Real-world use of cenobamate
New phase III data
Effect on mortality
Co-administration with cannabidiol
The International League Against Epilepsy (ILAE) published its updated classification of epileptic seizures earlier this year, maintaining four seizure classes (Focal, Generalized, Unknown, Unclassified) and 21 seizure types (Beniczky et al. Epilepsia 2025;66:1804-1823). For example, focal seizures may be classified as focal preserved consciousness (FPC), focal impaired consciousness (FIC) or focal-to-bilateral tonic-clonic seizures (FBTC). Consciousness was defined by awareness (i.e. recall of events) and responsiveness. The basic descriptors are whether seizures have observable manifestations or not.
The management of focal seizures was one of the highlights of the American Epilepsy Society (AES) meeting, held December 5-9, 2025, in Atlanta, Georgia. The following summarizes new data on the use of adjunctive cenobamate in selected populations.
Real-world use of cenobamate
Cenobamate is an adjunctive antiseizure medication (ASM) that acts primarily via blockade of persistent Na+ channels (Nakamura et al. Eur J Pharmacol 2019;855:175-182); and modulation of GABA-induced currents mediated by GABA-A receptors (Sharma et al. Eur J Pharmacol 2020:879:173117) (see also Cenobamate as adjunctive therapy for partial-onset seizures: a review, NeuroSens, October 24, 2024). A retrospective analysis of data from 20 European centres examined the use of cenobamate in a cohort of 290 patients with drug-resistant epilepsy (Bosak et al. AES 2025;2.269). Median age was 37 years; median age at epilepsy onset was 11 years; and median duration of cenobamate treatment was 16 months. About one-half of the cohort had a history of 4-7 prior ASMs, and 42.9% had received >7 prior ASMs. The median number of seizures at baseline was 8/month. The response rate, defined as a ≥ 50 % reduction in seizure frequency, was 63.6% with cenobamate; 16.3% achieved seizure freedom. Two-thirds of patients decreased or discontinued at least one ASM. The most common adverse effects were somnolence and dizziness.
New phase III data
Earlier this month, the phase III C035 trial was published on the efficacy of adjunctive cenobamate in an Asian population (N=519) with uncontrolled focal seizures (Wua et al. Seizure 2025:133:43-51. Free full text at www.seizure-journal.com/action/showPdf?pii=S1059-1311%2825%2900267-5). Patients received placebo or one of three doses of cenobamate (100, 200 or 400 mg/day); the starting dose was 12.5 mg/day, increased every two weeks over an 18-week titration phase and followed by a six-week maintenance phase. The reduction in seizure frequency was 76-100% with cenobamate 200 and 400 mg/day. The median seizure-free rate was 26.7% at weeks 7-8.
Two interim analyses of data from the long-term open-label extension study were presented at AES 2025. During the maintenance phase, the responder rate in patients receiving continuous cenobamate 300 mg/day (range 50-400 mg/day) was >70% for all focal epilepsy subtypes (Rosenfeld et al. AES 2025;1.378). For FBTC patients, the 100% responder rate was 55.6%. For patients initially randomized to placebo, there was a rapid reduction in seizure frequency after switching to cenobamate (Misra et al. AES 2025;3.364). After the first 8 weeks of dose titration (study week 32), the median reduction in seizure frequency was 66.2%, with 31.3% of patients in the cenobamate 100 mg/day group demonstrating a 100% responder rate.
Effect on mortality
An important therapeutic goal in patient management is to reduce mortality from Sudden Unexpected Death in Epilepsy (SUDEP) or other seizure-related causes. A University of Pittsburgh study analysed mortality data (N=30,072) for patients with and without medication-resistant epilepsy (MRE), defined as failure to achieve seizure freedom with at least two ASMs (McFarlane et al. AES 2025;2.343). The median follow-up was 3.2 years (86,443 patient-years). The standardized mortality ratio (SMR) was 2.46 for non-MRE patients and 3.56 for MRE patients. In the subgroup receiving adjunctive cenobamate, the mortality ratio was 2.23. The authors found that cenobamate was associated with a 92% lower mortality rate than for patients prescribed other ASMs.
A separate analysis of health records (N=3184) reported that the mortality rate for epilepsy patients who initiated cenobamate was similar to that seen in the general population (SMR 0.69) (Webber et al. AES 2025;1.396). However, patients treated with comparable ASMs had a mortality rate that was higher than expected (SMR 1.97). The difference in SMR was similar in a propensity-matched analysis of cenobamate vs. comparator ASMs (0.56 vs. 2.03). Overall, cenobamate was associated with a 68% reduction in the mortality rate compared to other ASMs.
Co-administration with cannabidiol
Also noteworthy was a pharmacokinetic study of potential drug-drug interactions with cannabidiol and adjunctive cenobamate (Vijan et al. AES 2025;1.545). Healthy subjects received a pharmaceutical formulation of oral cannabidiol (CBD) 7.5 mg/kg BID for four days and one additional dose on day 5. After a 7-day washout, subjects started a 12-week cenobamate titration phase (12.5 mg/day titrated to 200 mg/day on days 83-93). CBD 7.5 mg/kg + cenobamate 200 mg/day was administered on days 94-98.
No pharmacokinetic interactions between CBD and cenobamate were observed and there was no evidence of increased adverse effects. Four subjects receiving CBD + cenobamate reported adverse effects compared to 10 subjects receiving CBD alone and 12 subjects on cenobamate alone. The most common adverse effects were diarrhea and headache. No serious adverse effects were reported. The authors concluded that concomitant use of cenobamate with CBD does not warrant a reduction in the dose of CBD.