Xenon Pharmaceuticals, a neuroscience-focused biopharmaceutical company dedicated to drug discovery, clinical development and commercialisation of life-changing therapeutics for patients in need, has announced positive topline results from the phase 3 X-TOLE2 study of azetukalner in focal onset seizures (FOS).
Azetukalner is a novel, potent, KV7 potassium channel opener currently in clinical development for epilepsy and depression.
The study met its primary endpoint of MPC in monthly FOS frequency from baseline to week 12 in both the 25 mg and 15 mg azetukalner dose groups compared to placebo [MPC of -53.2% (p=0.000000000006), -34.5% (p=0.00007) and -10.4%, respectively]. The placebo-adjusted MPC in the 25 mg group was -42.7%, outperforming the previously completed Phase 2b X-TOLE study, which demonstrated a -34.6% placebo-adjusted MPC in the 25 mg dose group over eight weeks (-52.8% in the 25 mg group and -18.2% in the placebo group).
Azetukalner also demonstrated a safety and tolerability profile consistent with prior studies. Xenon plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the treatment of focal onset seizures in the third quarter of 2026. If approved, azetukalner would be the only KV7 potassium channel opener available for the treatment of epilepsy.
Study design and participant disposition
The X-TOLE2 clinical trial (NCT05614063) was a randomised, double-blind, placebo-controlled, multicenter phase 3 study evaluating the efficacy, safety, and tolerability of azetukalner, administered as an oral, adjunctive therapy once-daily with food in adult patients with FOS.
The study randomised participants in a blinded manner to either azetukalner 25 mg, 15 mg, or placebo, and included a total of 380 randomised participants, with 374 participants in the safety and modified intent-to-treat (mITT) population for the safety and efficacy analyses.
Participants had highly treatment-resistant epilepsy, with a median of five prior ASMs, a baseline seizure frequency of 12.75 per month, and 51.3% using three concomitant ASMs. Of the 332 participants who completed the double-blind period, 322 entered the open-label extension study.
Additional study results
In addition to meeting the primary endpoint of MPC in monthly FOS frequency, the study also met the key secondary endpoint of responder rate 50 (RR50), with 54.8% in the 25 mg group and 37.6% in the 15 mg group experiencing at least a 50% reduction in monthly FOS frequency from baseline, compared with 20.8% in the placebo group (p=0.00000008 and p=0.003 for 25 mg and 15 mg groups, respectively).
| Azetukalner 25 mg (n=124) | Azetukalner 15 mg (n=125) | Placebo (n=125) | |
| Primary endpoint: Median percent change (MPC) in monthly (28 days) FOS frequency from baseline to week 12 | -53.2% (p=0.000000000006) | -34.5% (p=0.00007) | -10.4% |
| Key secondary endpoint: Proportion of participants experiencing ≥50% reduction in monthly (28 days) FOS frequency from baseline to week 12 (RR50) | 54.8% (p=0.00000008) | 37.6% (p=0.003) | 20.8% |
The safety and tolerability profile of azetukalner remains consistent with the previously disclosed data from the X-TOLE study. The most common treatment-emergent adverse events (TEAEs) across both azetukalner dose groups were dizziness (20.5%), headache (8.8%), somnolence (8.8%), and fatigue (7.6%) as compared to the placebo group, which reported dizziness (3.2%), headache (6.4%), somnolence (7.2%), and fatigue (6.4%).
Some 14.5% of participants in the 25 mg group, 4.8% in the 15 mg group, and 3.2% in the placebo group had a TEAE leading to treatment discontinuation.
The incidence of serious TEAEs was low and similar across treatment groups, with 5.6% in the 25 mg group, 3.2% in the 15 mg group, and 2.4% in the placebo group experiencing a serious TEAE.
About Azetukalner
Azetukalner is a novel, potent KV7 potassium channel opener currently in phase 3 clinical trials for the treatment of epilepsy, major depressive disorder (MDD) and bipolar depression (BPD).
It represents the most advanced, clinically validated potassium channel modulator in late-stage clinical development. Azetukalner is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarising neurons.
This process helps reduce excessive neuronal firing, which is a key contributor to several neurologic and psychiatric disorders. It is the only KV7 potassium channel opener in development for multiple indications that is backed by long-term efficacy and safety data in epilepsy patients and proof-of-concept data in MDD patients.
