Phase 3 X-TOLE2 Data Support NDA Submission for Azetukalner in Focal Onset Seizures

Topline results from the phase 3 X-TOLE2 trial showed that azetukalner significantly reduced monthly focal onset seizure (FOS) frequency compared with placebo in adults with treatment-resistant epilepsy. The findings support Xenon Pharmaceuticals’ plan to submit a new drug application (NDA) to the FDA in the third quarter of 2026, positioning the therapy as a potential new option targeting KV7 potassium channels for patients with uncontrolled seizures.¹

Phase 3 X-TOLE2 Results

The phase 3 X-TOLE2 study (NCT05614063) evaluated azetukalner as adjunctive therapy in adults with focal onset seizures. The randomized, double-blind, placebo-controlled trial enrolled 380 participants, with 374 included in the safety and modified intent-to-treat analyses.

Participants had highly treatment-resistant epilepsy, with a median of five prior ASMs, a baseline seizure frequency of 12.75 per month, and more than half receiving three concomitant antiseizure medications.

The study met its primary endpoint, demonstrating significant reductions in monthly seizure frequency over 12 weeks.

Median percent change (MPC) in monthly FOS frequency was:

• 53.2% with azetukalner 25 mg (P = 0.000000000006)
• 34.5% with azetukalner 15 mg (P = 0.00007)
• 10.4% with placebo

The placebo-adjusted reduction in the 25-mg group was −42.7%, exceeding the efficacy observed in the earlier phase 2b X-TOLE trial (NCT03796962), which showed a placebo-adjusted reduction of −34.6%.

The trial also met its key secondary endpoint, responder rate 50 (RR50), defined as the proportion of patients achieving at least a 50% reduction in monthly seizure frequency:

1. 54.8% with azetukalner 25 mg
2. 37.6% with azetukalner 15 mg
3. 20.8% with placebo

These differences were statistically significant for both dose groups.

Commenting on the findings, Jacqueline A. French, MD, professor of neurology at NYU Langone Health and chair of the X-TOLE2 steering committee, said the results reinforce the therapeutic potential of the drug’s mechanism.

“Despite a large number of approved epilepsy treatments, there are only a handful of distinct mechanisms of action available, and the data from X-TOLE2 reinforce the value that azetukalner and its KV7 mechanism may bring to the treatment armamentarium for focal seizures,” French said in a statement.¹

Safety and Tolerability

Azetukalner demonstrated a safety and tolerability profile consistent with previous studies, including the earlier phase 2b X-TOLE trial. Overall, treatment-emergent adverse events (TEAEs) were generally manageable, and the incidence of serious events remained low across treatment groups.

The most commonly reported adverse events among patients receiving azetukalner included dizziness, headache, somnolence, and fatigue. Dizziness occurred in 20.5% of patients receiving azetukalner compared with 3.2% in the placebo group, while headache was reported in 8.8% of treated patients versus 6.4% of those on placebo. Somnolence and fatigue occurred in 8.8% and 7.6% of azetukalner-treated patients, respectively, compared with 7.2% and 6.4% in the placebo arm.

Treatment discontinuations due to adverse events were more common in the higher-dose azetukalner group, occurring in 14.5% of patients receiving the 25 mg dose and 4.8% of those receiving the 15 mg dose, compared with 3.2% in the placebo group. However, the incidence of serious treatment-emergent adverse events remained relatively low and comparable across groups, reported in 5.6% of participants receiving 25 mg azetukalner, 3.2% in the 15 mg group, and 2.4% among those receiving placebo.

Among the 332 participants who completed the double-blind portion of the trial, 322 chose to continue into the open-label extension study. Continued follow-up from this cohort is expected to provide additional insight into the long-term safety and durability of azetukalner treatment.

Mechanism and Clinical Context

Azetukalner is a KV7 potassium channel opener designed to stabilize neuronal excitability by enhancing potassium channel activity in the central nervous system. By promoting neuronal hyperpolarization, the therapy reduces excessive neuronal firing, a key driver of epileptic seizures.

KV7 channels have long been recognized as important regulators of neuronal excitability, and pharmacologic modulation of these channels represents a distinct mechanism compared with most currently available ASMs.³ If approved, azetukalner could become the first KV7 potassium channel opener available for epilepsy, adding a new mechanism to the current treatment landscape.

At the 2025 American Epilepsy Society (AES) Annual Meeting, Xenon presented data from the open-label extension of X-TOLE, with median percent change reductions in monthly FOS frequency that ranged from 61.6% to 81.9% during months 1-24 of the OLE. By month 48, these numbers continued to improve, reaching a 90.9% reduction. During the meeting, NeurologyLive® sat down with Christopher Kenney, MD, FAAN, chief medical officer at Xenon who is a trained neurologist with years of experience.²

In the clip below, Kenney provided insights on the 48-month data, and how seizure freedom rates continued to increase over time in this highly refractory population. Throughout the discussion, he noted the durable treatment effect of azetukalner, as well as how Xenon is reframing its analyses to address more practical clinical questions, such as whether patients who relapse after seizure freedom can reasonably expect to regain sustained control with continued treatment.

REFERENCES
1. Xenon Announces Positive Topline Data from Phase 3 X-TOLE2 Study of Azetukalner in Focal Onset Seizures (FOS). News release. Xenon Pharmaceuticals. March 9, 2026. Accessed March 11, 2026. https://investor.xenon-pharma.com/news-releases/news-release-details/xenon-announces-positive-topline-data-phase-3-x-tole2-study
2. French JA, Porter RJ, Perucca E, et al. Long-Term Safety and Efficacy of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener, in Adults With Focal Epilepsy: ≥48-Month Interim Analysis of the Ongoing 7-Year X-TOLE Open-Label Extension. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 3.356