Azetukalner in Adults With Focal Seizures

Importance Despite more than 30 approved antiseizure medications, many individuals with focal epilepsy continue to experience seizures, indicating a persistent need for novel therapies. Objective To determine efficacy and safety of the novel, potent K V 7 channel opener azetukalner for treatment of focal seizures. Design, Setting, and Participants This phase 3, placebo-controlled randomized clinical trial of azetukalner was conducted over a 12-week double-blind period (November 18, 2022, to February 3, 2026) at 138 sites in North America, South America, Europe, and Asia Pacific. Adults with focal epilepsy experiencing 4 or more focal seizures per month despite stable treatment with 1 to 3 antiseizure medications were enrolled. Data were analyzed using a dataset derived from the database lock dated February 26, 2026. Interventions Participants were randomized 1:1:1 to receive placebo or 15 or 25 mg of azetukalner once daily with the evening meal for 12 weeks with no titration period. Participants completing the double-blind period could enter an open-label extension. Main Outcomes and Measures The primary efficacy end point was median percentage change from baseline in monthly (28-day) focal seizure frequency during the double-blind period for azetukalner vs placebo. Safety and tolerability were assessed by recording treatment-emergent adverse events, changes in clinical laboratory findings, vital signs, and electrocardiogram. Results Of 607 adults screened, 374 participants (190 [50.8%] female; mean [SD] age, 40.0 [12.9] years) were enrolled, randomized and treated with placebo (125 participants), 15-mg azetukalner (125 participants), or 25-mg azetukalner (124 participants). Participants had a baseline median (IQR) of 12.75 (7.56 to 32.97) seizures per month and had previously tried and stopped a median (IQR) of 5 (3 to 8) antiseizure medications. Most (336 participants [89.8%]) were receiving 2 to 3 concomitant antiseizure medications. The median (IQR) change from baseline in monthly seizure frequency was −10.4% (−39.1% to 8.3%) for the placebo group, −34.5% (−61.6% to −12.3%) for the 15-mg azetukalner group ( P < .001 vs placebo), and −53.2% (−77.2% to −28.8%) for the 25-mg azetukalner group ( P < .001 vs placebo). Azetukalner was generally well tolerated, and treatment-emergent adverse events were comparable to those observed in the phase 2b X-TOLE trial. Conclusions and Relevance This randomized clinical trial found that azetukalner demonstrated robust, rapid, and durable reductions in seizure frequency with a favorable benefit-risk profile. Treatment with azetukalner resulted in one of the largest median percentage reductions in seizure frequency vs placebo reported to date in patients with drug-resistant epilepsy, supporting azetukalner as a promising novel antiseizure medication with significant opportunity to improve clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05614063