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Phase 3 trialPhase 3 trial. Stage 4 of 6 (Phase 3)

Xenon's Azetukalner Meets Primary Goal in Phase 3 X-TOLE2 Focal Seizure Trial

The once-daily Kv7 potassium channel opener cut monthly focal seizures by a median 53.2% at the 25 mg dose versus 10.4% on placebo, Xenon reported, and the company plans an FDA filing in the third quarter.

By News DeskMarch 9, 20262 min read
An EEG recording unit beside a computer monitor and a light stimulator.
An electroencephalograph, computer display and photic stimulator of the kind used to record brain activity in epilepsy care. Not connected to the X-TOLE2 trial. Yury Petrovich Masloboev, CC BY-SA 3.0, via Wikimedia Commons · CC BY-SA 3.0
Phase 3 triallarge clinical trialPhase 3 trial. Stage 4 of 6 (Phase 3)

These results come from a Phase 3 trial, the large trial usually needed before approval.

Key points

  • Both azetukalner doses met the Phase 3 X-TOLE2 primary endpoint of median percent change in monthly focal onset seizure frequency at Week 12, Xenon reported in topline results.
  • At least half of patients on the 25 mg dose had their seizure frequency cut by 50% or more (54.8%), versus 20.8% on placebo.
  • Xenon said it plans to submit a New Drug Application to the FDA in the third quarter of 2026 and to present the data at the AAN Annual Meeting in April.

Xenon Pharmaceuticals said on March 9 that its investigational epilepsy drug azetukalner met the primary endpoint of the Phase 3 X-TOLE2 study in adults with focal onset seizures, in both of the doses tested, according to the company's topline release, filed with the SEC.

Azetukalner is an oral, once-daily opener of Kv7 potassium channels. Xenon said the drug is designed to hyperpolarize neurons and reduce the excessive firing that drives seizures, a different mechanism from most existing antiseizure medicines. The results are company-reported topline data; the full efficacy and safety results are scheduled for a late-breaking oral presentation at the American Academy of Neurology (AAN) Annual Meeting on April 19.

Trial results

X-TOLE2 (NCT05614063) was a randomized, double-blind, placebo-controlled, multicenter study of azetukalner given with food as add-on therapy. It randomized 380 adults to 25 mg, 15 mg or placebo, with 374 in the analysis population. Participants had highly treatment-resistant epilepsy, Xenon said: a median of five prior antiseizure medicines, a baseline seizure frequency of 12.75 a month, and 51.3% taking three antiseizure drugs at the same time.

From baseline to Week 12, monthly focal seizure frequency fell by a median of 53.2% in the 25 mg group and 34.5% in the 15 mg group, compared with 10.4% on placebo. The placebo-adjusted reduction in the 25 mg group was 42.7%, against 34.6% in the earlier Phase 2b X-TOLE study, which ran for eight weeks.

The trial also met its key secondary endpoint. A 50% or greater reduction in monthly seizures was seen in 54.8% of the 25 mg group and 37.6% of the 15 mg group, versus 20.8% on placebo.

Chief executive Ian Mortimer said the data, "to our knowledge, show the highest placebo-adjusted efficacy ever observed in a pivotal epilepsy study." The company has not published the comparison behind that statement.

Safety and next steps

Xenon said azetukalner's safety and tolerability were consistent with the earlier X-TOLE study. The most common adverse events across both azetukalner groups were dizziness (20.5% versus 3.2% on placebo), headache (8.8% versus 6.4%), somnolence (8.8% versus 7.2%) and fatigue (7.6% versus 6.4%). Adverse events led to discontinuation in 14.5% of the 25 mg group, 4.8% of the 15 mg group and 3.2% of the placebo group, and serious adverse events occurred in 5.6%, 3.2% and 2.4%.

Of the 332 participants who completed the double-blind period, 322 entered an open-label extension. Xenon said it plans to submit a New Drug Application to the FDA for focal onset seizures in the third quarter of 2026. Azetukalner is also in Phase 3 trials for major depressive disorder and bipolar depression.

Xenon's shares rose 44% at the open on March 9, Clinical Trials Arena reported, citing William Blair analyst Miles Minter, who said the results beat the company's expectation of at least a 30% placebo-normalized improvement.

Sources

  1. Xenon Announces Positive Topline Data from Phase 3 X-TOLE2 Study of Azetukalner in Focal Onset Seizures (Form 8-K, Exhibit 99.1), Xenon Pharmaceuticals via SEC EDGAR, March 9, 2026
  2. Daily newsletter, March 9, 2026: item on Xenon's azetukalner Phase III results, Clinical Trials Arena, March 9, 2026