Abstracts

Rationale: Perampanel (PER), an orally active, highly selective, noncompetitive AMPA antagonist, has been evaluated as adjunctive treatment for partial-onset seizures (POS) in 3 double-blind (DB), randomized, placebo-controlled Phase 3 trials. Completers from these studies were eligible to participate in the open-label extension (OLE) study. The OLE allowed physicians a greater flexibility in the titration of PER dosage compared to the DB studies. Hence, we examined the impact of the rate of titration on the safety and efficacy of PER in patients who received placebo (PBO) in the Phase 3 DB trials and transitioned to PER in the OLE. Methods: Patients (≥12 y, receiving 1-3 AEDs) with uncontrolled POS were randomized to once-daily, PBO or PER (2, 4, 8, 12 mg). The DB study design included a 6-wk titration (weekly titration schedule), followed by the maintenance period. The OLE began with a 16-wk blinded conversion phase (biweekly titration schedule) and was followed by the maintenance phase. In the OLE patients previously assigned to PBO (DB-PBO, n=380) as well as those assigned to PER (DB-PER, n=838) during DB phase were titrated up to the maximum tolerated dose (≤12 mg/day) from 2 mg/day and last received PER dose, respectively. Efficacy endpoints were median % change in seizure frequency/28 days and 50% responder rate. Results: A total of 1218 patients entered the OLE (96.3% of DB completers). By the OLE conversion period, subjects in the DB-PBO group had achieved similar reductions in seizure frequency and responder rates as those in the DB-PER group, and these rates were maintained in both groups through 52 weeks of the OLE (Table 1). A comparison of DB-PBO patients converting to the OLE and patients randomized to 12 mg (PER-12 mg) during the DB studies showed that 72.4% DB-PBO patients in the OLE, compared to 78.8% PER-12 mg patients in the DB studies, achieved doses of 10 or 12 mg PER at the end of the conversion and titration periods, respectively (16 wks in OLE vs 6 wks in DB). Irrespective of the rate of titration, discontinuation due to AEs in the DB-PBO patients during OLE conversion period was 10.1% compared to 9.8% for PER-12 mg patients in the DB titration period. Rates of the most common treatment-emergent AEs (TEAEs) for DB-PBO were similar to DB-PER during OLE (Table 2). Conclusions: By the end of the conversion period, DB-PBO patients transitioning to PER during OLE achieved seizure reduction and responder rates comparable to DB-PER patients. Tolerability and safety profiles, as indicated by the discontinuation rates due to AEs and ability to achieve MTD during the titration and conversion periods, were similar between the DB-PBO during the OLE conversion and PER-12 mg group during the DB titration. Regardless of the rate of titration (weekly in DB vs biweekly in OLE), PER demonstrates a favorable risk-benefit ratio in this study population.