SEATTLE—Adjunctive perampanel may improve seizure control in patients with idiopathic generalized epilepsy and inadequately controlled primary generalized tonic–clonic seizures, according to study results presented at the 68th Annual Meeting of the American Epilepsy Society. The drug appears to reduce seizure frequency and increase the likelihood of achieving seizure freedom, compared with placebo.
“Perampanel has a novel mechanism of action. It works as an AMPA antagonist,” said Jacqueline A. French, MD, Director of Translational Research and Clinical Trials in Epilepsy at New York University Langone Medical Center in New York City. “This is the first time that a drug with this mechanism has been tried in this seizure type. It is … heartening to see that it worked very well.” Perampanel currently has FDA approval as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy age 12 and older.
Study Included Titration and Maintenance Periods
Dr. French and colleagues enrolled 307 participants in a phase III, double-blind trial to evaluate the safety and efficacy of adjunctive perampanel. Eligible patients were age 12 or older and had primary generalized tonic–clonic seizures and idiopathic generalized epilepsy. Participants with partial-onset seizures, Lennox–Gastaut syndrome, or progressive neurologic disease were excluded from the trial. An independent group reviewed information about patients’ diagnosis and seizure type to ensure that all participants met study criteria. Participants were taking between one and three antiepileptic drugs at the time of enrollment. Lamotrigine, valproic acid, levetiracetam, topiramate, and zonisamide were the most common.
After a four-week screening period and an eight-week baseline period, the investigators randomized 81 patients to perampanel and 82 patients to placebo. At the beginning of a four-week titration period, patients received 2 mg/day of perampanel or placebo. The dose of perampanel was increased by 2 mg per week until it reached 8 mg or the maximum tolerated dose. Finally, participants underwent a 13-week maintenance period on the highest dose that they had achieved during the titration period.
One of the study’s primary end points was percent change from baseline in primary generalized tonic–clonic seizures per 28 days. The other primary end point was the 50% responder rate. Secondary end points were the safety and tolerability of perampanel.
Perampanel Increased the Likelihood of Seizure Freedom
The two treatment groups had similar demographic characteristics and medical histories. The median baseline frequency of primary generalized tonic–clonic seizures per 28 days was 2.6 for the perampanel group and 2.5 for the placebo group. Females accounted for 56% of patients in the placebo group and 57% of patients in the perampanel group. A plurality of all participants (46%) were taking two antiepileptic drugs at baseline, compared with 34% who were taking one antiepileptic drug.
The majority of patients (84%) received 8 mg/day during the maintenance period. Participants receiving perampanel had a 76.5% reduction in the frequency of primary generalized tonic–clonic seizures, compared with a 38.4% reduction in the placebo group. The 50% responder rate was greater for patients receiving perampanel (64.2%) than for patients receiving placebo (39.5%). In addition, 30.9% of the perampanel group was free of primary generalized tonic–clonic seizures for the duration of the maintenance period, compared with 12.3% of the placebo group.
Approximately 83% of patients receiving perampanel and 72% of patients receiving placebo reported treatment-emergent adverse events. Adverse events associated with perampanel included dizziness, fatigue, headache, somnolence, and irritability. Serious adverse events associated with the drug included convulsion, constipation, cholecystitis, status epilepticus, suicide attempt, and suicidal ideation. Perampanel’s side effect profile was consistent with that observed in patients with focal epilepsy. “Those side effects are what is in the package insert already for the drug, so there were no surprises,” said Dr. French.
“This is the first report of a randomized, double-blind, placebo-controlled study of an AMPA receptor antagonist for the treatment of inadequately controlled primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy,” she continued. Only five available drugs are appropriate for this patient population. When treating these people, “we very quickly run out of options and have nowhere to go,” said Dr. French. “The fact that we have another drug to add is going to be welcome in the community.”
—Erik Greb
