Safety and Efficacy of Omaveloxolone in Friedreich's Ataxia (MOXIe Study): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial

Background: Friedreich’s ataxia (FRDA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in a variety of neurological disease models, including FRDA. We aimed to investigate the safety and efficacy of omaveloxolone in patients with FRDA. Methods: We conducted an international, multicentre, double-blind, randomised, placebo-controlled parallel-group, registrational phase 2 trial at 11 clinical institutions in the United States, Europe, and Australia. Eligible patients, 16 to 40 years of age with genetically confirmed FRDA and baseline modified Friedreich’s Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomised 1:1 to receive placebo or 150 mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone as compared with those treated with placebo at 48 weeks. Findings: Between October 20, 2017 and November 5, 2018, 155 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 analysed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (‒1·55 ± 0·69 [95% CI: ‒2·93, ‒0·18]) and placebo (0·85 ± 0·64 [95% CI: ‒0·43, 2·13]) patients showed a difference between treatment groups of ‒2·40 ± 0·96 ([95% CI: ‒4·31, ‒0·5]; p=0·014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone that were not associated with 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 is therefore a potential therapeutic agent in FRDA. Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02255435) and EudraCT (2015-002762-23). Funding: Funded by Reata Pharmaceuticals. Declaration of Interests: Dr. Delatycki reports other from Reata Pharmaceuticals, during the conduct of the study. Dr. Boesch reports grants from EFACTS consortium, grants from NICOFA E-rare (FWF I 3352-B28), other from Abvie, Ipsen, Grunenthal, outside the submitted work. Dr Hoyle reports other from Reata Pharmaceuticals, during the conduct of the study; personal fees from Reata Pharmaceuticals, outside the submitted work. Dr. Mariotti reports grants from Reata Pharmaceuticals, during the conduct of the study. Dr. Mathews reports grants from Reata Pharmaceuticals, during the conduct of the study; grants from Takeda, grants from Friedreich Ataxia Research Alliance (FARA), outside the submitted work. Dr. Perlman has nothing to disclose. Dr. Subramony reports grants from Reata Pharmaceuticals, during the conduct of the study; grants from Biohaven Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Acceleron Pharmaceuticals, personal fees from Reata Pharmaceuticals, personal fees from Stealth, personal fees from Avexis, personal fees from Dyne therapeutics, outside the submitted work. Dr. Wilmot report no conflicts or relevant disclosures. Dr Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific; Reata Pharmaceuticals, Inc; and Steminent Biotherapeutics; has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics; has received royalty payments as co-inventor of varenicline for treating imbalance (patent number 9,463,190) and nonataxic imbalance (patent number 9,782,404); has received research/grant support as principal investigator/ investigator for studies from AbbVie Inc; Biogen; Biohaven Pharmaceutics; Boston Scientific; Bukwang Pharmaceuticals Co, Ltd; Cala Health, Inc; Cavion; Friedreich’s Ataxia Research Alliance; Houston Methodist Research Institute; National Institutes of Health (READISCA U01); Retrotope Inc; and Takeda Development Center Americas, Inc. Dr Lynch receives grants from Reata, Takeda, Chondrial, the NIH, FDA MDA and FARA. Drs. Chin, Meyer, O’Grady, and Goldsberry report other from Reata Pharmaceuticals, outside the submitted work. Ethics Approval Statement: The trial was conducted at 11 clinical institutions in the United States, Europe, and Australia, and was approved by Institutional Review Boards or Independent Ethics Committees associated with the individual study sites.