BALTIMORE—A slow titration of cenobamate (Xcopri) will likely avoid early discontinuation of the newest drug approved for treatment of partial-onset epileptic seizures, researchers said here at the annual meeting of the American Epilepsy Society.
"Once patients were able to get through the titration phase of treatment with cenobamate in the clinical trials, they didn't have much problem with discontinuation or new adverse events," said William E. Rosenfeld, MD, FAAN, director of the Comprehensive Epilepsy Care Center for Children and Adults in St. Louis, and one of the researchers in the trials.
"Most treatment-emergent adverse events leading to discontinuations occurred during the six-week titration phase of the so-called CO13 and CO17 studies," he said. "We observed that more of these adverse events occurred in the CO17 study, which had a higher dose titration, and it was quickly seen that the titration in the CO17 appeared to be too rapid," he told Neurology Today At the Meetings.
About 100 patients participated in each arm of the studies, and each study had a placebo arm of about 100 patients in each group. The patients, who were about 38-40 years old, =had been diagnosed with epilepsy for at least 20 years. They were experiencing seizures five to 11 times a week depending on the trial arm. More than 80 percent of the patients were taking two or more concomitant medications.
In the trial, concomitant medications could not be changed, but in practice those medication can be altered and that may also reduce adverse events, Dr. Rosenfeld said.
In the CO13 study, which titrated patients every two weeks, 4.4 percent of the patients discontinued the drug due to adverse events and 1.8 percent of the patients experienced serious treatment-emergent adverse events. In the CO17 study, which utilized a weekly titration schedule, 14.6 percent of patients discontinued due to adverse events, and 6.7 percent of patients experienced treatment-emergent adverse events, Dr. Rosenfeld reported.
"Clearly, the two-week titration schedule was better," he said. "And that may be due to the long half-life of the drug, which ranges from about 30 to 70 hours."
The CO13 study involved a six-week titration course and then an eight-week maintenance phase, and a similar titration time but a 12-week maintenance phase was used for the CO17 study. The CO13 study titrated patients to 200 mg of cenobamate; the CO17 study tested 100 mg, 200 mg, and 400 mg dosages of cenobamate.
"About 71 percent of the adverse events leading to discontinuation occurred during the titration period," Dr. Rosenfeld said.
The adverse events that led to discontinuation were mainly somnolence, dizziness and fatigue, the researchers reported.
Dr. Rosenfeld said that about 85 percent of adults with epilepsy are diagnosed with partial-onset of focal seizures, and those are the patients who are the targets for cenobamate therapy.
He said that the company is planning to release cenobamate on even a slower and lower- dose titration, aimed at also preventing a rare rash that was seen about three times in more than 900 cases with the higher dose titration, but not seen in a lower-dose titration.
"The regimen is planned at 12.5 mg for the first two weeks; then 25 mg for the next two weeks; then 50 mg, and then increases by 50 mg intervals," he said. "It will always be on a two-week increment. We expect to see even fewer adverse events with this schedule."
Commenting on the study, Pavel Klein, MD, clinical professor of neurology at George Washington University and director of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, MD, told Neurology Today at the Meetings: "It was observed during the rapid titration in the CO17 study that the main adverse events of somnolence, dizziness and fatigue occurred early in the titration phase, which is not uncommon with these drugs."
Dr. Klein suggested that using the slow titration of cenobamate will give the patients and the physician a better chance of staying on the treatment. He also noted that another study also indicated that an even slower titration regimen would work even better in mitigating adverse events. He said that study, as discussed by Dr. Rosenfeld, involved starting at 12.5 mg and increasing doses every 2 weeks until achieving the level necessary to prevent seizures.
"I believe this is the route to go in the clinic," he said. Dr. Klein, who has done other work with SK Life Science and other companies in the epilepsy arena, did not participate in the current study.
"There is a general feeling among the investigators that another way to reduce adverse events may be to change some of the concomitant medications, especially if they develop adverse events known to be attributed to other drugs. In many cases if may be sufficient to stop these adverse events by reducing the concomitant drugs or maybe also reducing cenobamate," he said.
Dr. Rosenfeld disclosed relevant relationships with SK Life Sciences, UCB, Isaiah, Synovial, Ortho-McNeil, Take, and his research clinic has worked on almost all epileptic drugs in the last 40 years. Dr. Klein disclosed relevant relationships with SK Life Sciences, Lundbeck, UCB Pharma, Eisai, and Sunovion.
Link Up for Related Information
AES Abstract 1.322: Ferrari L, Rosenfeld WE, Kamin M. Cenobamate adverse events by time of onset and dose from two randomized clinical studies in patients with uncontrolled focal seizures.