Clin Transl Sci. 2025 Feb;18(2):e70139. doi: 10.1111/cts.70139.
ABSTRACT
Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose of 150 mg once daily. This double-blind, randomized, placebo- and active-controlled, three-way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 mg [open-label positive control]) administered with an FDA high-fat meal. Serial pharmacokinetic blood sampling and time-matched electrocardiogram assessments were performed. The primary endpoint was placebo-corrected change from baseline in QTcF (ΔΔQTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone Cmax was 319 ng/mL in this study (4.5-fold the mean steady-state Cmax [71.5 ng/mL] with the approved dose). The mean QTcF intervals were < 450 ms, and mean changes from baseline were < 10 ms at all timepoints following all doses. The upper limit of the 90% CIs of ΔΔQTcF following omaveloxolone administration was < 10 ms at all timepoints. At the Cmax of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model-predicted ΔΔQTcF were all < 10 ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst-case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.
PMID:39976332 | DOI:10.1111/cts.70139