New Treatment for Partial-Onset Seizures Gets FDA Approval

The Food and Drug Administration (FDA) has approved Xcopri (cenobamate; SK Life Science) for the treatment of partial-onset seizures in adult patients.

Although its exact mechanism in the treatment of partial-onset seizures is unknown, cenobamate has been shown to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the γ-aminobutyric acid (GABA_A) ion channel.

The approval of Xcopri was based on 2 double-blind, placebo-controlled studies in adult patients with partial-onset seizures with or without secondary generalization who were not adequately controlled with 1 to 3 concomitant antiepileptic drugs. Patients in these studies had a mean duration of epilepsy of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days.

In Study 1, Xcopri 200mg/day was compared with placebo, while in Study 2, three doses of Xcopri (100mg/day, 200mg/day, and 400mg/day) were investigated. Both studies had an 8-week period to establish a baseline seizure frequency, after which patients were randomized to a treatment arm. Patients entered a treatment period consisting of an initial titration phase (6 weeks), and a subsequent maintenance phase (6 weeks for Study 1 and 12 weeks for Study 2). The primary end point of both studies was the percent change from baseline in seizure frequency per 28 days. 

In Study 1, the median percent change from baseline in seizure frequency per 28 days was -55.6% for Xcopri 200mg/day vs -21.5% for placebo (P <.0001). In Study 2, the median percent change was -36.3% (P =.006), -55.2% (P <.001), and -55.3% (P <.001) for Xcopri 100mg/day, 200mg/day, and 300mg/day, respectively, compared with -24.3% for placebo. 

With regard to safety, the most common adverse reactions reported during clinical trials included somnolence, dizziness, fatigue, diplopia, and headache. Xcopri has been linked to drug reaction with eosinophilia and systemic symptoms (DRESS), including 1 fatality when treatment was titrated rapidly (weekly or faster titration). In addition, compared with placebo, a higher percentage of patients treated with Xcopri experienced QT shortening of >20msec, therefore treatment is contraindicated in patients with familial short QT syndrome. 

“Xcopri is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”

Xcopri is expected to be available in 6 tablet presentations (12.5mg, 25mg, 50mg, 100mg, 150mg, and 200mg) in the second quarter of 2020 pending scheduling review by the Drug Enforcement Administration. In a human abuse potential study conducted in recreational sedative abusers (N=39), single doses of Xcopri 400mg produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were statistically greater than the responses produced by placebo. In this study, euphoric mood occurred at greater extent with Xcopri 400 mg (8%) than with placebo (0%).

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