Cenobamate Shows Superior Effectiveness in Drug-Resistant Focal Epilepsy
Key Clinical Summary
- In a pooled real-world analysis of 1949 adults with drug-resistant focal epilepsy, cenobamate was associated with significantly higher 6- and 12-month responder rates compared with brivaracetam, lacosamide, and perampanel.
- Cenobamate demonstrated greater odds of seizure freedom and 12-month treatment retention.
- Adverse effects were more frequent with cenobamate (57.8%) than with other newer antiseizure medications (ASMs).
A large, pooled analysis published in JAMA Neurology found that cenobamate outperformed brivaracetam, lacosamide, and perampanel as adjunctive therapy in adults with drug-resistant focal epilepsy. However, adverse effects were more frequent with cenobamate than with the other antiseizure medications (ASMs).
Study Findings
The multicenter analysis combined real-world data from 4 Italian retrospective medical record–review studies conducted between January 2017 and January 2024. Investigators included adults aged 16 years or older with drug-resistant focal epilepsy, as defined by the International League Against Epilepsy (ILAE).
A total of 1993 ASM prescriptions from 1949 patients met inclusion criteria. The median age at prescription was 42 years (IQR, 29–55), and 53.2% of patients were female. Brivaracetam accounted for 47.8% of prescriptions (953), followed by perampanel (30.5%; 607), lacosamide (12.1%; 241), and cenobamate (9.6%; 192).
The primary outcome was a 50% or greater reduction in seizure frequency at 6 months. After adjustment using generalized linear mixed models, cenobamate demonstrated significantly higher effectiveness than comparator ASMs. Compared with cenobamate, the odds ratios (ORs) for achieving a 50% or greater response at 6 months were 0.18 (95% CI, 0.12–0.28; P < .001) for brivaracetam, 0.26 (95% CI, 0.16–0.42; P < .001) for perampanel, and 0.29 (95% CI, 0.17–0.49; P < .001) for lacosamide.
These results were consistent at 12 months, as cenobamate was associated with higher responder rates and seizure freedom. The drug also demonstrated greater likelihood of 12-month treatment retention 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).
Adverse effects were also more common with cenobamate (57.8%) than with other agents. Lacosamide had the lowest incidence of adverse effects (14.8%).
Clinical Implications
Drug-resistant focal epilepsy remains a major therapeutic challenge, with limited direct comparative evidence among newer ASMs. This large real-world pooled analysis provides clinically relevant data to guide adjunctive treatment selection.
The findings suggest that cenobamate may offer superior long-term effectiveness, including higher responder rates, greater seizure freedom, and improved treatment retention. For clinicians managing patients with persistent seizures despite prior therapy, these results may support consideration of cenobamate as a preferred adjunctive option.
Still, the higher incidence of adverse effects underscores the need for careful patient selection and monitoring, particularly in patients with complex comorbidities or polytherapy regimens. Individualized risk–benefit assessment remains central to optimizing outcomes.
Expert Commentary
“Additional consideration arises from the pharmacokinetic profile of cenobamate, a potent inhibitor of cytochrome P2C19 (CYP2C19) and inducer of CYP3A4 and CYP2B6,” noted Emanuele Cerulli Irelli, MD, PhD, Department of Human Neurosciences, Sapienza University, Rome, Italy, and study coauthors. “These characteristics may increase the risk of clinically significant drug-drug interactions, especially in patients receiving multiple ASMs or other medications metabolized via these pathways.”
The authors suggest that other ASM agents “may represent suitable options for frailer patients or those with less complicated epilepsy courses, where efficacy could still be obtained along with optimal tolerability.”
“Further prospective studies and pragmatic head-to-head trials are warranted to confirm these findings, define optimal treatment sequencing, and best ASM combination strategies,” they concluded.
