A potential oral treatment of mitochondrial myopathies called omaveloxolone (RTA 408) appears to improve the mitochondrial function of patients at an optimal dose of 160 mg, top-line data from a Phase 2 clinical trial shows.
Data comes from the 12-week, dose-ranging Phase 2 MOTOR trial (NCT02255422), which assessed the safety, efficacy and pharmacological profile of six doses of the treatment in groups of patients, Reata Pharmaceuticals announced in a press release.
Mitochondrial myopathies are a group of inherited disorders characterized by a wide range of defects in mitochondria, the cell’s power plants. DNA mutations lead to a complex clinical presentation, which involves reduced mitochondrial function, muscle weakness, fatigue, and exercise intolerance.
Omaveloxolone is an oral, once-daily Nrf2 activator in clinical development by Reata and AbbVie. Nrf2 leads to the expression of genes that improve mitochondrial function. Preclinical studies showed that omaveloxolone increases the number of mitochondria and their energy production.
Nrf2 activation also blocks inflammation and protects against oxidative stress.
In the MOTOR trial, 53 patients were randomly assigned in groups of six to 10 to omaveloxolone capsules, at doses that rose to 160 mg daily for 12 weeks, or to placebo in groups of two or three. The intent was to establish the appropriate dose to be used in subsequent clinical studies.
Results showed that the greatest improvement in markers of mitochondrial function was achieved with 160 mg of the investigational compound.
Clinical activity was assessed with the maximal exercise test, which evaluates physical capacity and oxygen consumption, and the 6-minute walk test, which assesses exercise tolerance.
Researchers also conducted a submaximal exercise test, which is a sensitive measurement of mitochondrial function, during activities of daily living. The analysis focused on variations in heart rate and blood lactate levels, which increase with reduced mitochondrial function and with intense exercise.
While no differences between treatment and placebo were observed in maximal exercise and the 6-minute walk test at week 12, 160 mg of omaveloxolone reduced heart rate and blood lactate levels in the submaximal exercise test, which are indicative of improved mitochondrial function.
Treated groups in a dose-ranging study like this one are too small, however, to “fully characterize” efficacy or other measures, the release noted.
No safety concerns were identified by an independent data safety monitoring board.
“In patients with mitochondrial disease, an important goal of interventional therapy is lowering perceived effort during every day activities of daily living,” John Vissing, MD, a professor at the University of Copenhagen, in Denmark, said in the release.
“By improving oxidative capacity, omaveloxolone lowered heart rate during submaximal exercise, which is a major achievement towards this goal. Likewise, lowering lactate production with omaveloxolone treatment reflects better mitochondrial function, which supports further investigation of omaveloxolone for treatment of patients with mitochondrial diseases,” he added.