Abstracts

Rationale: Perampanel is a selective, non-competitive AMPA receptor antagonist that has demonstrated broad-spectrum anti-seizure effects in various animal models. Two Phase II studies demonstrated tolerability of perampanel doses of 2-12 mg/day when administered adjunctively to patients who were refractory to ?3 AEDs with a maximum of one inducer. Based on this and population PK/PD (pop-PK/PD) analysis, we designed 3 randomized, double-blind, placebo-controlled, parallel-design global Phase III studies with perampanel doses ranging from 2 to 12 mg/day to establish the minimum effective dose and spectrum of efficacious doses. Here we report successful completion of enrollment of the first trial evaluating 3 different doses of perampanel (2, 4 and 8 mg/day) and placebo for treatment of partial-onset seizures (POS) in patients with drug-resistant epilepsy. Methods: Eligible patients were ?12 years of age with POS, with/without secondarily generalized seizures, treated with 1-3 antiepileptic drugs (AEDs) with a maximum of 1 inducer AED. There was a 6-week pre-randomization baseline phase and a 19-week double-blind (6-week titration, 13-week maintenance) phase. Primary endpoint is the percentage change in 28-day median seizure frequency in the maintenance period relative to pre-randomization. In addition to efficacy and safety, the pop-PK and exposure-response are evaluated with the sparse PK sampling approach for perampanel and concomitant AEDs. Results: Recruitment was completed in January 2010, with 706 subjects randomized in 24 countries in Europe and Asia-Pacific regions. Among randomized subjects, 49% are female, and the majority (65%) Caucasian, with 16% Chinese and 19% Asian non-Chinese. Median age was 32 years (range 12-72); 91% of patients were between 18 and 65 years; and 8% were <18 years. Most patients received ?2 concomitant AEDs; 15% had 1 AED, 47% 2 AEDs and 38% 3 AEDs. When looking at the use of the 4 older AEDs, 41.3% patients were taking valproic acid, 33.0% carbamazepine, 5.7% phenytoin and 4.1% phenobarbital. The three most commonly used newer AEDs were lamotrigine (35.2%), levetiracetam (33.0%) and topiramate (25.9%). Conclusions: This is the first Phase III study successfully completing enrollment for a selective AMPA antagonist in patients with POS, with results expected late in 2010. With the broad patient population enrolled and variety of background AEDs used, the study allows adequate assessment of perampanel as an adjunctive therapy. Testing a broad dosing range, including a likely minimum effective dose and expected therapeutic dose(s), will also provide valuable information needed for appropriate use of the drug. (Support: Eisai Inc.)