Phase III X-TOLE2 data support azetukalner filing in focal onset seizures

Xenon Pharmaceuticals announced positive results from the Phase III X-TOLE2 study of azetukalner in focal onset seizures on 19 April at the 2026 American Academy of Neurology meeting. Azetukalner met the primary endpoint of median per cent change in monthly focal onset seizure frequency from baseline to week 12 in both dose groups, and the company plans to submit a new drug application to the FDA for the treatment of focal onset seizures in Q3 2026.

The X-TOLE2 study evaluated azetukalner, a novel, potent, KV7 potassium channel opener, as an oral, adjunctive, once-daily therapy with food for adult patients with focal onset seizures. The study randomised participants in a blinded manner to one of three treatment arms: azetukalner 25 mg, azetukalner 15 mg, or placebo. The trial included 380 randomised participants, with 374 participants in the safety and modified intent-to-treat population for the safety and efficacy analyses.

The study focused on highly treatment-resistant patients, with a median of five prior anti-seizure medications being applied and a baseline seizure frequency of 12.75 per month. A total of 51.3% of participants were also using at least three concomitant anti-seizure medications.

Azetukalner met the primary endpoint with a decline of 53.2% in monthly focal onset seizure frequency in the 25 mg group and a decline of 34.5% in the 15 mg group. The placebo group achieved a decline of 10.4% in seizure frequency. Azetukalner also demonstrated a safety and tolerability profile consistent with prior studies.

Azetukalner is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarise neurons. Xenon has signalled that, if approved, azetukalner would be the first KV7 potassium channel opener to reach the market for the treatment of epilepsy.

Azetukalner would be entering a highly competitive and crowded market in epilepsy, particularly focal onset seizures, with the current landscape dominated by sodium channel blockers, SV2A ligands, benzodiazepines, and other mixed-mechanism agents such as cenobamate. Azetukalner is currently in Phase III clinical trials for the treatment of epilepsy, major depressive disorder, and bipolar depression.