Abstracts

Rationale: Two adequate and well-controlled studies demonstrated that adjunctive treatment of patients with focal (partial) seizures with cenobamate, an investigational antiepileptic drug, significantly decreased seizure frequency and was associated with high rates of seizure freedom. During early clinical development, among the first 953 patients exposed to cenobamate, three confirmed cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported. Serious cutaneous reactions such as DRESS may be mitigated by slower titration rates. A large open-label safety study was designed to assess whether a titration rate slower than the rates utilized in the early studies would reduce the incidence of DRESS in patients taking cenobamate. Methods: In this ongoing multicenter, open-label study, epilepsy patients 18-70 years old with uncontrolled focal (partial) seizures taking stable doses of 1-3 AEDs were enrolled. Increasing daily doses of cenobamate were administered (12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day) at 2-week intervals. Further increases to 400 mg/day using biweekly increments of 50 mg/day were allowed. Patient visits occurred every 2 weeks for 16 weeks and then every 1-3 months. Serious adverse events were reported in accordance with local regulatory requirements. An in-depth review of all hypersensitivity reactions was performed monthly to screen for DRESS. Although the study is ongoing, new enrollment ended when at least 1000 patients had been exposed to cenobamate for a minimum of 6 months. Results: At the time of study data cut-off, a total of 1348 patients had been enrolled, 1037 patients were exposed to cenobamate for at least 196 days, and 273 patients discontinued therapy. Four deaths have been reported: sudden death with no autopsy, traumatic intracerebral hemorrhage after a fall, fatal injuries after being struck by a car, and respiratory failure in a subject with Angelman syndrome. One hundred and fourteen (8.5%) patients were reported to have a serious adverse event, most commonly hospitalization for seizure. The most common adverse events were somnolence, dizziness, and fatigue. No cases of DRESS were identified. Conclusions: Results to date from this ongoing safety study of cenobamate found no cases of DRESS syndrome. Adverse events most commonly involved the central nervous system. Reduction in starting dose and slowing the titration rate of cenobamate to 2-week intervals appears to mitigate the risk of DRESS. Funding: SK Life Science, Inc.