Adjunctive cenobamate for the treatment of focal onset seizures in adults with epilepsy: a critical review

ABSTRACT

Introduction

Uncontrolled epilepsy has persisted despite development of numerous antiseizure medications (ASMs) over the past 25 years, and more effective treatments are needed. Cenobamate is a new ASM approved in the US for treatment of adults with focal onset seizures.

Areas covered

This review outlines cenobamate study results from preclinical animal models through phase 2 and 3 clinical studies. Topics include mechanisms of action, pharmacokinetics, efficacy, and safety of cenobamate. Information on dosing, tolerability, and special populations are included to help healthcare providers understand this new ASM.

Expert opinion

Adjunctive cenobamate shows a high level of efficacy in patients with refractory focal epilepsy compared to that reported for other ASMs. Most notable are reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%) with cenobamate in patients with refractory epilepsy despite the concomitant use of 1-3 ASMs. Cenobamate was generally safe and well-tolerated, with a safety profile similar to other ASMs. Due to 3 early cases of DRESS, however, the cenobamate starting dose was lowered and titration rate slowed; no additional cases occurred. If efficacy responses in real-world use reflect what have been observed in clinical studies, cenobamate would be a welcome new treatment option.

KEYWORDS:

• Epilepsy
• focal seizures
• partial-onset seizures
• adult
• antiseizure medication
• cenobamate
• YKP3089
• clinical studies

Article highlights

• Despite the development of dozens of new antiseizure medications (ASMs), the chances of seizure control still remain very low following failure of two ASMs, and more than 35% of patients continue to live with uncontrolled epilepsy

• Cenobamate (YKP3089) is a new ASM approved in the US for treatment of adults with focal onset seizures

• Coadministration of cenobamate with commonly used ASMs resulted in either non-clinically meaningful interactions or interactions that are manageable through adjustments in dosing; it is recommended that clinicians consider a reduction in doses of concomitant phenytoin, phenobarbital, clobazam, and CYP2C19 substrates as needed, and consider increasing dosages of concomitant lamotrigine, carbamazepine, and CYP2B6 and CYP3A substrates as needed when coadministered with cenobamate

• In clinical studies of patients with refractory focal epilepsy despite the use of 1-3 ASMs, adjunctive cenobamate showed a high level of efficacy; most notable were reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%)

• The most common adverse events (AEs) in the clinical studies of cenobamate included somnolence, dizziness, headache, and fatigue, which were dose-related and were most often mild or moderate in intensity

• Three cases of DRESS occurred among the first 953 patients exposed to high starting doses and/or weekly up-titrations of cenobamate

• In a large safety study (N=1347), lowering the starting dose of cenobamate to 12.5 mg and slowing the titration rate to biweekly resulted in no DRESS cases over ~9 months of treatment

• If efficacy responses in real-world use are as robust as those observed in clinical studies, cenobamate could be a welcome new treatment option for focal epilepsy

Acknowledgments

This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.”

Declaration of interest

JW Wheless has received grants from Aquestive, Eisai, Greenwich, LivaNova, Mallinckrodt, Neurelis, NeuroPace, Shainberg Foundation, and Zogenix; has been a consultant for Aquestive, BioMarin, Eisai, Greenwich, Mallinckrodt, Neurelis, Supernus, and West; and has participated in speaker’s bureaus for BioMarin, Eisai, Greenwich, LivaNova, Mallinckrodt, Supernus, and UCB. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

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

Supplemental materials

Supplemental data for this article can be accessed here.

Additional information

Funding

Medical writing and editing assistance were provided by Debika Chatterjea, PhD, and Don Fallon, ELS, of MedVal Scientific Information Services, LLC (Princeton, NJ), and were funded by SK Life Science, Inc. (Paramus, NJ).