Efficacy of adjunctive cenobamate by focal seizure subtypes: a randomized, double-blind, placebo-controlled, multicenter study in a multinational Asian population

Abstract

Objectives: To assess the efficacy of adjunctive cenobamate by seizure subtype in Asian patients with uncontrolled focal epilepsy during a 24-week controlled study (NCT04557085 [C035]). Methods: Adults 18-70 years old with >= 8 focal seizures (focal aware motor [FAM], focal impaired awareness [FIA], and/or focal to bilateral tonic-clonic [FBTC]) during an 8-week baseline, despite treatment with 1-3 antiseizure medications, were randomized 1:1:1:1 to receive placebo or cenobamate 100, 200, or 400 mg/day, starting at 12.5 mg/day and uptitrated at 2-week intervals. The study design included an 18-week titration phase and a 6-week maintenance phase. Median percent change from baseline in 28-day seizure frequency and responder rates for patients with FAM, FIA, and/or FBTC seizures were assessed during the maintenance phase and during a 12-week treatment period that combined the last 6 weeks of titration and the 6-week maintenance phase. Results: N = 519 patients were randomized (maintenance phase n = 446, 12-week period n = 478). During both periods assessed, numerically greater reductions vs placebo occurred across all cenobamate doses and seizure subtypes. For cenobamate 200 and 400 mg/day, maintenance-phase median seizure frequency reductions were 76 %-100 % across all seizure subtypes; seizure-free rates were up to 52.4 % (FAM), 57.5 % (FIA), and 75.0 % (FBTC). The most common cenobamate-related treatment-emergent adverse events (>= 20 %) were dizziness and somnolence. Conclusions: Cenobamate reduced all focal seizure subtypes in a generally dose-response manner in adult Asian patients, including maintenance-phase seizure frequency reductions of 76 %-100 %. Notably high seizure-free rates were observed for patients with FBTC seizures, an important contributor to morbidity/mortality in focal epilepsy patients.