PHILADELPHIA — Lacosamide, a new antiepileptic drug, showed safety and efficacy in a total of about 1,300 patients when used as an adjunctive agent for patients who failed treatment with one or more of the second-generation antiepileptic drugs, judging from findings from three phase III trials.
“If you look at the efficacy trials for the new antiepileptic drugs [now on the market], such as levetiracetam and lamotri-gine, the patients they were tested on had failed treatment with older drugs, like carbamazepine, phenytoin, and valproic acid. In the lacosamide trials, the patients often failed on the drugs that are more commonly used today, the second-generation drugs,” Dr. Steve S. Chung said while presenting a poster at the annual meeting of the American Epilepsy Society. “Patients who failed on newer drugs [such as oxcarbazepine, levetiracetam, and lamotri-gine] still had a very significant response to lacosamide.”
If lacosamide comes onto the U.S. market, it could be used as a second-line agent for patients who fail one or more newer drugs, said Dr. Chung, director of the epilepsy monitoring unit at the Barrow Neurological Institute, Phoenix. “I don't see using lacosamide as a first-line agent anytime soon,” he added.
Schwarz Pharma AG, a division of UCB SA, which is developing lacosamide (Vimpat), filed a New Drug Application with the Food and Drug Administration last September, and the company expects a decision by the agency by July 2008. Two indications were included in the application: the treatment of partial-onset seizures in adults with epilepsy, and the treatment of neuropathic pain in patients with diabetes. Dr. Chung received research support from and is a speaker for UCB and Schwarz.
The study that he led randomized 405 patients with simple or complex partial seizure to treatment with 400 mg or 600 mg of oral lacosamide or placebo daily. Patients were escalated to their target dosages by 100-mg/day increments weekly during an escalation phase that lasted up to 6 weeks. They were then maintained on treatment with their study medication as well as their background regimen for 12 weeks, when efficacy was assessed.
The most common antiepileptic drugs that the patients were on when they entered the trial were levetiracetam (Keppra) in 40%; lamotrigine (Lamictal) in 36%; carbamazepine (Tegretol), 25%; oxcarbazepine (Trileptal), 21%; phenytoin (Dilantin), 19%; topiramate (Topamax), 18%; and valproic acid (Depakote), 17%. (The total is greater than 100% because many patients were taking more than one drug.)
During maintenance treatment, the 204 patients on the 400-mg/day regimen and the 97 patients on the 600-mg/day regimen had an average drop in their seizure recurrence rate of 36% and 37%, respectively, compared with baseline. The 104 placebo patients had an average 21% reduction in seizures. The difference between the placebo group and each of the drug-treated groups was statistically significant.
Both lacosamide regimens also led to significant boosts in the percentage of patients who had a 50% or greater drop in their seizure frequency.
The magnitude of the drug's effect, compared with placebo, is similar to what had been previously shown for other second-generation antiepileptic drugs, such as levetiracetam and lamotrigine, Dr. Chung said in an interview.
The safety analysis showed that lacosamide treatment, compared with placebo, was associated with an increase in the incidence of certain adverse events, especially during the dose-escalation phase of the study. Most events were mild or moderate in intensity.
The most common adverse event was dizziness, which occurred during the dose-escalation phase in 37% of the patients treated with 400 mg/day and in 43% of those receiving 600 mg/day, compared with a 9% rate in the placebo patients. During the maintenance phase, dizziness was reported by 8% of patients receiving 400 mg/day, by 1% of those getting 600 mg/day, and by 2% of the placebo patients.
Other adverse events during the dose-escalation phase included nausea, diplo-pia, blurred vision, vomiting, headache, and tremor. Each of these occurred in 6%-19% of patients, compared with rates of 1%-7% in the placebo patients.
During the maintenance phase, all of these adverse events occurred in 1%-11% of patients treated with lacosamide, compared with rates of 1%-7% in the placebo patients.
Because the adverse events linked to lacosamide appeared to be greatest during the dose-escalation phase, it may help to introduce the drug more slowly, using 50- mg/day increments instead of 100- mg/day increases, and stretching out the dose-escalation phase for a longer period of time, Dr. Chung said. The target therapeutic dosage should be 400 mg/day because it seemed to have similar efficacy to the higher dosage while causing somewhat fewer adverse events, he said.