Xenon Pharmaceuticals Inc Presents Azetukalner Phase 3 X-TOLE2 Study Results And 48-Month Long-Term Data In Focal Onset Seizures at 2026 AAN Annual Meeting

Published: 2026-04-20 04:50:50 ET XENE

Published on 04/20/2026 at 04:50 am EDT

Xenon Pharmaceuticals Inc. presented positive data from the Phase 3 X-TOLE2 study highlighting the efficacy and safety of azetukalner in focal onset seizures at the American Academy of Neurology Annual Meeting, taking place April 18-22, 2026 in Chicago, Illinois. Xenon is also presenting data at the AAN meeting that reinforce the significant opportunity for azetukalner in epilepsy, including 48-month data from the ongoing X-TOLE open-label extension study, as well as real-world data reinforcing the potential value that no-titration options like azetukalner would bring to epilepsy management. Azetukalner (AZK) is a novel, potent, KV7 potassium channel opener currently in clinical development for epilepsy and depression.

X-TOLE2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the clinical efficacy, safety, and tolerability of AZK as adjunctive treatment in adults with focal onset seizures over a 12-week double-blind period. Participants had highly treatment-resistant epilepsy, with a median baseline seizure frequency of 12.75 per month, a median of five prior anti-seizure medications, and 51.3% using three concomitant anti-seizure medications. Approximately 40% of participants entering the study were taking concomitant cenobamate, while 19% had previously tried and discontinued cenobamate.

Treatment with 25 mg or 15 mg AZK resulted in a statistically significant -53.2% or -34.5% Median Percent Change, respectively, from baseline through the double-blind period in monthly focal onset seizures, compared to a -10.4% Median Percent Change for placebo. AZK demonstrated long-term efficacy and safety in the =48-month interim analysis of the X-TOLE open-label extension study, including continued reductions in seizure frequency and improvements in seizure freedom over time. X-TOLE is a completed Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, multicenter study, with an ongoing seven-year open-label extension evaluating the efficacy, safety, and tolerability of 20 mg azetukalner as adjunctive treatment in adults with focal onset seizures.

Participants treated for =48 months (n=131) in the open-label extension had a Median Percent Change reduction in monthly focal onset seizure frequency of -69.8% at month one in the open-label extension, which further increased to -85.1% at month 12 and reached -90.9% at month 48. Those receiving one or two anti-seizure medications at the beginning of the X-TOLE double-blind period (n=60) had greater Median Percent Change reductions in monthly focal onset seizure frequency than those receiving three anti-seizure medications (n=69) at month 48 (100% vs. 81.8% reduction in monthly focal onset seizure frequency, respectively).

The clinically accepted definition of seizure freedom is no seizures for at least 12 months. Among the participants treated for =48 months in the open-label extension (n=131), seizure freedom for any =12-month consecutive duration was attained by 38.2% of participants. Seizure freedom for any =24-, =36-, and =48- month consecutive duration was attained by 25.2%, 19.8% and 10.7% of the participants respectively.

As of data cut-off, the open-label extension has generated more than 775 patient-years of safety and exposure data. Long-term safety of AZK in the open-label extension was comparable with the safety observed in the X-TOLE double-blind period. In a real-world analysis, patient and healthcare professional perspectives suggest that anti-seizure medication titration imposes a meaningful burden for both groups, with patients reporting challenges related to medication schedules, daily life and quality-of-life during titration periods, and physicians reporting challenges related to treatment complexity and cross-titration.

When questioned on their perceptions of anti-seizure medications without titration, most patients noted that they either agree or strongly agree that initiating an anti-seizure medication without needing to titrate to a stable dose would boost their confidence (90%), reduce anxiety (77%), and improve adherence (84%). Physicians noted that no-titration options would cause less stress and increase simplicity for both physicians and patients, as many patients are already on complex drug regimens. These findings suggest using anti-seizure medications that do not require titration may offer benefits and underscore the potential value of avoiding a titration period to reduce stress and simplify focal onset seizure management for both patients and physicians.

Azetukalner is a novel, potent KV7 potassium channel opener currently in Phase 3 clinical trials for the treatment of epilepsy, major depressive disorder, and bipolar depression. It represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development. Azetukalner is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarizing neurons.

This process helps reduce excessive neuronal firing, which is a key contributor to several neurologic and psychiatric disorders. It is the only KV7 potassium channel opener in development for multiple indications that is backed by long-term efficacy and safety data in epilepsy patients and proof-of-concept data in major depressive disorder patients. The X-TOLE2 clinical trial was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study evaluating the efficacy, safety, and tolerability of azetukalner, administered as an oral, adjunctive therapy once-daily with food in adult patients with focal onset seizures.

The study randomized participants in a blinded manner to either azetukalner 25 mg, 15 mg, or placebo, and included a total of 380 randomized participants, with 374 participants in the safety and modified intent-to-treat population for the safety and efficacy analyses. Participants had highly treatment-resistant epilepsy, with a median of five prior anti-seizure medications, a baseline seizure frequency of 12.75 per month, and 51.3% using three concomitant anti-seizure medications. Of the 332 participants who completed the double-blind period, 322 entered the open-label extension study.