Azetukalner (XEN1101)

Azetukalner is an investigational once-daily oral KV7.2 and KV7.3 potassium channel opener. A New Drug Application for focal seizures was submitted to the US Food and Drug Administration on 17 September 2026, based on the Phase 2b X-TOLE trial and the Phase 3 X-TOLE2 trial. No filing acceptance, review designation, or action date has been announced, and no US launch date has been stated.

Both randomized trials met their primary endpoint of median percent change in monthly focal onset seizure frequency, in populations that had failed a median of five to six prior antiseizure medications and, in X-TOLE2, included approximately 40% of participants taking concomitant cenobamate. If approved, azetukalner would be the only KV7 potassium channel opener available for epilepsy, since ezogabine, the first agent of this class, was withdrawn from the US market in 2017 and its European marketing authorisation was withdrawn in 2018. The reported safety experience across more than 1,500 patient-years does not show the retinal and skin pigmentary changes that limited ezogabine, although pigmentary changes with that predecessor were generally reported after two or more years of treatment. Urinary retention, reported in 1.1% of open-label extension participants, is described as a possible class effect of KV7 channel openers.

Limits on the evidence should be weighed. As of September 2026 no peer-reviewed publication and no registry results record exist for X-TOLE2, so confidence intervals, the statistical testing hierarchy, and full adverse event tables are not publicly available. Both double-blind periods were short, 8 weeks in X-TOLE and 12 weeks in X-TOLE2, and long-term seizure outcomes come from an uncontrolled open-label extension in which retention was 60% at 24 months. Seizure freedom during the randomized period was uncommon, at 6.5% for 25 mg compared with 0.8% for placebo in X-TOLE2. Enrollment was restricted to adults with at least two prior failed antiseizure medications who were taking one to three concomitant medications, so the evidence does not address monotherapy, pediatric use, or newly diagnosed epilepsy. In September 2026 Xenon paused enrollment of new participants in its major depressive disorder and bipolar depression trials after an analysis of neuropsychiatric adverse events; the company states this action does not affect the epilepsy trials, but the finding is relevant to assessment of the neuropsychiatric profile of the molecule.