Early Cenobamate as a Third-Line Option in Drug-Resistant Focal Epilepsy: A Paradigm Shift?

Area of Science:

• Neurology
• Pharmacology
• Clinical Trials

Background:

• Drug-resistant epilepsy (DRE) impacts nearly 30% of epilepsy patients, with uncertain optimal sequencing of anti-seizure medications (ASMs).
• Limited comparative real-world evidence exists for early use of newer ASMs in DRE management.
• This study evaluates cenobamate (CNB) versus perampanel (PER) and brivaracetam (BRV) as early third-line therapy for focal-onset DRE.

Purpose of the Study:

• To compare the real-world effectiveness and safety of cenobamate (CNB) versus perampanel (PER) and brivaracetam (BRV) in adults with focal-onset DRE.
• To assess 12-month treatment retention rates for CNB compared to PER/BRV.
• To evaluate responder rates and adverse events at 3, 6, and 12 months post-initiation.

Main Methods:

• Multicenter observational study including 34 CNB patients and 37 matched PER/BRV controls, all with DRE after two prior ASM failures.
• Primary outcome: 12-month treatment retention. Secondary outcomes: responder rates (≥50%, ≥75%, 100% seizure reduction) and adverse events.
• Exploratory comparative analyses using univariate statistics and longitudinal generalized linear mixed-effects models (GLMMs).

Main Results:

• Cenobamate (CNB) achieved a 94.1% 12-month retention rate.
• Descriptive seizure freedom at 12 months was 62.5% for CNB versus 43.7% for PER and 16.6% for BRV.
• Adverse events were significantly less frequent with CNB (9.4%) compared to controls (35.3%), with GLMMs showing a steeper reduction in seizure frequency for CNB.

Conclusions:

• Early third-line cenobamate (CNB) shows potentially superior effectiveness and acceptable tolerability compared to other third-line ASMs in real-world DRE treatment.
• Findings suggest CNB may be a valuable option for optimizing treatment sequencing in focal-onset DRE.
• Larger prospective studies are warranted to confirm these findings and refine treatment strategies for DRE.