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 1, Study 301), retigabine 1200mg/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 303, a long-term open-label extension study of RESTORE 1 evaluating the maintenance of efficacy and the safety and tolerability profile of retigabine. Methods: RESTORE 1 was a Phase III, placebo-controlled, double-blind study in which patients received retigabine 1200mg/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 6-week titration phase, and a 12 week maintenance phase. Patients who completed the maintenance phase were invited to participate in this open-label extension study, in which they received retigabine 600-1200mg/day divided TID (investigator’s discretion). Selection and dosing for background AEDs was permitted at investigators discretion. Efficacy evaluation included median % change in 28-day total partial-seizure frequency from RESTORE 1 baseline. Tolerability evaluations included adverse events (AEs), laboratory values, vital signs, and neurological and physical examinations. Results: Of the 224 patients who completed RESTORE 1, 181 (81%) completed transition and entered this study. Prior to this interim data cut-off, 163 (73%) enrolled in the extension study and received at least one dose of open-label retigabine. The median time on open-label treatment was 175 days (6-562 days) with a mean daily dose of 1066mg. The median % reduction in 28-day total partial-seizure frequency from baseline in RESTORE 1 to the extension period was 62%. The responder rate (≥50% reduction in 28-day total partial-seizure frequency) was 60%, and 33% experienced a reduction of 75-100% from baseline to the extension period. For patients enrolled in this study, patient responses improved during open-label treatment vs RESTORE 1 whether treated with placebo (21% vs 55%) or retigabine (58% vs 72%). Of the patients who had ≥6 months of open-label treatment with retigabine, 9% were seizure-free for any continuous 6-month interval. The mean % of seizure-free days during open-label treatment was 79%. The most common AEs were dizziness (17%), somnolence (8%) and tremor (7%). Patients with serious AEs and AEs leading to discontinuation were 12% and 10%, respectively. There were no clinically abnormal results in laboratory values, vital signs, or physical and neurological examinations indicative of major safety issues. Transient elevations in liver function tests were observed in a small proportion of patients. Conclusions: Retigabine 600-1200mg/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 Pharmaceuticals International.