Early Cenobamate as a Third-Line Option in Drug-Resistant Focal Epilepsy: A Paradigm Shift?

Drug-resistant epilepsy (DRE) affects nearly 30% of patients with epilepsy, and the optimal sequencing of adjunctive anti-seizure medications (ASMs) remains uncertain. Comparative real-world evidence on early use of newer ASM is limited. This study explores real-world comparative effectiveness, safety and 12-month retention of cenobamate (CNB) introduced as early third-line adjunctive therapy compared with perampanel (PER) and brivaracetam (BRV) in adults with focal-onset DRE. This multicenter observational study included 34 CNB patients and 37 matched controls treated with PER or BRV, all after failure of two prior ASMs. Primary outcome was 12-month treatment retention; secondary outcomes included responder rates (≥ 50%, ≥ 75%, 100%) and adverse events at 3, 6 and 12 months. Comparative analyses were exploratory. Univariate analyses and longitudinal generalized linear mixed-effects models (GLMMs) were used to describe outcome trajectories over time. CNB showed a 12-month retention rate of 94.1%. Descriptively, seizure freedom was achieved in 62.5% of CNB patients at 12 months compared with 43.7% with PER and 16.6% with BRV. Adverse events were less frequent with CNB (9.4% at 12 months) than in controls (35.3%) and were generally non-treatment-limiting. GLMMs confirmed a significant time × treatment interaction for seizure frequency, indicating a steeper reduction in CNB patients, while no significant interaction emerged for adverse events. In this real-world study, early third-line CNB exhibits potentially favorable effectiveness compared with other commonly used third-line ASMs, and tolerability remained acceptable. These findings support the need for larger prospective studies to better define optimal treatment sequencing in focal-onset DRE.