Xenon Submits Azetukalner NDA to FDA for Focal Seizures, Pauses Psychiatry Enrollment on Neuropsychiatric Events
核心洞察
Xenon Pharmaceuticals has submitted a New Drug Application to the FDA for azetukalner in focal seizures (搜索), based on the Phase 2b X-TOLE and Phase 3 X-TOLE2 trials.
All four azetukalner doses produced statistically significant reductions in monthly seizure frequency versus placebo, with more than 1,500 patient-years of epilepsy (搜索) safety data.
Xenon voluntarily paused enrollment of new patients in its MDD and bipolar depression (搜索) studies after an analysis of neuropsychiatric adverse events not previously seen in Phase 2 X-NOVA.
Xenon Pharmaceuticals Inc. (Nasdaq: XENE) announced on Sept. 17, 2026, that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (搜索) for azetukalner in focal seizures (搜索), while simultaneously disclosing a voluntary, temporary pause on enrollment of new patients in its ongoing psychiatry studies in major depressive disorder (搜索) (MDD) and bipolar depression (搜索) (BPD).
The NDA submission rests on positive clinical data from two global, randomized, double-blind, placebo-controlled trials of azetukalner in focal seizures (搜索): the Phase 2b X-TOLE study and the Phase 3 X-TOLE2 study. Across both studies, treatment with all four doses of azetukalner demonstrated a statistically significant reduction from baseline in monthly seizure frequency compared with placebo. The drug was generally well-tolerated, with a consistent safety profile observed in both studies, and these results are comparable with the long-term safety observed in the X-TOLE open-label extension (OLE) study. The entire epilepsy (搜索) program has generated more than 1,500 patient-years of safety and exposure data.
"We are very pleased to announce completion of the NDA submission for azetukalner in focal seizures (搜索) in epilepsy (搜索)," said Ian Mortimer, President and CEO of Xenon. He cited the drug's "strong efficacy, a differentiated mechanism of action that may enable rational polytherapy, once-daily dosing with no dose adjustments for other antiseizure medications, and a consistent and generally well-tolerated safety profile." Mortimer described the submission as "a significant milestone for Xenon as we continue to work toward the potential of our first approval and launch and becoming a fully integrated neuroscience company."
Ongoing Epilepsy Studies Target Broader Seizure Types
The Phase 3 X-TOLE3 and X-ACKT studies continue to enroll patients to support expansion of azetukalner's use across seizure types and global regions. X-TOLE3, like the completed X-TOLE2, is a multicenter, randomized, double-blind, placebo-controlled study evaluating 15 mg or 25 mg of azetukalner administered orally with food as adjunctive treatment in approximately 360 patients per study with focal onset seizures (FOS). The primary efficacy endpoint is median percent change (MPC) in monthly seizure frequency from baseline through the 12-week double-blind period compared with placebo.
X-ACKT evaluates 25 mg of azetukalner administered with food as adjunctive treatment in approximately 160 patients with primary generalized tonic-clonic seizures (搜索) (PGTCS), with the primary efficacy endpoint being MPC in monthly PGTCS frequency from baseline through the 12-week double-blind period versus placebo. Upon completing the double-blind period in the Phase 3 epilepsy (搜索) studies, eligible patients may enter an OLE study for up to six years.
Psychiatry Enrollment Paused After Neuropsychiatric Event Analysis
The enrollment pause in the psychiatry programs followed an analysis of neuropsychiatric adverse events in the MDD and BPD studies. According to the company, the observed events, their rate and their severity are consistent with the known safety and tolerability profile of azetukalner and its mechanism; however, such adverse events had not previously been seen in the Phase 2 X-NOVA clinical study in MDD. The pause was implemented as a precautionary measure in consultation with Xenon's Data Safety Monitoring Board and is expected to be temporary. Xenon is evaluating potential dosing modifications to help mitigate these adverse events. The voluntary action does not impact ongoing epilepsy (搜索) studies.
Participants currently enrolled in the randomized controlled psychiatry studies and associated OLE studies will continue on study. X-NOVA2 enrollment has reached approximately 80% of its initial target of 450 patients, a sample size the company states is sufficiently powered to demonstrate a clinically meaningful change in the study's primary endpoint of HAM-D17. Xenon plans to complete the six-week dosing period for patients currently enrolled in the trial and unblind the data, with topline data for X-NOVA2 now expected in the first quarter of 2027.
"We remain very confident in the product profile of azetukalner as a potential new treatment option for patients with epilepsy (搜索) based on strong efficacy and safety data and a consistent safety profile across over 1,500 patient-years of data," said Chris Kenney, Chief Medical Officer of Xenon. "For potential expansion in psychiatry, we would like to evaluate whether modifying the dose regimen may help enhance azetukalner's tolerability profile in this indication. Completing the X-NOVA2 study will help assess the efficacy and tolerability of azetukalner in MDD, which will provide important data to guide us in the future clinical development in psychiatry indications."
Psychiatry Program Design
The Phase 3 X-NOVA MDD program comprises three multicenter, randomized, double-blind, placebo-controlled studies evaluating 20 mg of azetukalner administered orally with food over a 6-week double-blind period as monotherapy in approximately 450 patients per study with moderate-to-severe MDD. The primary efficacy endpoint is change from baseline in HAM-D17 score at week 6 versus placebo, with eligible patients able to enter an OLE study for up to 12 months after completing the double-blind period.
The Phase 3 X-CEED BPD program includes two multicenter, randomized, double-blind, placebo-controlled studies evaluating 20 mg of azetukalner administered orally with food over a 6-week double-blind period as monotherapy in approximately 400 patients per study with BPD I or II. The primary efficacy endpoint is change from baseline in MADRS score at week 6 versus placebo, with an OLE option of up to 12 months.
Mechanism and Unmet Need
Azetukalner is a novel, potent KV7 potassium channel (搜索) opener in development for epilepsy (搜索), MDD and BPD, and represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development. The molecule is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarizing neurons, thereby reducing excessive neuronal firing implicated in several neurologic and psychiatric disorders.
Epilepsy (搜索) is the fourth most common neurological condition and affects approximately three million adults in the U.S. Focal epilepsy is the most common form, characterized by recurrent seizures originating in a specific area of the brain that produce motor, sensory, autonomic or cognitive symptoms depending on the affected region. Although more than 30 epilepsy treatments are available, up to half of people with focal epilepsy still live with uncontrolled seizures, and treatment is further complicated by burdensome drug interactions and lengthy titration and dose-adjustment periods.
Xenon is also advancing an early-stage portfolio of potassium and sodium channel modulators, including KV7 and NaV1.7 programs in Phase 1 development for the potential treatment of pain. The company has offices in Vancouver, British Columbia, and Boston, Massachusetts.