Azetukalner Reduces Focal Seizure Frequency in Phase 3 Trial
Key Clinical Summary:
- Adjunctive azetukalner was evaluated over 12 weeks in a phase 3 randomized trial involving 374 adults with focal epilepsy experiencing at least 4 monthly focal seizures despite stable treatment with 1 to 3 antiseizure medications.
- Median seizure-frequency reductions were 34.5% with 15 mg and 53.2% with 25 mg daily versus 10.4% with placebo (both P < .001).
- Azetukalner was generally well tolerated, with treatment-emergent adverse events similar to those in a previous phase 2b trial; forthcoming open-label extension data will further assess long-term durability and seizure freedom.
In a randomized clinical trial of 374 participants with focal epilepsy, adjunctive azetukalner demonstrated a rapid and durable reduction in seizure frequency during a 12-week treatment period. Published in JAMA Neurology, the study also found that the novel KV7 channel opener was generally well tolerated, supporting further evaluation of its potential as a next-generation antiseizure medication (ASM).
Study Findings
The phase 3, placebo-controlled X-TOLE2 trial enrolled adults with focal epilepsy experiencing 4 or more monthly focal seizures despite stable treatment with 1 to 3 antiseizure medications. Participants were randomized to receive placebo or 15 or 25 mg of azetukalner once daily in addition to their existing treatment regimen for 12 weeks.
Researchers evaluated median percentage change from baseline in monthly focal seizure frequency during the double-blind period as the primary end point. Safety and tolerability were also assessed.
Participants receiving either 15 or 25 mg of azetukalner experienced greater reductions in seizure frequency than those in the placebo group; the median (IQR) change from baseline was −10.4% (−39.1% to 8.3%) for those receiving placebo, −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).
Safety findings also indicated that the drug was generally well tolerated. Common treatment-emergent adverse events, including dizziness, somnolence, headache, and fatigue, were similar to those reported in a previous phase 2b trial.
Clinical Implications
Many patients with focal epilepsy continue to experience seizures despite pharmacologic intervention, underscoring a need for new therapeutic options.
The findings suggest that azetukalner may be an effective adjunctive option for adults with persistent focal seizures, though forthcoming data from an open-label extension will better assess long-term treatment durability and seizure freedom outcomes.
Expert Commentary
“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,” wrote Jacqueline A. French, MD, New York University Grossman School of Medicine and NYU Langone Health, New York, New York, and study coauthors.
“These findings support azetukalner, a novel KV7 channel opener, as a highly effective next-generation ASM that may help advance patient care by expanding therapeutic options available to improve the lives of people with epilepsy,” they concluded.
