Abstracts

Rationale: Despite the numerous pharmacological agents available to treat seizures, about 30% of patients remain refractory to current therapies. Evidence from surgically resected brain tissue from patients with refractory epilepsy and rodent models suggests that inflammation may be both a cause and a consequence of seizure activity. VX-765 is a selective, reversible inhibitor of the interleukin-1 beta converting enzyme thought to be involved in inflammatory epilepsy. The objective of this study was to evaluate the efficacy, safety and tolerability of adjunctive treatment with VX-765 in patients with treatment-resistant focal seizures.Methods: This 13-week randomized, double-blind, parallel-group, dose-ranging study enrolled patients 18-64 years with a diagnosis of treatment-resistant focal seizures (i.e. failure to achieve seizure-free status despite adequate trials of 2 antiepileptic drugs [AEDs]) taking 1 to 4 concomitant AEDs. Patients were randomized to receive placebo or VX-765 300 mg, 600 mg, 900 mg, or 1200 mg three times daily (TID). Primary efficacy measures were percent reduction in weekly seizure frequency and response rate (patients with 50% reduction in weekly seizure frequency) during the late treatment period (LTP; weeks 5-13) compared with baseline (B; -56 days to day -1). Safety and tolerability were assessed by medical examinations and laboratory tests, and by spontaneous reporting of adverse events (AEs), respectively. The study, originally intended to enroll up to 500 patients to ensure at least 400 completed at least 8 weeks of treatment, was terminated early for administrative reasons. To accommodate the small sample size, nonparametric analyses, i.e., Jonckheer-Terpstra trend test across groups and Van Elteren pairwise comparison between groups for percent reduction; Cochran-Armitage trend test across groups and Cochran-Mantel-Haenszel pairwise comparison between groups for response rate, were used.Results: A total of 55 patients (11% of planned sample size) were randomized prior to study termination and received at least one dose of study drug; 49 (89%) completed 13 weeks of treatment. Baseline characteristics were similar among the groups; the mean age was 39 years, 51% (n=28) male, 86% (n=47) white race; 2 patients discontinuing treatment in the VX-765 300 mg TID group did so because of AEs (increase in gamma glutamyltransferase n=1; stress n=1). The percent change in seizure from B to LTP is shown in Figure 1 and response rate is shown in Figure 2. Overall, 63% of patients receiving VX-765 reported 1 AE, with 1 serious AE of carbon monoxide poisoning in the VX-765 600 mg TID group. The Table shows the most common AEs.Conclusions: The study was administratively terminated; the small sample size lacks the power for statistical comparisons. VX-765 was generally tolerable across the doses included in the study. Further research would appear feasible and is needed to ascertain whether VX-765 is efficacious in patients with treatment-resistant focal epilepsy.