Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy

Abstract

Background and Objectives:Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely impacting physical function, exercise capacity, and quality of life (QoL). Current PMM standards-of-care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically-confirmed PMM.Methods:Following screening, eligible participants were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day or placebo subcutaneously. Primary efficacy endpoints included change from baseline to Week 24 on the distance walked on the 6-minute Walk Test (6MWT), and Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included Most Bothersome Symptom Score on the PMMSA, NeuroQoL Fatigue Short Form scores, and the Patient– and Clinician–Global Impression of PMM Symptoms.Results:Participants (N=218) were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women; 94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA) mutations, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, mean distance walked on the 6MWT was 336.7±81.2 meters, mean score for Total Fatigue on the PMMSA was 10.6±2.5, and mean T-score for the Neuro-QoL Fatigue Short Form was 54.7±7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA Total Fatigue Score (TFS). Between the participants receiving elamipretide versus placebo, the difference in the Least Squares Mean (SE) from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3;p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26;p=0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.Discussion:Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.Trial Registration Information:Trial registered withclinicaltrials.gov, Clinical Trials Identifier:NCT03323749; submitted on October 12, 2017;first patient enrolled October 9, 2017.https://clinicaltrials.gov/ct2/show/NCT03323749?term=elamipretide&draw=2&rank=9Classification of Evidence:This study provides Class I evidence that elamipretide does not improve the 6 minute walk test or fatigue at 24 weeks compared to placebo in patients with primary mitochondrial myopathy.

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2

“…The neuroprotective effects of Elamipretide are mediated by inhibition of neural oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis [ 93 ]. Subcutaneous injections of this tetrapeptide have been tested in a phase-3 clinical trial for mitochondrial myopathy ( https://www.clinicaltrials.gov/study/NCT03323749 ) demonstrating that it is well-tolerated but could not improve the outcome [ 98 ]. Clinical studies are now required to assess the pharmacokinetics and pharmacodynamics of elamipretide and other mitochondria-targeted peptides in patients with neurodegenerative diseases, including PD.…”

A clinical approach to diagnosis and management of mitochondrial myopathies

“… [ 86 , 87 ] Protecting mitochondria from damage Elamipretide Shown to be associated with clinical and functional improvements in children and adults with MM. [ [88] , [89] , [90] , [91] , [92] , [93] ] Restoring mitochondrial homeostasis Deoxynucleoside therapy Use in patients with TK2 deficiency showed improved motor and respiratory function [ [94] , [95] , [96] ] Enzyme replacement Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP) Use of patients with MNGIE showed clinical improvement and reductions in thymidine, and deoxyuridine. [ [97] , [98] , [99] ] Dietary supplementation Correct taurine modification defect at the first anticodon nucleotide of mitochondrial tRNA Leu(UUR) High dose taurine Use in MELAS patients was shown to reduce frequency of stroke-like episodes and improved taurine modification of mitochondrial tRNA Leu(UUR) from peripheral blood leukocytes [ 100 ] Improve systemic NAD+ deficiency Niacin Oral niacin supplement increased blood NAD+ up to 8-fold and muscle NAD+ up to level of controls [ 101 , 102 ] Influencing glutamate-glutamine cycle and glutamine transporters in the blood-brain barrier High dose glutamine Significant reduction in CSF glutamate and increment of CSF glutamine level in MELAS patients [ 103 ] Stimulate mitochondrial function Resveratrol In vitro studies suggest improvements in mitochondrial fatty oxidation.…”

Emerging antioxidant therapies in Friedreich’s ataxia

“…Elamipretide (ELAM, SS-31, Bendavia, ELViS-FA, MTP-131) is a mitochondria-targeted peptide, capable of localising to the inner mitochondrial membrane (IMM) where it associates with cardiolipin and modulates mitochondria function ( ClinicalTrials, 2022 ; Karaa et al, 2023 ; Pharaoh et al, 2023 ). This leads to increased production of supercomplexes, greater membrane stability, reducing ROS levels and elevating ATP synthesis ( Karaa et al, 2023 ). Elamipretide treatment was also shown to increase ADP sensitivity in vivo and decrease ROS production in vitro ( Pharaoh et al, 2023 ).…”

“…A phase III clinical trial (MMPOWER-3) investigating elamipretide in primary mitochondrial myopathy (PMM) was finished in 2020 ( ClinicalTrials, 2017 ; Karaa et al, 2023 ). It was reported that, whilst the drug was well tolerated by participants, there were no significant differences in walking (evaluated using the 6-min walk test) or fatigue (evaluated using the PMM Symptom Assessment Total Fatigue Score) ( ClinicalTrials, 2017 ; Karaa et al, 2023 ). In 2022, a phase I/II clinical trial was set up to investigate elamipretide as a potential therapeutic target for FRDA ( ClinicalTrials, 2022 ).…”