Xenon Pharmaceuticals (Nasdaq: XENE) has submitted a New Drug Application (NDA) to the US FDA for azetukalner, a KV7 potassium channel opener, seeking approval as adjunctive treatment for focal seizures in adults. The filing marks the Vancouver and Boston-based company's first regulatory submission and is supported by data from the Phase IIb X-TOLE study and the Phase III X-TOLE2 study, together generating more than 1,500 patient-years of safety and exposure data.
The X-TOLE2 trial, which enrolled 380 adults with treatment-resistant focal onset seizures, reported a 53.2% median reduction in monthly seizure frequency at the 25 mg dose versus 10.4% for placebo (p=0.000000000006), with a 50% responder rate of 54.8% at 25 mg compared to 20.8% on placebo. The placebo-adjusted reduction of 42.7% exceeded the 34.6% observed in the earlier Phase IIb X-TOLE study. The most common adverse events 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 versus 3.2% on placebo.
Azetukalner opens KV7.2/KV7.3 potassium channels in the central nervous system, hyperpolarizing neurons and raising the threshold for action potential firing. No KV7 opener has been available for epilepsy since ezogabine (retigabine) was withdrawn from the market in 2017 due to retinal and skin pigmentation; azetukalner was designed with selectivity for KV7.2/KV7.3 to avoid those liabilities. The company said the drug requires no titration and no dose adjustments for co-administered antiseizure medications, which may offer a practical advantage in polytherapy — the standard management approach for focal epilepsy, where up to half of patients continue to experience uncontrolled seizures despite more than 30 approved options.
The nearest competitive threat in the same mechanistic class is opakalim (BHV-7000), a selective Kv7.2/7.3 activator licensed by Biohaven to SK Biopharmaceuticals in a deal worth up to USD 795 million, with pivotal Phase II/III RISE3 data expected in the second half of 2026. Cenobamate (Xcopri), approved in 2019 for focal seizures, represents the most established recent entrant in the adjunctive therapy space.