Rapid Onset of Efficacy of XEN1101, a Novel Potassium Channel Opener, in Adults with Focal Epilepsy: Results from a Phase 2b Study (X-TOLE)
Abstract number :
2.236
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2204715
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Christopher Kenney, MD, FAAN – Xenon Pharmaceuticals; Jacqueline French, MD – NYU Grossman School of Medicine; Roger Porter, MD – University of Pennsylvania; Emilio Perucca, MD, PhD – Department of Medicine (Austin Health) – The University of Melbourne; Martin Brodie, MD – University of Glasgow; Michael Rogawski, MD, PhD – University of California, Davis; Cynthia Harden, MD – Xenon Pharmaceuticals; Constanza Luzon-Rosenblut, MD – Xenon Pharmaceuticals; Jenny Qian, MS – Xenon Pharmaceuticals; Jennifer Leung, MSc – Xenon Pharmaceuticals; Greg Beatch, PhD – Xenon Pharmaceuticals
Rationale: XEN1101 is a novel, potent, selective KCNQ2/3 (KV7.2/7.3) potassium channel opener, currently in development as a treatment for epilepsy. In the X-TOLE Phase 2b study, treatment with XEN1101 (10, 20 and 25 mg QD) was associated with a dose-dependent, highly statistically significant, reduction in monthly focal onset seizure (FOS) frequency in patients who had failed a median of 6 anti-seizure medications (ASMs), with 50.8% on 3 background ASMs, and a median seizure frequency of 13.5/month at baseline. The pharmacokinetic properties of XEN1101 support once daily oral dosing without titration. In this analysis, rapid onset of action was assessed by evaluating the change in weekly FOS frequency and the number of patients achieving ≥50% reduction (RR50) at week 1 compared to baseline.
Methods: X-TOLE was a double-blind, placebo-controlled, dose-ranging study. Patients were aged 18-75 years with ≥4 FOS per month recorded with an eDiary, and on stable treatment with 1 to 3 ASMs. Weekly FOS frequency was defined as the total number of seizures every consecutive 7 assessed days. For the double-blind period (DBP) the weekly period started on the randomization date. A prespecified assessment of weekly seizure frequency was conducted followed by a post-hoc statistical pair-wise comparison between placebo and each dose. Monthly and weekly response (RR50) was computed as those subjects having achieved ≥50% seizure reduction, based on percent change from baseline in monthly and weekly FOS frequency.
Results: A total of 325 subjects were randomized and treated across four treatment arms in a 2:1:1:2 ratio with no titration (25 mg:20 mg:10 mg:placebo). At week 1, XEN1101 demonstrated a reduction of 39.1% (p=0.002), 41.5% (p=0.039) and 55.4% (p< 0.001) in the 10, 20, and 25 mg groups, respectively, from baseline in median weekly FOS compared to placebo (20.2%). At week 1, RR50 was 43.5% (p=0.034), 47.1% (p=0.015) and 53.6% (p< 0.001) for 10, 20 and 25 mg, respectively, compared to placebo (28.1%).
Anti-seizure Medications