Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial.

Objective: To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.

Methods: In cohorts of 8-13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).

Results: No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.

Conclusions: Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.

Clinicaltrialsgov Identifier: NCT02255422.

Classification Of Evidence: This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.