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Cenobamate Shows Long-Term Benefits for Focal Seizures

Cenobamate leads to sustained, long-term seizure freedom from focal epilepsy in many patients who were refractory to other treatments, according to post-hoc phase 3 findings presented at the 2021 virtual AAN Annual Meeting.

“We know that once two drugs have failed, the likelihood of other drugs working is extremely low," said Michael Sperling, MD, FAAN, professor of neurology at Thomas Jefferson University and lead investigator of the study. “This drug worked in some people who had already failed multiple drugs. So I think it will probably be justifiable to consider using this as drug number three in people with focal epilepsy once we've got some more safety data."

The findings were based on a post-hoc analysis of an open-label, phase 3 study of cenobamate. Phase 2 findings covered just 12 weeks and, as Dr. Sperling noted, “epilepsy is not a 12-week disease."

Cenobamate reduces repetitive neuronal firing by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium current. It also modulates the GABA-A ion channel. It was approved by the FDA in November 2019.

A subset of patients continuing cenobamate after a 12-week titration period were included in the analysis. At baseline, the patients had an average of 18.1 seizures; the median was 2.8 seizures per 28 days.

Researchers found that, at their last visit, 25.8 percent of the 240 patients were free of seizures at 12 months, 35 percent at six months or longer, and 44.6 percent at three months or longer. Thirty-six percent had gone for a period of 12 months or longer with no seizures at one point, Dr. Sperling said.

As part of cenobamate's development program, three participants developed drug reaction eosinophilia and systemic symptoms (DRESS), but no cases have been seen in patients treated with the “start low, go slow" approach that has been adopted since then. Patients start at 12.5 mg a day for the first two weeks and move to 25 mg a day for the next two weeks until reaching 200 mg a day at weeks 11 and 12. During the maintenance phase, up to 400 mg per day was allowed, reached at biweekly increases of 50 mg per day.

The most common treatment-emergent adverse events were fatigue (34.6 percent), dizziness (32.1 percent), and excessive sleepiness (29.6 percent). Dr. Sperling said that most of these issues were transient. Researchers reported that 20.8 percent of participants experienced serious treatment-emergent adverse events.

Patients had responses across all seizure types: 88.5 percent of those with focal aware motor seizures had at least a 50 percent seizure reduction and 23.1 percent had a 100 percent reduction; 77.9 percent of those with focal impaired awareness seizures had at least a 50 percent response rate, and 19.1 percent had a 100 percent reduction; and 85.4 percent of those with focal to bilateral tonic-clonic seizures had a reduction of at least 50 percent, with 35.4 percent having a 100 percent reduction.

Dr. Sperling said the drug could potentially alter the way surgery is considered in epilepsy patients.

“Should we make sure a patient's had the chance to try this drug before we operate on them?" he asked. “It's one of the things we'll have to think about for the future."

Shawniqua Williams Roberson, MEng, MD, assistant professor of neurology at Vanderbilt University Medical Center, said that “the idea that such a robust percentage of patients with refractory epilepsy can go from a median of two to three seizures per month to complete seizure freedom for over a year is quite encouraging."

Dr. Williams Roberson, whose division chief is one of the study authors, said she wondered what drove the study withdrawals and the loss to follow-up and what clinical characteristics might serve as predictors of success or of intolerable adverse effects.

“This would help to more precisely target the patient population that would be most likely to benefit from this medication," she said.

Alexis Boro, MD, coordinator of the epilepsy surgery program at Montefiore Medical Center and principal investigator of one of the cenobamate trial sites, said the high rates of seizure freedom are welcome.

“They tend to confirm what was seen in previous blinded trials with this drug—these results are unusual in that seizure-freedom rates like this are not expected with medical management alone in the medically refractory patients," he said. “Cenobamate is an important addition to the neurologist's toolbox."

But he said cenobamate is “not the easiest drug to use" due to remaining concerns about DRESS, the need for meticulous screening for a history of cutaneous drug reactions, and the slow titration that is necessary.

“Sedation is often an issue as the dose is increased. Interactions with other antiseizure medications are often an issue and can complicate dose titration further. In some patients, the option of a trial of cenobamate can make decision-making more complex," he said. “Which patients should undergo a trial of cenobamate versus referral for a palliative implanted device such as responsive neurostimulation? But this is a welcome complication. This is an exciting time in epilepsy."

Dr. Sperling has received personal compensation for serving on a speakers bureau for Eisai and Medscape. Dr. Williams Roberson has no disclosures.

Link Up for More Information

AAN Abstract S1.002: Sperling MR, Abou-Khalil B, Aboumatar S, et al. Efficacy of cenobamate for uncontrolled focal seizures: Post-hoc analysis of a phase 3, multicenter, open-label study.

Neurology Today Video. Cenobamate Shows Long-Term Benefits for Focal Seizures.