Efficacy in drug-resistant epilepsy
Adjusting medications
Safety studies
An estimated 50% of epilepsy patients do not achieve seizure control with their first anti-seizure medication (ASM), with only 2.1% obtaining optimal seizure control with subsequent therapies (Chen et al. JAMA Neurol 2018;75:279-286). However, in recent years there has been considerable progress in the management of refractory epilepsy with the adjunctive use of cenobamate, a dual-action agent that blocks persistent Na+ channels and modulates GABA-induced currents mediated by GABA-A receptors (Nakamura et al. Eur J Pharmacol 2019;855:175-182. Sharma et al. Eur J Pharmacol 2020:879:173117).
Recent studies on the efficacy and safety of cenobamate were among the highlights of the 36th International League Against Epilepsy (ILEA) congress, held August 30 to September 3, 2025, in Lisbon, Portugal. The following is a summary of key studies.
Efficacy in drug-resistant epilepsy
The Cenobamate in Focal Epilepsy Study (CIFES) was a six-month observational study in Spain of 41 patients with refractory epilepsy (Ruiz-Perella et al. ILAE 2025). A total of 65.8% of patients were male; mean age was 37 years; 75% had focal motor or non-motor epilepsy; and a majority of patients had an epilepsy duration of 11-20 years. After initiation of adjunctive cenobamate, the number of seizures was significantly reduced from 13.12 at baseline to 1.96 at three months and 1.69 at six months. Twelve percent were seizure-free at six months. The number of concomitant ASMs was significantly reduced during treatment with cenobamate; the defined daily dose was significantly reduced from 5.87 to 4.34 after six months. Treatment was well tolerated. The most common adverse effect was dizziness (4.8%). The six-month retention rate was 97.5%.
A separate study (N=487) evaluated the efficacy of cenobamate in early users (2-3 prior ASMs) and those who had not adequately responded to >7 ASMs (Bosaka et al. ILAE 2025). Median age was 37 years; median age at epilepsy onset was 9-12 years. In the early user group, 69.5% experienced a >50% reduction in seizure frequency and 26% were seizure-free. For the group with a history of failing to respond to >7 ASMs, 54.6% achieved a >50% reduction in seizure frequency and 7.7% were seizure-free. The most common adverse events were somnolence and dizziness. The authors noted that earlier initiation of cenobamate may improve outcomes.
Adjusting medications
A U.S. study examined the final medication adjustment in a cohort of drug-resistant patients that achieved seizure freedom with adjunctive cenobamate (Abou-Khalil et al. ILAE 2025). The mean seizure frequency at baseline was 7.6 seizures/month. The mean duration of seizure freedom was 34 months (range 6-80 months). The mean cenobamate dose at the time of achieving seizure freedom was 262 mg (range 100-400 mg). Clobazam was the most common concomitant medication; mean dose was 8.3 mg (range 2.5-15.0 mg).
The last medication adjustment prior to seizure freedom was the addition of cenobamate (33% of patients), a cenobamate dose increase (20% of patients), a clobazam dose increase (27% of patients), and the addition of clobazam to the regimen (10% of patients). Most patients who became seizure-free with clobazam add-on or dose titration had previously failed clobazam monotherapy. The authors concluded that the results demonstrate that cenobamate and clobazam have synergistic effects. The data support a strategy of adding or titrating clobazam in patients who have not become seizure-free on cenobamate.
Safety studies
Cenobamate is associated with a dose-dependent shortening of the QT interval, with 31% experiencing QT shortening >20 msec at a dose of 200 mg. A new prospective study assessed ECG changes in 40 refractory epilepsy patients receiving cenobamate >200 mg for at least three months (Barros et al. ILAE 2025). Mean age was 35 years. The mean QTc interval declined significantly from 397 msec at baseline to 365 msec at six months. However, QT shortening remained within safe limits and did not appear to be clinically significant; mean change was -12.2 msec. One patient (2.5%) discontinued therapy following a cardiorespiratory event.
The use of enzyme-inducing ASMs (e.g. carbamazepine, phenytoin, phenobarbital) is associated with long-term cardiovascular risk; the hazard in patients taking multiple ASMs (HR 2.38) is dose-dependent and appears to become clinically significant after 10 years of medication exposure (Josephson et al. JAMA Neurol 2021;78:1367-1374).
An observational study evaluated lipid changes in treatment-refractory epilepsy patients receiving a mean of three ASMs who started adjunctive cenobamate (Fernandez et al. ILAE 2025). LDL cholesterol levels increased during treatment, although it should be noted that one-third of patients experienced an increase in body weight (mean 3.95 kg) during the observation period. The number of patients on a ketogenic diet was not reported. The authors concluded that serum cholesterol levels and body weight should be routinely monitored, most notably in patients with prior cardiovascular risk factors.