Xenon Submits New Drug Application for Azetukalner as Treatment for Focal Seizures

Xenon Pharmaceuticals has submitted a New Drug Application (NDA) to the FDA for azetukalner (XEN1101) as adjunctive treatment for focal seizures in adults with epilepsy, based on data from the phase 3 X-TOLE2 trial and the earlier phase 2b X-TOLE study. If approved, azetukalner would be the first KV7 potassium channel opener available for epilepsy, a mechanism distinct from currently marketed antiseizure medications.¹

The NDA was supported by more than 1500 patient-years of safety data across the azetukalner epilepsy program, with Xenon describing the safety profile as consistent and generally well tolerated across studies. The company is separately developing azetukalner in psychiatry, with topline data from the ongoing phase 3 X-NOVA2 study in major depressive disorder expected in the first quarter of 2027.

“Azetukalner has the potential to deliver much needed innovation to treat people living with focal seizures, with strong efficacy, a differentiated mechanism of action that may enable rational polytherapy, once-daily dosing with no dose adjustments for other antiseizure medications, and a consistent and generally well-tolerated safety profile,” Ian Mortimer, president and chief executive officer of Xenon, said in a statement.¹

Mechanism of action

Azetukalner opens KV7 (KCNQ2/3) potassium channels in the central nervous system, allowing potassium ions to flow out of neurons and promoting a hyperpolarized state that raises the threshold for excessive or repetitive firing.¹ An earlier KV7 opener, ezogabine, reached the epilepsy market but was later discontinued after reports of blue-gray skin and eye discoloration with long-term use; in the phase 2b X-TOLE trial, no treatment-emergent adverse events of tissue discoloration were reported with azetukalner, a distinction investigators highlighted as separating the drug from its predecessor.²

Phase 3 data

X-TOLE2 (NCT05614063) was a randomized, double-blind, placebo-controlled phase 3 trial in 380 adults with treatment-resistant focal onset seizures, 374 of whom were included in the safety and modified intent-to-treat populations. Enrolled patients had a median of 5 prior antiseizure medications and a baseline seizure frequency of 12.75 per month, and more than half were taking 3 or more concurrent antiseizure medications during the 12-week double-blind treatment period.^3,4

Over 12 weeks, median percent change in monthly focal seizure frequency was -53.2% with azetukalner 25 mg and -34.5% with the 15-mg dose, compared with -10.4% with placebo (P <.001 for both doses versus placebo). The placebo-adjusted effect for the 25-mg dose, -42.7%, exceeded the -34.6% placebo-adjusted effect seen at the same dose in the earlier phase 2b study. A 50% or greater reduction in seizure frequency (RR50) was achieved by 54.8% of patients on the 25-mg dose and 37.6% on the 15-mg dose, compared with 20.8% on placebo.³

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The most common adverse events (AEs) with azetukalner were dizziness (20.5% vs 3.2% with placebo), headache (8.8% vs 6.4%), somnolence (8.8% vs 7.2%), and fatigue (7.6% vs 6.4%). Discontinuations due to AEs occurred in 14.5% of patients on the 25-mg dose, 4.8% on the 15-mg dose, and 3.2% on placebo, and serious treatment-emergent AEs occurred in 5.6%, 3.2%, and 2.4% of those groups, respectively.³

“Despite a large number of approved epilepsy treatments, there are only a handful of distinct mechanisms of action available, and the data from X-TOLE2 reinforce the value that azetukalner and its KV7 mechanism may bring to the treatment armamentarium for focal seizures,” Jacqueline A. French, MD, professor of neurology at NYU Langone Health and chair of the X-TOLE2 steering committee, said in a previous statement.³

Phase 2b data and long-term follow-up

In the earlier phase 2b X-TOLE trial, published in JAMA Neurology, median percent reduction in monthly focal-onset seizure frequency was 52.8% with the 25-mg azetukalner, 46.4% with 20 mg, and 33.2% with 10 mg, compared with 18.2% with placebo (P <.001 for the 2 higher doses, P =.04 for 10 mg). RR50 was 54.5%, 43.1%, and 28.3% across the same descending doses, compared with 14.9% with placebo. Dizziness (24.6%), somnolence (15.6%), and fatigue (10.9%) were the most common AEs, and serious AEs occurred at similar rates across all groups (2.6% to 3.9%).²

Longer-term data from the ongoing open-label extension of X-TOLE, presented at the 2025 American Epilepsy Society Annual Meeting, found that among 275 patients with 48-month interim follow-up, 20.7% achieved 1 year of seizure freedom, rising to 38% among patients followed the longest; 10% of patients had remained seizure-free for 48 months or longer. Among patients who experienced a breakthrough seizure, 69% went on to achieve at least another 6 months of seizure freedom.⁵

REFERENCES
1. Xenon announces azetukalner NDA submission to FDA for focal seizures. News release. Xenon Pharmaceuticals Inc. Published September 17, 2026. Accessed September 21, 2026. https://investor.xenon-pharma.com/news-releases/news-release-details/xenon-announces-azetukalner-nda-submission-fda-focal-seizures
2. French JA, Porter RJ, Perucca E, et al. Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy: a phase 2b randomized clinical trial. JAMA Neurol. 2023;80(11):1145-1154. doi:10.1001/jamaneurol.2023.3542
3. Xenon announces positive topline data from phase 3 X-TOLE2 study of azetukalner in focal onset seizures. News release. Xenon Pharmaceuticals Inc. Published March 9, 2026. Accessed September 21, 2026. https://investor.xenon-pharma.com/news-releases/news-release-details/xenon-announces-positive-topline-data-phase-3-x-tole2-study
4. A study to evaluate azetukalner (XEN1101) as adjunctive treatment for focal onset seizures in adults with epilepsy (X-TOLE2). ClinicalTrials.gov identifier: NCT05614063. Accessed September 21, 2026. https://clinicaltrials.gov/study/NCT05614063
5. French JA, et al. Long-term safety and efficacy of azetukalner in adults with focal epilepsy (48-month interim analysis). Abstract 3.356. Presented at: 2025 American Epilepsy Society Annual Meeting; December 5-9, 2025; Atlanta, Georgia.