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Written By: Kirti Kumbhar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
Xenon Pharmaceuticals has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for azetukalner as an adjunctive treatment for focal seizures, while temporarily pausing enrollment in its ongoing major depressive disorder (MDD) and bipolar depression programs after reviewing neuropsychiatric adverse events.
FDA Submission Follows Positive Phase 2b and Phase 3 Data
The NDA is supported by results from the Phase 2b X-TOLE (NCT03796962) and Phase 3 X-TOLE2 (NCT05614063) trials, both randomized, double-blind, placebo-controlled studies in patients with focal seizures. Across the two studies, all four evaluated azetukalner doses produced statistically significant reductions from baseline in monthly seizure frequency compared with placebo.
Azetukalner was generally well tolerated, with a consistent safety profile across the two trials. The broader epilepsy development program has accumulated more than 1,500 patient-years of safety and exposure data, including long-term follow-up from the X-TOLE open-label extension.
The submission advances azetukalner toward potential U.S. approval while the company continues its Phase 3 program across additional seizure types.
KV7 Potassium Channel Modulation
Azetukalner is a potent KV7 potassium channel opener that acts in the central nervous system. By increasing potassium ion flow, the drug hyperpolarizes neurons and reduces excessive neuronal firing.
The mechanism is being evaluated across epilepsy and psychiatric disorders. In epilepsy, azetukalner is being developed as a once-daily oral adjunctive treatment administered with food. The clinical program has also reported no need for dose titration and no meaningful drug-drug interactions, factors that could simplify treatment alongside existing antiseizure medications.
Phase 3 Epilepsy Program Continues
The Phase 3 X-TOLE3 trial continues to enroll patients with focal onset seizures. The study is evaluating 15 mg and 25 mg doses of azetukalner as adjunctive therapy in approximately 360 patients, with median percent change in monthly seizure frequency during the 12-week double-blind period as the primary endpoint.
The Phase 3 X-ACKT study is also enrolling approximately 160 patients with primary generalized tonic-clonic seizures (PGTCS). It evaluates 25 mg of azetukalner as adjunctive treatment, with median percent change in monthly PGTCS frequency during the 12-week double-blind period as the primary efficacy endpoint.
Eligible participants can enter long-term open-label extension studies following the double-blind treatment periods.
Psychiatry Programs Face Temporary Enrollment Pause
The company has voluntarily paused enrollment of new patients in its ongoing MDD and bipolar depression studies following an analysis of neuropsychiatric adverse events.
Patients already enrolled will remain in the randomized controlled studies and associated open-label extensions. Xenon said the observed events, including their frequency and severity, were consistent with the known safety and tolerability profile of azetukalner and its mechanism. However, such events had not previously been observed in the Phase 2 X-NOVA study (NCT05376150) in MDD.
The company is consulting its Data Safety Monitoring Board (DSMB) and evaluating potential modifications to the azetukalner dosing regimen to help mitigate these adverse events. Xenon has not disclosed the specific dosing or regimen changes under consideration. The precautionary enrollment pause is expected to be temporary and does not affect the ongoing epilepsy studies.
X-NOVA2 Data Expected in Q1 2027
Enrollment in X-NOVA2 has reached approximately 80% of its initial 450-patient target, which Xenon said provides sufficient statistical power to demonstrate a clinically meaningful change in the primary endpoint, the change from baseline in the HAM-D17 score at week six.
The company plans to complete the six-week dosing period for participants already enrolled before unblinding the study. Topline X-NOVA2 results are now expected in the first quarter of 2027.
The results will provide additional evidence on azetukalner’s efficacy and tolerability in MDD and help inform the future development strategy for psychiatric indications.
Reference
Xenon Announces Azetukalner NDA Submission to FDA for Focal Seizures and Provides Update on Psychiatry Clinical Program, Xenon, 17 September 2026
A Study to Evaluate XEN1101 as Adjunctive Therapy in Focal Epilepsy (X-TOLE), ClinicalTrials.gov ID NCT03796962
A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE2), ClinicalTrials.gov ID NCT05614063
A Study to Evaluate the Safety, Tolerability and Efficacy of XEN1101 in Major Depressive Disorder (X-NOVA), ClinicalTrials.gov ID NCT05376150
About the Writer
Kirti Kumbhar (LinkedIn) is an M.Pharm graduate with experience in Quality Assurance at Lupin Limited and a strong interest in clinical research, regulatory affairs, and Trial Master File (TMF) management. She has developed knowledge of regulatory documentation, quality systems, compliance, and healthcare research through her professional experience. Passionate about clinical development and continuous learning, Kirti is committed to supporting high-quality healthcare documentation, regulatory excellence, and research-driven healthcare advancements.