Cenobamate bests newer antiseizure medications in drug-resistant focal epilepsy: JAMA

A new study published in the Journal of the American Medical Association showed that in patients with drug-resistant focal epilepsy, cenobamate has better long-term efficacy than other more recent antiseizure drugs (ASMs).

Since there is no direct comparative data between the more recent antiseizure drugs, treatment choices for drug-resistant focal epilepsy are still primarily empirical. Randomized clinical trials can be supplemented by real-world data, which can offer insights into long-term safety and efficacy across a range of groups. Thus, this study evaluated the safety and efficacy of perampanel, lacosamide, cenobamate, and brivaracetam as supplementary treatments for people with drug-resistant focal epilepsy.

Four prior retrospective real-world medical record-review studies (January 2017–January 2024) were merged and analyzed across several centers. Adult patients with drug-resistant focal epilepsy, as defined by the International League Against Epilepsy, who were at least 16 years old were included. 71 epilepsy centers provided participants.

The responder rate at six months, which was defined as more than or equivalent to a 50% decrease in seizure frequency from baseline, was the main outcome. 12-month responder rate, seizure freedom (≥3 months at 6 months and ≥6 months at 12 months), and 12-month ASM retention were secondary objectives. The frequency of negative effects was used to evaluate safety. 

1993 from 1949 individuals (median age 42 years; 53.2% female) were included in the 2386 ASM prescriptions that were reviewed. The most often given medication was brivaracetam (47.8%), which was followed by cenobamate (9.6%), lacosamide (12.1%), and perampanel (30.5%).

Following adjustment, cenobamate shown comparable superiority for response and seizure independence at 12 months, with substantially higher chances of attaining at least 50% seizure reduction at 6 months when compared to the other ASMs. Lacosamide had the lowest rate of side effects (14.8%), whereas cenobamate had the greatest rate (57.8%).

At 12 months, cenobamate was preferred over brivaracetam and perampanel in terms of treatment retention; there was no discernible difference when compared to lacosamide. Overall, cenobamate was linked to the best chance of attaining therapeutic response and seizure independence among the assessed newer-generation ASMs despite a greater rate of side effects, in individuals with drug-resistant focal epilepsy.

Source:

Cerulli Irelli, E., Roberti, R., Borioni, M. S., Anzellotti, F., Belcastro, V., Beretta, S., Boero, G., Bonanni, P., Chiesa, V., D’Aniello, A., Dainese, F., Deleo, F., De Maria, G., Di Gennaro, G., Di Gennaro, G., Didato, G., Dono, F., Falcicchio, G., Ferlazzo, E., … Comparative REal-World Evidence (CREW) Study Group. (2026). Comparative effectiveness of brivaracetam, cenobamate, lacosamide, and perampanel in focal epilepsy. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2025.5625