Understanding the Mechanism and Rationale of Azetukalner to Treat Focal Epilepsy: Christopher Kenney, MD, FAAN

[WATCH TIME: 3 minutes]

"Azetukalner brings a completely new mechanism to the epilepsy toolbox by prolonging potassium channel opening and keeping hyperexcitable neurons in a stabilized state. This offers the potential to both prevent seizure initiation and limit propagation in ways existing therapies do not."

The antiseizure medication (ASM) landscape has expanded considerably in the past two decades, yet most available therapies continue to rely on well-known mechanisms such as sodium channel blockade, GABAergic modulation, or synaptic vesicle protein targeting. As a result, patients with focal epilepsy who remain refractory despite multiple treatment attempts often cycle through mechanistically similar agents, highlighting the need for therapies that interrupt hyperexcitability through novel pathways.

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, Xenon Pharmaceuticals shared new data on azetukalner, a first-in-class potassium channel opener being evaluated for focal onset seizures (FOS). The long-term efficacy and safety findings were from the X-TOLE trial (NCT03796962) and its open-label extension (OLE), which follows patients for an additional 7 years. A total of 325 participants were randomized in X-TOLE (placebo n=114; 10 mg n=46; 20 mg n=51; 25 mg n=114), and of the 285 who completed the double-blind phase, 275 (96.5%) entered the open-label extension.

Findings showed that across the overall population, median percent change (MPC) reductions in monthly FOS frequency from the double-blind baseline ranged from 61.6% to 81.9% during months 1–24 of the OLE (n = 266 to n = 165) and continued to improve, reaching a 90.9% reduction by month 48 (n = 129). Among participants treated for at least 48 months (n=131), MPC reductions were –69.8% at OLE month 1, –85.1% at month 12, and again –90.9% at month 48. At the 48-month mark, participants who had been on 1–2 ASMs at DBP baseline showed a 100% reduction in monthly FOS frequency (n=60), compared with an 81.8% reduction in those receiving 3 ASMs (n=69).

During the meeting, NeurologyLive^® caught up with Christopher Kenney, MD, FAAN, chief medical officer at Xenon, to discuss the mechanism and rationale behind azetukalner in treating FOS. Kenney, a board-certified neurologist with more than 20 years of experience, spoke on why this therapy differs from fundamentally available antiseizure medications, and how its pharmacology may translate into clinical benefit. In addition, he touched on the agent’s broad potential both within epilepsy and potentially with psychiatry.

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REFERENCE
1. 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