Friedreich Ataxia (FA)

Skyclarys™ (omaveloxolone), previously known as RTA 408, is an Nrf2 activator and the first therapy approved by the U.S. Food and Drug Administration for the treatment of Friedreich ataxia. Skyclarys was approved by the FDA on February 28, 2023.⁸

Friedreich ataxia (FA) is an inherited neurodegenerative disease caused by mutations in the FXN gene, which codes for the frataxin protein. Frataxin plays an important role in the synthesis of iron sulfur clusters and the production of adenosine triphosphate (ATP) in mitochondria. Patients with FA develop problems with ambulation, coordination, and speech. As the disease progresses, most patients lose the ability to walk. Cardiomyopathy, metabolic disturbances, and skeletal abnormalities are also frequently reported.^1,2 

Currently, there are no disease-modifying therapies approved for treating FA.² However, several compounds such as nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators are undergoing clinical development and study.³

Nrf2 Activators

Nrf2 is a transcription factor that plays an important role in decreasing oxidative stress within cells. In physiological conditions, Nrf2 translocates to the nucleus when oxidative stress occurs, increasing the expression of antioxidant genes. Nrf2 deficiency renders cells more susceptible to oxidative stress and therefore to the effects of reactive oxygen species (ROS) and inflammation.^4,5 

Nrf2 activation is suppressed in patients with FA, which contributes to oxidative stress, mitochondrial dysfunction, and decreased production of ATP. In cells from patients with FA, the activation of Nrf2 was shown to promote mitochondrial activity. The Nrf2 pathway is therefore a potential therapeutic target in FA.¹

Read more about FA pathophysiology

Omaveloxolone in Preclinical Studies

Skyclarys is an Nrf2 activator.³ In various in vitro FA models, omaveloxolone reverted the pathological phenotype by decreasing lipid peroxidation and the production of ROS in the mitochondria, ultimately preventing cell death caused by oxidative stress.³ Mitochondrial function was restored in fibroblasts from patients with FA and in neurons from FA mouse models.⁵ Studies have also shown a loss of activity with higher cellular concentrations. This allows regulation of the cellular redox status and is similar to what is observed with other Nrf2 activators.¹

Read more about FA histology

Omaveloxolone in Clinical Studies

The pharmacokinetics, safety, pharmacodynamics, and clinical effects of omaveloxolone were studied in a 2-part multicenter trial, MOXIe (NCT02255435), which was funded by Reata Pharmaceuticals and involved 11 study sites in the United States, Europe, and Australia.^1,2,6 

The first part of the trial consisted of a 12-week phase 2, double-blind, randomized, placebo-controlled, dose-ranging, multicenter study involving 69 patients.¹ The goal of Part 1 of the trial was to determine the optimal dose of omaveloxolone for the induction of pharmacodynamic measures of Nrf2.⁵

In this part of the study, the primary outcome measure was cardiopulmonary exercise testing of “peak workload” on a stationary bike. Secondary outcome measures included the modified Friedreich Ataxia Rating Scale (mFARS; an abbreviated form of the Friedreich Ataxia Rating Scale) scores at 4 and 12 weeks.⁴ Omaveloxolone did not significantly change the primary outcome measure at the study endpoint, but it improved mFARS scores in a dose-dependent manner.⁴ A dose level of 160 mg/day improved the neurological function of the patients, so the study selected an optimal convenient daily dose of 150 mg.¹

The second part (Part 2) of the MOXIe clinical trial consisted of a double-blind, randomized, placebo-controlled, parallel-group, 48-week study that included 103 patients to determine the safety and efficacy of 150 mg of omaveloxolone administered once a day in patients with FA in terms of neurological function.⁵ Results of this part of the study showed that the primary outcome measure — change from baseline in mFARS score at 48 weeks in those treated with omaveloxolone compared with those on placebo — was achieved and that the mFARS score significantly improved after 48 weeks of treatment.^1,3 

In MOXIe, omaveloxolone was well tolerated and the adverse events observed were mild. The most common adverse events reported included headache, nausea, and fatigue. An elevation in transaminase levels was reported without an increase in total bilirubin levels or signs of liver injury.^1,5 

The open-label extension study includes 87% of the patients enrolled in MOXIe (either Part 1 or Part 2) monitors the safety and tolerability of omaveloxolone in long-term use.⁶

Read more about FA clinical trials

Approval Status of Omaveloxolone

While omaveloxolone is still not a cure for FA, it is the first therapy targeting downstream events that has been submitted for New Drug Application. The US Food and Drug Administration (FDA) accepted the filing and granted Priority Review status in May 2022. The therapy was reviewed with a prescription drug user fee act (PDUFA) date of February 28, 2023, and approved by the FDA on this date as well. Omaveloxolone also received Fast Track and Orphan Drug designations from the FDA.⁷

Read more about FA experimental therapies

References

 1. Lynch DR, Farmer J, Hauser L, et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018;6(1):15-26. doi:10.1002/acn3.660

2. Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich’s ataxia: delayed-start analysis of the MOXIe extension. Mov Disord. Published online November 29, 2022. doi:10.1002/mds.29286

3. Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant therapies and oxidative stress in Friedreich’s ataxia: the right path or just a diversion? Antioxidants (Basel). 2020;9(8):664. doi:10.3390/antiox9080664

4. Zesiewicz TA, Hancock J, Ghanekar SD, Kuo SH, Dohse CA, Vega J. Emerging therapies in Friedreich’s ataxia. Expert Rev Neurother. 2020;20(12):1215-1228. doi:10.1080/14737175.2020.1821654

5. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934

6. RTA 408 capsules in patients with Friedreich’s ataxia – MOXIe. ClinicalTrials.gov. October 2, 2014. Updated December 6, 2022. Accessed February 13, 2023.

7. Profeta V, McIntyre K, Wells M, Park C, Lynch DR. Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia. Expert Opin Investig Drugs. Published online February 8, 2023. doi:10.1080/13543784.2023.2173063

8. Reata Pharmaceuticals Announces FDA Approval of SKYCLARYS™ (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia. reatapharma.com. February 28, 2023. Accessed March 1, 2023.

Reviewed by Harshi Dhingra, MD, on 2/13/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.