Cenobamate stands out for drug-resistant focal epilepsy in ASM showdown

Cenobamate demonstrates superior effectiveness over other newer-generation antiseizure medications (ASMs) in the treatment of adult patients with drug-resistant focal epilepsy, according to a pooled analysis of four real-world studies.

For the primary outcome of response at 6 months, cenobamate was associated with a significantly greater likelihood of achieving at least a 50-percent reduction in seizure frequency as compared with brivaracetam (odds ratio [OR], 0.18, 95 percent confidence interval [CI], 0.12–0.28; p<0.001), perampanel (OR, 0.26, 95 percent CI, 0.16–0.42; p<0.001), and lacosamide (OR, 0.29, 95 percent CI, 0.17–0.49; p<0.001). [JAMA Neurol 2026;doi:10.1001/jamaneurol.2025.5625]

Results for secondary effectiveness outcomes at 12 months also favoured cenobamate. The odds of a response at 12 months were much lower with brivaracetam (OR, 0.16, 95 percent CI, 0.10–0.25; p<0.001), lacosamide (OR, 0.21, 95 percent CI, 0.12–0.37; p<0.001), and perampanel (OR, 0.24, 95 percent CI, 0.14–0.41; p<0.001) relative to cenobamate.

The same was true for the odds of being seizure-free for 6 months or more at 12 months, with cenobamate outperforming brivaracetam (OR, 0.26, 95 percent CI, 0.14–0.50; p<0.001), perampanel (OR, 0.41, 95 percent CI, 0.21–0.82; p=0.01), and lacosamide (OR, 0.43, 95 percent CI, 0.21–0.90; p=0.02).

In terms of safety and tolerability, the incidence of adverse effects during follow-up was highest with cenobamate (57.8 percent) and lowest with lacosamide (14.8 percent). This higher rate of adverse effects did not translate into lower treatment retention, the investigators noted.

The odds of treatment retention at 12 months were significantly higher with cenobamate vs brivaracetam (OR, 0.43, 95 percent CI, 0.26–0.69; p<0.001) and perampanel (OR, 0.56, 95 percent CI, 0.32–0.99; p=0.047) but did not significantly differ between cenobamate and lacosamide (OR, 0.81, 95 percent CI, 0.41–1.59; p=0.53).

“This suggests that the adverse effects of cenobamate may be considered acceptable in light of its substantial efficacy,” the investigators pointed out.

“Alternatively, the high retention observed may reflect use of cenobamate within an early access program, where clinicians—viewing cenobamate as a last-resort option for patients with few remaining alternatives—may have been more inclined to manage adverse effects by adjusting concomitant ASMs rather than discontinuing cenobamate,” they noted.

When considering the use of cenobamate though, the investigators highlighted several considerations. First, cenobamate both inhibits and induces different enzymes, making it likely to interfere with other medications. Additionally, the drug has been linked to an increased risk of cardiovascular events and possible bone mineral density reduction, with evidence suggesting increased bone turnover after 1 year of use. [Arch Toxicol 2020;94:3671-3722; JAMA Neurol 2024;81:1178-1186; JAMA Neurol 2023;80:843-850; CNS Drugs 2025;39:95-106]

“The other analysed newer-generation ASMs lack [cenobamate’s] substantial pharmacokinetics interactions and may represent suitable options for frailer patients or those with less complicated epilepsy courses, where efficacy could still be obtained along with optimal tolerability,” they said.

The pooled analysis included 1,993 prescriptions from 1,949 patients (median age at ASM prescription 42 years, 53.2 percent female) with drug-resistant focal epilepsy across four previously conducted retrospective, real-world, medical record–review studies. Brivaracetam was the most frequently prescribed medication (47.8 percent), followed by perampanel (30.5 percent), lacosamide (12.1 percent), and cenobamate (9.6 percent).

“Further prospective studies and pragmatic head-to-head trials are warranted to confirm the findings, define optimal treatment sequencing, and identify the best ASM combination strategies,” the investigators said.