Narrative Review: Efficacy, Safety, and Tolerability of Newer Third-Generation Antiseizure Medications for Focal Epilepsy: A New Benchmark in Treatment Outcomes?

INTRODUCTION: Focal seizures are the most common form of epilepsy. This narrative review analyzes the efficacy, safety, and tolerability of five newer third-generation antiseizure medications (ASMs) approved for treatment of focal seizures: lacosamide, perampanel, eslicarbazepine acetate, brivaracetam, and cenobamate. METHODS: A search of PubMed and ClinicalTrials.gov identified phase 2/3 randomized controlled trials and long-term open-label extension (OLE) studies for the five most recently approved ASMs for focal seizures. Efficacy data were summarized, including median percent reduction in seizure frequency, ≥ 50% responder rates, ≥ 75% responder rates (when reported), and seizure freedom rates. Safety and tolerability were assessed based on treatment-emergent adverse events (TEAEs), serious adverse events, and discontinuation rates. Long-term efficacy, safety, and treatment retention rates were also summarized. RESULTS: All five ASMs had statistically significant efficacy vs. placebo in short-term trials, with cenobamate demonstrating higher median percent seizure reduction (35.5-100%), ≥ 50% responder rates (40-81.6%), and seizure freedom rates (up to 52.4%) compared to the other four third-generation ASMs. In long-term OLEs, cenobamate had ≥ 50% responder rates > 70% and the highest estimated treatment retention rates at 3 years (61-65%) compared to lacosamide (51-53%), perampanel (46%), and brivaracetam (48%). Common TEAEs across all ASMs included dizziness, somnolence, fatigue, and headache. Brivaracetam and lacosamide had favorable profiles in multiple network meta-analyses. Specific safety considerations include psychiatric adverse events for perampanel and brivaracetam, and a risk of drug reaction with eosinophilia and systemic symptoms (DRESS) for cenobamate (significant risk reduction achieved using a gradual titration schedule). CONCLUSION: All third-generation ASMs were effective adjunctive therapies. Cenobamate was associated with higher responder and seizure freedom rates and higher long-term retention rates. Brivaracetam and lacosamide had favorable tolerability profiles. The notable seizure freedom rates with cenobamate suggest a potential new benchmark in focal seizure treatment. Comparator trials are needed to confirm possible efficacy and tolerability differences among third-generation ASMs.