Real‐world effectiveness of cenobamate in drug‐resistant and ultra‐refractory epilepsy: A multicenter study

OBJECTIVE: To evaluate the real-world effectiveness, safety, and treatment retention of cenobamate (CNB) in patients with drug-resistant epilepsy (DRE), including ultra-refractory epilepsy (URE), high seizure burden, and extensive prior treatment history. METHODS: We conducted a retrospective, multicenter study of 500 adults with DRE (focal or combined epilepsy) who were treated with CNB at three Czech tertiary epilepsy centers. Among these patients, 83.4% met criteria for URE. Seizure outcomes, treatment retention, and adverse events were analyzed, with stratification by treatment duration and cumulative ASM exposure (number of previous and concomitant anti-seizure medications). Primary outcomes were ≥ 50% responder rate and seizure freedom at 12 months. RESULTS: Among 436 patients with evaluable seizure data after ≥ 3 months of CNB treatment, 55.7% achieved ≥ 50% seizure reduction and 16.5% became seizure-free. At 12 months (n = 331), ≥ 50% response was achieved in 61.6%, and 18.1% became seizure-free. Among patients with focal to bilateral tonic-clonic seizures or bilateral tonic-clonic seizures, 46.1% achieved seizure freedom at 12 months. CNB efficacy persisted across high cumulative ASM burden, with seizure freedom in 22.7%, 20.2%, and 10.4% of patients with ≤ 5, 6-10, and > 10 ASMs, respectively. Multivariable analyses identified high baseline seizure burden, greater cumulative ASM exposure (> 10 ASMs), and concomitant use of sodium channel blockers as independent negative predictors of treatment response. Treatment retention at 12 months was 83.0%. SIGNIFICANCE: CNB was effective and well-tolerated in a highly treatment-resistant population. Although seizure freedom rates declined with increasing cumulative ASM burden, CNB retained clinically meaningful efficacy even in highly refractory patients. PLAIN LANGUAGE SUMMARY: The study examined the effectiveness of cenobamate in routine clinical practice in adults with highly treatment-resistant epilepsy. In a large multicenter cohort, many patients achieved substantial seizure reduction, including complete seizure freedom, despite extensive prior treatment. Most patients remained on cenobamate during follow-up, consistent with good effectiveness and tolerability in routine clinical practice. These findings indicate that cenobamate can offer meaningful benefits even in very difficult-to-treat epilepsy and may inform treatment decisions in clinical practice.