New Postmarketing Registry to Evaluate Real-World Safety and Patient Experience With Omaveloxolone

Susan Perlman, MD

At the 2024 International Congress for Ataxia Research (ICAR), held November 12-15, in London, United Kingdom, investigators presented the design outline of a new postmarketing registry, named SKYCLARYS PASS (NCT06623890), that will collect long-term safety and patient experience data on omaveloxolone (Skyclarys; Biogen), an FDA-approved treatment for Friedreich ataxia (FA). The hope is that through the registry, which will follow omaveloxolone-naïve patients for up to 5 years, findings will help guide healthcare professionals in their clinical decisions.¹

Omaveloxolone, a nuclear factor-like 2 activator, became approved as the first therapy to treat patients with FA in 2022, using data from the MOXIe Part 2 clinical trial (NCT02255435) as supportive evidence. SKYCLARYS PASS, an observational, multicountry cohort registry, is expected to consist of around 300 omaveloxolone-naïve patients who are enrolled in the Freidreich’s Ataxia Global Consortium UNIFIED natural history study (UNIFAI).

Presented by Susan Perlman, MD, clinical professor of neurology at the David Geffen School of Medicine of UCLA, the study will primarily assess long-term safety, including characterization of drug-induced liver injury (DILI) and congestive heart failure (CHF), considered potential risks of omaveloxolone. Secondary outcomes include treatment interruptions, discontinuations, and drug overdoses. Each year, a report from the study will be provided to the European Medicines Agency and interim analyses of DILI and CHF adverse events (AEs) will be performed for the FDA.

SKYCARYS PASS combines both the Friedreich Ataxia Clinical Outcome Measures Study (FACOMS) and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS). FACOMS, originally created in 2004, includes over 1000 patients with FA across Australia, Canada, India, New Zealand, and the USA. EFACTS, which has been around since 2013, includes more than 1000 patients from Belgium, Czech Republic, France, Germany, Greece, Ireland, Italy, Spain, and the United Kingdom.

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In terms of inclusion and exclusion criteria, the study allows only patients with a documented diagnosis of FA, including confirmation via genetic testing. Patients must be at least 16 years of age, omaveloxolone-naïve, and must be willing and able to comply with visits. The study excludes those previously enrolled in a clinical trial of omaveloxolone, those participating in a blinded interventional trial, and patients who are unable to comply with the requirements of the registry or are unsuitable for any reason.

In this study, DILI events are defined by Hy’s law criteria: either total bilirubin levels reaching at least twice the upper limit of normal (ULN) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels reaching three times ULN, or ALT/AST levels reaching ten times ULN. Any other significant liver abnormalities may also be assessed as potential DILI events. Similarly, CHF events are defined as a New York Heart Association (NYHA) class III or IV status, or death due to CHF, following the Standardized MedDRA Query (SMQ) for cardiac failure. Additional significant cardiac abnormalities may be considered CHF events at the investigator’s discretion. Data on DILI and CHF, including descriptions and incidence rates, will be gathered via AE and serious AE forms, covering events from baseline through 60 days after omaveloxolone is discontinued.

In addition to mainly focusing on safety, the trial includes several exploratory objectives, assessing health-related quality of life (HRQOL) and healthcare resource utilization in treated patients. HRQOL will be assessed through the FA-Health Index, a 17-item FA-specific questionnaire, and the Modified Fatigue Impact Scale, a 21-item scale providing assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning.

When omaveloxolone was approved in 2022, the treatment label indicated a recommended dosage of 100 mg once daily for individuals with moderate hepatic impairment, to be further reduced to 50 mg once daily in the instance of adverse reactions. For those with severe hepatic impairment, the treatment is not recommended. The label also indicates that ALT, AST, bilirubin, B-type natriuretic peptide, and lipid parameters should be obtained prior to and during treatment.^2,3

REFERENCES
1. Perlman S, Lynch D, Mariotti C, et al. Study design of an observational, multinational, postmarketing registry of omaveloxolone-treated patients with Friedreich ataxia. Presented at: International Congress for Ataxia Research (ICAR) 2024; November 12-15; London, UK.
2. Reata Pharmaceuticals Announces FDA Approval of SKYCLARYS™ (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia. Reata Pharmaceuticals. News release. February 28, 2023. Accessed November 15, 2024. https://www.reatapharma.com/investors/news/news-details/2023/Reata-Pharmaceuticals-Announces-FDA-Approval-of-SKYCLARYS-Omavaloxolone-the-First-and-Only-Drug-Indicated-for-Patients-with-Friedreichs-Ataxia/default.aspx
3. SKYCLARYS. FDA Label. Updated February 28, 2023. Accessed November 15, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216718Orig1s000lbl.pdf