On 19 April, at the 2026 American Academy of Neurology (AAN) meeting, in the late-breaking science session, 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) (NCT05614063). The study sought to evaluate the efficacy, safety, and tolerability of azetukalner, administered as an oral, adjunctive, once-daily therapy with food for adult patients with FOS. The results are pivotal and could mark a shift in the treatment paradigm for FOS; as a result of azetukalner’s differentiated KV7 mechanism of action, the drug could challenge currently marketed anti-seizure medications (ASMs) for epilepsy. However, the epilepsy treatment landscape is highly crowded, with effective incumbent therapies already in place, and there are concerns over KV7 potassium channel openers as a drug class, given the failure of previously developed assets in this class.
Azetukalner is a potent KV7 potassium channel opener, currently in Phase III clinical trials for the treatment of epilepsy, major depressive disorder, and bipolar depression. It is designed to open potassium channels in the central nervous system, allowing potassium ions to flow and hyperpolarise neurons. This process helps to reduce excessive neuronal firing, which is a key contributor to several neurological and psychiatric disorders, including epilepsy. Epilepsy is a neurological condition characterised by abnormal electrical activity in the brain that leads to spontaneous, recurrent, and unprovoked seizures. Focal epilepsy, which leads to FOS, is the most common form of epilepsy and is characterised by recurrent seizures that originate in a specific area of the brain.
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The X-TOLE2 study evaluated azetukalner for the treatment of FOS. The study randomised participants in a blinded manner to one of three treatment arms: either azetukalner administered at 25mg, 15mg, or placebo. The trial 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. The study focused on highly treatment-resistant patients, with a median of five prior ASMs being applied, as well as a baseline seizure frequency of 12.75 per month; 51.3% of participants were also using at least three concomitant ASMs.
The study results were impressive, with azetukalner meeting the primary endpoint of a median per cent 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. For further context, 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. Moreover, given that the results were achieved amongst highly refractory epilepsy patients, it displays azetukalner’s capacity to address unmet needs in the epilepsy treatment landscape. Xenon has signalled that it plans to submit a new drug application (NDA) to the FDA for the treatment of FOS in Q3 2026. If approved, azetukalner would be the first KV7 potassium channel opener to reach the market for the treatment of epilepsy.
Azetukalner would be entering 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. Such a busy treatment landscape may be difficult for a new entrant to navigate, but key opinion leaders (KOLs) previously interviewed by GlobalData have noted that they found several features of azetukalner attractive. KOLs noted that its efficacy in clinical trials, and its convenience of use, in that it is 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 was then later withdrawn from the market in 2017 as its use declined after safety concerns accumulated. Xenon Pharmaceuticals will therefore have to present a strong safety profile for azetukalner, and may have to run additional safety analyses, in order to create distance between it and ezogabine, or else the reputational baggage may slow its approval and entry to the market.
The Phase III clinical trial results for azetukalner are promising, displaying strong efficacy data amongst highly refractory epilepsy patients, as well as demonstrating a consistent safety profile, and could act as a strong base from which to submit an NDA. However, Xenon faces challenges as it is 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, as a novel KV7 potassium channel opener, but Xenon will have to consider how to differentiate and market azetukalner in a crowded treatment landscape to assuage any doubts and gain traction in the market.
