Overview

  • FA is an inherited, life-shortening, debilitating, and degenerative neuromuscular disorder for which there are no approved therapies1
  • FA is diagnosed in about one in 50,000 people worldwide, making it the most common in a group of related disorders called hereditary ataxias, affecting approximately 6,000 patients in the US2,3
  • FA, an autosomal recessive, single-gene disorder is caused by mutations in the FXN gene, which provides instruction for making the protein frataxin. Frataxin helps assemble clusters of iron and sulfur critical for energy production in the mitochondria4
  • Reata is developing omaveloxolone, which has the potential to prevent long-term consequences and improve FA symptoms by addressing the underlying pathologic processes associated with inflammation, mitochondrial dysfunction, and oxidative stress
  • Omaveloxolone is being studied in the pivotal, registration, phase 2 MOXIe trial for the treatment of FA

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Pathophysiology

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.

Impaired-Mitochondrial-1

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

Development Program

MOXIe Trial14

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.

clinical-global-impression

References
  1. Aranca TV, Jones TM, Shaw JD, et al. Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag. 2016;6(1):49-65.
  2. Vankan P. 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;126(suppl 1):11-20.
  3. Polek B, Roach MJ, Andrews WT, Ehling M, Salek S. Burden of Friedreich’s ataxia to the patients and healthcare systems in the United States and Canada. Front Pharmacol. 2013;4:66.
  4. Li K, Besse EK, Ha D, Kovtunovych G, Rouault TA. Iron-dependent regulation of frataxin expression: Implications for treatment of Friedreich ataxia. Hum Mol Genet. 2008;17(15):2265-2273.
  5. Santos R, Lefevre S, Sliwa D, Seguin A, Camadro JM, Lesuisse E. Friedreich ataxia: Molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010;13(5):651-690.
  6. Paupe V, Dassa EP, Goncalves S, et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One. 2009;4(1):e4253.
  7. Dürr A. Friedreich’s ataxia: Treatment within reach. Lancet Neurol. 2002;1(6):370-374.
  8. Abeti R, Baccaro A, Esteras N, Giunti P. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich’s ataxia models. Front Cell Neurosci. 2018;12:188.
  9. Tai G, Corben LA, Yiu EM, Milne SC, Delatycki MB. Progress in the treatment of Friedreich ataxia. Neurol Neurochir Pol. 2018;52(2):129-139.
  10. Dinkova-Kostova AT, Kostov RV, Kazantsev AG. The role of Nrf2 signaling in counteracting neurodegenerative disease. FEBS J. 2018;285(19):3576-3590.
  11. Lupoli F, Vannocci T, Longo G, Niccolai N, Pastore A. The role of oxidative stress in Friedreich’s ataxia. FEBS Lett. 2018;592(5):718-727.
  12. 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(4):7853-7865.
  13. Hayashi G, Cortopassi G. Oxidative stress in inherited mitochondrial diseases. Free Radic Biol Med. 2015;88:10-17.
  14. Reata Pharmaceuticals, Inc. announces positive data from part one of MOXIe trial of omaveloxolone for Friedreich’s ataxia [press release]. Irving, TX: Reata Pharmaceuticals; June 1, 2017.