Omaveloxolone|Friedreich’s Ataxia

Friedreich’s Ataxia

Friedreich’s ataxia is an inherited, debilitating, and degenerative neuromuscular disorder that is normally diagnosed during adolescence and can lead to early death. Patients with FA experience progressive loss of coordination, muscle weakness, and fatigue, which commonly progresses to motor incapacitation and wheelchair reliance1. 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-30s2,3,4.

There are no currently approved therapies for the treatment of FA. Patients are usually given guidelines around certain lifestyle habits. They are recommended to follow a diet that is low in iron and encouraged to take vitamins and supplements5. Because omaveloxolone targets molecular pathways involved in impaired bioenergetics and chronic inflammation and penetrates the blood-brain barrier, we believe that the drug could provide a benefit to FA patients.

FA is an ultra-orphan disease. There are an estimated 22,000 people globally with FA, including an estimated 6,000 to 7,000 in the United States and approximately 9,500 in the European Union6.


Pathophysiology


Friedreich’s ataxia is an autosomal recessive cerebellar ataxia caused by triplet-repeat expansions of trinucleotides (GAA) in the frataxin gene, leading to impaired transcription of frataxin and reduced expression of the mitochondrial protein frataxin. Deficiency of frataxin in cells leads to mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and impaired mitochondrial ATP production. Impaired ATP production in FA patients likely accounts for the decreased coordination, progressive muscle weakness, exercise intolerance, and fatigue observed in these patients, as well as other disease manifestations7,8,9.

Mechanism of Action


Omaveloxolone targets molecular pathways involved in impaired bioenergetics and mitochondrial function. Because 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. Further, data demonstrate that Nrf2 signaling is significantly impaired in both FA patients and in preclinical models of frataxin deficiency, resulting in impairment of antioxidant defense mechanisms, while silencing of frataxin gene expression has been linked to decreases in expression of Nrf29,10,11. Accordingly, we believe that Nrf2 activation through omaveloxolone may result in a clinical benefit to FA patients12.

Development Program


Reata has initiated the MOXIe study, a placebo-controlled, multi-center Phase 2 study of omaveloxolone in Friedreich’s ataxia.

References


  1. 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.
  2. Santos et al. Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010 Sep 1;13(5):651-90.
  3. Parkinson. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J. Neurochem. 2013; 126:103-117.
  4. Marmolino. Friedreich’s ataxia: past, present and future. Brain Res Rev 2011; 67:311-30.
  5. Schulz et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009 Apr;5(4):222-34.
  6. 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.
  7. Delatycki MB, Camakaris J, Brooks H, et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann Neurol 1999; 45:673-5.
  8. 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.
  9. 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.
  10. 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.
  11. Paupe et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS One 2009; 4:4253-64.
  12. 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.