CHICAGO — Azetukalner (AZK), a novel and potent Kv7 potassium channel opener, reduced median seizure frequency by up to 53% in patients with treatment-resistant focal onset seizures (FOS) in a phase 3 trial, with a rapid onset of effect and no need for titration.

“In addition to the good efficacy, the drug has characteristics that neurologists will definitely welcome,” study investigator Jacqueline French, MD, professor at the Comprehensive Epilepsy Center, New York University in New York City, told Medscape Medical News.

“This includes the ability to start at an efficacious dose without titration, good efficacy within 1 week, and a very long half-life, which hopefully will translate into a buffer if a pill is missed or late,” she said.

French added that the novel antiseizure medicine (ASM) is likely to be the next agent approved for use in focal epilepsy.

The findings were presented online on April 19 at the American Academy of Neurology (AAN) 2026 Annual Meeting.

Rapid Response, No Titration

AZK is among a few potassium channel openers in development for epilepsy. The only approved potassium channel opener (ezogabine) was voluntarily removed from the market because of tissue pigmentation.

Focal epilepsy is marked by seizures from a single brain region that often affect one side of the body. It’s the most common type of epilepsy, accounting for more than 50% of cases, so finding effective treatments is particularly important, French noted.

The analysis included 374 adults with FOS and a mean age of 40 years, who were experiencing an average of four or more focal seizures per month and taking one to three ASMs. Participants had a median epilepsy duration of 25 years and had failed a median of five ASMs.

Participants were randomly assigned to receive AZK 15 mg or 25 mg, or a placebo, once daily with food for 12 weeks, with no titration period.

The primary endpoint was the median percent change (MPC) in monthly FOS frequency at 12 weeks. The study demonstrated statistically significant dose-dependent reductions: -34.5% (P < .0001) in the 15-mg group and -53.2% (P < .0001) in the 25-mg group compared with -10.4% in the placebo group.

A key secondary endpoint was MPC in the first week of the study. Here, the reductions were -33.3% for the 15-mg dose (P = .08), -45.2% for the 25-mg dose (P < .01), and -19.3% for placebo.

“It’s interesting to see how quickly we get a response. There was quite a significant reduction in seizures even at the 1-week timepoint, and that continued across the study with the three arms separating very nicely until the very end of the trial,” said French.

There was a statistically significant, dose-dependent increase in the proportion of participants achieving a ≥ 50% reduction in monthly seizure frequency: 37.6% (P < .01) with the lower dose and 54.8% (P < .0001) with the higher dose than 20.8% with placebo.

There were also dose-dependent increases in the proportion of participants with a ≥ 75% and a ≥ 90% reduction in monthly seizure frequency.

In addition, there were significant improvements in the proportion of participants scoring “much improved” or “better” on the Patient Global Impression of Change vs placebo at week 12.

French noted that the drug “can be started at a therapeutic dose right from the get-go, with no titration, which makes it very convenient for people to try and use in the clinic.”

Seizure Freedom for Some

The drug was safe and generally well tolerated. Treatment-emergent adverse events (TEAEs) included dizziness (20.5%), headache (8.8%), and somnolence (8.8%), with higher rates observed at the higher dose.

The most common TEAEs leading to discontinuation were dizziness (3.2%), headache (1.6%), fatigue (1.6%), gait disturbance (1.2%), abnormal coordination (1.2%), and speech disorder (1.2%). No single event accounted for more than 5% of discontinuations, and no deaths were reported.

The rate of serious AEs in the lower-dose group was not significantly different from placebo and was only slightly higher in the 25-mg group.

Notably, there were no cases of significant weight gain, severe allergic rash, retinal pigment epithelium or macular abnormalities, or cardiovascular events, French reported.

Looking at efficacy together with safety, French concluded that “the risk-benefit profile remains quite favorable.”

Responding during the late-breaking session where the study was presented, an audience member asked which treatment-resistant patients might benefit most from AZK. French noted that about one third of participants were also receiving cenobamate, and another 10%-15% had previously failed it. Cenobamate was approved by the FDA for focal epilepsy in 2019.

“We looked at those patients, and they responded similarly to the overall population,” French said. “This suggests benefit even in those who have not responded to newer antiseizure medications, with some achieving seizure freedom.”

Jorg Dietrich, MD, PhD, associate professor of neurology, Harvard Medical School in Boston, and director of the Brain Repair Research Program, who co-moderated the session featuring the study, called the work “outstanding” and congratulated French and her team on the research.

Xenon Pharmaceuticals Inc. funded the study. French reported being an advisor to Xenon Pharmaceuticals but reported receiving no personal remuneration from this or any of the other companies she is associated with that are developing new therapies for epilepsy; all funds are donated to the nonprofit Epilepsy Study Consortium.

Dietrich reported receiving personal compensation for serving as a consultant for Novartis and Ono Pharmaceutical, Co., Ltd., for serving on a scientific advisory or data safety monitoring board for Johnson & Johnson and for receiving publishing royalties from a publication relating to healthcare.