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Ann Clin Transl Neurol. 2018 Nov 10;6(1):15-26. doi: 10.1002/acn3.660. eCollection 2019 Jan.

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

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Division of Neurology The Children's Hospital of Philadelphia 502 Abramson Research Center 3615 Civic Center Blvd Philadelphia Pennsylvania 19104-4318.
Friedreich's Ataxia Research Alliance 533 W Uwchlan Ave Downingtown Pennsylvania 19335.
Department of Systems Pharmacology and Translational Therapeutics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania 19104.
Department of Neurology Medizinische Universität Innsbruck Christoph-Probst-Platz 1 Innrain 52 6020 Innsbruck Austria.
Reata Pharmaceuticals 2801 Gateway Drive Suite 150 Irving Texas 75063.
Victorian Clinical Genetics Services Murdoch Children's Research Institute Flemington Road Parkville Victoria 3052 Australia.
Institute of Neurology University College of London Queen Square London United Kingdom WC1N 3BG.
Department of Neurology The Ohio State University 395 W. 12th Ave. 7th Floor Columbus Ohio 43210.
Department of Neurology University of California Los Angeles BOX 956975 1-167 RNRC Los Angeles California 90095.
Department of Neurology McKnight Brain Institute Room L3-100 1149 Newell Drive Gainesville Florida 32611.
Department of Neurology Emory University 1365 Clifton Rd Atlanta Georgia 30322.
Department of Neurology University of South Florida 12901 Bruce B Downs Blvd. MDC 55 Tampa Florida 33612.



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).


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.


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 (= 0.0001) and by 2.3 points versus placebo (= 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 (< 0.0001) and by 4.4 points versus placebo (= 0.01) at the 160 mg/day.


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.

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