Efficacy of adjunctive cenobamate based on number of concomitant antiseizure medications, seizure frequency, and epilepsy duration at baseline: A post-hoc analysis of a randomized clinical study

Abstract

Background: In an 18-week, double-blind, placebo-controlled study (YKP3089C017; NCT01866111), cenobamate was effective for the treatment of focal-onset seizures. This post-hoc analysis examined the effects of baseline clinical features on the efficacy of adjunctive cenobamate during the study.

Methods: Adults with uncontrolled focal seizures despite treatment with 1-3 antiepileptic drugs/antiseizure medications (AEDs/ASMs) were randomized 1:1:1:1 to placebo or cenobamate 100, 200, or 400 mg once daily. Median percent seizure frequency reduction/28 days and ≥50% responder rates were assessed during the 12-week maintenance phase (n = 397) by number of baseline (concomitant) ASMs (1, 2, >2), median baseline seizure frequency/28 days (≤9.5 vs >9.5), and median baseline duration of epilepsy (≤23 vs >23 years).

Results: For patients taking 1 concomitant ASM, median percent seizure frequency reductions ranged from 44.7% to 86.0% for cenobamate-treated patients vs 24.1% for placebo; for 2 concomitant ASMs, reductions were 41.4-57.9% with cenobamate vs 33.3% for placebo; and for >2 concomitant ASMs, reductions were 41.5-67.4% with cenobamate vs 26.4% for placebo. The highest reductions occurred in the 200- and 400-mg/day cenobamate groups. For patients with baseline seizure frequency ≤9.5, the greatest reduction in median percent seizure frequency occurred in the 200-mg/day cenobamate group (66.5%); for patients with baseline seizure frequency >9.5 the greatest reduction occurred in the 400-mg/day cenobamate group (70.7%). Similar improvements were observed when assessed by median duration of epilepsy at baseline. For cenobamate-treated patients taking 1, 2, or >2 ASMs respectively, ≥50% responder rates of up to 66.7% (400 mg), 62.2% (200 mg), and 66.0% (400 mg) were observed, vs 20.0%, 29.3%, and 23.9% for placebo, respectively; 100% seizure reductions were observed in up to 25.0% (400 mg/day), 22.2% (400 mg/day), and 19.1% (400 mg/day) of cenobamate-treated patients, vs 0%, 0%, and 2.2% for placebo, respectively. Incidence of common (≥10%) central nervous system adverse events (dizziness, somnolence, fatigue, and diplopia) were highest in the >2 ASM group, but the rates were within the range reported in the primary study.

Conclusions: Clinically relevant reductions in seizure frequency including 100% seizure reductions occurred with adjunctive cenobamate regardless of number of concomitant ASMs, baseline seizure frequency, or disease duration. The greatest reductions occurred in the 200- and 400-mg/day groups.

Keywords: Antiseizure medication; Cenobamate; Concomitant; Efficacy; Focal epilepsy; Partial epilepsy.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.