Cenobamate long-term efficacy and concentration reference range

Administering cenobamate in patients with uncontrolled focal seizures leads to long-term (≥12 months) 100% seizure reduction in a high proportion of patients. This was concluded from the post-hoc efficacy data of the long-term, global, open-label phase 3 safety study YKP3089C021 (NCT02535091) [1], presented at the AAN 2021 virtual meeting. Also, cenobamate trough plasma concentrations in patients with 50-100% seizure reduction suggest a reference concentration range.

The YKP3089C021 trial demonstrated that a starting dose of 12.5 mg cenobomate and titrating with a 2-week interval reduces the risk of drug reaction with eosinophilia and systemic symptoms (DRESS), but the study did not assess long-term efficacy. Therefore, post-hoc efficacy data from US study sites was analysed by Dr Michael R. Sperling (Thomas Jefferson University, Pennsylvania, USA).

For the analysis, 240 patients (median baseline seizure frequency 2.8/28 days, median duration of cenobamate exposure 30.2 months) were included in the analysis and 177 patients (73%) were still taking cenobamate at the last visit. Long-term efficacy data showed that 25.8% of all patients and 33.9% of the patients continuing on cenobamate had 100% seizure reduction for ≥12 months at the last visit. During the maintenance phase (maintenance population n=214, median duration of cenobamate exposure 29.5 months), responder rates (RR) of 50% and 100% were obtained in 75.7% and 13.1% of the patients respectively. Dr Sperling stressed the importance of the results found in the focal to bilateral tonic-clonic subgroup. Within this subgroup, ≥50% and 100% RR were reported for respectively 85.4% and 35% of the patients. Even though the sample size is rather small for this subgroup (n=48) this is an excellent result for this severe condition, according to Dr Sperling.

To provide more insight into the dosing of cenobamate in clinical practice, Stephen Greene (PharmD, SK Life Science, Inc.) presented a study on cenobamate trough plasma concentrations among patients with uncontrolled focal seizures who reached ≥50% and 100% seizure reduction during the maintenance phase of 2 studies (YKP3089CO13 [NCT01397968] and YKP3089C017 [NCT01866111]) of adjunctive cenobamate next to 1-3 other anti-seizure medications [2]. For physicians, trough plasma concentrations provide a tool to evaluate treatment and patient characteristics (compliance, side effects, breakthrough seizures). Trough plasma concentrations among the patients with ≥50% seizure reduction were 4.60-9.32 μg/mL for 100 mg/day, 11.40-18.70 μg/mL for 200 mg/day, and 20.80-35.20 μg/mL for 400 mg/day. Similar percentages were obtained for the 100% seizure reduction group. In conclusion, 95% of the patients with ≥50 % SR and 100% SR showed cenobamate trough concentrations ranging from 5-35 μg/mL, providing a suggested cenobamate reference concentration range.

1. Sperling MR, et al. Efficacy of Cenobamate for Uncontrolled Focal Seizures: Post-hoc Analysis of a Phase 3, Multicenter, Open-Label Study. S1.002, AAN 2021 Virtual Congress, 17-22 April.
2. Greene S, Kamin M. Cenobamate Trough Plasma Concentrations In Patients With Uncontrolled Focal Seizures Achieving 50% and 100% Seizure Reduction In Two Randomized Clinical Studies, S1.003, AAN 2021 Virtual Congress, 17-22 April.

Posted on 19 April 202117 June 2021