Abstracts

Rationale: Recently, a white paper has advocated a unified indication for antiepileptic drugs (AEDs), irrespective of concomitant AED use. As a consequence, the FDA has determined it is acceptable to extrapolate data from adjunctive trials to the monotherapy setting; it should be demonstrated that efficacy does not depend on a particular adjunctive AED mechanism and drug exposure remains comparable in the setting of other AEDs or that differences are accounted for. PER, a selective, non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures, with or without secondary generalization, and primary generalized tonic-clonic seizures in pts with epilepsy aged ≥12 years. Here, we report extrapolation of adjunctive PER efficacy and safety data from three randomized, double-blind, placebo-controlled Phase III trials in pts with partial seizures to evaluate PER as monotherapy. Methods: Pts aged ≥12 years with refractory partial seizures, with or without secondary generalization, despite treatment with 1–3 AEDs, received once-daily placebo or adjunctive PER 8 or 12 mg (Studies 304 and 305), or 2, 4, or 8 mg (Study 306), across a 19-week Double-blind Phase (6-week Titration; 13-week Maintenance). Median % change in seizure frequency/28 days and incidence of treatment-emergent adverse events (TEAEs) were analyzed using Baseline concomitant AED use subgroups: mechanism of action (MOA) of AEDs; presence/absence of enzyme-inducing AEDs (EIAEDs); number of AEDs; most frequently reported AEDs. A pharmacokinetic/pharmacodynamic (PK/PD) analysis evaluated the exposure-response relationship of PER by concomitant AED use. Results: Overall, 1480 pts were treated. Demographics were similar across subgroups (mean age, 33.5–45.3 years; 49.3–69.2% female). A greater median % reduction in seizure frequency/28 days was generally observed with increasing PER in all subgroups (Table 1). Incidence of TEAEs was generally unaffected by AED MOA or number of Baseline AEDs, but was higher with non-inducers compared with EIAEDs. Across subgroups, the most common TEAE was dizziness; there were no notable differences in the types of TEAEs. PK/PD analysis showed % change in seizure frequency/28 days and 50% responder rates were correlated with plasma PER exposure; this was not affected by co-administration of any particular AED. Conclusions: PER was efficacious and well tolerated regardless of concomitant AED use, suggesting the efficacy and safety of PER is not dependent on the presence of any particular concomitant AED or combination. Without EIAEDs, the exposure-response relationship is expected to be similar with PER monotherapy compared with adjunctive PER; pts previously treated with EIAEDs may require dosage adjustments as EIAEDs lower PER exposure. A supplemental application is under review with the FDA for a proposed change to the PER label to allow its use as monotherapy for the treatment of partial seizures with or without secondary generalized seizures. Funding: Eisai Inc.