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

Abstract

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, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 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.

© 2020 American Academy of Neurology.

Figures

Figure 1. Diagram of the participant flow in the MOTOR study

In the MOTOR study (Safety, Efficacy, and Pharmacodynamics of Omaveloxolone in Mitochondrial Myopathy Patients), 116 patients were screened. Fifty-three passed the criteria of inclusion/exclusion and were randomized to treatment with omaveloxolone (Omav) or placebo. Forty participants received treatment with omaveloxolone and 13 received placebo treatment. Six of the omaveloxolone-treated participants discontinued the intervention due to adverse events (unrelated or possibly related) or for personal reasons. Two of the participants were excluded from the final efficacy analysis as they had performed no postbaseline efficacy assessments. All 13 participants randomized to placebo treatment completed the study and were included in the final efficacy analysis. All participants were included in the safety analysis.

Figure 2. Design and visit schedule in a randomized double-blind dose-escalation study on omaveloxolone in mitochondrial myopathy

Participants with mitochondrial myopathy were included in cohorts (8–13) and randomized 3:1 to omaveloxolone (Omav) or placebo treatment for 12 weeks. After 2 weeks of treatment, a data safety monitoring board (DSMB) reviewed the safety data and decided on the opening of the next dose level cohort. Six cohorts completed the protocol with 5, 10, 20, 40, 80, and 160 mg omaveloxolone, respectively. Study visits are indicated by vertical arrows and took place on day 1 (D1) and after the indicated number of weeks (W) of treatment. Laboratory measures were collected on all visits. Week 4 and 12 visits were conducted as a 2-day visit with a 6-minute walk test and a submaximal exercise test on the first and a maximal exercise test on the second day.

Figure 3. Changes in plasma biomarkers of nuclear factor erythroid 2-like 2 (Nrf2) induction in patients with mitochondrial myopathy

Changes in biomarkers of Nrf2 induction in patients with mitochondrial myopathy from baseline to after 4 weeks of treatment with a range of doses of omaveloxolone (Omav, 38 participants) and placebo (0 mg, 13 participants). (A) Alanine transaminase (ALT). (B) Aspartate transaminase (AST). (C) Ferritin. (D) γ-Glutamyl transferase (GGT). Presented are mean % change with SE bars after 4 weeks treatment vs baseline.

Figure 4. Changes in peak work and submaximal exercise heart rate with omaveloxolone treatment

Change in peak work in a maximal exercise test (A) and change in heart rate at the end of a 30-minute submaximal exercise test (B) on a recumbent ergometer in patients with mitochondrial myopathy after 12 weeks of treatment vs baseline. Presented are mean changes with SE bars in the placebo group (0 mg), the 160 mg omaveloxolone (Omav) group, and in all participants treated with omaveloxolone.

Figure 5. Change from baseline in blood lactate during submaximal exercise with 12 weeks omaveloxolone treatment

Change in blood lactate (A) at the end of and (B) during 30 minutes of submaximal exercise on a recumbent cycle ergometer in patients with mitochondrial myopathy with 12 weeks of treatment with placebo and 160 mg omaveloxolone (Omav) vs baseline (BL). Presented are mean values with SE bars.