Cenobamate tablets as a treatment for focal-onset seizures in adults

ABSTRACT

Introduction: Despite the introduction of numerous new antiseizure medications (ASMs) still about one-third of epilepsies remain drug-resistant. Therefore, new compounds with advanced efficacy are urgently needed. Cenobamate (CNB) is a new ASM that has been recently introduced in the United States for the treatment of adults with focal-onset seizures. The approval in Europe is under way.

Areas covered: This review covers the pharmacological profile of CNB, the proof-of-concept trial, the two double-blind, placebo-controlled phase 2 trials investigating adjunct CNB in adults with focal-onset seizures, one open-label safety trial, and a variety of published abstract material that provided additional post hoc data.

Expert opinion: In two placebo-controlled randomized multicenter phase 2 trials adjunct CNB showed unusually high efficacy with rates of seizure-free people with epilepsy (PWE) partially beyond 20%. However, during the clinical program cases of drug-related reactions with eosinophilia and systemic symptoms (DRESS syndrome) occurred. Therefore, an open-label safety study was performed in more than 1300 PWE with particularly slower titration schedules which did not add more cases with similar reactions. Taking into consideration the promising efficacy and the safety experience from the open-label trial, CNB applied according to the meanwhile recommended titration strategy, might offer a new prospect.

KEYWORDS:

• Antiseizure medication
• cenobamate
• controlled trials
• efficacy
• epilepsy
• open-label trial
• review
• tolerability
• treatment

Article highlights

• Cenobamate (CNB) is a new antiseizure medication (ASM) recently labeled in the United States for the use in people with epilepsy (PWE) with focal-onset seizures. Approval in the European Union is under way.

• CNB reduces repetitive neuronal discharges by the inhibition of voltage-dependent sodium channels. In addition, CNB acts as a positive allosteric modulator of high-affinity GABA_A receptors, activated by GABA at a site independent of the benzodiazepine binding site.

• Due to the pharmacokinetic profile once daily dosing in the evening is possible and recommended.

• CNB is metabolized in a complex manner mainly by glucuronidation and oxidation. Interactions with other ASMs and other drugs have to be taken into consideration.

• Two pivotal placebo-controlled trials were performed. In both studies (C013 and C017), the rate of seizure-free PWE lay partially beyond 20% and thus in a range comparable trials with other new ASDs never reached over the last decades.

• The most frequent adverse events encompassed somnolence and dizziness. However, in early trials, three cases of drug-related eosinophilia with systemic symptoms (DRESS syndrome) occurred.

• In an open-label safety trial that implemented a low starting dose and a slow titration, allergic reactions such as DRESS syndrome could be avoided.

• CNB applied accordingly appears to be a promising new treatment option.

Acknowledgments

I Fazekas was the study nurse for all PWE who participated in the trials CO17 and CO21 at the Kork Epilepsy Center. T. Intravooth and C. Kurth were participating as investigators. These contributions are greatly acknowledged.

Declaration of interest

Bernhard J. Steinhoff has received speaker’s honoraria from Al-Jazeera, Desitin, Eisai, GW Pharmaceuticals, Hikma, Novartis, Sandoz, and UCB and has served as a paid consultant for Arvelle, Bial, B. Braun, Desitin, Eisai, GW Pharmaceuticals, Neuraxpharm, UCB, and Zogenix. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.