Post Hoc Analysis Suggests Cenobamate Efficacy Starts Early in Titration and Improves With Increasing Dose and Time
Cenobamate (Xcopri; SK Life Science, Paramus, NJ) was recently approved for the treatment of partial-onset seizures in adults, with a recommended starting dose of 12.5 mg/day titrated up to a recommended dose of 200 mg/day over a 12-week period. The maximum daily dose is 400 mg. The titration schedule was determined in an open-label safety schedule (Study C021) to reduce the risk of drug reaction with eosinophilia and systemic symptoms (DRESS), which did not occur in those for whom this titration schedule was followed. In pivotal trials, adjunctive treatment with 200 mg or 400 mg of cenobamate reduced monthly focal seizure frequency by 55.2% compared baseline vs 24.3% seen with placebo.
Post-hoc analysis of a subset of participants in this open-label study, from whom seizure frequency data was collected (as per a study ammendment), has been presented at the American Epilepsy Society 2020 Virtual meeting. Participants were taking between 1 and 3 other antiseizure medications (ASMs) during the trial, including lacosamide, levetiracetam, lamotrigine, zonisamide, clobazam, and carbamazepine. Monthly seizure frequency ranged from 18.1 to 562 seizures/month with a median of 2.8 seizures/month.
Reduction of seizures with cenobamate treatment was observed as early as the first 2 weeks of treatment with a 12.5 mg/day dose. More than half of patients achieved seizure freedom by weeks 5 and 6 at a dose of 50 mg/day. Considering these early effects reduction of concomitant medications whilst taking cenobamate may begin as early as weeks 2 to 6 of treatment with cenobamate. Additional seizure reduction, including 100% seizure reduction, occurred with continued dose increases in cenobamate dose over time.
Seizure reduction of 100% occurred in 25.8% (62/240) of participants for 1 year or more, with a mean duration of 100% seizure reduction of 23.5 months (range 11.6-40.1 months). During the maintenance phase of the trial (median treatment duration >2 years; n=214), ≥50%, ≥75%, and 100% responder rates were 75.7% (162/214), 57.5% (123/214), and 13.6% (29/214), respectively. Of those with 100% seizure reduction for at least 12 months at the last visit, 33.3% achieved 100% seizure reduction for the entire maintenance phase.
When participants were stratified by baseline seizure frequency of less than 3 vs 3 or more, the proportion achieving seizure freedom was approximately the same in each group. Amongh those who achieved seizure freedom, those who had lower seizure frequency at baseline (<3 seizures/month) had a mean effective dose of cenobamate that was 30 mg/day lower than those who had a baseline of 3 or more seizures/month.