Discussion
mitochondrial myopathy, PMD, fatigue, Fatigue
SECONDARY, DRUG MECHANISM, MITOCHONDRIAL MYOPATHY
We present the results of the first phase 3 trial in PMM with elamipretide. Overall, participants who received elamipretide did not meet either primary or secondary endpoints. Specifically, there were no statistically significant changes between elamipretide and placebo in the 6MWT or the PMMSA Total Fatigue Score. MMPOWER-3 uncovered several findings, specifically the importance of considering pathogenic genotypes within the PMM population when evaluating the effect of investigational treatments. Among the most interesting findings of the trial, identified in a post hoc analysis, was that participants with PMM with nDNA defects performed significantly better on the 6MWT, whereas participants with mtDNA alteration did not differ from placebo. The insight from these subgroups are novel findings and are expected to contribute substantially to future PMM studies.Patient improvements in 6MWT and PMMSA TFS from this study showed a similar trend as those results obtained from the phase 1/2 (MMPOWER-1) and phase 2 (MMPOWER-2) clinical trials of elamipretide in patients with PMM.While this study did not meet either of its primary endpoints (changes in the 6MWT and PMMSA Total Fatigue Score), participants treated with elamipretide did report slightly less total fatigue (between-group difference was not statistically significant) at the end of treatment, as assessed by the PMMSA Total Fatigue Score. Future studies are needed to elucidate whether the slight change in PMMSA Total fatigue score in treated and untreated participants is within the test variability range or a true measure of fatigue improvement not reaching statistical significance due to the mild-to-moderate impairment of participants at baseline and increased heterogeneity in participant selection.The response in 6MWT in the nDNA cohort, as a function of plasma area under the curve (AUC0-24), demonstrates a statistically significant correlation, which supports this subgroup finding, and suggests that the therapeutic dose may not be optimized. It is possible that the exposure-response relationship may differ by genotype/phenotype. These findings warrant further investigation and clearly underscore the importance of considering genetic subtypes in mitochondrial myopathy and the drug mechanism of action. All the genes responsible for mtDNA maintenance are expressed in the nuclear genome.Although the patient population with PMM included in the MMPOWER-3 study was impaired on the 6MWT at baseline compared with literature-based healthy controls (655 [±91] meters),In this phase-3 study, elamipretide was generally well tolerated. Most AEs were mild to moderate in severity, with the most commonly reported AEs including injection site reactions. This safety was similar to that observed in the MMPOWER-2 studyThere are important lessons to be learned from this clinical trial regarding trial design in PMD. The first is that a better understanding of the natural history of PMM will help in future studies. Although the RePOWER pretrial, noninterventional registryThe second lesson is that there is a clear need to further study meaningful endpoints in this patient population. Fatigue has been identified as the primary issue which this patient population experiences, identifying a definitive focal point to be addressed in future therapeutic trials. Refining the sensitivity of the PMMSA fatigue scores in PMD and PMM further to capture signals is tantamount for future studies to address data gaps.The lack of available biomarkers for PMM also presented challenges. The variability of participant responses to the PMMSA Total Fatigue score, which is susceptible to a placebo effect were all challenges that skewed the objectivity of the study endpoints. Furthermore, the mild-to-moderate fatigue scores observed at baseline point to a lack of sensitivity of this endpoint. The identification of objective endpoints or biomarkers assessing PMM would be beneficial for future trial design because the availability of biomarkers helps to target individuals who are most likely to respond to treatment, providing the ability to verify target engagement, which could allow the use of enrichment strategies and reduce reliance on effort-dependent endpoints. For example, altered plasma acylcarnitine levels have previously been seen in patients with PMM,The third lesson is from the basket design from MMPOWER-3, which pooled both nDNA and mtDNA participants. The placebo effect on 6MWT was prominent in mtDNA participants in the prespecified subgroup analysis, and given the size of this subgroup, this drove the placebo effect observed in the trial. Conversely, there was not a discernible placebo response on 6MWT in nDNA participants (depicted in The MMPOWER clinical development program was the most advanced and complete in PMM and provided significant lessons regarding study design and patient enrollment parameters. MMPOWER-3 was the first trial that progressed into phase 3 to assess a therapy for participants with PMM. Although the primary endpoints were not met for the overall population, the observation of the improvement in the 6MWT in the nDNA subgroup is encouraging and hypothesis generating. Efforts are currently underway to confirm this positive benefit and these findings in a follow-up and targeted phase 3 trial in participants with PMM with pathogenic nDNA variants.