Ezogabine

Vancouver and Boston-based Xenon Pharmaceuticals announced positive topline results from the Phase III 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first drug in its mechanistic class to reach a potential US FDA filing since retigabine (from GSK/Valeant Pharma) was withdrawn from the market in 2017 due to safety concerns, and the data exceeded those from the earlier Phase IIb X-TOLE trial. X-TOLE2 was a randomized, double-blind, placebo-controlled, multicenter Phase III 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 IIb 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. If approved, it would be the only KV7 potassium channel opener available for epilepsy treatment. 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. Epilepsy affects approximately three million adults in the US, and focal epilepsy is its most common form. Despite more than 30 approved antiseizure medications, up to half of patients with focal epilepsy continue to experience uncontrolled seizures. Most available therapies act through sodium channel blockade or GABAergic modulation, and few mechanistically distinct options have emerged in recent years. Key competitors and pipeline assets include: Cenobamate (SK Life Science), a dual sodium channel blocker and GABAA receptor modulator approved by the US FDA in 2019 for focal onset seizures in adults, currently in additional Phase III studies. PRAX-562 (Praxis Precision Medicines), a selective persistent sodium current blocker in Phase II development for focal onset seizures. Brivaracetam (UCB Pharma), an SV2A ligand approved by the US FDA in 2016 for focal onset seizures, with ongoing Phase III trials in pediatric populations. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website