Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial

by Selleckchem | Sep 23 2023

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.

Comments:

The provided text describes the background, objectives, methods, and results of a clinical trial called MMPOWER-3. The trial aimed to evaluate the efficacy and safety of a drug called elamipretide in individuals with genetically-confirmed Primary Mitochondrial Myopathies (PMMs). PMMs are a group of genetic disorders that affect mitochondrial function and can lead to impairments in physical function, exercise capacity, and quality of life.

The study enrolled a total of 218 participants who were randomly assigned to receive either elamipretide or a placebo for a duration of 24 weeks. The primary endpoints of the trial were changes in the distance walked on the 6-minute Walk Test (6MWT) and the Total Fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) from baseline to Week 24. Secondary endpoints included other measures of fatigue and the assessment of symptom impact by patients and clinicians.

The results of the study showed that elamipretide did not meet its primary endpoints in terms of improving the 6MWT distance and the Total Fatigue score on the PMMSA compared to the placebo. The difference between the elamipretide and placebo groups in terms of these endpoints was not statistically significant. However, the treatment with elamipretide was found to be well-tolerated, with most adverse events being mild to moderate in severity.

In summary, the MMPOWER-3 trial did not demonstrate significant efficacy of elamipretide in improving physical function and fatigue in individuals with PMMs. However, it did establish the safety and tolerability of subcutaneous elamipretide treatment. These findings highlight the need for further research and alternative therapeutic approaches to address the unmet needs of individuals with PMMs.