The nuclear factor erythroid 2-related factor 2 (Nrf2) activator, omaveloxolone, was evaluated in a pivotal, international, double-blind, placebo-controlled trial (MOXIe; NCT02255435).

Friedreich’s ataxia (FRDA) is a neurodegenerative disorder affecting approximately 5,000 patients in the US.  Frataxin deficiency in FRDA causes dysregulation in the antioxidant defenses contributing to disease pathology through a vicious cycle of mitochondrial dysfunction, impaired Nrf2 signaling, and decreased ATP production.  Through activation of Nrf2, omaveloxolone, an investigational drug, improves mitochondrial function, restores redox balance, and reduces inflammation in a variety of neurological disease models.

Part 2 of the MOXIe trial enrolled 103 patients between 16 to 40 years old with genetically confirmed FRDA.  Patients were randomized 1:1 to receive either omaveloxolone 150 mg or placebo administered once daily for 48 weeks.  The primary outcome was the modified Friedreich’s Ataxia Rating scale (mFARS) score at 48 weeks, with secondary outcomes including the patient’s global impression of change (PGIC), the clinician global impression of change (CGIC), and an activities of daily living (ADL) score.

Omaveloxolone treatment met the primary endpoint, producing a statistically significant, placebo-corrected 2.40 point improvement in mFARS (n=82; p=0.014).  Improvements in mFARS were consistent across multiple subgroups and most pronounced in the pediatric patient subset.  PGIC and CGIC scores at Week 48 were numerically improved but were not statistically different from placebo. In addition, ADL scores at Week 48 improved from baseline with omaveloxolone treatment and reached significance relative to placebo (p=0.042). Transient reversible increases in aminotransferases were commonly observed with omaveloxolone treatment but were not associated with increases in total bilirubin or other signs of liver injury.

In the MOXIe trial, omaveloxolone improved neurological function, as measured by mFARS, in a clinically significant manner compared to placebo and was safe and well tolerated.  It remains a potential therapeutic in FRDA.