PHILADELPHIA — Carisbamate, a new antiepileptic drug, showed safety and efficacy in a phase II study with more than 500 patients.
Carisbamate's ability to cut seizure frequency and boost the response rate, compared with placebo, was notable because the study involved very refractory patients with a history of numerous partial seizures at entry, despite ongoing treatment with as many as three antiepileptic drugs, said Dr. R. Edward Faught Jr. in a poster presentation at the annual meeting of the American Epilepsy Society.
Carisbamate will be assessed in a phase III study for preventing seizures in patients with epilepsy. The drug is also undergoing testing in additional phase III studies in patients with diabetic peripheral neuropathy, essential tremor, and postherpetic neuralgia. The drug's mechanisms of action for all of these indications are not known.
The phase II seizure study enrolled patients aged 8–70 years who had been diagnosed with epilepsy for at least 1 year, had an established pattern of at least three partial-onset seizures per month, and had failed treatment with at least three drugs. At enrollment, patients had to be on treatment with one to three antiepileptic drugs at stable dosages for at least 4 weeks.
The patients who actually entered the study had a history of epilepsy for an average of 19–25 years, and experienced an average of 9–11 seizures per month. About 15% were treated with antiepileptic monotherapy, about 50% were on two drugs, and about 35% were on three drugs. Nearly half of the patients had been treated with seven or more different antiepileptic drugs during the course of their illness.
About 100 patients were randomized to receive each of four carisbamate regimens or placebo, with a total enrollment of 537 patients. The carisbamate dosages tested were 100 mg, 300 mg, 800 mg, and 1,600 mg per day.
Following a baseline observation phase of 4 weeks, patients underwent a dose-escalation phase of 4 weeks until they reached their target dosage. They remained on a stable dose for 12 weeks, when their response rate was assessed.
The three highest carisbamate dosages all led to significant reductions in seizure frequency, versus placebo. The reductions in these groups were 21%-29%, compared with a 6% drop in seizure frequency in the placebo patients, reported Dr. Faught, director of the epilepsy center at the University of Alabama, Birmingham. Patients in the 100 mg/day group had an average 15% cut in seizure frequency, but this was not significantly different from the placebo group.
The percentage of responding patients (those with at least a 50% decrease in their seizure rate) was 24% in the 300 mg/day group and 25% in the 1,600 mg/day group. Both rates of lessening seizure frequency were significantly higher than the 10% rate among placebo patients. The prevalence of responders was 12% in the 100 mg/day group and 19% in the 800 mg/day group; neither was significantly higher than that of placebo.
The incidence of adverse events was similar to placebo in the three lowest carisbamate dosage groups. Patients on the 1,600 mg/day dosage had significantly more adverse events, compared with placebo patients. The most frequent adverse events were headache, somnolence, nasopharyngitis, and nausea. Adverse events led to study discontinuation in 8% of the placebo patients, and in 5%-12% of patients in the three lowest-dosage carisbamate groups. (The discontinuation rate was 19% in the highest-dosage group.) The rate of serious adverse events was similar in the placebo and carisbamate groups. Clinically significant elevation of liver enzymes (at least three times the upper limit of normal) occurred in one patient on the 800 mg/day dosage and in three patients on the 1,600 mg/day dosage; enzyme levels normalized in all four patients once treatment stopped.
A 300 mg/day dosage of carisbamate appears optimal. The study was sponsored by Johnson & Johnson, which is developing the drug. Dr. Faught has received research support and honoraria from Johnson & Johnson.