At the 2026 American Academy of Neurology (AAN) meeting, Xenon Pharmaceuticals announced positive results from the Phase III X-TOLE2 study of azetukalner, a novel, potent, KV7 potassium channel opener, in focal onset seizures (FOS). The study evaluated the efficacy, safety, and tolerability of azetukalner, administered as an oral, adjunctive, once-daily therapy taken with food for adult patients with predominantly refractory FOS. The results are pivotal and could mark a shift in the treatment paradigm for FOS, says GlobalData, a leading intelligence and productivity platform.

The X-TOLE2 study was unique in that participants had highly treatment-resistant epilepsy, with a median of five prior anti-seizure medications (ASMs), a baseline seizure frequency of 12.75 per month, and 51.3% of participants using three concomitant ASMs. The study results were impressive, with azetukalner meeting the primary endpoint of a median percent change (MPC) in monthly FOS frequency from baseline to week 12 in both the 25mg (decline of 53.2%) and the 15mg (decline of 34.5%) dose groups. By comparison, the placebo group achieved a decline in MPC of 10.4% in seizure frequency. Azetukalner also demonstrated a safety and tolerability profile consistent with prior studies.

Jos Opdenakker, Neurology Analyst at GlobalData, comments: “Given that the results were achieved among highly refractory epilepsy patients, it displays azetukalner’s capacity to address unmet needs in the epilepsy treatment landscape.”

However, if azetukalner enters the market, it will do so in a highly competitive and crowded market in epilepsy, particularly FOS, with the current landscape dominated by sodium channel blockers, SV2A ligands, benzodiazepines, and other mixed-mechanism agents such as cenobamate.

Opdenakker continues: “Such a crowded treatment landscape may be difficult for a new entrant to navigate.”

Key opinion leaders (KOLs) previously interviewed by GlobalData noted that they found several features of azetukalner attractive. They highlighted its efficacy in clinical trials and its convenience of use as a once-daily treatment that does not require any titration would certainly help its case. However, KOLs also noted that azetukalner belongs to the same drug family as ezogabine (marketed as Potiga), which was approved by the FDA in 2011 as an adjunctive treatment, but later withdrawn from the market in 2017 as its use declined after safety concerns accumulated. Xenon may therefore need to demonstrate a strong safety profile for azetukalner and may have to run additional safety analyses to distinguish it from ezogabine.

Opdenakker concludes: “The Phase III results for azetukalner are promising, displaying strong efficacy data among highly refractory epilepsy patients and a consistent safety profile, which could act as a strong base from an NDA submission. However, Xenon faces challenges in entering a highly competitive market filled with established therapies and strong long-term safety and efficacy data. Azetukalner has the potential to become a valuable addition to the epilepsy treatment paradigm, but Xenon will need to consider how to differentiate it in a crowded treatment landscape to gain traction in the market.”

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Notes to Editors

• Quotes provided by Jos Opdenakker, Neurology Analyst at GlobalData
• This press release was written using data and information sourced from proprietary databases, primary and secondary research, and in-house analysis conducted by GlobalData’s team of industry experts

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