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. 2026 Feb 9:e255625.
doi: 10.1001/jamaneurol.2025.5625. Online ahead of print.

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

Emanuele Cerulli Irelli  1 , Roberta Roberti  2 , Maria Sole Borioni  1 , Francesca Anzellotti  3 , Vincenzo Belcastro  4 , Simone Beretta  5   6 , Giovanni Boero  7 , Paolo Bonanni  8 , Valentina Chiesa  9 , Alfredo D'Aniello  10 , Filippo Dainese  11 , Francesco Deleo  12 , Giovanni De Maria  13 , Giancarlo Di Gennaro  11 , Gianfranco Di Gennaro  2 , Giuseppe Didato  14 , Fedele Dono  3   15 , Giovanni Falcicchio  16 , Edoardo Ferlazzo  17   18 , Francesco Fortunato  19 , Angela La Neve  16 , Oriano Mecarelli  1 , Elisa Montalenti  20 , Alessandra Morano  1 , Annacarmen Nilo  21 , Francesca Felicia Operto  2   19 , Francesco Paladin  22 , Angelo Pascarella  17   18 , Giada Pauletto  23 , Nicola Pietrafusa  24 , Pietro Pignatta  25 , Patrizia Pulitano  1 , Rosaria Renna  26 , Eleonora Rosati  27 , Ilaria Sammarra  18 , Carlo Di Bonaventura  1 , Emilio Russo  2 , Simona Lattanzi  28 ; Comparative REal-World Evidence (CREW) Study Group
Collaborators, Affiliations

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

Emanuele Cerulli Irelli et al. JAMA Neurol. .

Abstract

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-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 vs 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cerulli Irelli reported receiving speaker fees from Angelini Pharma and travel support from UCB Pharma, Jazz Pharmaceuticals, Angelini Pharma, and Eisai outside the submitted work. Dr Roberti reported receiving personal fees from Eisai, UCB Pharma, and Jazz Pharmaceuticals outside the submitted work. Dr Chiesa reported receiving consultant fees from UCB Pharma and advisory board fees from Jazz Pharma outside the submitted work. Dr D’Aniello reported receiving personal fees from UCB Pharma, Angelini Pharma, and Lusofarmaco outside the submitted work. Dr Dainese reported receiving grants from Angelini, Livanova, and UCB Pharma outside the submitted work. Dr Deleo reported receiving personal fees from Angelini Pharma for participation in editorial projects and from Roche for participation in a randomized clinical trial in autoimmune encephalitis outside the submitted work. Dr Dono reported receiving travel support from Eisai, UCB Pharma and Angelini Pharma and speaker honoraria from Eisai outside the submitted work. Dr Ferlazzo reported receiving grants from ASA Angelman American Association outside the submitted work. Dr Morano reported receiving personal fees from Eisai, UCB pharma, Angelini Pharma, Jazz Pharmaceuticals, Ecupharma, and Lusofarmaco outside the submitted work. Dr Pulitano reported receiving personal fees from Angelini Pharma, UCB Pharma, and Eisai outside the submitted work. Dr Rosati reported receiving personal fees from Eisai, Angelini, Livanova, Jazz Pharmaceuticals, and UCB Pharma outside the submitted work. Dr Di Bonaventura reported receiving personal fees from Angelini Pharma, Jazz Pharmaceuticals, Ecupharma, Eisai, UCB Pharma, and Lusofarmaco outside the submitted work. Dr Lattanzi reported receiving speaker and/or consultancy fees from Angelini Pharma, Eisai, GW Pharmaceuticals, Medscape, NewBridge Pharmaceuticals, and UCB Pharma and serving on advisory boards for Angelini Pharma, Arvelle Therapeutics, Bial, Eisai, GW Pharmaceuticals, and Rapport Therapeutics outside the submitted work. No other disclosures were reported.

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