Xenon Pharmaceuticals Reports Positive Azetukalner Phase 3 Data in Focal Onset Seizures
Vancouver and Boston-based Xenon Pharmaceuticals announced positive topline results from the Phase 3 X-TOLE2 study of azetukalner, a KV7 potassium channel opener, in adults with focal onset seizures. The X-TOLE2 study results position azetukalner as the first drug in its mechanistic class to reach a potential US FDA filing since retigabine was withdrawn from the market in 2017 due to safety concerns, and the data exceeded those from the earlier Phase 2b X-TOLE trial.
Trial specifics
X-TOLE2 was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study evaluating azetukalner as adjunctive oral therapy, administered once daily with food, in adults with focal onset seizures. The trial randomized 380 participants across three arms — azetukalner 25 mg, azetukalner 15 mg, and placebo — with 374 entering the modified intent-to-treat population. Participants had treatment-resistant epilepsy, with a median of five prior antiseizure medications and a baseline seizure frequency of 12.75 per month; 51.3% were taking three concomitant antiseizure medications. The primary endpoint was median percent change in monthly focal onset seizure frequency from baseline to week 12. The 25 mg group achieved a -53.2% reduction (p=0.000000000006) and the 15 mg group achieved -34.5% (p=0.00007), compared with -10.4% for placebo. The placebo-adjusted reduction for the 25 mg dose was -42.7%, compared with -34.6% in the Phase 2b X-TOLE study. The key secondary endpoint, the proportion of participants with at least 50% seizure reduction, was 54.8% at 25 mg and 37.6% at 15 mg, versus 20.8% for placebo. The most common adverse events across azetukalner groups were dizziness (20.5%), headache (8.8%), somnolence (8.8%), and fatigue (7.6%). Discontinuation due to adverse events occurred in 14.5% of the 25 mg group, 4.8% at 15 mg, and 3.2% on placebo. Of 332 participants completing the double-blind period, 322 entered the open-label extension.
Xenon anticipates submitting a New Drug Application to the US FDA in Q3 2026. Ian Mortimer, President and CEO, said the company is "focusing next on submitting our new drug application to the FDA later this year, as well as advancing our commercial-readiness activities in anticipation of our first commercial launch." Azetukalner has no prior regulatory approvals in any indication. If approved, it would be the only KV7 potassium channel opener available for epilepsy treatment.
Research context
Azetukalner opens KV7.2/KV7.3 potassium channels in the central nervous system, enhancing the M-current that stabilizes neuronal resting membrane potential and reduces excessive firing — the core pathophysiology of seizure generation. This mechanism was clinically validated by retigabine (ezogabine), which received US FDA approval for focal seizures in 2011 but was voluntarily withdrawn after reports of skin and retinal discoloration linked to off-target activity at KV7.4/KV7.5 subtypes. Azetukalner was designed with selectivity for KV7.2/KV7.3 to avoid those liabilities.