Early response rates with adjunctive cenobamate in uncontrolled focal seizures: Prospective analysis of a randomized, double-blind, placebo-controlled study in a multinational Asian population

Abstract

Objective: To examine early responses to cenobamate therapy using prospective data from a dose-response study in Asian patients with focal seizures (YKP3089C035, C035) that employed a titration regimen starting at 12.5 mg/day. Methods: In Study C035, adults 18-70 years of age with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications were randomized 1:1:1:1 to receive placebo or adjunctive cenobamate 100, 200, or 400 mg/day. The 24-week double-blind study included an 18-week titration and 6-week maintenance phase. During the first 8 weeks of titration ("early titration phase"), all cenobamate patients received the same dosing regimen: 12.5 mg/day for 2 weeks, 25 mg/day for 2 weeks, 50 mg/day for 2 weeks, and 100 mg/day for 2 weeks. Change in seizure frequency from baseline and responder rates were assessed at these 2-week intervals for combined cenobamate dose groups vs placebo. Analyses were performed on the modified intent-to-treat maintenance (MITT-M) population (>= 1 study drug dose and seizure data in the maintenance phase); all patients completed early titration. Results: Of 519 patients randomized, 446 were included in the MITT-M population (placebo n = 117, cenobamate n = 329). During Weeks 1-2, 3-4, 5-6, and 7-8 of titration, cenobamate patients experienced a median reduction in 28-day seizure frequency of 16.0% (vs 20.0% placebo, p = .81), 27.3% (vs 22.2% placebo, p = .42), 42.9% (vs 15.4% placebo, p = .002), and 55.6% (vs 20.0% placebo, p < .001), respectively. During Weeks 5-6 and 7-8, the 100% responder rates for cenobamate 50 and 100 mg/day were 17.0% (vs 12.8% placebo, p = .29) and 26.7% (vs 8.5% placebo, p < .001), respectively. Significance: Statistically significant responses to cenobamate treatment occurred within the first 8 weeks of titration, including a 42.9% median reduction in 28-day seizure frequency (Weeks 5-6) and a seizure-free rate of 26.7% (Weeks 7-8). These data show that substantial seizure reductions occurred in many patients early during cenobamate titration.