Gastrointestinal Disorders and Aminotransferase Elevations Cited as Most Noted Adverse Events of Omaveloxolone

David R. Lynch, MD, PhD

A newly presented safety analysis of the phase 3 MOXIe Part 2 trial (NCT0225435) highlighted the frequency and timing of treatment-emergent adverse events (TEAEs) of omaveloxolone (Skyclarys; Biogen), an FDA-approved treatment for Friedreich ataxia (FA). All told, most treatment-emergent adverse events (TEAEs) occurred during the first 12 weeks of treatment, with gastrointestinal disorders and aminotransferase elevations (AST/ALT) as the most commonly observed TEAE.

The analysis, presented at the International Congress at Ataxia Research 2024, included 103 patients aged 16 to 40 years with genetically confirmed FA who were randomized to either omaveloxolone (n = 51) or placebo (n = 52) for a 52-week treatment period. Led by David R. Lynch, MD, PhD, professor of neurology at the University of Pennsylvania Perelman School of Medicine, TEAEs occurred in both treatment arms, a majority of which were mild or moderate in severity.

Elevated AST/ALT, noted as the most common, occurred in 29.4% (n = 15) of omaveloxlone-treated patients within the first 12 weeks and 9.8% (n = 5) after 12 weeks. For context, there was only 1 case of elevated AST/ALT in the placebo group, occurring after the 12-week mark. After week 12 the incidence of several TEAEs started to decrease in the omaveloxolone group. These included elevated ALT/AST, headache, nausea, abdominal pain, fatigue, diarrhea, influenza, vomiting, muscle spasms, and decreased appetite.

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For participants treated with omaveloxolone, the median time for certain side effects to appear was shorter than in the placebo group. These side effects included nausea (7 days), diarrhea (14 days), vomiting (11 days), increased ALT (16 days), increased AST (16 days), and fatigue (34 days). The median time to onset of ALT and AST elevations averaged 16 days in those on omaveloxolone while the median duration of elevated ALT and AST was 33 days. Of note, the median duration of fatigue was the longest in the placebo arm, with numerically less days of fatigue observed for those on omaveloxolone. In contrast, those on the novel medication experienced numerically longer median durations of muscle spasms and back pain than those on placebo.

Omaveloxolone, a potent activator of Nrf2 signaling, has been reported to increase the expression of aminotransferases, in part, because of its pharmcodynamic effects. In the analysis, investigators observed no cases of concomitant elevation of transferases and total bilirubin observed in the study. They also noted that the transient increase in aminotransferases found in omaveloxolone-treated patients may be a result of beneficial metabolic adaptations driven by the activation of Nrf2.

An additional aspect of the analysis revealed that the maximum increases of ALT, AST, and GGT occurred within the first 12 weeks of omaveloxolone treatment. Despite this, the frequency of aminotransferases trended gradually down over time, even during the first 12 weeks of treatment. All together, the study authors concluded that these findings provide evidence to guide patient treatment expectations and suggest the importance of dosing compliance among physicians and patients.

Omaveloxolone was approved as the first treatment for patients with FA in 2023 based on efficacy and safety data from MOXIe Part 2 and a post hoc propensity-matched analysis of the open-label MOXIe extension trial (NCT02255435). In the supporting trial data, treatment with the therapy resulted in a statistically significant lower modified Friedreich Ataxia Rating Scale scores relative to placebo at week 48, accounting for a placebo-corrected difference between the groups of –2.41 points (P = .0138). The therapy, an oral once-daily medication, is indicated with a recommended dose of 150 mg (taken in 3 capsules).²

REFERENCES
1. Lynch D, Boesch S, Delatycki M, et al. The MOXIe trial of omaveloxolone in Friedreich ataxia: exploring the transient nature of treatment-emergent adverse events. Presented at: International Congress at Ataxia Research 2024
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 14, 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