Azetukalner cut focal seizure frequency in a phase 3 trial of 374 adults with epilepsy
In the phase 3 X-TOLE2 trial, the KV7 channel opener azetukalner at 15 mg lowered median monthly focal seizure frequency by 34.5%, versus 10.4% on placebo.
Azetukalner, a KV7 channel opener, reduced the frequency of focal seizures in adults in the phase 3 randomized trial X-TOLE2, according to a report in JAMA Neurology. jamanetwork.com
JAMA neurologyjamanetwork.comOpen source ↗ The double-blind period ran from November 18, 2022 to February 3, 2026 at 138 sites in North America, South America, Europe and Asia Pacific. Of 607 adults screened, 374 were enrolled, randomized and treated.
Trial design
Participants had focal epilepsy and 4 or more focal seizures per month despite stable treatment with 1 to 3 antiseizure medications. They were randomized 1:1:1 to placebo (125 participants), 15 mg azetukalner (125) or 25 mg azetukalner (124). The drug was taken once daily with the evening meal for 12 weeks, with no titration period. Those who completed the double-blind period could enter an open-label extension.
The primary end point was the median percentage change from baseline in monthly (28-day) focal seizure frequency, azetukalner versus placebo. Safety was assessed by recording treatment-emergent adverse events, laboratory findings, vital signs and electrocardiogram.
The mean age was 40.0 years (SD 12.9), and 190 participants (50.8%) were female. At baseline the median was 12.75 seizures per month (IQR 7.56 to 32.97). Participants had previously tried and stopped a median of 5 antiseizure medications (IQR 3 to 8), and 336 (89.8%) were receiving 2 to 3 concomitant ones. jamanetwork.com
JAMA neurologyjamanetwork.comOpen source ↗
Results
The median change from baseline in monthly seizure frequency was -10.4% (IQR -39.1% to 8.3%) in the placebo group and -34.5% (IQR -61.6% to -12.3%) in the 15 mg azetukalner group.
The authors concluded that azetukalner produced rapid and durable reductions in seizure frequency with a favorable benefit-risk profile. They described the effect as one of the largest median percentage reductions in seizure frequency versus placebo reported to date in drug-resistant epilepsy. The trial is registered at ClinicalTrials.gov as NCT05614063.
