Xenon reports positive Phase 3 X-TOLE2 results showing azetukalner significantly reduced focal onset seizure frequency versus placebo. The company plans an FDA NDA filing in Q3 2026.
Written By: Nikita Jha, BPharm
Reviewed By: Pharmacally Editorial Team
Xenon Pharmaceuticals has reported positive topline results from the Phase 3 X-TOLE2 trial evaluating azetukalner, an investigational KV7 potassium channel opener, as an adjunctive therapy for adults with focal onset seizures (FOS). The study met its primary endpoint, showing a statistically significant reduction in monthly seizure frequency compared with placebo.
Ian Mortimer, CEO of Xenon, said the Phase 3 results showed strong placebo-adjusted efficacy and a favorable safety profile, supporting azetukalner’s potential as a new treatment option for patients with uncontrolled seizures. The company plans to submit an FDA new drug application later this year and is preparing for its first commercial launch.
In the trial, azetukalner demonstrated a median percent change (MPC) in monthly focal seizure frequency of −53.2% with the 25 mg dose and −34.5% with the 15 mg dose, compared with −10.4% for placebo at week 12.
The placebo-adjusted reduction reached −42.7% in the 25 mg group, surpassing results from the earlier Phase 2b X-TOLE study, where the same dose achieved a −34.6% placebo-adjusted reduction over eight weeks.
Based on these findings, Xenon plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration in the third quarter of 2026 for the treatment of focal onset seizures. If approved, azetukalner would become the only KV7 potassium channel opener available for epilepsy treatment.
Phase 3 X-TOLE2 Trial Overview
The X-TOLE2 trial (NCT05614063) was a randomized, double-blind, placebo-controlled Phase 3 study evaluating once-daily oral azetukalner as an adjunctive therapy in adults with focal onset seizures.
A total of 380 patients were randomized to receive azetukalner 25 mg, azetukalner 15 mg, or placebo. The safety and modified intent-to-treat population included 374 participants.
Patients enrolled in the study had highly treatment-resistant epilepsy, with a median history of five prior antiseizure medications, a baseline seizure frequency of 12.75 per month, and more than half of participants (51.3%) using three concomitant antiseizure drugs.
Of the 332 participants who completed the double-blind phase, 322 transitioned into the ongoing open-label extension study.
Secondary Endpoint and Safety Results
The trial also met its key secondary endpoint, the 50% responder rate (RR50). A ≥50% reduction in monthly seizure frequency was observed in:
- 54.8% of patients in the 25 mg group
- 37.6% in the 15 mg group
- 20.8% in the placebo group
The safety profile of azetukalner remained consistent with earlier studies. The most common treatment-emergent adverse events were dizziness (20.5%), headache (8.8%), somnolence (8.8%), and fatigue (7.6%).
Treatment discontinuation due to adverse events occurred in 14.5% of patients in the 25 mg group, 4.8% in the 15 mg group, and 3.2% in the placebo group. Rates of serious adverse events were low and similar across groups.
Differentiated Mechanism May Expand Epilepsy Treatment Options
Azetukalner works by opening KV7 potassium channels in the central nervous system, allowing potassium ions to flow outward and hyperpolarize neurons, which reduces abnormal neuronal firing associated with seizures.
Jacqueline A. French, MD, professor of neurology at NYU Langone Health and chair of the X-TOLE2 steering committee noted that despite the availability of multiple antiseizure drugs, mechanistic diversity remains limited, and many patients continue to experience uncontrolled seizures. Azetukalner’s once-daily dosing, no titration requirement, and minimal drug-drug interactions may provide advantages over existing therapies.
Detailed results from the X-TOLE2 study will be presented as a late-breaking oral session at the American Academy of Neurology (AAN) Annual Meeting on April 19 in Chicago.
Disease Background
Epilepsy affects around three million adults in the United States and is among the most common neurological disorders. Focal epilepsy, in which seizures originate in a specific brain region, represents the most prevalent form of the disease.
Despite polytherapy approaches using multiple antiseizure medications, up to half of patients with focal epilepsy continue to experience uncontrolled seizures, underscoring the need for therapies with new mechanisms of action.
Reference
Xenon Announces Positive Topline Data from Phase 3 X-TOLE2 Study of Azetukalner in Focal Onset Seizures (FOS), 09 March 2026, https://investor.xenon-pharma.com/news-releases/news-release-details/xenon-announces-positive-topline-data-phase-3-x-tole2-study
A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE2), ClinicalTrials.gov ID NCT05614063, https://clinicaltrials.gov/study/NCT05614063
About the Writer
Nikita Jha is a pharmacy graduate with a strong interest in new therapies and healthcare innovations. She is enthusiastic about exploring scientific developments and keeping up with emerging updates in pharmaceutical research. Her work focuses on learning, analyzing, and communicating developments in the healthcare and life sciences space.