The director of the Jefferson Comprehensive Epilepsy Center and the Jefferson Clinical Neurophysiology Laboratory provided insight about the phase 3 safety trial of cenobamate.
Michael Sperling, MD
An ongoing multicenter, open-label safety study of cenobamate has suggested that utilizing a low-dose initiation of the therapy can reduce the incidence of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.1
Presented at the American Epilepsy Society’s 72nd annual meeting, in New Orleans, Louisiana, the study assessed the drug in more than 1000 patients for 6 months. Patients were administered gradually increasing doses of cenobamate 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day at 2-week intervals. Additionally, biweekly increases of 50 mg/day to increase dosage to 400 mg/day were allowed.
To find out more about the trial and its findings thus far, NeurologyLive spoke with lead author Michael Sperling, MD, the director of the Jefferson Comprehensive Epilepsy Center and the Jefferson Clinical Neurophysiology Laboratory.
Michael Sperling, MD: The trial included patients with uncontrolled focal seizures, with no particular minimum seizure frequency required. It was open-label—there was no placebo needed because it was a safety study looking at adverse events and serious adverse events. More patients were actually enrolled than were originally proposed, which I think ensured that there would be a sufficient number of patients treated long-term to adequately assess safety of the drug. Over 1300 people were enrolled in this trial. Patients who had serious concomitant medical illnesses that were not stable were excluded, but this is actually a broader population that you would usually see in a trial because of the lack of a minimum seizure frequency.
Patients with a history of an allergic skin reaction to any drug were excluded from enrolling in this trial. We know that people who have an allergy to one drug are more likely to have allergies to others, so by excluding people with rashes, it reduced the risk of someone having an allergic response and, potentially, a serious allergic reaction as well. But, once the drug gets out into the real world, a question will have to be answered. How will patients who have a history of allergic skin reaction with other drugs fare on this medication?
Patients were followed carefully with laboratory tests and frequent office visits. In the early part of the study, they came in every 2 weeks, and then they had monthly visits. The visits, after a period of time, became less frequent, every three months. Patients were all carefully assessed for drug response and for any adverse events. Patients who had did not have a favorable response to the drug or untoward side effects would not be left on the drug for an extended period of time.
The initial phase 2 studies evaluated close to 1000 individuals with the drug, and the drug demonstrated good efficacy such that the FDA did not require additional efficacy studies. However, 3 individuals in the early studies developed DRESS syndrome, and this had to be evaluated further in the phase 3 trial. The decision was made, after careful consultation with experts, that the rate of titration of drug is critical in determining the incidence of allergic reactions, particularly for a serious idiosyncratic reaction like DRESS syndrome.
In the earlier studies, patients had been started at either 50 mg or 100 mg per day with weekly dose increases. For this Phase 3 study, the decision was made to start with the lower dose of 12.5 mg daily. Patients took that dose for 2 weeks and then increased the dose to 25 mg daily for another 2 weeks. Then, they took 50 mg for another 2 weeks, after which the dose was raised to 100 mg daily. No cases of DRESS syndrome occurred, which was a relief. There were still [adverse] effects, as would happen with any drug, and there were still some patients who had skin reactions, but fortunately, nothing nearly as serious as DRESS.
The implications of this study are that titration rate matters and starting people at the lower dose and gradually increasing it appears to reduce the risk of serious idiosyncratic reaction like DRESS. In my opinion, gradual titration of medication usually enhances drug tolerability. You are less likely to produce a significant [adverse] effect.
Transcript edited for clarity.
1. Sperling M, Klein P, Kamin M. Safety of cenobamate (YKP3089) as adjunctive treatment for uncontrolled partial seizures in a large, multi-center, open-label study. Presented at: American Epilepsy Society Annual Meeting; New Orleans, LA; December 2, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/500991.