Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Abstract

Objective: Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).

Methods: Sixty-nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5-300 mg/day.

Results: Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day.

Interpretation: Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.

Figure 1

Consort diagram of MOXie, part 1.

Figure 2

Pharmacokinetics of Omav. Maximal concentration of Omaveloxolone C_max levels are shown at different doses. Data are presented as a Box and whisker plot. Plasma concentrations increased exponentially over the dose range of the study.

Figure 3

Pharmacodynamic effects of Omav. Omav had dose dependent effects on Ferritin (A), GGT (B), AST (C) and creatine kinase (D). In general, effects of Omav increased through doses of 180 mg, then were blunted at the highest dose (300 mg).

Figure 4

Platelet isotopologue analysis. Isotopic incorporation from [¹³C₆] glucose (A) and [¹³C₁₆] palmitate (B) to HMG‐CoA (%) was determined in subjects at different dose of Omav. Cohorts were pooled into placebo (n = 3), cohorts 1 and 2 (n = 8) and cohorts 3‐8 (n = 13) for analysis due to the small number of participants in each individual cohort.

Figure 5

Effect of Omav on mFARS exam results. Omav produced a dose dependent improvement in mFARS score. The difference was more apparent at the higher doses in the study, with less benefit at 300 mg, consistent with AST, ferritin, GGT and CK changes at 300 mg.

Figure 6

Pes cavus is associated with less response to Omav. The magnitude of improvement from Omav was higher on the mFARS exam in subjects without pes cavus compared with those with pes cavus. Similarly, a benefit of Omav on cardiac exercise stress testing was noted in the subgroup without pes cavus, whereas there was minimal effect in the overall cohort. Without pes cavus: n = 30 Omav, n = 7 placebo. With pes cavus: n = 22 Omav, n = 10 placebo