Omaveloxolone Sustains Benefit Effect in Friedreich Ataxia at 3 Years


In a cross-study analysis, omaveloxolone slowed progression in FA by at least 50% each year for 3 years compared with corresponding data from an external control group in a natural history study.

 David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine

David R. Lynch, MD, PhD

Newly published post-hoc research from the phase 3 MOXIe trial and its extension (NCT02255435) showed that patients treated with omaveloxolone (Skyclarys; Reata Pharmaceuticals), an FDA-approved therapy for Friedreich ataxia (FA), maintained benefits for up to 3 years.1 These findings suggest that omaveloxolone has a meaningful effect in slowing of disease progression among patients with FA.

After 3 years of treatment, the change from baseline in Friedreich Ataxia Rating scale (mFARS) score significantly differed between omaveloxolone-treated patients in the MOXIe extension and patients in the untreated, matched, Friedreich Ataxia Clinical Outcome Measures Study (FACOMS). In the pooled primary population consisting of 136 patients, matched patients from FACOMS progressed 6.6 points on mFARS compared with omaveloxolone-treated patients in MOXIe extension who progressed 3.0 points (difference, −3.6 points; nominal P = .0001). Overall, omaveloxolone reduced progression in mFARS by 55% compared with the matched group.

“During treatment in the MOXIe extension, omaveloxolone treatment in the primary pooled population slowed progression by at least 50% at each year compared with the corresponding FACOMS external control group, indicating benefit that persisted and accrued over 3 years. Subsets of MOXIe extension patients that differed in prior treatment status also had slowed disease progression when matched to FACOMS controls,” lead author David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, and colleagues wrote.1 “All of the primary analysis populations suggested a benefit of omaveloxolone as did sensitivity analyses at all points during the 3-year duration of the study.”

READ MORE: Phase 1 Data on Friedreich Ataxia Agent DT-216 Shows Promising Results, Increase in Frataxin Levels

Researchers performed a propensity-matched comparison of data from the open-label MOXIe extension assessing omaveloxolone with patients from FACOMS, a multi-center longitudinal study on FA. Patients in the MOXIe extension were matched to the patients from FACOMS utilizing a logistic regression to estimate propensity scores based on multiple covariates. The multiple covariates included sex, baseline age, age of onset, baseline modified mFARS score, and baseline gait score.

"The FACOMS natural history study presents an opportunity for identification of suitable external control groups. The significant overlap in trial sites and investigators ensures a similar approach to overall patient management for FA and comorbid conditions. In addition, at the time of the study, there were no approved or effective disease modifying therapies for FA, minimizing confounding in the comparison of groups from 2 different studies,” Lynch et al noted.1

Between the placebo and treatment populations, omaveloxolone slowed progression in mFARS by at least 50% (treatment difference, nominal P <.05). In the primary placebo population, progression in mFARS was slowed by 56% compared with the natural history controls. In the primary omaveloxolone-treated population, where patients previously received 48 weeks of omaveloxolone in Part 2 of the study, progression in mFARS was slowed by 61% in patients from MOXIe extension compared with patients from FACOMS. Notably, patients from the MOXIe extension experienced an improvement from baseline in mFARS at the first year, with a treatment difference of −2.8-mFARS points (nominal P = .0035).

All told, potential limitations included the scheduled assessments for mFARS, as the assessments were annually in the FACOMS study and biannually in MOXIe extension. In addition, the Mixed Models for Repeated Measures analysis used for annual visits was not using all mFARS assessments from the MOXIe extension. Notably, authors reported that using external controls from a natural history study did not account for a placebo effect.

“Although there are limitations to this cross-study analysis, the approach leads to readily interpretable results on the potential benefit of omaveloxolone. The FACOMS cohort identified by propensity score matching is highly comparable to the MOXIe extension patients for baseline characteristics and standard of care; therefore, the observed difference in disease progression may be attributed to omaveloxolone treatment,” Lynch et al noted.1 “Thus, such propensity-matched analysis from the FACOMS natural history study compared with MOXIe extension provide evidence for the possible use of omaveloxolone for the treatment of FA and demonstrates the value and methodology for utilization of natural history data in clinical trials in rare diseases.”

1. Lynch DR, Goldsberry A, Rummey C, et al. Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann Clin Transl Neurol. 2023;10.1002/acn3.51897. doi:10.1002/acn3.51897
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