A recent published letter affirmed the safety of cenobamate, an FDA-approved antiseizure medication, in a large global patient population.
Louis Ferrari, RPh, MBA
Credit: SK Life Science
In a recent update published as a letter in Epilepsia, real-world data on cenobamate (Xcopri; SK Life Science), an FDA-approved antiseizure medication (ASM), showed no reported cases of drug reaction with eosinophilia and systemic symptoms (DRESS) in over 100,000 patients with epilepsy globally at almost 4 years.1,2 These results provide clinicians with information on the safety of this therapy in a global setting who have been treated with the drug over an extended period of time using the approved cenobamate titration schedule.
The letter addressed that the approved cenobamate titration schedule was created with the intention of reducing the risk of DRESS among patients on the treatment and was developed according to results observed in clinical trials. In early clinical development, authors noted that 3 cases of DRESS were reported among the first 953 participants treated with cenobamate. Notably, these prior studies had faster titration rates and a higher starting dose than the current approved cenobamate titration schedule.3
"Because clinical trials are conducted under very controlled conditions, real-world data shows us how cenobamate has been utilized in the general epilepsy population," lead author Louis Ferrari, RPh, MBA, vice president of medical affairs at SK Life Science, told NeurologyLive®."Reaching this 100K patient milestone shows the product has been well adopted by healthcare providers for the treatment of epilepsy in the U.S. and around the world, specifically in European Union, the UK, Switzerland, Israel, and Canada. It allows us to look at the safety of cenobamate when the titration schedule is followed." In the letter, Ferrari and colleagues acknowledged that understanding of the immunopathogenesis of DRESS and other severe cutaneous adverse reactions is consistently evolving.
In the phase 3 open-label Study C021 (NCT02535091) study, investigators used the strategy of lowering starting doses and slowing titration rates to decrease the occurrence of immune-mediated hypersensitivity reactions with some ASMs.3 In the study, the target (200 mg) and maximum doses (400 mg) of cenobamate were maintained, and researchers evaluated a lower starting dose (12.5 mg) as well as slower titration rate every 2 weeks for 12 weeks. Findings showed no cases of DRESS among 1339 patients who initiated cenobamate using the titration schedule. Additionally, no cases of DRESS occurred in 2 long-term, open-label extension studies.4,5 In the letter, authors noted that all of these studies reported a consistent safety profile with cenobamate use in participants.
In recent news, the FDA has required manufacturers of select ASMs to add new warnings about DRESS to prescribing information and medication guides. This decision was based on reports submitted to the FDA Adverse Event Reporting System and a review of medical literature.6 Ferrari and colleagues noted in the letter that there is difficulty in determining how likely a patient will have a rare adverse event with a treatment, but specific biomarkers could play a role in better identifying patients at risk for hypersensitivity reactions to ASMs. Thus, authors noted that a slower titration strategy with a lower starting dose that builds immune tolerance could benefit ASM development and serve as a path forward for managing of other therapies associated with rare reactions such as DRESS.
Presented at the 2023 American Epilepsy Society (AES) annual meeting, held December 1-5, in Orlando, Florida, pharmacokinetic (PK) and pharmacodynamic (PD) data from a post-hoc analysis of Study C021 showed that adjustments of concomitant ASM should be performed earlier in the treatment with cenobamate.7 In the analysis, investigators examined the dose adjustments of concomitant ASMs of patients with uncontrolled focal seizures on cenobamate. For context, increased doses of cenobamate (12.5, 25, 50, 100, 150, and 200 mg/day) were administered biweekly in Study C021. Additional increases for patients were allowed to 400 mg/day in biweekly 50-mg/day increments as well as adjustments to concomitant ASMs.
Among 1340 patients included, CYP2C19 substrates clobazam (Onfi; Lundbeck), phenytoin, and phenobarbital had pharmacokinetic interactions with cenobamate that led to increased plasma exposure and early dose reductions. At week 52 of the study, the total clobazam dose was reduced by a mean of 30.9% and the total daily dose of lacosamide (Vimpat; UCB) decreased by 21.7% by the fourteenth visit. As the investigators gained more experience, it was noted that these dose reductions were made earlier and more proactively, which reflected current consensus recommendations.
