Abstracts

Rationale: Results from two multicenter, placebo-controlled studies (YKP3089C013 [C013] and YKP3089C017 [C017]) showed that adjunctive treatment with cenobamate (CBN) 100 mg, 200 mg, and 400 mg/day significantly decreased focal (partial) seizure frequency over the course of the study and was associated with high rates of seizure freedom during the maintenance phase. Each study had a 6-week titration phase leading into a maintenance phase of 6 or 12 weeks. The results were analyzed to provide a determination of when the onset of efficacy may have occurred. Methods: Both studies enrolled adult patients with poorly controlled focal seizures and who had =3 seizures per 28 days despite treatment with stable doses of 1-3 AEDs. In study C013 patients were randomized to placebo or CBN 200 mg/day. During the titration phase patients received 50 mg for 2 weeks, 100 mg/day for 2 weeks, and 150 mg/day for 2 weeks before reaching 200 mg at the beginning of the maintenance phase. In study C017 patients were randomized to placebo or 100 mg/day, 200 mg/day, or 400 mg/day CBN. During the titration phase, patients received increasing doses to reach their target dose: 50 mg/day for 1 week, then 100 mg/day for 1 week, then 150 mg/day for 1 week, then 200 mg/for 1 week, then 300 mg/day for 1 week, then 400 mg/day for 1 week. Following the titration period, patients entered a 6-week (C013) or 12-week (C017) maintenance phase. In each study, the time to first seizure for patients taking cenobamate was compared to the time to first seizure for patients taking placebo, and in each a moving average of seizure frequency reduction during sequential 4-week intervals (Week 1-4, Week 2-5, etc) was compared for each treatment group. Results: In study C013, 109 patients were randomized to placebo and 113 to CBN 200 mg. In study C017, 108 patients were randomized to placebo and 108, 110, and 111 were randomized to 100, 200, and 400 mg CBN, respectively. The mean time to first seizure after the first dose was 13.9 days for the 200-mg CBN group (n=113) and 8.8 days for the placebo group (n=108) in study C013; and 14.7 days for all CBN groups (n=293) and 6.4 days for the placebo group (n=97) in study C017. In the study C013 200-mg CBN group, seizure frequency was reduced a median 40.6% from baseline in the first 4 weeks of treatment compared to placebo (14.3%), followed by greater reductions from baseline over each subsequent 4-week interval for CBN. In study C017, seizure frequency was reduced a median 45% (CBN 100 mg) and 50% (CBN 200 mg and 400 mg) from baseline in the first 4 weeks, compared to 17% for placebo. Median reduction in seizure frequency continued to improve during Weeks 4-8 for the CBN 400 mg group (82%). Conclusions: These results suggest that the effect of cenobamate at doses of 50-100 mg/day may be clinically evident 2 weeks after a starting dose of 50-mg cenobamate. Funding: SK Life Science, Inc.