Xenon Files Azetukalner NDA as It Pauses Psychiatry Trials for Tolerability Review

Key Points

• Xenon filed an NDA for azetukalner to treat focal-onset seizures, supported by positive X-TOLE and X-TOLE2 results and more than 1,500 patient-years of epilepsy exposure. FDA review is expected to take about 12 months, with potential DEA scheduling adding roughly three months after approval.
• Psychiatry trials have been paused while Xenon evaluates dose-escalation changes intended to improve tolerability in major depressive disorder and bipolar depression studies. The company said the adverse events under review, including dizziness, somnolence and occasional cognitive effects, are known and generally not serious, and that the epilepsy program is unaffected.
• Xenon expects its pain candidates XEN1701 and XEN1120 to enter Phase 2 proof-of-concept studies in 2027, while a separate Nav1.7 program has begun Phase 1 testing.

Xenon Pharmaceuticals NASDAQ: XENE said it has filed its first new drug application for azetukalner as a treatment for focal-onset seizures, while pausing portions of its late-stage psychiatry program to evaluate changes intended to improve tolerability.

Speaking at the 2026 TD Cowen Neuropsychiatry Summit, President and CEO Ian Mortimer said the NDA submission for azetukalner in focal-onset seizures is supported by the company’s X-TOLE and X-TOLE2 randomized, placebo-controlled studies. Mortimer said X-TOLE2, for which results were released in March, showed what Xenon believes was the strongest placebo-adjusted efficacy demonstrated in a focal-onset seizure study.

The company has also accumulated 1,500 patient-years of epilepsy exposure for azetukalner, including patients from the X-TOLE trial who have received the medicine for more than five years, Mortimer said. Xenon plans to present updated 60-month open-label X-TOLE data at the American Epilepsy Society meeting in December. The company said the long-term data have shown seizure reductions and longer periods of seizure freedom.

FDA Review and Commercial Preparation

CFO Tucker Kelly said Xenon expects a standard FDA review rather than priority review for the epilepsy application. The company is modeling a 12-month review from its September 2026 filing, although it intends to advocate for the drug during the review process. Kelly added that Drug Enforcement Administration scheduling, which is common for anti-seizure medicines, could add approximately three months after NDA approval.

Mortimer said the company filed for four azetukalner doses: 10 milligrams, 15 milligrams, 20 milligrams and 25 milligrams. While all four doses demonstrated statistical separation from placebo in seizure reduction, he said Xenon expects physicians may commonly begin patients at 15 milligrams, reflecting the general practice of starting anti-seizure medicines at lower doses.

According to Mortimer, the 10-milligram and 15-milligram doses were nearly indistinguishable from placebo in safety tables, aside from somewhat more dizziness at 15 milligrams. He said azetukalner’s once-daily administration, lack of required titration and limited drug-drug interaction concerns could make it easier to use for both epilepsy specialists and general neurologists.

Xenon has hired Darren Cline as chief commercial officer and has built a commercial leadership team ahead of a potential launch. Kelly said the company views azetukalner as having potential to reach a broader group of prescribers than XCOPRI, but he did not provide launch guidance. He said anti-seizure medicine launches historically can be gradual and that Xenon expects to provide additional qualitative guidance closer to a potential approval.

Psychiatry Program Paused for Dosing Review

In psychiatry, Xenon is developing azetukalner in major depressive disorder and bipolar depression. The company has paused its X-NOVA3 major depressive disorder study and X-CEED bipolar depression study while it evaluates changes to dose escalation. Xenon’s X-NOVA2 Phase 3 major depressive disorder study is more than 80% enrolled and is expected to produce unblinded data in the first quarter of 2027.

Mortimer said the safety profile emerging from the Phase 3 psychiatry program appears more similar to the profile established in the epilepsy program than to the company’s earlier Phase 2 X-NOVA study. He emphasized that the adverse events being evaluated are not new for either the molecule or its mechanism, and that Xenon does not believe rates or severity differ from those seen in epilepsy.

The company described more common events such as dizziness and somnolence, as well as less common neuropsychiatric events that may include confusion, concentration difficulties, aphasia and word-finding issues. Serious adverse events have been rare, Mortimer said.

Following discussion with the program’s data safety monitoring board, Xenon decided to pause the studies to assess whether changes in dose escalation could improve tolerability for psychiatry patients. Mortimer said the company has information from epilepsy patients who moved from lower doses to 25 milligrams in open-label studies, as well as clinical pharmacology studies involving dose escalation, that supports its view that tolerability can be improved through titration.

“There’s absolutely no changes to the epilepsy program,” Mortimer said.

The X-NOVA2 readout is expected to provide a better view of azetukalner’s benefit-risk profile in major depressive disorder, including effects on depression as measured by the HAM-D17 scale, anhedonia and safety. Xenon plans to update study protocols and regulatory documents after determining the appropriate revised dose-escalation approach.

Pain Candidates Moving Toward Phase 2

Xenon also discussed its early-stage pain portfolio. The company expects its Nav1.7 inhibitor, XEN1701, and Kv7 drug candidate, XEN1120, to enter Phase 2 proof-of-concept pain studies in 2027. A separate Nav1.7 program has entered Phase 1 testing.

Mortimer said Phase 1 work with XEN1701 has supported the company’s belief that it can achieve receptor occupancy levels that could produce an analgesic effect while maintaining a therapeutic index. Xenon is also assessing cardiovascular risks such as orthostasis and orthostatic hypotension that have been observed with rapid inhibition of the target by prior drugs.

For XEN1120, Mortimer said Phase 1 results showed exposure levels that Xenon believes could predict analgesic activity based on preclinical work. The company expects to share additional Phase 1 information before beginning Phase 2 studies. He said planned acute pain proof-of-concept trials, such as post-surgical bunionectomy or abdominoplasty studies, could produce results relatively quickly.

About Xenon Pharmaceuticals (NASDAQ:XENE)

Xenon Pharmaceuticals Inc NASDAQ: XENE is a clinical-stage biopharmaceutical company focused on developing medicines for neurological and psychiatric disorders. The company uses its expertise in ion channels, which regulate the electrical activity of nerve cells, to discover and advance potential treatments for conditions with significant unmet medical needs.

Xenon's leading investigational product is azetukalner (XEN1101), an oral, small-molecule potassium-channel opener being studied in epilepsy, including focal-onset seizures, and major depressive disorder.

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