Friedreich’s ataxia (FA) is an inherited, debilitating, and degenerative neuromuscular disorder that is normally diagnosed during adolescence and can lead to early death. FA affects approximately 6,000 patients in the United States and 22,000 globally1,2. Patients with FA experience progressive loss of coordination, muscle weakness, and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance3. FA patients may also experience visual impairment, hearing loss, diabetes, and cardiomyopathy. Childhood-onset FA can occur as early as age five, is more common than later-onset FA, and typically involves more rapid disease progression. The majority of FA patients have disease onset by approximately 13 to 15 years of age, and thereafter have a mean duration until wheelchair use of 10 to 15 years. The median age of death is in the mid-30s4,5,6.
There are no currently approved therapies for the treatment of FA. We are studying omaveloxolone in the MOXIe trial, a two-part, randomized, placebo-controlled, double-blind, dose-escalation Phase 2 trial to evaluate the safety and efficacy of omaveloxolone. Part one focuses on the evaluation of safety and efficacy of omaveloxolone doses ranging from 2.5 mg to 300 mg. Data for multiple endpoints are being collected, with the primary efficacy endpoint being the change in peak work, as measured by exercise testing on a recumbent bicycle. The key secondary endpoint is a functional assessment based on the modified Friedreich’s Ataxia Rating Scale (mFARS). Part two is designed to provide additional efficacy and safety data and has the potential to support registration.
In June 2017, Reata received orphan drug designation for omaveloxolone for the treatment of FA and announced initial data from the ongoing first part of MOXIe. We are screening patients for the second part of MOXIe.
Mechanism of Action
Since patients suffering from FA experience increased sensitivity to oxidative stress and impaired mitochondrial ATP production, we believe that omaveloxolone may be effective in treating this indication. In FA patients, mitochondrial function is correlated with measures of neurologic function. Further, data demonstrate that Nrf2 signaling is significantly impaired in FA patients, resulting in impairment of antioxidant defense mechanisms, while silencing of frataxin gene expression has been linked to decreases in expression of Nrf210,11. Additionally, omaveloxolone has been shown in vitro to restore mitochondrial transmembrane potential in fibroblasts isolated from FA patients. Accordingly, we believe that Nrf2 activation through omaveloxolone may result in a clinical benefit to FA patients12.
In June 2017, Reata received orphan drug designation for omaveloxolone for the treatment of FA and announced initial data from the ongoing first part of MOXIe.
We are screening patients in part two of the two-part Phase 2 MOXIe trial, a double-blind, randomized, placebo-controlled, multi-center, international trial designed to evaluate the safety, tolerability, and efficacy of omaveloxolone in patients with FA. During August 2017, the FDA confirmed that mFARS was acceptable as the primary endpoint for part two of the MOXIe trial. The FDA communication was made in response to Reata’s request that the FDA confirm its prior guidance that, depending on the MOXIe trial results, mFARS could be appropriate to support approval of omaveloxolone for FA under Subpart H. In the recent communication, FDA indicated that it may consider either accelerated or full approval based on the overall results of the trial and strength of the data. FDA recommended that we extend the treatment duration of the study and add a straightforward patient-reported or performance-based outcome endpoint to the study.
The trial will enroll approximately 100 FA patients randomized evenly to either 150 mg of omaveloxolone or placebo. The primary endpoint of the trial will be the change from baseline in mFARS of omaveloxolone compared to placebo at 48 weeks. Additional endpoints will include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and Clinical Global Impression of Change. We plan to randomize the first patient during the second half of 2017.
- Schulz et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009 Apr;5(4):222-34.
- Vankan et al. Prevalence gradients of Friedreich’s Ataxia and R1b haplotype in Europe co-localize, suggesting a common Palaeolithic origin in the Franco-Cantabrian ice age refuge. J Neurochem. 2013 Aug;126 Suppl 1:11-20.
- Parkinson. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J. Neurochem. 2013; 126:103-117.
- Klockgether T, Ludtke R, Kramer B, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998;121:589-600.
- Santos et al. Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010 Sep 1;13(5):651-90.
- Marmolino. Friedreich’s ataxia: past, present and future. Brain Res Rev 2011; 67:311-30.
- Delatycki MB, Camakaris J, Brooks H, et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann Neurol 1999; 45:673-5.
- Lodi R, Cooper JM, Bradley JL, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA. 1999; 96:11492-5.
- Shan Y, Schoenfeld RA, Hayashi G, et al. Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich’s ataxia YG8R mouse model. Antioxid Redox Signal 2013; 19:1481-93.
- D’Oria V, Petrini S, Travaglini L, et al. Frataxin deficiency leads to reduced expression and impaired translocation of NF-E2-Related Factor (Nrf2) in cultured motor neurons. Int J Mol Sci 2013; 14:7853-65.
- Paupe et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One 2009; 4:4253-64.
- Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open 2013; 0:1-10.