Friedreich’s Ataxia|Omav

Friedreich’s Ataxia

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. We have recently completed enrollment in part one of the trial. Data from the first part of MOXIe are expected in mid-year 2017.


Pathophysiology


In Friedreich’s ataxia, a mutation in the frataxin gene leads to impaired transcription 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



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.

Development Program


We are evaluating omaveloxolone in the MOXIe trial to evaluate the safety and efficacy of omaveloxolone in patients with Friedreich’s ataxia under an IND that we sponsored and filed in July 2014. MOXIe is being conducted at sites in the United States, Europe, and Australia. In 2014, we met with the FDA to discuss our FA program. Based on these discussions with the FDA, we designed a two-part, randomized, placebo-controlled, double-blind, dose-escalation Phase 2 trial with evaluation of a broad dose range in part one and a confirmatory evaluation of efficacy and safety in part two. Part one focuses on the evaluation of safety and efficacy of omaveloxolone doses ranging from 2.5 mg to 300 mg, and enrolled 69 patients, with enrollment completed in February 2017. Data for multiple endpoints are being collected, with the part one primary efficacy endpoint being the change in peak work, as measured by
exercise testing on a recumbent bicycle. The key secondary endpoint in part one is a functional assessment based on the modified Friedreich’s Ataxia Rating Scale (mFARS). Data from MOXIe part one are expected in mid-year 2017. Part two will be designed to provide additional efficacy and safety data and it has the potential to be used to support registration. If part one is successful, we expect to evaluate the data and make any changes needed to the protocol for the second part of MOXIe, and then initiate part two of MOXIe as soon as possible.

References


  1. Schulz et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol. 2009 Apr;5(4):222-34.
  2. 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.
  3. Parkinson. Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J. Neurochem. 2013; 126:103-117.
  4. 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.
  5. Santos et al. Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010 Sep 1;13(5):651-90.
  6. Marmolino. Friedreich’s ataxia: past, present and future. Brain Res Rev 2011; 67:311-30.
  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.