SAN ANTONIO – Treatment options for epilepsy may soon be expanding in light of the results of several recently reported phase III trials.
Two drugs, including one that has not yet been approved in any country, demonstrated efficacy and safety as adjunctive treatments for different forms of epilepsy. Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist was tested as an add-on therapy for partial onset seizures in the first of three multinational, placebo-controlled trials. Adjunctive therapy with the benzodiazepine derivative clobazam significantly reduced the occurrence of drop seizures in the largest clinical trial to date in patients with Lennox-Gastaut syndrome.
Perampanel
In the Eisai-sponsored study of perampanel, 712 patients aged between 12 and 72 years with refractory partial seizures were randomized to treatment with 2, 4, or 8 mg/day of perampanel or placebo following a 6-week baseline phase. The patients were being treated with 1-3 concomitant antiepileptic drugs, Dr. Gregory L. Krauss reported at the annual meeting of the American Epilepsy Society.
At the end of the 19-week treatment phase, the median change in seizure frequency from baseline for the intention-to-treat population was significant in the 4-mg and 8-mg groups, with reductions of 28.6% and 33.5%, respectively, compared with nonsignificant reductions of 16.3% and 13.8% in the 2-mg and placebo groups, respectively. The treatment phase included 6-week titration and 13-week maintenance periods, according to Dr. Krauss, professor of neurology at Johns Hopkins University in Baltimore.
"The responder rates were similar," he noted, referring to the percentage of patients in each group who experienced at least a 50% reduction in seizure frequency during the maintenance phase relative to baseline. Nearly 29% of the 4-mg group and 35% of the 8-mg group were responders, compared with 21% of the 2-mg group and 17.6% of the placebo group, he said.
Treatment-related adverse events – most often dizziness, somnolence, and headache – caused a low number of patients in each group to withdraw from the trial. The few serious adverse events that occurred also were similarly distributed across the groups, according to Dr. Krauss.
In addition to confirming the safety and efficacy of 4-mg and 8-mg perampanel as an add-on treatment for partial-onset seizures, the findings also "help to establish the range of therapeutic doses and to identify the potential lower dose range for treatment," he said.
Clobazam
The frequency of drop seizures declined significantly for patients with Lennox-Gastaut Syndrome (LGS) who received the highest doses of clobazam in a double-blind, placebo-controlled trial.
"Patients in the 0.5-mg dose group experienced an average decrease of 47.8% and those in the 1.5-mg group had an average decrease of 69.5%," said Dr. Joan Conry of Children’s National Medical Center in Washington.
Dr. Conry said that the drug "is much needed" because the drop attacks experienced by LGS patients often lead to injury.
In the trial, 238 patients aged 2-60 years with clinical and EEG-confirmed LGS who experienced drop seizures during a 4-week baseline phase were randomized to placebo or 0.25 mg, 0.5 mg, or 1.5 mg of clobazam up to a maximum daily dose of 40 mg. Following the treatment period (a 3-week titration phase and a 12-week maintenance phase), the investigators compared the percentage decrease in mean weekly drop seizures during the maintenance phase against the baseline rate for the modified intention-to-treat population of 217 patients.
Patients who experienced 75% and 50% reductions in drop seizures showed significant decreases relative to placebo in the medium and low dosage groups. Seizure frequency was reduced by 75% in 38% of patients who received 0.5 mg and 63% of patients who received 1.5 mg, compared with 11% of placebo-treated patients. Seizure reductions of at least 50% occurred in 59% of the medium dosage group and 78% of the high dosage group, compared with 32% of the placebo patients, she said.
High dosage clobazam patients also had a significant decline in the frequency of nondrop seizures – a secondary study outcome – in comparison with placebo. Physician and caregiver global assessment scores also improved across all three dosages, Dr. Conry stated.
The most frequent adverse events included somnolence, lethargy, upper respiratory tract infections, drooling, and behavioral abnormalities, she noted.
Lundbeck, the manufacturer of clobazam and sponsor of the trial, will likely submit an application to the Food and Drug Administration in the first quarter of 2011, according to Dr. Conry. The drug is already available in more than 100 countries.
Dr. Krauss reported relationships with UCB Pharma, Bristol-Meyers Squibb, Eisai, SK Biosciences, and Johnson & Johnson. Dr. Conry received compensation from Lundbeck for the clobazam study.