Objective:

Report the efficacy of azetukalner by focal seizure subtype in the double-blind Phase 2b X-TOLE study 

Background:

325 participants with FOS who failed a median of 6 antiseizure medications (ASMs), and on stable treatment with 1-3 ASMs were treated with placebo or azetukalner, a novel, potent K_V7 potassium channel opener. Azetukalner showed a dose-dependent, significant, and rapid onset reduction in FOS frequency vs placebo. 

Design/Methods:

The median percentage change (MPC) in monthly (28 days) seizure frequency and proportion of participants experiencing a ≥50% reduction in monthly seizure frequency (RR50) were calculated by seizure subtypes as an exploratory analysis, after 8 weeks treatment with azetukalner (25 mg; n=112) or placebo (n=114), taken once daily with food and no titration. Seizure subtypes were focal aware with motor signs (type 1), focal impaired awareness with motor signs (type 2), focal impaired awareness nonmotor (type 3), and focal to bilateral tonic-clonic (type 4).

Results:

At baseline, 80 (24.8%), 241 (74.6%), 72 (22.3%), 77 (23.8%) participants had type 1, 2, 3 and 4 seizure subtypes, respectively. Median monthly baseline seizure frequencies for type 1, 2, 3 and 4 seizure subtypes for azetukalner 25 mg were 12.6, 9.5, 11.2, and 2.9 vs 16.2, 9.0, 11.4, and 1.9 for placebo respectively. MPC reduction from baseline for types 1, 2, 3, and 4 was higher for azetukalner 25 mg (54.6%, 58.8%, 45.2%, 86.9%) vs placebo (21.4%, 19.5%, 23.8%, 36.5%). RR50 rates were also higher for azetukalner 25 mg (51.9%, 59.8%, 46.2%, 78.3%) vs placebo (24.1% 21.7%, 17.4%, 40.0%) for types 1-4, respectively. The most common treatment-emergent adverse events for azetukalner 25 mg were dizziness (31.6%), somnolence (14.9%), and fatigue (12.3%).

Conclusions:

Compared with placebo, azetukalner 25 mg reduced seizure frequency rate across focal seizure subtypes, including those that progressed from focal to bilateral tonic-clonic, in the X-TOLE study.