Novel Agent Reduces Seizures in Treatment-Resistant Epilepsy

Investigational azetukalner met its primary endpoint of reducing focal onset seizure frequency across two doses, initial findings from the phase III X-TOLE2 trial showed.

Over 12 weeks, adjunctive treatment with 25 mg azetukalner led to a 53.2% median decline from baseline in monthly focal onset seizure frequency, compared with a 10.4% drop for placebo (P<0.001), reported Jacqueline French, MD, of NYU Langone Health in New York City.

Adjunctive treatment with 15 mg azetukalner led to a 34.5% decline versus placebo (P<0.001), French said at a late-breaking science presentation at the American Academy of Neurology annual meeting.

With the 25 mg dose, reductions in weekly seizures were seen in the first week of treatment, she noted. At 12 weeks, Patient Global Impression of Change scores significantly improved.

“There was demonstrated rapid onset of efficacy — something we like to see in the epilepsy community — as assessed by a statistically significant reduction achieved within 1 week versus placebo, and then reductions continuing over the course of the treatment,” French said.

Azetukalner is a novel K_V7 potassium channel opener currently in development for epilepsy and depression. It is designed to help reduce excessive neuronal firing, preventing hyperexcitability and seizures. In 2023, a phase IIb X-TOLE study of azetukalner in focal epilepsy showed positive results.

In the phase III X-TOLE2 trial, the most common treatment-emergent adverse events with add-on azetukalner included dizziness, somnolence, headache, and fatigue. “There was a dose-dependent incidence of treatment-emergent adverse events,” French observed. “The adverse events were quite consistent with the X-TOLE double-blind, placebo-controlled study that had already been completed.”

X-TOLE2 randomized 380 adults with focal epilepsy who were on one, two, or three antiseizure medications to either 15 or 25 mg of azetukalner or placebo once daily for 12 weeks with no titration period. After 12 weeks, eligible participants could enter a 6-year open-label extension.

Participants had highly treatment-resistant epilepsy: they used a median of five prior anti-seizure medications and had a baseline seizure frequency of 12.75 per month. About half of participants (51.3%) were using three concomitant anti-seizure medications.

The mean age of trial participants was 40 years and 50.8% were women. The mean age at epilepsy onset was 15.9 years.

At 12 weeks, there was a dose-dependent increase in the proportion of azetukalner-treated participants with at least a 50% reduction in monthly focal onset seizure frequency from baseline, French noted. A greater proportion of participants in the 25 mg group had a 100% reduction in monthly seizure frequency compared with placebo.

In the azetukalner groups, the most common treatment-emergent adverse events leading to permanent treatment discontinuation were dizziness (3.2%), headache (1.6%), fatigue (1.6%), gait disturbance (1.2%), abnormal coordination (1.2%), and speech disorder (1.2%).

Four nonserious treatment-emergent adverse events of urinary retention were reported in the trial: two in the 25 mg group, one in the 15 mg group, and one in the placebo group. The participant in the 15 mg group was hospitalized for acute psychosis, which included catheterization and azetukalner discontinuation; both psychosis and urinary retention resolved after that.

There were no reports of notable weight gain, severe allergic rashes, retinal pigment epithelium or macular abnormalities, or notable cardiovascular adverse events during the 12-week trial, the researchers said.

Data from the X-TOLE2 and X-TOLE trials will support a planned new drug application (NDA) for azetukalner in focal onset seizures, developer Xenon Pharmaceuticals said. The company aims to submit an NDA to the FDA in the third quarter of this year.