Antiepileptic shows efficacy in refractory disease.

PHILADELPHIA -- Carisbamate, a new antiepileptic drug, showed safety and efficacy in a phase II study with more than 500 epilepsy 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, Dr. R. Edward Faught Jr. said while presenting a poster at the annual meeting of the American Epilepsy Society.

Based in part on these results, 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 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 antiepileptic drugs.

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 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, 300, 800, and 1,600 mg/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 dosage for 12 weeks, after which their response rate was assessed.

The three highest carisbamate dosages all led to significant reductions in seizure frequency, compared with 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 their 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 of these rates 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.

Based on the safety and efficacy results, a 300-mg/day dosage of carisbamate appears to be optimal, concluded the investigators. The study was sponsored by Johnson & Johnson, which is developing the drug. Dr. Faught has received research support and honoraria from Johnson & Johnson for consulting and speaking.

BY MITCHEL L. ZOLER

Philadelphia Bureau

Patients With Epilepsy Who Had At Least a 50% Reduction In Seizure Rate

Carisbamate dosage

100 mg/day          12%
300 mg/day          24%
800 mg/day          19%
1,600 mg/day        25%
Placebo             10%

Note: Based on a 20-week randomized study of 537 8- to 70-year-olds.
Source: Dr. Faught
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Note: Table made from bar graph.