Abstracts

Rationale: Perampanel is a novel, selective non-competitive AMPA receptor antagonist with broad spectrum anti-seizure effects in rodent models. The primary objective of this study was to determine MTD of perampanel given once daily (QD) or twice daily (BID) as adjunctive therapy in subjects with refractory partial-onset seizures, including secondarily generalized seizures. Secondary objectives were assessment of safety, efficacy, and PK of perampanel. Methods: In this randomized, double-blind, placebo-controlled, dose-escalation, parallel-group study, subjects with refractory partial seizures (N=153) were randomized to either placebo, BID dosing or QD dosing groups. Subjects were stratified according to their concomitant use of cytochrome P450 inducing or noninducing antiepileptic drugs (AEDs) and assessed for seizure frequency for up to 4 weeks in the baseline phase. Subjects were titrated from 1 mg/d (0.5 mg BID or 1 mg QD) to MTD, or 4 mg/d, over a period of 8 weeks. The primary end point was defined as MTD or 4 mg/d in the majority of subjects, as assessed during a 4-week maintenance phase. Secondary analyses included responder rate (percentage of subjects with ≥50% reduction from baseline in seizure frequency) and median percentage seizure reduction. Subjective improvement (Clinical and Patient’s Global Impression of Change [CGIC and PGIC]), PK, and AEs were also assessed. Results: Mean age across all groups in the ITT population (n=152) was 40.2 years; 55.9% were female. The highest dose tested, or 4 mg/d, was tolerated by the majority of subjects in the ITT population: perampanel 83.2% and placebo 82.4%. An analysis of responders in the maintenance phase (LOCF) showed a trend in antiepileptic effect for perampanel: 30.7% in perampanel groups (BID + QD) vs. 21.6% in placebo groups; P=0.1894. The perampanel groups in the maintenance phase (LOCF) showed a median percentage seizure reduction from baseline of 25.7%, vs. 19.5% with placebo. More subjects had overall improvements in PGIC and CGIC with perampanel: 58.4% perampanel vs. 49% placebo in PGIC (9.4% difference) and 48.5% perampanel vs. 41.2% placebo in CGIC (7.3% difference). Perampanel plasma concentrations were lower in the presence of concomitant-inducing AEDs. Perampanel did not affect plasma concentrations of concomitant AEDs used in this study. In both BID and QD groups, perampanel doses up to 4 mg/d were well tolerated. Conclusions: In this study, the highest dose of perampanel (4 mg/d) was well tolerated in the majority of subjects with refractory partial seizures. Thus, the MTD of perampanel may be higher than 4 mg/d. The observed trend in antiepileptic effect for perampanel 4 mg/d was comparable to other AEDs in lower dose ranges. The results of this phase II dose-ranging study support investigation of higher perampanel doses in subjects with refractory partial seizures to identify the maximum effective dose.