Abstracts

Rationale: Retigabine is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of Kv7 potassium channels. In the Retigabine Efficacy and Safety Trial for Partial Onset Epilepsy (RESTORE 2, Study 302), retigabine 600 or 900 mg/day proved effective and was generally well-tolerated as adjunctive treatment for adult patients with partial-onset seizures. Here we present an interim analysis of Study 304, a long-term open-label extension study of RESTORE 2 evaluating the maintenance of efficacy and the safety profile of retigabine. Methods: RESTORE 2 was a Phase III, placebo-controlled, double-blind study in which patients received retigabine 600 or 900 mg/day divided TID or placebo as adjunctive therapy to a stable regimen of 1-3 background AEDs, with or without VNS. The study consisted of an 8-week baseline phase, a 4-week titration phase, and a 12 week maintenance phase. Patients who successfully completed the maintenance phase were invited to participate in this open-label extension study of retigabine 600-1200 mg/day divided TID (investigator’s discretion). Selection and dosing for background AEDs was permitted at investigator discretion. Efficacy evaluation included median % change in 28-day total partial-seizure frequency from RESTORE 2 baseline. Tolerability evaluations included adverse events (AEs), laboratory values, vital signs, and neurological and physical examinations. Results: Of the 409 patients who completed RESTORE 2, 376 (92%) completed transition and entered the open-label extension study. Prior to this interim data cut-off, 281 (69%) received at least one dose of open-label retigabine. The median time on open-label treatment for all patients was 194 days (1-388 days) with a mean daily dose of 824 mg. The median % reduction in 28-day total partial-seizure frequency from baseline to the extension period was 60%. The responder rate (≥50% reduction in 28-day total partial seizure frequency) was 61%, and 30% of patients experienced a reduction in 28-day total partial-seizure frequency of 75-100% from baseline to the extension period. For patients enrolled in this study, patient responses improved during open-label treatment whether treated with placebo or retigabine in RESTORE 2 (Figure). Of the patients who had ≥6 months of open-label treatment, 7% were seizure-free for any continuous 6-month interval. The mean % of seizure-free days was 79% during the extension period. The most common AEs were dizziness (15.3%), somnolence (14.9%), and headache (8.2%). Patients with serious AEs and AEs leading to discontinuation were 6% and 12%, respectively. No clinically relevant changes in laboratory values, vital signs, or physical and neurological examinations were observed. Conclusions: Retigabine 600-1200 mg/day maintains effectiveness and an acceptable safety profile during long-term open-label use as an adjunctive therapy for adult patients with partial-onset seizures. Funded by Valeant Pharmaceutical International.