The Impact of Disease Severity on Responder Rates in a Phase 2b Study of XEN1101, a Potent, Selective Potassium Channel Opener, in Adults with Focal Epilepsy (X-TOLE)
Abstract number :
2.259
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2023
Submission ID :
543
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Roger Porter, MD – University of Pennsylvania, Philadelphia, PA
Jacqueline French, MD – New York University Grossman School of Medicine and NYU Langone Health, New York, NY; Emilio Perucca, MD, PhD – Monash University, Melbourne, Victoria, Australia, and University of Melbourne (Austin Health), Heidelberg, Victoria, Australia; Martin Brodie, MD – University of Glasgow Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; Cynthia Harden, MD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada; Constanza Luzon Rosenblut, MD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada; Jenny Qian, MS – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada; Christopher Kenney, MD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada; Gregory Beatch, PhD – Xenon Pharmaceuticals Inc., Vancouver, BC, Canada
Rationale: XEN1101 is a potent, selective KV7 potassium channel opener in development as a treatment for epilepsy. In the X-TOLE phase 2b study, XEN1101 (10, 20, and 25 mg QD with food) showed a dose-dependent, highly statistically significant, and rapid-onset reduction in focal onset seizure (FOS) frequency in adult patients who at baseline had a median of 13.5 monthly seizures and had tried and discontinued a median of six antiseizure medications (ASMs). A total of 50.5% were taking three concomitant ASMs. Based on these indicators of disease severity, the X-TOLE study population represents a difficult-to-treat group compared with the previous adult FOS clinical trial populations. The study population included a spectrum of disease severity, allowing for comparison of the effect of disease severity characteristics on efficacy outcomes. A post hoc analysis of X-TOLE suggested that the efficacy of XEN1101, measured by the median percentage change in monthly focal seizure frequency, may be most pronounced in patients with less-severe disease. Another widely used efficacy endpoint for evaluating ASM efficacy is the percentage of patients with a ≥50% reduction in seizure frequency during a given treatment period compared with baseline, known as the RR50. We report the potential impact of baseline disease severity on the RR50 in X-TOLE.
Methods: A total of 325 patients were randomized and treated across three active treatment groups or placebo in a 2:1:1:2 ratio (25 mg: 20 mg: 10 mg: placebo, QD with food). The data presented pertain to the 25-mg treatment group. Post hoc analyses were performed to assess the influence of baseline disease severity (as indicated by seizure frequency, number of concomitant ASMs, and number of previously tried ASMs) on the responder rate, defined as the RR50 in FOS frequency from baseline to the double-blind period. The subgroup analysis data presented below pertain to the 25-mg treatment group.
Results: Overall, 14.9% (n=114) in the placebo group and 54.5% (n=112) in the XEN1101 25-mg group achieved RR50. With XEN1101 treatment, RR50 was achieved by 65.5% of patients with ≤8.5 seizures per month at baseline (n=29) and 50.6% with >8.5 seizures per month (n=83), 64.2% of patients with ≤6 prior ASMs (n=67) and 40.0% with >6 ASMs (n=45), and 56.9% of patients with one to two concomitant ASMs (n=58) and 51.9% with three concomitant ASMs (n=54).
Conclusions: Consistent with the significant median percentage seizure reduction in X-TOLE, 54.5% of the patients in the 25-mg XEN1101 group achieved the benchmark of RR50. This effect was observed in a population with characteristics of severe disease. XEN1101 was relatively more effective in patients with indicators of less-severe disease in the trial population. These findings suggest that XEN1101 may be appropriate for use in patients with focal epilepsy across the spectrum of disease severity.
Funding: Xenon Pharmaceuticals Inc.
Anti-seizure Medications