Abstracts

Rationale: Ezogabine/retigabine (EZG/RTG) is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (Kv7) potassium channels. The efficacy of EZG/RTG was assessed in a flexible dosing regimen reflective of clinical practice, and used in combination with one of 4 specified single AEDs in patients with uncontrolled seizures.Methods: Study 905 was an open-label, uncontrolled, multi-center, multi-country study of EZG/RTG using a flexible dosing regimen in adult patients ( 18 years of age) with partial-onset seizures. To be eligible for entry, patients must have been taking one of the following AED treatments: carbamazepine/oxcarbazepine (C/O), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA), and must have had at least 4 partial seizures during the 8-week Baseline Phase. The study consisted of a Screening Phase, a Baseline Phase, a 4-week Titration Phase (starting dose of 150 mg/day [50 mg three times daily (TID)] with weekly increases of 150 mg/day [50 mg TID] to 600 mg/day over 4 weeks), and a 16-week Flexible Dose Evaluation (FDE) Phase (optional weekly dose changes of 50 150 mg/day, staying between 300 and 1200 mg/day). Additionally, there was a 3-week Taper/Follow-Up Phase for patients who decided not to enter an optional Open-Label Extension study or who prematurely withdrew from the study. The primary efficacy endpoint was the percentage of subjects experiencing a 50% reduction from Baseline in 28-day partial seizure frequency (responder rate) during the Treatment Phase (i.e. Titration and FDE Phases).Results: A total of 203 patients (110 female, 93 male; age range 18 79 years [median 36 years]; 93% Caucasian, 7% Asian) were enrolled and received at least one dose of EZG/RTG. Demographics and baseline characteristics were well matched across the 4 AED groups. The AED groups differed with respect to baseline percentage having previously failed only 0 or 1 AED: C/O (25%), LTG (29%), LEV (39%), and VPA (54%). The most frequently prescribed total daily dose of EZG/RTG during the Treatment Phase was 600 mg for all AED groups. During the FDE Phase, the median total daily EZG/RTG dose was also 600 mg for all AED groups combined. A total of 40.0%, 32.0%, 50.0%, and 56.9% of patients in the C/O, LTG, LEV, and VPA groups, respectively, had a 50% decrease from baseline in partial seizure frequency during the Treatment Phase. The responder rates were 40.4%, 51.1%, 60.0%, and 66.0%, respectively, in the FDE Phase only (Table 1). The median reductions in seizure frequency from Baseline to Treatment Phase for the C/O, LTG, LEV, and VPA groups were 23.7%, 41.9%, 48.7%, and 59.0%, respectively. The percentages of patients who were seizure-free during the FDE Phase were: C/O (4.3%), LTG (0), LEV (5.7%), and VPA (2.1%).Conclusions: Using a flexible dosing regimen, EZG/RTG was efficacious as adjunctive therapy with C/O, LTG, LEV, and VPA in patients with partial-onset seizures.