A global update on cenobamate based on real‐world experience in over 100 000 patients

Abstract

Since cenobamate's launch in 2020, more than 100 000 patients have been treated with the medication worldwide. Here, we provide an important update to the epilepsy community on real-world experience with cenobamate almost 4 years post-launch. When a new anti-seizure medication (ASM) is approved, postmarketing data provide health care professionals with a valuable source of information for large numbers of patients who have been treated over an extended period. These data are especially important for the detection of rare adverse events such as drug reaction with eosinophilia and systemic symptoms (DRESS). To date, there have been no confirmed cases of DRESS with cenobamate since U.S. Food and Drug Administration (FDA) approval, and we attribute this to the approved titration schedule. Although these real-world findings do not negate the risk of DRESS, they offer further support for the approved cenobamate titration schedule. The approved titration schedule for cenobamate was developed based on clinical trial experience, with an intent to lower the risk of DRESS. During early clinical development, three cases of DRESS occurred among the first 953 participants exposed to cenobamate. These early studies used faster titration rates (weekly or faster) and higher starting doses (50 mg/day or greater) than the currently approved cenobamate titration schedule.1 Although our understanding of the immunopathogenesis of DRESS and other severe cutaneous adverse reactions is still evolving, the strategy of lowering starting doses and slowing titration rates has been shown to decrease the occurrence of immune-mediated hypersensitivity reactions with some ASMs.2, 3 A phase 3, open-label safety study evaluated such an approach with cenobamate.1 The target and maximum cenobamate doses (200 and 400 mg, respectively) were maintained, and a lower starting dose (12.5 mg) and slower titration rate (every 2 weeks for 12 weeks) were evaluated.1 In that study, no cases of DRESS were identified in 1339 patients initiating cenobamate using this titration schedule.1 In addition, no cases of DRESS were identified in two long-term, open-label extension studies.4, 5 All reported a consistent cenobamate safety profile. Recently, the FDA required that the manufacturers of select ASMs add new warnings about DRESS to their prescribing information and medication guides. This guidance was based on reports submitted to the FDA Adverse Event Reporting System (FAERS) and a review of the medical literature.6 It is difficult to determine how likely it is that a patient will experience a rare adverse event. Eventually, specific biomarkers may better identify patients at risk for hypersensitivity reactions to ASMs.3 Until this goal is fully realized, a slower titration strategy with a lower starting dose that builds immune tolerance may be of benefit in ASM development and serve as a path forward for the management of other drugs associated with rare reactions such as DRESS. Development of this letter was funded by SK Life Science, Inc. Medical writing and editing assistance were provided by June Stevens, PharmD, and Don Fallon, ELS, of MedVal Scientific Information Services, LLC (Princeton, NJ, USA) and were funded by SK Life Science, Inc. L.F.: Employee, SK Life Science, Inc.; W.E.R.: Consultant/advisor: SK Life Science, Inc.; Speaker: SK Life Science, Inc.; Research support: SK Life Science, Inc., UCB Pharma; M.K.: Former employee and current consultant/advisor, SK Life Science, Inc. 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.

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