USA: A phase 2b randomized clinical trial has shed light on the safety and efficacy of XEN1101 in adults with focal epilepsy. XEN1101 is a novel, small molecule, selective Kv7.2/Kv7.3 potassium channel opener that is being developed for treating focal-onset seizures (FOSs), the most common type of seizures experienced by individuals with epilepsy.
The findings of the trial, published in JAMA Neurology, support the further clinical development of XEN1101 for the treatment of focal-onset seizures. The study showed that XEN1101 reduced seizure frequency by more than 50% in some patients and sometimes eliminated them altogether.

According to the authors, unlike several treatments that must be started at low doses and slowly ramped up, the new drug can safely be taken at its most effective dose from the start.
Led by researchers at NYU Grossman School of Medicine, a new clinical trial found that patients who added XEN1101 to their current antiseizure treatments saw a 33% to 53% drop in monthly seizures, depending on their dose. By contrast, those given a placebo had on average 18% fewer seizures during the treatment phase of the trial, which lasted eight weeks. Most patients then volunteered to extend the trial, with about 18% of those treated with the new drug remaining entirely seizure-free after six months, and about 11% having no seizures after a year or longer.
Focal seizures, the most common type seen in epilepsy, occur when nerve cells in a particular brain region send out a sudden, excessive burst of electrical signals. Along with seizures, this uncontrolled activity can lead to abnormal behaviour, periods of lost awareness, and mood changes. Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs). Therefore, there is a need for more effective ASMs, specifically for ones that confer greater seizure reduction or seizure freedom.
ASMs act through an interaction with diverse molecular targets in the brain. The Kv7.2/Kv7.3 voltage-gated potassium channels, which exhibit axonal and perisomatic expression in brain neurons, represent an attractive target. Therefore, Jacqueline A. French, New York University Comprehensive Epilepsy Center, New York, New York, and colleagues aimed to evaluate the safety and efficacy of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures in a phase 2b, double-blind, randomized, placebo-controlled, parallel-group, dose-ranging adjunctive trial.
The researchers investigated XEN1101 over an 8-week treatment period from 2019 to 2021 and included a safety follow-up of 6 weeks. They enrolled adults experiencing four or more monthly FOSs 0while receiving stable treatment (1-3 ASMs) at 97 sites in Europe and North America.
Three hundred and twenty-five patients (mean age 40.8 years, 51.7 were females) were randomized in the ratio of 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks; 285 completed the 8-week double-blind phase. On completion of the double-blind phase, patients were offered the option to enter an open-label extension (OLE). Those who did not participate in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).
The primary efficacy endpoint was determined as the median per cent change from baseline in monthly FOS frequency. Comprehensive laboratory assessments were made and treatment-emergent adverse events (TEAEs) were recorded. A modified intention-to-treat analysis was conducted.
The researcher reported the following findings:
Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner.
The median per cent reduction from baseline in monthly FOS frequency was 52.8% for 25 mg, 46.4% for 20 mg, and 33.2% for 10 mg, compared with 18.2% for placebo.
XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported.
"Our study findings support the further clinical development of XEN1101 for the treatment of focal-onset seizures," the researchers wrote. "The findings suggest the potential of XEN1101 to address the unmet need for a treatment with a novel mechanism of action for FOS patients."
Reference:
French JA, Porter RJ, Perucca E, et al. Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial. JAMA Neurol. Published online October 09, 2023. doi:10.1001/jamaneurol.2023.3542