Do the third-generation antiseizure medications provide the “magic bullet” for drug-resistant epilepsy? Focus on cenobamate

Abstract

Achieving seizure freedom remains elusive for a substantial number of patients, particularly those designated as having drug-resistant epilepsy. Over the past 30 years, 24 new antiseizure medications (ASMs) have been developed and licensed in the United States and Europe, some of which offer improved safety and tolerability profiles.^{1, 2} However, landmark studies conducted in Glasgow, Scotland, on individuals with newly diagnosed epilepsy have suggested that the proportion of patients with uncontrolled epilepsy has not decreased significantly during this time. In the most recent updated analysis of the Glasgow cohort,³ which included 1795 adolescents and adults who began ASM treatment between 1982 and 2012, the use of second-generation drugs increased from 21% in the first decade to 74% in the last. Despite this shift in availability and choice, the probability of achieving seizure freedom—defined as no seizures for at least the previous year—has remained unchanged across three consecutive decades. In this latest update, 64% of patients were seizure-free, a proportion identical to that reported in the earlier, smaller study undertaken in the same clinical setting and published in 2000.⁴ These findings were confirmed in a recent systematic review and meta-analysis of observational studies involving 10 109 children and adults with newly diagnosed epilepsy, published between 1995 and 2021.⁵ The pooled proportion of those achieving seizure freedom for 1 year at the last follow-up was 68% (95% confidence interval [CI]: 63%–72%), with outcomes not linked to the publication year or the earliest date of cohort recruitment. This lack of fundamental progress in treatment outcomes has underpinned the relentless search for the “magic bullet” that will result in long-term seizure freedom for the majority of people designated as having drug-resistant epilepsy.

The arrival of a number of third-generation ASMs over the past decade has sparked recent optimism that a breakthrough in epilepsy drug treatment may be on the horizon. These ASMs, omitting those limited to licensing for rare epilepsy syndromes, include lacosamide, eslicarbazepine, perampanel, brivaracetam, and cenobamate—listed in chronological order of approval. Among these, cenobamate arguably appears the most promising, as reviewed in this special supplement of articles.

In this supplement, Sperling and coworkers highlight the risks associated with uncontrolled seizures, particularly those with a focal onset leading to bilateral tonic–clonic seizures, which pose the highest risk for sudden unexpected death in epilepsy (SUDEP). They then summarize the impressive efficacy and tolerability of cenobamate in initial clinical trials and the high proportion of patients achieving seizure freedom, which was sustained in an open-label extension study. It is important to note that the reduction in seizures was associated with improved quality of life measures, accompanied by emerging evidence of reduced mortality and a lower risk of SUDEP. Their article underscores the importance of employing aggressive treatment strategies to prevent high-risk seizures and advocates for a shared decision-making model between patient and physician. This article also highlights the value of addressing the needs of patients with epilepsy beyond their seizures, aiming ultimately at enhancing overall patient care and quality of life.

It can be said that efficacy and tolerability are two sides of the same coin in determining the effectiveness and clinical utility of an ASM.⁶ In this supplement, the tolerability of ASMs has been addressed specifically by Krauss and colleagues. The authors review a range of strategies for minimizing adverse effects, such as the flexible dosing and adjustment of the number and/or doses of concomitant ASMs in clinical practice. They also provide practical advice to proactively manage known pharmacokinetic and pharmacodynamic interactions with concomitant ASMs, with the eventual goal of optimizing the overall effectiveness of cenobamate for the individual patient.

Klein focuses on the challenges associated with managing epilepsy in specific populations, including older adults, children, and people with rare developmental epileptic encephalopathies, reviewing the evidence supporting the use of cenobamate in these challenging patient populations. Ongoing studies in children will further inform the utility of cenobamate in this age group. Given the unique health and social needs and treatment outcomes of older adults,^7-9 we suggest that a specific study of cenobamate in this population is urgently warranted.

Despite its proven efficacy, cenobamate remains underutilized. In this supplement, Rosenfeld discusses barriers that could have hindered the prescription of newer ASMs in clinical practice. These include treatment complacency, inadequate trial of new adjunctive therapies, and pitfalls of rational polytherapy based on a rudimentary understanding of mechanisms of action, thereby restricting the use of newer drugs as “last resort” treatments. Strategies to overcome these barriers are proposed and discussed by this author.

Together, these articles provide an overview of the evolving landscape of epilepsy treatment with ASMs, emphasizing the need for continued innovation, proactive management, and patient-centered care. By highlighting the newer ASMs, in particular cenobamate, this collection of reviews underscores the importance of optimizing treatment strategies to improve outcomes for people with epilepsy, particularly those who remain the most vulnerable to the potentially devastating consequences of uncontrolled epilepsy. Although it is open to question whether or not they are the “magic bullets,” the availability of cenobamate and other third-generation ASMs has raised hope that the long sought-after breakthroughs in the pharmacological treatment of epilepsy may be in sight.¹⁰ Real-world studies to evaluate their impact in this setting, such as the decision to refer for non-pharmacologic options, are needed and should be undertaken without further delay. This may be addressed, for instance, through an updated analysis of the Glasgow cohort.

All authors contributed to writing – original draft preparation and writing – review and editing. All authors approved the final version of this manuscript for submission.

Dr. Kwan is supported by the National Health and Medical Research Council (NHMRC) Investigator Grants (GNT2025849). Outside the submitted work he/his institution has received consultancy fees and/or research grants from Eisai, Jazz, LivaNova, SK Life Science, Inc., and UCB Pharma. Dr. Brodie has nothing to disclose.

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.