LOS ANGELES—Adjunctive treatment with an investigational antiepileptic drug (AED) reduces the median frequency of partial-onset seizures, according to trial results presented at the 70th Annual Meeting of the American Academy of Neurology.

“The results with cenobamate demonstrated a decrease in overall median seizure frequencies compared to placebo at all doses studied,” said study principal investigator Gregory Krauss, MD, Professor of Neurology at Johns Hopkins University in Baltimore.

To assess the efficacy, safety, and tolerability of adjunctive cenobamate (previously known as YKP3089) treatment for different types of partial-onset seizures, including simple partial motor seizures, complex partial seizures, and secondary generalized tonic-clonic seizures, investigators conducted an 18-week, randomized, double-blind, placebo-controlled, dose-response study.

After a prospective eight-week baseline period during which researchers documented patients’ seizures, patients were randomized to one of three doses of cenobamate or placebo. The trial included a six-week titration period and a 12-week maintenance phase.

The primary end point was median percent reduction from baseline in seizure frequency for the complete cohort. Researchers also assessed seizure frequency for each seizure type when those seizures were present at baseline.

Seizure Types

In all, 437 patients received 100 mg per day of cenobamate (n = 108), 200 mg per day of cenobamate (n = 110), 400 mg per day of cenobamate (n = 111), or placebo (n = 108). Patients’ average age was about 40, and patients had a median seizure frequency of between 8.4 and 11 seizures per month. Most patients had a history of complex partial seizures (78.9%) or secondary generalized tonic-clonic seizures (60.0%) and were receiving two or three concomitant AEDs.

Median seizure frequencies decreased for all doses of cenobamate (100 mg/day: 35.5%, 200 mg/day: 55.0%, and 400 mg/day: 55.0%), compared with placebo (24.0%). Median frequencies for simple partial seizures decreased with all doses of cenobamate (100 mg/day: 48.0%; 200 mg/day: 63.0%; and 400 mg/day: 58.5%), compared with placebo (7.0%). Median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with 200 mg per day of cenobamate (55.0% and 91.0%, respectively) and 400 mg per day of cenobamate (60.0% and 78.0%, respectively), compared with placebo (28.5% and 33.0%, respectively).

Compared with patients who received placebo, patients who received cenobamate were more likely to have greater than 50% reductions and 100% reductions in seizure frequency, Dr. Krauss said.

Investigators Adjusted Titration

The most common adverse events were somnolence, dizziness, headache, and balance disorder. The percentage of patients with common adverse events increased with dose, and slightly more patients who received 400 mg per day of cenobamate dropped out of the trial, compared with patients who received lower doses, Dr. Krauss said. Some patients with adverse events in the 400 mg group required modest dose reductions, and some adverse events were related to titration, he said.

Two allergic reactions occurred during initial rapid titration of the drug. After rapid dose titration for the first 10% of patients in the trial, doses for the remaining patients were titrated more slowly. One patient in the fast titration group developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Two patients in the trial had the common morbilliform rash without systemic signs—one during fast titration and one during slower titration.

Most adverse events were mild to moderate, and there were no deaths. In all, 37 adverse events occurred in 28 patients, and the number of adverse events was comparable between placebo and cenobamate, Dr. Krauss said. The most common serious adverse events were seizures in four patients, ataxias in two patients, dizziness in two patients, nystagmus in two patients, and suicidal ideation in two patients.

SK Life Science, based in Fair Lawn, New Jersey, is developing cenobamate.

—Jake Remaly

Cenobamate Reduces the Frequency of Partial-Onset Seizures