FA is characterized by a decrease in frataxin expression, which is caused by the transcriptional silencing of the FXN gene. Frataxin deficiency leads to mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and mitochondrial dysfunction that impairs ATP production.1,4,5 Impaired ATP production likely accounts for the decreased coordination, progressive muscle weakness, exercise intolerance, and fatigue, as well as other disease manifestations seen in patients with FA.
Mechanism of Action of Omaveloxolone
Omaveloxolone targets the mitochondrial dysfunction associated with FA. It is being studied in the registrational part 2 of Reata’s MOXIe trial for the treatment of FA.
Since patients suffering from FA experience increased sensitivity to oxidative stress and impaired mitochondrial ATP production, omaveloxolone may be effective in treating this condition.13 In patients with FA, mitochondrial function is correlated with neurologic function measurements. Impaired ATP production likely accounts for the decreased coordination, progressive muscle weakness, exercise intolerance, and fatigue observed in patients with FA.
Data demonstrate that Nrf2 signaling is significantly affected in patients with FA, resulting in impaired antioxidant defense mechanisms. Silencing of frataxin gene expression has been linked to decreases in expression of Nrf2.6,12 In in vitro studies, omaveloxolone has been shown to restore mitochondrial transmembrane potential in fibroblasts isolated from patients with FA. Omaveloxolone may result in a clinical benefit to patients with FA.8
The MOXIe trial is a 2-part, randomized, placebo-controlled, double-blind, dose-escalation, phase 2 trial evaluating the efficacy and safety of omaveloxolone.
Part 1: The first part of the MOXIe trial is a dose-escalation portion that is designed to evaluate the efficacy and safety of omaveloxolone. Reata announced data from the first part of MOXIe in June 2017.
In the first part of the MOXIe trial, 69 patients received escalating doses of omaveloxolone or placebo to evaluate the maximum tolerated dose between 5 mg and 300 mg. Other endpoints included the modified Friedreich’s ataxia rating scale (mFARS) and peak workload during exercise.