Adjunctive cenobamate in highly active and ultra‐refractory focal epilepsy: A “real‐world” retrospective study

Abstract Objective Recent clinical trials have shown that cenobamate substantially improves seizure control in focal‐onset drug‐resistant epilepsy (DRE). However, little is known about cenobamate's performance in highly active ( ≥ 20 seizures/month) and ultra‐refractory focal epilepsy ( ≥ 6 failed epilepsy treatments, including antiseizure medications [ASMs], epilepsy surgery, and vagus nerve stimulation). Here, we studied cenobamate's efficacy and tolerability in a “real‐world” severe DRE cohort. Methods We conducted a single‐center retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment‐emergent adverse events, and adjustments to concomitant ASMs were analyzed. Results Fifty‐seven patients received cenobamate for at least 3 months (median duration, 11 months). The median cenobamate dose was 250 mg/day (range 75–350 mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra‐refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75%–99% reduction in seizures (42.1% of cohort), and 16 had a 50%–74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic–clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ≥ 250 mg/day. Three‐fourths of patients reported at least one side‐effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ≥ 250 mg/day. Side‐effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine, and perampanel. Significance Patients with highly active and ultra‐refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250 mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.