Abstracts

Rationale: Perampanel is an orally active, non-competitive AMPA receptor antagonist under review as an adjunctive therapy for refractory partial seizures. Primary data from three placebo-controlled phase III trials (studies 304 [NCT00699972]; 305 [NCT00699582]; 306 [NCT00700310]) are reported elsewhere (French et al. Annual Meeting of the AAN 2011: Abstract LBS.002; French et al. Epilepsia 2011; 52 (Suppl 6): 10; Krauss et al. Neurology 2012; 78: 1408-1415). Here we report pooled analyses of responder rates and seizure freedom from these trials. The impact of common concomitant AEDs on responder rates was also assessed. Methods: Patients (≥12 years), with uncontrolled partial seizures despite receiving 1-3 AEDs, were randomized to once-daily placebo, perampanel 8 or 12 mg (Studies 304 and 305), or placebo, perampanel 2, 4, or 8 mg (Study 306). Trials included 6-week Baseline, 6-week Titration, and 13-week Maintenance Periods. Patients recorded seizures in daily diaries. Responder rates (percentages of patients with ≥50% or ≥75% reductions in the frequency of all partial seizures, complex partial plus secondary generalized seizures [CPS+SGS], or secondary generalized seizures [SGS] only; Maintenance vs Baseline) were assessed in the intent-to-treat (ITT) analysis set (all randomized and treated patients with any seizure data). Seizure freedom (percentage of patients seizure free during Maintenance) was assessed for all partial seizures and SGS in the Maintenance completer set. 50% responder rates were analyzed by the most common concomitant AEDs. P-values are used to highlight effects of interest; these are multiple, non-independent, unadjusted values. Results: Overall, 1480 patients were randomized and treated. In the pooled ITT analysis set (n=1478), perampanel 4-12 mg (effective dose range) was associated with greater 50% and 75% responder rates and greater seizure freedom rates vs placebo (Table 1). At Baseline, the mean number of concomitant AEDs was 2.2; the most common were carbamazepine (n=491; 33.2%), valproic acid (n=478; 32.3%), lamotrigine (n= 458; 30.9%), and levetiracetam (n=435; 29.4%). In patients receiving ≥1 of these AEDs, perampanel 8 and 12 mg consistently improved 50% responder rates vs placebo (all seizure types; Table 2, statistical significance not evaluated). Conclusions: In pooled analyses of Phase III data by randomized dose, adjunctive perampanel improved responder and seizure freedom rates vs placebo in patients with refractory partial seizures. Responder rates were improved at higher doses, for all partial seizures, including SGS, irrespective of co-administration of the most common AEDs. Previous analyses, based on actual dose and within-patient responses, showed a benefit of perampanel 12 mg over 8 mg (Kramer et al. AAN 2012: Abstract P06.117), and pharmacokinetic/pharmacodynamic data indicated a linear exposure-efficacy relationship across doses 2-12 mg, independent of concomitant AEDs (Hussein et al. AAN 2012: Abstract P06.127). Support: Eisai Inc