Xenon Pharmaceuticals has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval of azetukalner for the treatment of Focal Seizures (FS) in patients with epilepsy.

The NDA submission is supported by positive results from two global, randomised, double-blind, placebo-controlled clinical trials—the Phase 2b X-TOLE study and the Phase 3 X-TOLE2 study. Across both trials, all four evaluated doses of azetukalner demonstrated statistically significant reductions from baseline in monthly seizure frequency compared with placebo.

Azetukalner was generally well tolerated across the studies, with a consistent safety profile observed in both trials. The findings were also consistent with long-term safety data from the X-TOLE open-label extension study. According to Xenon, its epilepsy development programme has generated more than 1,500 patient-years of safety and exposure data.

Ian Mortimer, President and Chief Executive Officer of Xenon, said the NDA submission represents a significant milestone for the company as it advances azetukalner toward its potential first approval and commercial launch.

The Phase 3 X-TOLE3 study evaluating azetukalner in focal seizures and the X-ACKT study evaluating the therapy in Primary Generalised Tonic-Clonic Seizures (PGTCS) continue to enrol patients. The studies are intended to support potential expansion of azetukalner across additional seizure types and geographic regions.

Separately, Xenon has voluntarily paused enrolment of new patients in its ongoing clinical studies evaluating azetukalner in Major Depressive Disorder (MDD) and Bipolar Depression (BPD). The decision follows an analysis of neuropsychiatric adverse events observed in these studies.

Patients who are already enrolled in the randomised controlled psychiatry studies and associated open-label extension studies will continue participating.

Xenon said the observed events, including their frequency and severity, were consistent with the known safety and tolerability profile of azetukalner and its mechanism of action. However, similar events had not previously been observed in the Phase 2 X-NOVA study in MDD.

The temporary enrolment pause was implemented as a precautionary measure in consultation with the company’s Data Safety Monitoring Board (DSMB). Xenon is evaluating potential dosing modifications that could help mitigate the adverse events. The company said the action does not affect its ongoing epilepsy studies.

Enrolment in the X-NOVA2 Phase 3 study in MDD has reached approximately 80 percent of its initial target of 450 patients. Xenon said the study remains sufficiently powered to assess a clinically meaningful change in its primary endpoint, the Hamilton Depression Rating Scale-17 (HAM-D17).

The company plans to complete the six-week dosing period for patients already enrolled in X-NOVA2 before unblinding the study data. Topline results are now expected in the first quarter of 2027.

Chris Kenney, Chief Medical Officer of Xenon, said the company remains confident in azetukalner’s potential in epilepsy based on its efficacy and safety data. For psychiatric indications, Xenon plans to assess whether modifications to the dosing regimen could improve tolerability.

Azetukalner is a novel potassium voltage-gated channel subfamily Q (KV7) opener being developed for epilepsy, MDD and BPD. The therapy is designed to activate potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarising neurons. This mechanism is intended to reduce excessive neuronal firing associated with neurological and psychiatric disorders.

Epilepsy is a neurological disorder characterised by abnormal electrical activity in the brain that causes spontaneous, recurrent and unprovoked seizures. The condition affects approximately three million adults in the US.

Focal epilepsy is the most common form of epilepsy and is characterised by seizures originating in a specific area of the brain. Depending on the affected region, focal seizures can result in motor, sensory, autonomic or cognitive symptoms.

Many people with epilepsy require polytherapy, involving the use of multiple antiseizure medications. Despite the availability of numerous treatments, a substantial proportion of people with focal epilepsy continue to experience uncontrolled seizures. Drug interactions, treatment titration and dose adjustments can further complicate epilepsy management, highlighting the need for additional treatment options.