X-TOLE OLE interim analysis shows long-term efficacy of novel agent for focal epilepsy

Interim data from the ongoing 7-year open-label extension (OLE) of the phase IIb X-TOLE study reflect the long-term efficacy and safety of azetukalner, an investigational, potent K_v7 potassium channel opener, for the treatment of adults with focal epilepsy.

“Azetukalner 20 mg QD with food yielded long‑term efficacy in this interim analysis, with 52 percent retention at 36 months,” said the researchers.

For ongoing OLE participants, monthly median percentage change (MPC) reductions in the frequency of focal onset seizures (FOS) ranged between 61 percent and 82 percent from month 1 to OLE month 24. By OLE month 36, the monthly MPC reduction was sustained at 85 percent. [AAN 2025, poster 9‑001]

At month 36, there was a higher monthly MPC reduction in FOS frequency from baseline among individuals taking 1–2 antiseizure medications (ASMs) at baseline as opposed to those who were on three ASMs (100 percent vs 80.6 percent).

Month 36 also saw about 19 percent of all OLE participants achieving ≥50-percent seizure reduction threshold, 12.4 percent achieving ≥75-percent seizure reduction threshold, and 7.6 percent achieving ≥90-percent seizure reduction threshold. The corresponding rates in the subgroup of participants treated for ≥36 months were 35.4, 23.1, and 14.3 percent, respectively.

Among all participants who entered the OLE, 18.2 percent achieved seizure freedom or 100-percent seizure reduction for any consecutive ≥12‑month duration, 10.9 percent were seizure-free for ≥24 months, and 5.5 percent were seizure-free for ≥36 months. Among those treated for ≥36 months in the OLE, the corresponding rates of seizure freedom at ≥12, ≥24, and ≥36 months were 32.7, 20.4, and 10.2 percent, respectively.

“Azetukalner continues to be generally well tolerated in the OLE, with adverse events (AEs) consistent with prior results and other ASM AEs. There were no new safety signals identified,” said the researchers. The most common AEs were dizziness (23.3 percent), headache (17.5 percent), COVID-19 (17.1 percent), and somnolence (16 percent).

About 15 percent of participants had at least one serious treatment-emergent AE (TEAE), and 12 percent had at least one TEAE leading to permanent treatment discontinuation. There were two deaths due to at least one serious TEAE (one from sudden unexplained death in epilepsy [SUDEP] and another from viral pneumonia). According to the researchers, the SUDEP was unrelated to the study drug.

Offers hope for difficult-to-treat, uncontrolled seizures

In the 8-week double-blind phase (DBP), 325 participants were randomized 2:1:1:2 to receive azetukalner 25, 20, or 10 mg or placebo QD. Of those who have completed the DBP, 275 enrolled in the OLE. The mean age was 41.1 years at study entry and 18.1 years at epilepsy onset. Half of the OLE cohort were women. Fifty-two percent were on three background ASMs. The median baseline seizure rate per month was 13.5.

The number of participants who received treatment at ≥12, ≥24, and ≥36 months were 182, 165, and 143, respectively. Retention rates with the experimental drug at the respective timepoints were 66, 60, and 52 percent.

The current results build on the findings of the DBP, wherein the investigational agent yielded a dose-dependent, statistically significant reduction from baseline in FOS across treatment arms. [JAMA Neurol 2023;80:1145-1154]

“These promising data suggest long‑term efficacy and tolerability of azetukalner in a difficult‑to‑treat population,” the investigators concluded.

“[The 36-month data] show sustained monthly reduction in seizure frequency, impressive seizure freedom rates, and a consistent AE safety profile, suggesting the long-term efficacy and tolerability of azetukalner,” said Xenon Chief Medical Officer Dr Christopher Kenney in a separate news report. “[These] support our conviction that azetukalner may offer hope for individuals who continue to seek new, efficacious, and well-tolerated therapies to address the debilitating impacts of uncontrolled seizures.”

Apart from FOS, azetukalner is also being developed for the treatment of primary generalized tonic-clonic seizures (X‑ACKT study) and major depressive disorder (X‑NOVA study), the investigators noted.