Newly Approved Epilepsy Drug Significantly Cuts Seizure Frequency

BALTIMORE ― Adjunctive cenobamate (SK Life Science Inc) may help reduce the frequency of seizures for patients with focal epilepsy, regardless of the number of antiseizure medicines patients take or the severity or duration of their illness.

The new analysis of almost 400 patients showed that, depending on the dose, "This is one of the most promising antiepileptic drugs that we've ever seen," study investigator William Rosenfeld, MD, director of the Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Missouri, and a consultant for SK Science, told Medscape Medical News.

"The number of patients who became seizure free is in the 20% range, and this has been persistent throughout the studies," Rosenfeld added.

The findings were presented here at the American Epilepsy Society (AES) 73rd Annual Meeting 2019.

Highly Intractable Population

As reported by Medscape Medical News, cenobamate was recently approved by the US Food and Drug Administration (FDA) following the release of results from a number of safety, pharmacokinetics, and efficacy trials.

Previous results from a double-blind, placebo-controlled, dose-response study showed that cenobamate at doses of 100, 200, and 400 mg was effective for the treatment of focal seizures.

In the current post hoc analysis, the investigators assessed the effects of different baseline features, including the number of concomitant antiepileptic drugs (AEDs), baseline seizure frequency, and disease duration.

The analysis included 397 adult patients aged 18 to 70 years. The study population consisted of "very intractable patients," said Rosenfeld.

"All subjects had to have at least four seizures per month, but they averaged about 9.5 seizures per month. Their epilepsy also had to be intractable for at least 2 years, but they actually averaged 23 years of intractability," he added.

Approximately 80% of participants were taking two or three other AEDs, and some were taking many more, said Rosenfeld.

Patients were randomly assigned to receive placebo or 100, 200, or 400 mg of cenobamate daily. The study included a 6-week titration phase followed by a 12-week maintenance phase.

Seizure Freedom

Results showed that about 20% of the participants experienced freedom from seizures, said Rosenfeld.

Achieving freedom from seizures can make a huge difference in a patient's day-to-day quality of life, he noted.

"I'm excited about how cenobamate can impact the lives of patients who struggle with epilepsy," he said. There was also "a nice dose response," said Rosenfeld. "Those most likely to get the best success were in the 200- and 400-mg groups."

The analysis also showed that the number of concomitant AEDs made little difference to seizure frequency outcome.

In patients who were taking one AED at baseline, the median reduction in seizure frequency was 24.1% for placebo and 44.7%, 57.6%, and 86.0% for cenobamate at 100, 200, and 400 mg/day, respectively.

For patients taking two AEDs, the median frequency of seizures was reduced by 33.3% in the placebo group vs 41.4% (100 mg), 57.9% (200 mg), and 57.0% (400 mg).

Results for those taking three AEDs were 26.4% for placebo vs 41.5% (100 mg), 49.3% (200 mg) and 67.4% (400 mg).

"Patients in all groups did well, and the amazing part was that whether they were on one, two, or three concomitant antiepileptic drugs, they had an excellent response," said Rosenfeld.

The data were not categorized with respect to individual medications. Researchers plan to evaluate this in the future, he noted.

Clinically Relevant Reduction

At 65.5%, the greatest median percent reduction in seizure frequency for patients with 9.5 fewer seizures or less per month was in the 200-mg cenobamate group. At 70.7%, the greatest reduction for those with 9.5 or more seizures per month was in the 400-mg cenobamate group.

"The patients with fewer than 9.5 seizures did slightly better, so they may only need 200 mg, as opposed to those with lots of seizures, who might need 400 mg," Rosenfeld said.

In addition, the drug's efficacy was not affected by disease duration. For patients who had had focal epilepsy for less than 23 years, reduction in seizure frequency was similar to those of patients who had had the disorder for more than 23 years.

"Clinically relevant reductions in seizure frequency occurred with adjunctive cenobamate regardless of the baseline number of AEDs, seizure frequency, or disease duration," Rosenfeld said.

Adverse events (AEs) included dizziness, somnolence, fatigue, diplopia, and headaches. However, because the drug was administered as an adjunctive treatment with other AEDs, these side effects were "not unexpected," said Rosenfeld.

In a later open-label study, researchers were able to reduce the dose of other AEDs, so "the potential for side effects was lower," he added.

In addition, there were few mood-related AEs, including irritability, moodiness, or cognitive side effects, Rosenfeld reported.

Although a few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) were reported among patients for whom the drug was rapidly titrated, there were no cases among the 1339 patients in the open-label trial whose treatment started with a low dose (12.5 mg/day) and was titrated slowly (every 2 weeks).

Researchers are now testing the drug in patients with primary generalized clonic-tonic seizures and may conduct future studies of the drug in children.

Impressive Efficacy

Commenting on the study for Medscape Medical News, Elizabeth Thiele, MD, PhD, professor of neurology, Harvard Medical School, and director of the Pediatric Epilepsy Program, Massachusetts General Hospital, Boston, Massachusetts, said she's "excited" about this new drug.

"The efficacy in the trials is very impressive," said Thiele, who was not involved with the research.

She noted that another drug, felbamate, which is in same drug class, came on the market in the 1990s. Although that drug is very effective, it is associated with "significant toxicity."

"We still use a lot of felbamate, but this new drug is an improvement on the structure, and hopefully it will prove to be very efficacious" in clinical practice, Thiele said.

Even with the recent FDA approval of cannabidiol and possibly fenfluramine, in the near future "there is still going to be an unmet need for safe and well-tolerated medications, and at least in this trial data, cenobamate looks really exciting," Thiele said.

The study was funded by SK Life Science Inc. Rosenfeld is a consultant for SK Life Science and was previously a consultant for other companies, including Eisai, Greenwich, Sunovian, and UCB. Thiele is a consultant for GW Pharmaceuticals, Zogenix, West Therapeutics, Biocodex, and Aquestive Therapeutics.

American Epilepsy Society (AES) 73rd Annual Meeting 2019: Abstract 1.295. Presented December 7, 2019.

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Cite this: Newly Approved Epilepsy Drug Significantly Cuts Seizure Frequency - Medscape - Dec 09, 2019.