Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

Abstract

Objective: Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA.

Methods: We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.

Results: One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.

Interpretation: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.

FIGURE 1

Study schema for the MOXIe Part 2 trial and CONSORT diagram. FARS = Friedreich's Ataxia Rating Scale; Scr=screening. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

(A) Mean changes from baseline in modified Friedrich's Ataxia Rating Scale (mFARS) score over time in the full analysis set (FAS) for patients randomized to omaveloxolone (n = 40) or placebo (n = 42). The change from baseline in mFARS and p value was estimated using mixed models repeated measures (MMRM) analysis. Significant differences in the change from baseline in mFARS in the omaveloxolone group, as compared with the placebo group, were observed at week 48 (p = 0.014). The error bars indicate standard errors. SEM = standard error of the mean. (B) Mean changes from baseline in the upright stability scores (Section E) of mFARS over time estimated using MMRM analysis. (C) Forest plot representing the difference between omaveloxolone and placebo treatment groups for the change from baseline in mFARS score at week 48 for the following prespecified analysis populations: FAS (n = 82), all randomized patients (ARP; n = 103), and prespecified subgroups. The change from baseline at week 48 was estimated using MMRM analysis, and each p value was estimated from a test comparing the difference in means between the omaveloxolone and placebo groups.

FIGURE 3

Post hoc analyses of change from baseline in modified Friedreich's Ataxia Rating Scale (mFARS) at week 48 with additional baseline covariates (full analysis set population). Data are presented as bar graphs comparing mean changes from baseline in mFARS at week 48 for patients randomized to omaveloxolone (Omav; n = 40) or placebo (n = 42) using the primary mixed model repeated measures (MMRM) methodology (A) or analysis of covariance (ANCOVA; B) with the inclusion of history of cardiomyopathy, GAA1 repeat length, or history of cardiomyopathy and GAA1 repeat length included as covariates. Note that the model with GAA1 repeat length as a covariate includes only those patients with baseline GAA1 repeat length data (n = 31 for omaveloxolone and n = 36 for placebo). [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

(A–C) Mean (± standard error [SE]) alanine aminotransferase (ALT; A), aspartate aminotransferase (B), and total bilirubin values (C) for all randomized patients in the omaveloxolone (Omav; n = 51) or placebo (n = 52) groups through 48 weeks of treatment. Post‐treatment values collected at week 52, 4 weeks after the last dose of study drug was administered, are also shown. (D) eDISH (Evaluation of Drug‐Induced Serious Hepatotoxicity) plot. Vertical lines correspond to 3 × the upper limit of normal (ULN) for ALT. Horizontal lines correspond to 2 × ULN for total bilirubin. No patients met potential Hy's criteria in the upper‐right quadrant.

FIGURE 5

Data shown are mean (± standard error of the mean [SEM]) changes in serum ferritin (μg/l) and estimated glomerular filtration rate (eGFR; ml/min/1.73m²) over time for patients randomized to omaveloxolone or placebo.