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

• Authors: David R Lynch, The Children's Hospital of Philadelphia; Melanie P Chin, Reata Pharmaceuticals; Martin B Delatycki, Murdoch Children's Research Institute; SH Subramony, University of Florida Health; Manuela Corti, University of Florida Health; Chad J Hoyle, The Ohio State University College of Medicine; Sylvia Boesch, Medizinische Universitat Innsbruck; Wolfgang Nachbauer, Medizinische Universitat Innsbruck; Caterina Mariotti, Foundation IRCCS Neurological Institute "C. Besta"; Katherine D Mathews, University of Iowa Carver College of Medicine; Paola Giunti, University College London Hospitals NHS Foundation Trust; George Wilmot, Emory University; Theresa Zesiewicz, University of South Florida, Tampa; Susan Perlman, University of California, Los Angeles; Angie Goldsberry, Reata Pharmaceuticals; Megan O'Grady, Reata Pharmaceuticals; Colin J Meyer, Reata Pharmaceuticals
• Journal Title: Annals of Neurology
• Volume: Volume 89, Number 2
• Publisher: John Wiley & Sons, Inc | 2021-02-01, Pages 212-225
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/ana.25934
• Subjects: Chemistry, Pharmaceutical; Biology, Neuroscience; Health Sciences, Medicine and Surgery
• Keywords: Accidental Falls; Activities of Daily Living; Adolescent; Adult; Antioxidants; Double-Blind Method; Exercise Test; Female; Friedreich Ataxia; Humans; Male; Mitochondria; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Treatment Outcome; Triterpenes; Young Adult

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.