Interim analysis of the long-term efficacy and safety of azetukalner in an ongoing open-label extension study following a phase 2b clinical trial (X-TOLE) in adults with focal epilepsy

Objective: To report interim data from an ongoing, open-label extension (OLE) of a Phase 2b study (X-TOLE) of azetukalner in adults with focal onset seizures (FOS) receiving 1-3 antiseizure medications. Methods: Eligible participants enrolled in the 7-year OLE at 20 mg azetukalner once daily with food. Long-term seizure outcomes included median percentage change (MPC) in monthly (28 days) FOS frequency from the double-blind phase (DBP) baseline and achievement of >= 50%, >= 75%, >= 90%, and 100% seizure reductions. Results:285 participants completed the DBP, and 275 (96.5%) enrolled in the OLE. At the 24-month interim analysis (September 5, 2023), 182 participants had been treated for >= 12 months and 165 for >= 24 months; 152 (55.3%) continued in the study. The median (range) treatment duration in the OLE was 26.3 (0.1-46.6) months. MPC reduction was 83.2% at 24 months in the OLE vs. DBP baseline. For all participants who entered the OLE, 56.4% (155/275) and 44.4% (122/275) achieved a >= 50% seizure reduction, 28.4% (78/275) and 19.6% (54/275) achieved a >= 90% seizure reduction, and 22.2% (61/275) and 14.9% (41/275) achieved seizure freedom (100% seizure reduction) for any consecutive >= 6- and >= 12-month period, respectively. For those who reached >= 24 months in the OLE, seizure freedom was achieved by 34.5% (57/165) and 23.6% (39/165) for any consecutive >= 6- and >= 12-month period, respectively. The majority of treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were dizziness (21.8%), headache (15.3%), coronavirus infection (15.3%), somnolence (12.7%), fall (12.7%), and memory impairment (10.9%). Serious AEs were reported in 35 (12.7%) participants. Significance: The efficacy demonstrated by azetukalner in reducing FOS seizure frequency in the DBP was sustained in this interim analysis. Azetukalner was generally well tolerated, with no new safety signals compared to the DBP. These data suggest sustained long-term efficacy and safety of azetukalner in a difficult-to-treat population.