Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy

Abstract

ObjectiveTo investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.MethodsIn 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).ResultsNo 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.ConclusionsOmaveloxolone 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.Clinicaltrials.gov identifierNCT02255422.Classification of evidenceThis study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

“…While there is very little evidence regarding therapeutic options arising from oxidative stress in mtDNA-associated diseases, a pilot study using a combination of different antioxidants has gained promising results [ 72 , 73 ]. In contrast, the results of a recently published phase I/II clinical trial focusing on omaveloxolone as potent inductor of Nrf2-signalling did not show a significant change in muscle weakness (measured by exercise workload and 6-min walk test), while submaximal exercise heart rate and plasma lactate were significantly lowered [ 74 ]. The small cohort size (8–13 participants per dosing group), as well as the short treatment period (12 weeks), may be considered as reasons for not meeting the efficacy endpoint.…”

Clinical trials in mitochondrial disorders, an update

“…However, treatment resulted in reduced heart rate and lactate levels during submaximal exercise, indicating improved mitochondrial function and submaximal exercise tolerance. The authors suggested further studies need to be conducted with a more homogenous population, and a larger number of patients [ 74 ] ( https://clinicaltrials.gov/ct2/show/NCT02255422 ).…”

Treatment for mitochondrial diseases

“…NRF2 is a promising therapeutic target with antiinflammatory and antioxidation effects because it regulates the expression of genes related to inflammation, redox metabolism and proteostasis (Liu et al 2016). Madsen et al (2020) tried to prove its effect among 53 patients with MM (18 with CPEO, one with KSS, two with Leigh syndrome, five with MELAS, four with myoclonic epilepsy associated with ragged-red fibers, two with neuropathy, ataxia and retinitis pigmentosa and 21 with unclear disease) with a multicenter double-blind, randomized, placebo-controlled trial. Patients received omaveloxolone at 5, 10, 20, 40, 80 or 160 mg or placebo once daily for 12 weeks.…”