Overviewing Positive Phase 2 Data on Potassium Channel Inhibitor XEN1101: Jacqueline French, MD

WATCH TIME: 4 minutes

"The main benefit is that this drug was started at the maintenance dose immediately from day one, and it only needs to be taken once a day—something we've all been looking for in drugs that are also highly efficacious."

XEN1101 (Xenon Pharmaceuticals), is a novel, potent, selective KCNQ2/3 (Kv7.2/7.3) potassium channel opener under investigation for the treatment of focal onset seizures and primary generalized tonic-clonic seizures. The agent is currently being investigated in the phase 3 X-TOLE2 (NCT05614063) and X-TOLE3 (NCT05716100) studies, 2 randomized, multicenter, double-blind, placebo-controlled trials. In the studies, adults diagnosed with focal onset seizures will be randomly assigned 1:1:1 to either XEN1101 in doses of 25 mg or 15 mg, or placebo.

X-TOLE2 and X-TOLE3 include a screening/baseline period up to 9.5 weeks duration to assess the frequency of seizures. Following that, patients enter a double-blind, 12-week treatment period, with an optional open-label extension that lasts up to 3 years. The studies also include a follow-up period after the double-blind portion that lasts 8 weeks for those who do not complete the double-blind portion or those who complete the double-blind period and do not enter the open-label extension. Earlier this year, Xenon announced it anticipated completion of patient enrollment of X-TOLE2 to occur later this year, with approximately 360 participants expected in the study.

Prior to the new phase 3 X-TOLE studies, the drug was evaluated in a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging, multicenter study (NCT03796962) that included an open-label extension. The extension trial’s cohort included 188 patients who had been treated for at least 12 months, with 111 patients treated for at least 18 months at the analysis cutoff of September 22, 2022. All told, X-TOLE met the primary and key secondary end points, with XEN1101-treated patients demonstrating a statistically significant reduction in monthly focal onset seizure frequency compared with placebo.

Lead investigator Jacqueline A. French, MD, a professor of neurology at NYU Grossman School of Medicine, recently sat down with NeurologyLive® to discuss the clinical development of XEN1101 and the results from the phase 2b trial. In the conversation, French highlighted that the drug’s once-daily dosing without titration offers a major advantage over other treatments, such as cenobamate (Xcopri; SK Life Science), which requires slow titration due to the risk of serious adverse effects.