Perampanel, a Selective, Non-Competitive AMPA Receptor Antagonist as Adjunctive Therapy in Patients with Refractory Partial-Onset Seizures: A Dose Response Analysis from Phase III Studies (P06.117)

Abstract

Objective: Examine perampanel dose-response by pooled analysis of randomized, double-blind phase III studies (304/305/306) and open-label extension (OLE) study (307). Background Pharmacokinetic/pharmacodynamic analyses show a linear perampanel exposure-response relationship, without change in slope across doses tested (2-12 mg/day). However, randomized dose efficacy analyses did not consistently demonstrate improvement with 12 mg/day versus 8 mg. Dose-response analyses utilizing actual-dose data were performed to better understand these differences. Design/Methods: Analyses used integrated actual-dose data from the double-blind studies and OLE blinded Conversion Period (data cut-off 01/12/10). Seizure frequency data were analyzed from patients randomized to and completing at 8 mg during the double-blind studies, and whose last dose was 12 mg during the Conversion Period. Additionally, pooled analysis of patients completing studies 304 and 305 (trials including 12 mg doses) was performed. All analyses excluded Central/South American patients due to a significant treatment-by-region interaction. Results: Of 372 patients randomized to 8 mg (double-blind), 273 completed at this dose; 267/273 entered the OLE; 209/267 (78.3%) had dose increases from 8 mg (double-blind) to 12 mg (Conversion Period) by data cut-off. Median percent change in seizure frequency/28 days improved from -32.4% to -43.3%; 50% responder rate increased from 37.8% to 43.5%. Patients completing the double-blind studies and the Conversion Period on 12 mg experienced similar benefits (change in seizure frequency -39.5% to -42.1%; responder rate 41.8% to 42.9%). In a 304/305 combined completers analysis (actual dose: placebo n=182; 8 mg n=158; 12 mg n=114), 12 mg improved seizure-free rates versus 8 mg (4.4% versus 2.5%). Secondarily generalized seizures also improved with 12 mg versus 8 mg (change in seizure frequency -54.0% versus -46.0%). Conclusions: In actual-dose analyses, perampanel 12 mg/day demonstrated slightly improved efficacy over 8 mg/day. Inter-related factors intrinsic to standard epilepsy study designs may not reflect the effect of the target randomized doses. Supported by: Eisai, Inc. Disclosure: Dr. Kramer has received personal compensation for activities with Eisai Inc. as an employee. Dr. Kramer has received research support from Eisai Inc. Dr. Perucca has received personal compensation for activities with UCB Pharmaceuticals as a speaker.Dr. Perucca has received personal compensation in an editorial capacity for Epilepsia. Dr. Ben-Menachem has received personal compensation for activities with Eisai Inc, UCB Pharma, Cyberonics, Inc., GlaxoSmithKline, Inc. and Lundbeck Research USA as an advisory board participant and/or speaker. Dr. Ben-Menachem has received personal compensation in an editorial capacity for Acta Neurologica Scandinovica. Dr. Ben-Menachem has received research support from Eisai Inc, UCB Pharma and Bial. Dr. Kwan has received personal compensation for activities with Pfizer Inc and UCB Pharma for serving on an advisory board for Pfizer and for speaking activities for UCB Pharma and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant, speaker and participant on an advisory board. Dr. Kwan has received personal compensation in an editorial capacity for Epilepsy & Behavior, Epilepsy Research, Epileptic Disorders, CNS Special Issue editor, and Advanced Drug Delivery Review. Dr. Kwan has received research support from UCB Pharma, Pfizer Inc, and Eisai Inc. Dr. Shih has nothing to disclose. Dr. Squillacote has received personal compensation for activities with Eisai as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Zhu has received personal compensation for activities with Eisai Inc., as an employee. Dr. Laurenza has received personal compensation for activities with Eisai as an employee.