HONOLULU – Daily adjunctive therapy with the investigational oral drug perampanel significantly reduced the frequency of seizures by 5%-14%, compared with placebo in a multinational phase III clinical trial in 388 patients with hard-to-control epilepsy. Even better results were seen in the approximately half of patients who were in North America in a post hoc analysis.
The frequency of seizures declined by 5% over a 28-day period in patients who were randomized to 8 mg/day of perampanel and by 14% in patients who got 12 mg of perampanel, compared with patients on placebo in an intent-to-treat analysis of all treated patients, Dr. Jacqueline A. French and her associates reported at the annual meeting of the American Academy of Neurology.
Dr. Jacqueline A. French
Patients in the study had uncontrolled epilepsy despite being on one to three other antiseizure drugs, and they continued their usual medications during the trial.
The placebo group saw a 21% decline in the seizure rate, compared with a 26% decline in the 8-mg perampanel group and a 35% decline in the 12-mg group, said Dr. French, professor of neurology at New York University and director of the clinical trials consortium at the university’s comprehensive epilepsy center.
Speaking at a press conference, she also gave results for a separate measure of success preferred by European regulators: the percentage of patients with at least a 50% decline in seizures on the drug. The 50%-responder rate was relatively high in the placebo group at 26% and was 38% in the 8-mg group and 36% in the 12-mg group. These differences were not statistically different among groups.
There was a significant difference in the 50%-responder rates, however, looking at only patients with complex partial seizures and secondarily generalized seizures and ignoring patients with simple partial seizures or seizures that tend to be less disabling, she added. Among these more-severe patients, seizure rates were at least halved in 18% on placebo and by 33% in each of the perampanel arms.
Treatment-related adverse effects were the typical ones expected from antiepileptic drugs, mainly dizziness, drowsiness, irritability, headache, falls, and ataxia. There was a clear dose-response relationship to side effects. "This stuff doesn’t scare us as clinicians," Dr. French said. "In epilepsy, we know how to handle that."
In the 8-mg group, 7% stopped the drug because of side effects, compared with 6% on placebo, which was not significantly different. In the 12-mg group, 17% stopped the drug because of adverse events.
A surprising finding in the double-blind study came from post hoc analyses showing that the results varied significantly depending on the location of the patients, Dr. French said.
About half of patients enrolled in the trial were from the United States and Canada. Seizure frequency rates in those patients declined by only 10% in the placebo group and by 27% with 8-mg perampanel and 39% in the 12-mg group. The differences between the drug groups and placebo were highly significant.
Among non–North American patients in Central and South America, however, the seizure rate in the placebo group fell by approximately 25%, and the drug treatment effect was not statistically different.
"I tend to believe the North American data, but that has to be confirmed," Dr. French said. She speculated that patient selection influenced the regional differences. "In North America, we have EEG monitoring and can confirm that they have epilepsy before we enroll them in trials," which is less likely to happen in some other areas, she said.
Perampanel is a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. Most antiepileptics are channel-acting drugs or work via inhibition, Dr. French noted. "This is the first drug to block the excitatory side," she said.
Dr. Marc Nuwer, professor of neurology at the University of California, Los Angeles, said in an interview that the most exciting thing about perampanel is that it establishes a new category of drugs. "We’re all going to be trying it out" if perampanel gets approved.
Dr. Nuwer did not have a role in the perampanel studies. He said he has no conflicts of interest.
A second phase III trial identical in design to this one is underway to verify the results, Dr. French said. Results are expected to be available in the summer of 2011.
The study’s design was similar to an earlier multinational, randomized, placebo-controlled study of lower doses of perampanel in 712 patients with refractory partial seizures that was reported at the annual meeting of the American Epilepsy Society in 2010. In that study, 19 weeks of adjunctive perampanel therapy significantly reduced the frequency of seizures by 34% in patients randomized to receive a once-daily 8-mg dose and by 29% in patients randomized to a 4-mg dose, compared with a 14% reduction in the placebo group. Patients randomized to a 2-mg dose saw a 16% drop in seizures, which was not significantly different, compared with placebo.