Abstracts

Rationale: Ezogabine/retigabine (EZG/RTG) 600 1200 mg/day is approved as adjunctive therapy to other antiepileptic drugs (AEDs) for partial-onset seizures in adults. Across 3 pivotal trials that used fixed dosing with forced titration, treatment-emergent adverse event (TEAE) rates for EZG/RTG ranged from 73.7% in the 600-mg arm to 87.6% in the 1200-mg arm vs 74.5% for placebo.^1-3 The current study assessed the tolerability of EZG/RTG in adults with partial-onset seizures on single, specified AEDs using a flexible dosing regimen and a slower titration schedule than that used in the Phase 3 trials.Methods: Study 905 was an open-label, uncontrolled, multi-center, multi-country exploratory study of EZG/RTG using a flexible dosing regimen in adult patients. To be eligible for entry, patients with partial-onset seizures must have been taking either carbamazepine/oxcarbazepine (C/O), lamotrigine (LTG), levetiracetam (LEV) or valproic acid (VPA). The study consisted of a Screening/Baseline Phase, a 4-week Titration Phase (150 mg/day starting dose, with weekly increases of 150 mg/day, up to 600 mg/day) and a 16-week Flexible Dose Evaluation (FDE) Phase (optional weekly dose changes of 50 150 mg/day, staying within 300 1200 mg/day). Safety and tolerability endpoints included type and incidence of TEAEs; premature study discontinuation; change from Baseline in laboratory values, vital signs, body weight and ECGs; and change from Baseline in American Urological Association Symptom Scale (AUA SS) and Post Void Residual (PVR) bladder ultrasound.Results: A total of 203 patients (110 female, 93 male; aged 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 most frequently prescribed total daily dose during the Treatment Phase was 600 mg/day for all AED groups. Sixty (30%) patients withdrew during the Treatment Phase (28 patients during titration and 32 during the FDE Phase). The proportions of patients that reported TEAEs, TEAEs related to study drug, TEAEs leading to withdrawal, TEAEs leading to dose reduction or temporary discontinuation and serious TEAEs are shown in Table 1. TEAEs with a frequency 10% are listed in Table 2. There were no clinically significant results or trends in laboratory values, vital signs, ECGs or body weight. For the majority of patients post-Baseline, AUA SS scores were within the mild range (94%) and PVR volumes were normal (94%). There were no spontaneous reports of TEAEs of retinal pigmentation or skin discoloration. Specific assessments are being conducted on patients who rolled over to Study 413. Conclusions: In this study, the safety and tolerability of EZG/RTG was consistent with that observed in the placebo-controlled trials that utilized fixed dosing with forced titration.^1-3 References: 1. Brodie MJ et al. Neurology 2010;75:1817 24. 2. French J et al. Neurology 2011;76:1555 63. 3. Porter RJ et al. Neurology 2007;68:1197 1204.