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)
Roger Porter1, Jacqueline French2, Emilio Perucca3, Martin Brodie4, Cynthia Harden5, Constanza Luzon Rosenblut5, Jenny Qian5, Christopher Kenney5, Gregory Beatch5
1University of Pennsylvania, 2New York University Grossman School of Medicine and NYU Langone Health, 3Monash University, Melbourne, VI, Australia, and University of Melbourne (Austin Health), 4University of Glasgow Department of Medicine and Therapeutics, Western Infirmary, 5Xenon Pharmaceuticals Inc.
Objective:
To report the impact of baseline disease severity on the percentage of patients achieving a ≥50% reduction in seizure frequency (RR50) in the double-blind period (DBP) of a phase 2b study (X-TOLE) of XEN1101 in adults with focal onset seizures (FOS).
Background:
In the DBP, XEN1101 showed a significant, dose-dependent, and rapid-onset reduction in FOS frequency in adults with a median of 13.5 seizures/month and 6 tried and stopped antiseizure medications (ASMs) at baseline. 50.5% were taking 3 concomitant ASMs. A post hoc analysis suggested that the efficacy of XEN1101, measured by the median percentage change (MPC) in monthly FOS frequency, may be most pronounced in patients with less-severe disease. We report the potential impact of baseline disease severity on the RR50, another widely used endpoint for evaluating ASMs.
Design/Methods:
Patients (n=325) received 25, 20, or 10 mg XEN1101 or placebo in a 2:1:1:2 ratio, QD with food, with no titration required. Post hoc analyses assessed the influence of baseline disease severity (seizure frequency, number of concomitant ASMs, and number of previously tried ASMs) on the RR50 in FOS frequency through the 8-week DBP.
Results:
RR50 was achieved by 14.9% of placebo (n=114) and 54.5% of XEN1101 25-mg (n=112) patients. With XEN1101 25-mg treatment, RR50 was achieved by 65.5% of patients with ≤8.5 seizures/month (n=29) and 50.6% with >8.5 seizures/month (n=83) at baseline, 64.2% of patients with ≤6 prior ASMs (n=67) and 40.0% with >6 ASMs (n=45), and 56.9% of patients with 1–2 concomitant ASMs (n=58) and 51.9% with 3 concomitant ASMs (n=54).
Conclusions:
Consistent with the significant MPC seizure reduction, 54.5% of patients in the 25-mg XEN1101 group achieved RR50. XEN1101 was relatively more effective in patients with indicators of less-severe disease. XEN1101 may be appropriate for patients with focal epilepsy across the spectrum of disease severity.