Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.

Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.