A pooled real-world comparison of newer antiseizure medications found higher seizure response and seizure freedom with cenobamate vs brivaracetam, lacosamide, or perampanel in patients aged 16 years or older with drug-resistant focal epilepsy.
The Comparative Real-World Evidence (CREW) study combined harmonized data from four retrospective medical record–review cohorts conducted across 71 epilepsy centers, encompassing nearly 2,000 patients with focal epilepsy that had failed at least two prior antiseizure medications. The analysis compared effectiveness, retention, and tolerability of four commonly used newer-generation agents in routine practice.
After adjustment for demographic and clinical factors, cenobamate was associated with statistically significant higher odds of achieving a 50% or greater reduction in seizure frequency at 6 months vs all three comparators. The advantage persisted at 12 months. Cenobamate was also associated with statistically significant higher seizure-freedom rates vs brivaracetam and perampanel at 12 months.
Although unadjusted outcomes did not consistently favor cenobamate, adjusted models revealed differences after accounting for baseline seizure burden, prior treatment exposure, and concomitant therapy. Patients prescribed cenobamate tended to have more refractory disease, including higher baseline seizure frequency and greater prior antiseizure medication exposure—factors typically associated with poorer treatment response.
Treatment retention at 12 months was higher with cenobamate vs brivaracetam and perampanel and comparable with lacosamide. Cenobamate was also associated with the highest incidence of adverse effects, most commonly somnolence, dizziness, and other central nervous system symptoms. Despite this, higher adverse-event rates did not translate into lower long-term retention.
By contrast, lacosamide had the most favorable tolerability profile, with the lowest reported adverse-event rates. Perampanel and brivaracetam showed intermediate effectiveness and safety profiles.
The authors note that treatment selection in focal epilepsy remains largely empirical because head-to-head randomized trials among newer agents are lacking. They write that large adjusted real-world analyses such as CREW may help inform treatment sequencing by placing efficacy and tolerability findings within the context of routine clinical practice.
Although the retrospective design limits causal inference, the authors call for prospective comparative studies to refine treatment sequencing and clarify which patients benefit most from agents such as cenobamate.
Disclosures can be found in the study.
Source: JAMA Neurology