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.
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.
Study design:
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.
Part 2: The second part of MOXIe is a double-blind, placebo-controlled, randomized, multicenter, international trial designed to assess the efficacy, safety, and tolerability of omaveloxolone in individuals with FA.
MOXIe’s primary endpoint is the change from baseline in mFARS of omaveloxolone versus placebo at 48 weeks. Other endpoints include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and the Clinical Global Impression of Change.