Analyzing Positive 48-Month Data on Azetukalner for Focal Onset Seizures: Christopher Kenney, MD, FAAN

[WATCH TIME: 4 minutes]

“This is the most impaired focal epilepsy population ever assembled in a clinical trial, yet we are seeing seizure freedom rates that simply are not expected once patients have failed multiple antiseizure medications. Importantly, even after breakthrough events, many patients are able to regain meaningful periods of seizure freedom.”

Despite steady growth in the antiseizure medication armamentarium, long-term seizure freedom remains elusive for many patients with focal epilepsy who have failed multiple prior therapies. Most available options rely on overlapping mechanisms, leaving clinicians with limited strategies once patients cycle through several agents without durable control. This challenge has intensified interest in therapies that act through fundamentally different neurophysiologic pathways.

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, investigators presented promising data from a phase 2b trial dubbed X-TOLE (NCT03796962), that assessed the efficacy and safety of investigational azetukalner (Xenon Pharmaceuticals) in adults with focal onset seizures. The double-blind, placebo-controlled portion of the trial featured 325 patients with FOS, with 275 entering the extension phase, which followed participants for up to 7 additional years. All told, the therapy was shown to be effective, 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 (n = 129).

To paint a better picture of the findings, NeurologyLive® sat down with Christopher Kenney, MD, FAAN, lead presenter and chief medical officer at Xenon. Kenney, a trained neurologist, 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.

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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