Cenobamate: A comprehensive review

This article provides a review of cenobamate's (CNB's) pharmacology, mechanisms of action, efficacy, safety, and seizure/epilepsy types treated. CNB is an antiseizure medication approved in the U.S. in 2019 for treatment of adults with focal (partial-onset) seizures. Preclinical data indicated CNB had a broad spectrum of antiseizure activity in rodent models of generalized and focal seizures. CNB has two mechanisms of action that may contribute additively or synergistically to powerfully counter the development of the paroxysmal depolarizing shift in neurons: selective inhibition of persistent sodium currents (I_NaP), sparing transient sodium currents, and augmentation of GABA-mediated tonic currents. In 3 randomized, placebo-controlled trials in adults with focal seizures, median 28-day seizure frequency reductions ranged from 36.0%-100% at CNB doses of 100-400 mg/day. During the maintenance phases of these trials, CNB at higher doses demonstrated 100% seizure-free rates in 21.0%-52.4% of patients. In a recent randomized, controlled study of patients aged 12-65 years with primary generalized tonic-clonic seizures, the seizure-free rates with CNB and with placebo were 43% and 20%, respectively (p=0.0034). Since CNB's approval in multiple countries, many open-label extension, postmarketing, and observational studies have been published for patients with focal epilepsy and other epilepsy types, and remarkably high seizure freedom rates have been consistently reported. Seizure-free rates reported are also very high among treatment-resistant patients, but many studies report even higher rates in patients with milder or shorter-duration epilepsy.