Newly Initiated Phase 3 BRAVE Study Tests Omaveloxolone in Pediatric Friedreich Ataxia

Susan Perlman, MD

According to an announcement, Biogen has initiated a new phase 3 trial dubbed BRAVE (NCT06953583) that tests the therapeutic potential of omaveloxolone (Skyclarys), the only FDA-approved therapy for adults with Friedreich ataxia (FA), in pediatric patients living with the disease. The 52-week trial will include 255 children with FA, both non-ambulatory and ambulatory, testing efficacy, safety, pharmacokinetics and pharmacodynamics of the approved therapy.^1,2

The newly initiated study, split into 2 parts, includes children with genetically confirmed FA aged 2 to 16 who will receive either omaveloxolone once a day (QD) or placebo. Part 1, the randomized controlled portion, uses change in Upright Stability Score (USS), a part of the validated modified FA Rating Scale (mFARS), as the primary end point. Part 2, or the open-label extension phase, lasts up to 104 weeks, giving patients from either cohort the opportunity to experience omaveloxolone treatment.

"Early onset patients often have the most aggressive and fast progressive form of Friedreich ataxia and through the BRAVE study we aim to determine the potential safety and efficacy of omaveloxolone for children living with the disease," Susan Perlman, MD, professor of neurology and director of the Ataxia Center, David Geffen School of Medicine, UCLA, said in statement. "This vulnerable population faces significant unmet need, with no approved treatments currently available."

Omaveloxolone, an Nrf2 inhibitor, was approved in adults and adolescents aged 16 years and older in 2023 using data from the MOXIe Part 2 Trial and a propensity-matched analysis of the study’s open-label extension as the supportive data. The oral medication, taken once daily, is indicated with a recommended dose of 150 mg (taken in 3 capsules). In addition to BRAVE, it is currently being studied in the SKYCLARYS PASS registry (NCT06623890), as well as a phase 4 post-marketing trial (NCT0662687) assessing maternal, fetal, and infant outcomes.^3,4

In the newly initiated BRAVE study, investigators will look at several other end points aside from USS, including change in Columbia Suicide Severity Rating Scale, Friedreich’s Ataxia-Health Index, Patient and Clinician Global Impressions scales, and Friedreich’s Ataxia-Activities of Daily Living. In addition, the trial will collect data on plasma concentrations of omeveloxolone, change in body mass index, and change in cardiac function, as assessed by echocardiogram.

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To be included in the trial, patients must have a confirmed genetic diagnosis of FA, either through homozygous GAA repeat expansion in the frataxin gene or a combination of GAA expansion with another mutation (point mutation or deletion). Individuals must be symptomatic for FA, as reported by themselves or a caregiver. Children aged 7 to under 16 must also demonstrate moderate upright stability, with a baseline USS score between 10 and 34. Eligibility for the open-label extension requires successful completion of Part 1 without meeting discontinuation criteria and a favorable safety profile as judged by the investigator.

Key exclusions for BRAVE include uncontrolled diabetes (HbA1c > 11%), severe cardiac dysfunction (BNP > 200 pg/mL or ejection fraction < 40%), or clinically significant cardiac disease beyond mild to moderate cardiomyopathy. For Part 2, participants must not have significant liver abnormalities (ALT/AST > 1.5× ULN, TBL > 2× ULN) or elevated BNP levels (> 200 pg/mL) at the most recent assessment. Any unresolved lab abnormalities or health changes may delay Part 2 entry, pending reassessment and investigator approval.

Stephanie Fradette, PharmD

"Recognizing the symptoms of Friedreich ataxia typically begin in childhood, and earlier onset of symptoms is associated with faster disease progression, there is tremendous unmet need in the pediatric community. Building on the work of Reata we have been urgently advancing the pediatric development plan for omaveloxolone and are thrilled that the Phase 3 BRAVE study has now begun,” Stephanie Fradette, PharmD, head of the neuromuscular unit, Biogen, said in a statement. “We are immensely grateful for the input from the entire FA community that has helped shape the design of this important study."

REFERENCES
1. Biogen Initiates Phase 3 Pediatric Study of Omaveloxolone for the Treatment of Friedreich Ataxia. News release. June 18, 2025. Accessed June 18, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-initiates-phase-3-pediatric-study-omaveloxolone-treatment
2. A Study to Learn More About the Effects and Long-Term Safety of BIIB141 (Omaveloxolone) in Participants With Friedreich's Ataxia Aged 2 to 15 Years Old. Clinicaltrials.gov. Updated June 17, 2025. Accessed June 18, 2025. https://clinicaltrials.gov/study/NCT06953583
3. 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.
4. Farmer J, Dobay P, Domingo-Horne RM, et al. Treatment of Friedreich Ataxia With Omaveloxolone During Pregnancy and/or Lactation: Design and Rationale of a Post-Marketing Observational Study. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19; Dallas, TX. ABSTRACT P180.