December 14, 2020
Cenobamate (Xcopri), a new epilepsy drug, is safe and effective up to 1 year, new research shows.
Post hoc analyses from an open-label study showed that seizure frequency was significantly reduced and the seizure-freedom rate was significantly improved among 240 adult participants who received cenobamate. The patients' use of concomitant antiseizure medications (ASMs) was also reduced, with no effect on efficacy.
These results are "fascinating" and "very, very exciting," said lead author William E. Rosenfeld, MD, director, Comprehensive Epilepsy Care Center for Children and Adults, St. Louis, Missouri.
Although responder rates were impressive, at ≥50% and ≥75%, "what patients really want is to have seizure freedom, or at least a 90% reduction in seizures," Rosenfeld told Medscape Medical News.
The findings were presented at the American Epilepsy Society (AES) 74th Annual Meeting 2020, which was held online this year because of the COVID-19 pandemic.
Cenobamate reduces seizures by inhibiting sodium current or affecting the GABA A channel, or potentially through a combination of these two mechanisms, said Rosenfeld.
As reported by Medscape Medical News, the drug was approved by the US Food and Drug Administration in November 2019 for the treatment of uncontrolled partial-onset seizures in adults, which represent about 60% of all epileptic seizures. It has been on the market since May 2020.
During the drug's development, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. This condition typically involves a skin rash, fever, swollen lymph nodes, and characteristic blood abnormalities, including a high level of eosinophils.
However, an open-label study, published earlier this year in Epilepsia, that assessed safety and pharmacokinetics in 1347 patients aged 18 to 70 years who received stable doses of one to three ASMs showed that with "slow and low titration" of cenobamate, there were no case of DRESS, Rosenfeld said.
In that safety study, investigators administered increasing daily doses of cenobamate at 12.5, 25, 50, 100, 150, and 200 mg/d at 2-week intervals. If necessary, the dose could be increased to 400 mg/d via 50-mg/d increments every other week.
The researchers presented post hoc analyses regarding 240 patients from 10 US sites who participated in the safety study. Rosenfeld noted, "These are all good epilepsy centers, and they all kept seizure records."
Of these participants, 177 continued taking the drug as they had at their last visit for a mean of more than 30 months; for some, it was up to 44 months.
"So we had a 73.8% retention rate over the course of the open label, which is the maintenance phase of the study," Rosenfeld said.
Among the entire group of 240 patients, 25.8% had been seizure free for more than 12 months at their last visit. Of the 177 who continued to take cenobamate, 33.9% were seizure free for an average of 23.5 months.
"We have never seen those kinds of numbers in the past," said Rosenfeld, adding, "it's so important for patients to get seizure freedom."
These promising results may be related to the fact that the drug works on more than one mechanism of seizure, he speculated.
For some patients, the drug will "make a big difference" by providing them with the best quality of life and allow them to resume normal activities, Rosenfeld noted.
In addition, the drug was well tolerated. The most common adverse events were dizziness/diplopia and sleepiness/drowsiness.
Concomitant Drug Reductions
Another post hoc analysis of the 240 patients showed that many patients were able to reduce use of other ASMs. At study outset, about 41% were taking lacosamide, 35.7% were taking levetiracetam, and 27.7% were taking lamotrigine.
Among patients who continued to take cenobamate, 22.7% of concomitant baseline ASMs were discontinued. Carbamazepine was discontinued by 31.3%, oxcarbazepine by 26.7%, lacosamide by 23.4%, eslicarbazepine by 23.1%, clobazam by 26.7%, lamotrigine by 14.6%, and levetiracetam by 20.3%.
"We found that the patients who stayed in the study the longest had greater reductions in their concomitant antiepileptic mediation," said Rosenfeld. Lowering concomitant medications did not reduce efficacy at a target dose of 200 mg/d.
The investigators hope to test the drug in children and in patients with different seizure types.
Promising, With Caveats
Commenting on the research for Medscape Medical News, Jong Woo Lee, MD, PhD, associate professor of neurology, the Edward B. Bromfield Epilepsy Program, Brigham and Women's Hospital, Boston, Massachusetts, said cenobamate "has certainly given new hope" to some of his patients.
He noted that a few of these patients had been experiencing daily or nearly daily seizures and had been taking three or more medications for many years.
"The chances of another medication being effective for these patients is very low," said Lee, who was not involved with the research. "But several of these patients responded to cenobamate, and some of them achieved complete seizure freedom."
However, as with all new promising medications, there are some caveats. "The concern is for long-term efficacy for more than 5 years and, of course, unforeseen side effects," Lee said.
The studies were funded by SK Life Science Inc. Rosenfeld has been a consultant for SK Life Science. Lee has disclosed no relevant financial relationships.