Latest Perampanel Results Launch Approval Application

Kate Johnson

September 15, 2011

September 15, 2011 — The experimental epilepsy drug perampanel significantly reduced the frequency of partial-onset seizures as an adjunct therapy in treatment-resistant patients, according to the latest phase 3 results presented at the 2011 International Epilepsy Congress.

With these results, the drug's manufacturer, Eisai Inc, is submitting an application for US Food and Drug Administration (FDA) approval, presenter Jacqueline French, MD, told Medscape Medical News.

Dr. Jacqueline French

"The FDA has already given them some response saying they need to do some different analyses of the trials that they've done, so that's in progress," said Dr. French, who is director of clinical trials at the New York University Comprehensive Epilepsy Center in New York City.

Perampanel is a first-in-class drug with a new mechanism of action that "selectively and non-competitively antagonizes [alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid]-type glutamate receptors," company documents note.

"I think it's got good efficacy with a reasonably low drop-out rate. It doesn't jump head and shoulders above other drugs that are out there, but it's certainly within the high range of the drugs that are out there, and now the thing is to find out what its particular niche is going to be," said Dr. French.

EXPLORE Program

The latest study, known as Study 305, is the last of 3 phase 3 studies in the Examining Perampanel Observations from Research Experience (EXPLORE) clinical trial program. Top-line positive results from the first perampanel trial, known as Study 306, were reported in August 2010. The results of Study 304 were presented in April at the American Academy of Neurology annual meeting and reported by Medscape Medical News at that time.

All 3 studies were designed as global, randomized, double-blind, placebo-controlled, dose-escalation, parallel-group studies.

Study 305 evaluated the safety and efficacy of perampanel in 386 patients with uncontrolled epilepsy who continued to take between 1 and 3 other epilepsy drugs.

Participants from the United States, the European Union, Asia, Australia, and South Africa were assigned to take either 8 mg (n = 129) or 12 mg (n= 121) perampanel or placebo (n = 136) once daily for 19 weeks (6 weeks of titration and 13 weeks of maintenance therapy), in addition to their regular therapy.

For the primary outcome, which was reduction in seizure frequency over the course of 28 days, participants receiving the 12-mg dose had less reduction in seizure frequency (17.6%) compared with patients receiving the 8-mg dose (30.5%). However, both doses resulted in statistically significant responses compared with placebo (P = .0011 and P = .001, respectively), which was associated with a 9.7% reduction in seizure frequency.

Looking at the overall response rate, defined as a reduction of 50% or more in seizure frequency over the course of 28 days, patients receiving either the 8-mg or the 12-mg dose of perampanel showed a statistically significant response rate (33% and 34%, with P values of .002 and < .001, respectively) compared with placebo (15%).

For the secondary endpoint of reduction in complex partial plus secondarily generalized seizures, patients receiving either the 8-mg or the 12-mg dose of perampanel showed a significant response (a 33% and 22% reduction, respectively; P < .001 and P < .01) compared with placebo (a reduction of 8%).

Discontinuations resulting from treatment-emergent adverse events (TEAE) occurred in 4% of the placebo group and 9% and 19% of the 8-mg and 12-mg perampanel groups, respectively.

The most common TEAE was dizziness, occurring in 33% of patients receiving the 8-mg dose and 48% receiving the 12-mg dose compared with 7% of patients receiving placebo. Other common TEAEs included somnolence, fatigue, and headache.

As was reported in Study 304, regional differences were again seen in these new results, but "they were not as marked, and did not impact the overall significance of the study," Dr. French noted. The regional differences in that previous study, attributed by the researchers to possible problems in trial operations in those centers, had been sufficient to confound the results to some degree.

"Healthy Skepticism"

"I look at the latest information as a very promising piece for this agent," said Joseph Sirven, MD, professor of neurology at the Mayo Clinic in Phoenix, Arizona, and editor-in-chief of Epilepsy.com. "The responder rate places it very much in the context of other antiepileptic drugs," he said in an interview with Medscape Medical News.

"This may not be the magic bullet to cure and stop seizures, but what becomes more important, is that this is a first-in-it's class in terms of mechanism of action. If you were to add this agent to perhaps another agent, will that perhaps get us somewhere with a certain population of patients with epilepsy?"

Our fingers remain crossed because ultimately, someone will benefit from this drug, and we want to have as much choice as possible.

He said clinicians are anticipating the expected approval of the drug with "healthy skepticism"; that is, "hopeful that this will be amazing when it goes into real clinical practical, but skeptical about any claims until they've used it."

"I think as long as it still favors a good responder rate with no significant adverse effect profile, I think [the FDA] will go for it," he added.

"Our fingers remain crossed because ultimately, someone will benefit from this drug, and we want to have as much choice as possible, as long as we understand the risk associated with the use of any of these agents."

The study was supported by Eisai Inc, and Dr. French serves as a consultant for the company. Dr. Sirven has received research support from UCB and Neuropace.

2011 International Epilepsy Congress: Abstract 122. Presented August 30, 2011.

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