Abstracts

Rationale: Retigabine (referred to as ezogabine in North America) is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (Kv7) potassium channels. The efficacy of retigabine 600-1200 mg/day was assessed by number of background AEDs at baseline in a pooled analysis of 3 randomized studies. Methods: Study 205 (Phase IIb), and RESTORE 1 and 2 (Studies 301 [NCT00232596] and 302 [NCT00235755], Phase III) were multicenter, randomized, double-blind, placebo-controlled, parallel-group trials in adults with drug-resistant epilepsy, ?4 partial-onset seizures per 28 days, receiving 1-2 (Study 205) or 1-3 (RESTORE 1 and 2) AEDs, with or without vagus nerve stimulator. Patients were randomized to retigabine or placebo (administered tid) and underwent forced-titration to retigabine 600 or 900 mg/day (Study 205, RESTORE 2) or 1200 mg/day (Study 205, RESTORE 1) followed by an 8- (Study 205) or 12-week (RESTORE 1 and 2) maintenance phase. Change in 28-day total partial-seizure frequency from baseline to double-blind period (titration maintenance) utilizing rank transformational ANCOVA, and responder rate (?50% reduction in seizure frequency per 28 days) utilizing logistic regression from baseline to maintenance phase, were assessed in the pooled population and analyzed by number of background AEDs at baseline. As the integrated analysis determined that some patients received 4 AEDs, efficacy endpoints were analyzed by 1, 2 or ?3 AEDs at baseline. Results: Retigabine 600 (n=281) and 900 mg/day (n=273) were compared with placebo (n=275) in patients from Study 205 and RESTORE 2; 1200 mg/day (n=259) was compared with placebo (n=248) from Study 205 and RESTORE 1. Overall for both endpoints, results showed no significant interaction between treatment and baseline number of background AEDs. The majority of patients (55.1%) were receiving 2 background AEDs at baseline, with similar proportions of patients receiving 1 or ?3 AEDs (23.5% and 21.5%, respectively). Statistically significant differences were observed in the change from baseline in 28-day total partial-seizure frequency with retigabine 900 and 1200 mg/day vs placebo for patients receiving 1, 2 or ?3 AEDs at baseline, and with 600 mg/day for patients receiving 2 AEDs (Table 1). Statistically significant differences in responder rate were seen in patients receiving 1, 2, or ?3 AEDs with retigabine 1200 mg/day vs placebo, 900 mg/day vs placebo in patients receiving 2 or ?3 AEDs, and 600 mg/day vs placebo in patients receiving 2 AEDs (Table 2). For both endpoints, there was some evidence of variability in the magnitude of response to treatment by number of background AEDs at baseline and retigabine dosage. Conclusions: In this analysis, retigabine 600-1200 mg/day demonstrated efficacy in adults with drug-resistant partial-onset seizures receiving 1-3 background AEDs at baseline. Overall, the response to treatment with retigabine was not affected by the number of background AEDs used. Funded by Valeant Pharmaceuticals International and GlaxoSmithKline.