Abstracts

Rationale: : Perampanel is an orally-active, selective, non-competitive AMPA receptor antagonist with a long half-life, which has shown broad-spectrum anti-seizure effects in various animal models. Following favorable tolerability in Phase I studies, this study evaluated the maximum tolerated dose and safety of perampanel in a randomized, double-blind, placebo-controlled, parallel-group Phase II trial with a secondary endpoint of efficacy. Methods: In this study, adult patients with refractory partial-onset seizures with/without secondary generalization receiving 1-3 concomitant antiepileptic drugs were randomized in a 3:1 ratio to one of two treatment arms: perampanel (2-12 mg) or placebo. Perampanel (or placebo) was increased by 2 mg every 2 weeks to a maximum of 12 mg (if the current dose was tolerated). This was a four-part study: 4-week baseline, 12-week titration, 4-week maintenance, and a 4-week follow-up. Secondary endpoints included proportion of responders (patients with ?50% reduction in seizure frequency from baseline) and seizure reduction. Results: Of 48 patients randomized (38 perampanel and 10 placebo), all were analyzed for safety and 47 for efficacy. Six patients (60%) in the placebo arm and 12 patients (32%) in the perampanel arm reached the 12 mg dose level. During the maintenance period, 11 of the 12 patients remained on the 12 mg dose for the entire duration. From a Kaplan-Meier analysis of the safety population, the proportion of patients estimated to tolerate each perampanel dose was: 2 mg (100%; n=38), 4 mg (97%; n=36), 6 mg (86%; n=34), 8 mg (55%; n=28), 10 mg (48%; n=16), 12 mg (44%; n=12). No drug-related serious adverse events occurred and the incidence of treatment-emergent adverse events (TEAEs) was similar between groups (84% perampanel vs 80% placebo). TEAEs considered to be probably/possibly drug-related and occurring more frequently in the perampanel group were dizziness (58% vs 10%), somnolence (32% vs 0%), abnormal coordination (8% vs 0%), diplopia (5% vs 0%), nausea (5% vs 0%), asthenia (5% vs 0%), gait disturbance (5% vs 0%) and insomnia (5% vs 0%). Drug-related nausea, gait disturbance and insomnia were only observed at perampanel doses >6 mg. These TEAEs were all mild to moderate, except severe dizziness (n=3). The study was not powered to detect statistical significance in efficacy endpoints. Compared with the placebo group, patients receiving perampanel tended towards a higher responder rate (40% vs 22%; P=0.333) and median percentage seizure reduction (40% vs -2%; P=0.130) in the overall treatment phase. Conclusions: The study demonstrated the tolerability of perampanel doses of 2 mg to 12 mg/day with no safety issues identified in this small study. There was also a preliminary suggestion of efficacy. Based on results from this and other studies, 3 Phase III studies are ongoing to further evaluate the efficacy and safety of perampanel. (Support: Eisai Inc.)