Investigational Antiseizure Medication Reduced Seizure Frequency in Phase 3 Focal Epilepsy Trial
KEY TAKEAWAYS
- Treatment with azetukalner was associated with greater reductions in monthly seizure frequency than placebo in the phase 3 X-TOLE2 trial.
- The 25-mg dose was associated with a 53.2% median reduction in monthly seizure frequency during the 12-week double-blind treatment period.
- Xenon Pharmaceuticals announced plans to submit a New Drug Application to the FDA in the third quarter of 2026.
Treatment with azetukalner (Xenon Pharmaceuticals, Needham, MA), an investigational antiseizure medication (ASM), was associated with reductions in monthly seizure frequency in adults with treatment-resistant focal onset seizures, according to results from the phase 3 X-TOLE2 study (NCT05614063) presented at the 2026 American Academy of Neurology (AAN) Annual Meeting. The therapy is being evaluated as an adjunctive ASM for adults with focal epilepsy.
X-TOLE2 was a randomized, double-blind phase 3 trial that included 380 adults with highly treatment-resistant focal epilepsy. Many of the participants previously had inadequate response to multiple ASMs. Participants received add-on azetukalner at either 25 mg or 15 mg, or placebo, during a 12-week double-blind treatment period.
Seizure Reduction Results
- Participants receiving azetukalner 25 mg had a 53.2% median reduction in monthly seizure frequency, compared with a 10.4% reduction among participants receiving placebo.
- Participants receiving azetukalner 15 mg had a 34.5% median reduction in monthly seizure frequency.
- Improvements were reported across responder thresholds, including at least 50%, 75%, and 90% reductions in seizure frequency.
- During the final 4 weeks of the double-blind period, 13.7% of participants receiving azetukalner 25 mg achieved seizure freedom, compared with 4% of those receiving placebo.
In longer-term data also presented at the Meeting, 40% of participants treated with azetukalner for at least 48 months achieved seizure freedom for at least 12 consecutive months, while approximately 25% remained seizure-free for at least 24 consecutive months.
The treatment was described as generally favorable in safety and tolerability over extended follow-up. The most commonly reported adverse events included dizziness, headache, somnolence, and fatigue. No major cardiovascular safety concerns or significant weight gain were reported during the double-blind phase.
Azetukalner is being studied as a once-daily treatment that does not require dose titration. According to an announcement from the company, Xenon Pharmaceuticals plans to submit a New Drug Application to the Food and Drug Administration (FDA) during the third quarter of 2026. Azetukalner remains investigational and has not been approved by the FDA.
Source
ACNR. Phase 3 azetukalner data show promising seizure control in focal epilepsy. Published May 29, 2026. Accessed June 16, 2026. https://acnr.co.uk/azetukalner-phase-3-focal-epilepsy-results/?utm_source=chatgpt.com