Azetukalner (XEN1101)

Two randomized, double-blind, placebo-controlled trials support the New Drug Application. In the Phase 2b X-TOLE trial, 325 participants were randomized and treated and 323 were analyzed for efficacy. The median percent reduction in monthly focal onset seizure frequency over the 8-week double-blind period was 52.8% at 25 mg, 46.4% at 20 mg, and 33.2% at 10 mg, compared with 18.2% for placebo. The proportions of participants with at least a 50% reduction were 54.5%, 43.1%, and 28.3%, compared with 14.9% for placebo. In the Phase 3 X-TOLE2 trial, 380 participants were randomized and 374 were analyzed. The median percent change was -53.2% at 25 mg and -34.5% at 15 mg, compared with -10.4% for placebo, and the proportions with at least a 50% reduction were 54.8% and 37.6%, compared with 20.8% for placebo. The placebo-adjusted median percent change in the X-TOLE2 25 mg group was -42.7%.

In the X-TOLE open-label extension, among participants treated for at least 48 months (n = 131) the median percent reduction in monthly focal onset seizure frequency rose from 69.8% in the first month to 90.9% at month 48, and seizure freedom for any consecutive period of at least 12 months was attained by 38.2% of that group. The most common treatment-emergent adverse events in X-TOLE2 across both azetukalner doses were dizziness (20.5%), headache (8.8%), somnolence (8.8%), and fatigue (7.6%), compared with 3.2%, 6.4%, 7.2%, and 6.4% for placebo. Discontinuation for a treatment-emergent adverse event occurred in 14.5% of the 25 mg group, 4.8% of the 15 mg group, and 3.2% of the placebo group. No retinal pigment epithelium or macular abnormalities occurred during the X-TOLE2 double-blind period, and the epilepsy trials have generated more than 1,500 patient-years of safety and exposure data.