DAY 3 | Azetukalner Demonstrates Long-Term Efficacy and Safety in the Treatment of Focal Seizures

Long-term data from the open-label extension phase of the X-TOLE clinical trial showed that patients with focal onset seizures (FOS) treated with azetukalner achieved sustained reductions in seizure frequency, and a meaningful proportion of participants achieved prolonged intervals of seizure freedom of 12 months or longer. The results of the latest, 48-month interim analysis were presented at the 2025 American Epilepsy Society Annual Meeting in Atlanta, Georgia. 

Azetukalner is a potent, selective Kv7 potassium channel opener that is currently being evaluated in the ongoing 7-year X-TOLE open-label extension study enrolling adults with FOS aged 18 to 75 years. Of the 285 participants who completed the X-TOLE double-blind period, 275 enrolled in the open-label extension phase, continuing treatment with azetukalner 20 mg once daily. As of October 6, 2025, 122 patients still participated in the open-label study. The most common reasons cited for treatment discontinuation were lack of efficacy, study withdrawal by the participant, and adverse events, reported in 13.1% of the study population. 

The long-term data reinforced the early findings from the double-blind period of X-TOLE, which showed that treatment with azetukalner yielded a statistically significant, dose-dependent reduction from baseline in monthly seizure activity in participants with difficult-to-treat FOS. The interim analysis of results obtained through October 6, 2025 revealed that reductions in monthly seizure frequency from the baseline in the double-blind period ranged from 61.6% to 81.9% during months 1 to 24 of the open-label extension phase, and increased further to a 90.9% reduction at month 48. 
Nearly half (47.6%) of the 275 participants in the open-label extension phase achieved periods of 12 months or longer of at least 50% reduction in seizure frequency, while 30.5% of the participants achieved at least a 75% reduction in frequency, and one-quarter of the cohort experienced at least a 90% reduction in seizure frequency for at least 12 consecutive months. A reduction in seizure frequency of at least 50% for 48 months or longer was recorded in 17% of the cohort. 

Moreover, the long-term data showed that the gains were sustained over time. Nearly 40% of the 131 participants treated for 4 years or longer experienced at least a 50% reduction in seizure frequency for at least 48 consecutive months. Periods of seizure freedom of 12 months or longer were reported in 20.7% of the participants in the open-label extension phase of the study, and in 38.2% of the participants treated with azetukalner for 48 months or longer. 

The long-term safety of azetukalner was comparable with the safety profile observed in the initial, double-blind period of the trial, with dizziness and headache reported as the most common adverse events. Serious treatment-related adverse events were reported in 45 (16.4%) participants. “Azetukalner was generally well tolerated, with a low incidence of serious adverse events,” the authors noted. “These promising data suggest long-term efficacy and tolerability of azetukalner in patients with difficult-to-treat disease.”