New-Generation Antiseizure Medications: Who Takes the Lead in the Real World?

Comparative Effectiveness of Brivaracetam, Cenobamate, Lacosamide, and Perampanel in Focal Epilepsy

Cerulli Irelli E, Roberti R, Sole Borioni M, Anzellotti F, Belcastro V, Beretta S, Boero G, Bonanni P, Chiesa V, D’Aniello A, Dainese F, Deleo F, DeMaria G, DiGennaro G, DiGennaro G, Didato G, Dono F, Falcicchio G, Ferlazzo E, Fortunato F, LaNeve A, Mecarelli O, Montalenti E, Morano A, Nilo A, Operto F, Paladin F, Pascarella A, Pauletto G, Pietrafusa N, Pignatta P, Pulitano P, Renna R, Rosati E, Sammarra I, DiBonaventura C, Russo E, Lattanzi S; for the Comparative REal-World Evidence (CREW) Study Group. JAMA Neurol . 2026 Apr 1;83(4):320–328. PMID: 41661607 PMCID: PMC12887838 DOI: 10.1001/jamaneurol.2025.5625

Importance: Treatment decisions in drug-resistant focal epilepsy remain largely empirical, as direct comparative evidence among newer antiseizure medications (ASMs) is limited. Real-world data can complement randomized clinical trials by providing insights into long-term effectiveness and safety across diverse populations. Objective: To compare effectiveness and safety of brivaracetam, cenobamate, lacosamide, and perampanel as adjunctive therapies in adults with drug-resistant focal epilepsy. Design, setting, and participants: This was a multicenter pooled analysis of 4 previously conducted retrospective real-world medical record-review studies (January 2017 to January 2024). Included were adult patients (aged ≥16 years) with drug-resistant focal epilepsy, as defined by the International League Against Epilepsy. Participants were recruited from 71 epilepsy centers. Exposures: Add-on treatment with brivaracetam, cenobamate, lacosamide, or perampanel. Main outcomes and measures: The primary outcome was the responder rate at 6 months, defined as greater than or equal to 50% seizure frequency reduction from baseline. Secondary outcomes included 12-month responder rate, seizure freedom (≥3 months at 6 months and ≥6 months at 12 months), and 12-month ASM retention. Safety was assessed by incidence of adverse effects. Generalized linear mixed models adjusted for demographic and clinical covariates were used to compare treatment outcomes, with cenobamate as reference ASM. Results: Of 2386 ASM prescriptions screened, 1993 prescriptions from 1949 patients (1036 of 1947 female [53.2%]; sex information was missing in 0.1% of prescriptions) with a median (IQR) age of 42 (29-55) years at ASM prescription, met inclusion criteria and were included in the pooled analysis. Brivaracetam accounted for 953 prescriptions (47.8%), followed by perampanel (607 [30.5%]), lacosamide (241 [12.1%]), and cenobamate (192 [9.6%]). After adjustment, cenobamate demonstrated significantly higher odds of 50% or greater response at 6 months compared with brivaracetam (odds ratio [OR]: 0.18; 95% CI: 0.12-0.28; P  < .001), perampanel (OR: 0.26; 95% CI: 0.16-0.42; P  < .001), and lacosamide (OR: 0.29; 95% CI: 0.17-0.49; P  < .001). Results were consistent for secondary effectiveness outcomes at 12 months, with cenobamate outperforming other ASMs in terms of 50% or greater response and seizure freedom. Cenobamate was associated with the highest rate of adverse effects during follow-up (111 [57.8%]), and lacosamide was associated with the lowest (35 [14.8%]). Cenobamate was associated with a higher likelihood of treatment retention at 12 months compared with brivaracetam (OR: 0.43; 95% CI: 0.26-0.69; P  < .001) and perampanel (OR: 0.56; 95% CI: 0.32-0.99; P  = .047), with no significant difference versus lacosamide (OR: 0.81; 95% CI: 0.41-1.59; P  = .53). Conclusions and relevance: These study findings suggest superior effectiveness of cenobamate over brivaracetam, lacosamide, and perampanel in adults with drug-resistant focal epilepsy in a large real-world setting.