A safety analysis from the phase 3 MOXIe Part 2 trial (NCT0225435), presented at the International Congress at Ataxia Research 2024, provides insights into the treatment-emergent adverse events (TEAEs) associated with omaveloxolone (Skyclarys; Biogen), a drug approved for Friedreich ataxia (FA). The analysis focused on the frequency and timing of these events, revealing that most occurred within the first 12 weeks of treatment, with gastrointestinal disorders and elevated aminotransferase levels (AST/ALT) being the most common.
The study included 103 patients aged 16 to 40 years with genetically confirmed FA, randomized to either omaveloxolone (n = 51) or placebo (n = 52) for 52 weeks. TEAEs were observed in both groups, with the majority classified as mild or moderate in severity. Notably, elevated AST/ALT occurred in 29.4% (n = 15) of omaveloxolone-treated patients within the first 12 weeks, compared to only one case in the placebo group after 12 weeks. After this initial period, the incidence of several TEAEs, including elevated ALT/AST, headache, nausea, abdominal pain, and fatigue, began to decrease in the omaveloxolone group.
Timing and Duration of Adverse Events
The analysis revealed that the median time to onset for certain side effects was shorter in the omaveloxolone group compared to placebo. Nausea appeared at a median of 7 days, diarrhea at 14 days, vomiting at 11 days, and increased ALT/AST at 16 days. The median duration of elevated ALT and AST was 33 days in the omaveloxolone group. Interestingly, the median duration of fatigue was longer in the placebo arm, while those on omaveloxolone experienced longer durations of muscle spasms and back pain.
Mechanism and Clinical Implications
Omaveloxolone, a potent activator of Nrf2 signaling, is known to increase the expression of aminotransferases due to its pharmacodynamic effects. The investigators observed no instances of concomitant elevation of transferases and total bilirubin. They suggest that the transient increase in aminotransferases may reflect beneficial metabolic adaptations resulting from Nrf2 activation.
The maximum increases in ALT, AST, and GGT were observed within the first 12 weeks of omaveloxolone treatment, with a gradual downward trend over time. The study authors concluded that these findings can help guide patient treatment expectations and emphasize the importance of dosing compliance.
Efficacy and Approval Context
Omaveloxolone received FDA approval in 2023 as the first treatment for FA, based on data from the MOXIe Part 2 trial and a post hoc analysis of the open-label MOXIe extension trial (NCT02255435). The pivotal trial demonstrated a statistically significant reduction in modified Friedreich Ataxia Rating Scale scores in the omaveloxolone group compared to placebo at week 48 (P = .0138), with a placebo-corrected difference of -2.41 points. The recommended dose is 150 mg taken orally once daily.
