 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.
Cornelia KornblumDepartment of Neurology, University Hospital of Bonn, Neuromuscular Diseases Section, Bonn, Germany.
Costanza LampertiFondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Anna LehmanVancouver General Hospital, Vancouver, BC, Canada.
Nicola LongoUniversity of Utah, Salt Lake City, UT, USA.
Maria Judit MolnarInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary.
Sumit ParikhCleveland Clinic Neurological Institute, Cleveland, OH, USA.
Han PhanRare Disease Research, Atlanta, GA, USA.
Robert D S PitceathlyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Russekk SanetoSeattle Children's Hospital, Seattle, WA, USA.
Fernando ScagliaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Serenella ServideiFondazione Policlinico Universitario A. Gemelli and Istituto Di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
Mark TarnopolskyDivision of Neuromuscular and Neurometabolic Disorders, McMaster University Children's Hospital, Hamilton, ON, Canada.
Antonio ToscanoDepartment of Clinical and Experimental Medicine, ERN-NMD Center for Neuromuscular Disorders of Messina, University of Messina, Messina, Italy.
Johan L K Van HoveUniversity of Colorado and Children's Hospital Colorado, Aurora, CO, USA.
John VissingCopenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Jerry VockleyChildren's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Jeffrey S FinmanJupiter Point Pharma Consulting, LLC, Jupiter, CT, USA.
Anthony AbbruscatoStealth BioTherapeutics, Needham, MA, USA.
David A BrownStealth BioTherapeutics, Needham, MA, USA.
Alana SullivanStealth BioTherapeutics, Needham, MA, USA.
James A ShifferWrite On Time Medical Communications, LLC, Medford, NJ, USA.
Michelango MancusoDepartment of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
MMPOWER-3 Trial Investigators

Funding

Harvard Clinical and Translational Science CenterUL1TR001102 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2013 to 2017
$106.2M
NCATS NIH HHS UL1 TR001102
6 · The paper itself

Abstract

backgroundAs 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.

resultsSubjects 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.

conclusionsPost 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.

Indexed as

GenotypeMitochondrial MyopathiesOligopeptidesAdultDNA, MitochondrialFemaleHumansMaleMiddle Agedarginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamideDNA, MitochondrialOligopeptidesElamipretideMitochondriaMtDNA maintenanceMtDNA multiple deletionsPMMReplisome

Identifiers

PMID39574155
PMCPMC11583740

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.