Perampanel Showing Benefit in Treatment-Resistant Epilepsy

Allison Shelley

December 14, 2011

December 14, 2011 (Baltimore, Maryland) — New evidence from a phase 3 study of perampanel (E2007, Eisai) demonstrates that the new first-in-class drug reduces seizure frequency in even the most clinically severe cases.

"I have one patient who is seizure-free for the first time and just got a driver's license," lead investigator Bernhard Steinhoff, MD, from Kork Epilepsy Center in Germany, told Medscape Medical News. "It's almost a miracle."

Although Dr. Steinhoff acknowledges cases like this are not typical, he says that for some patients, the new option will be important.

Most epilepsy drugs target channel activity, but this agent uses a different approach and focuses instead on excitatory damage.

New subgroup analyses, presented here at the American Epilepsy Society (AES) 65th Annual Meeting, were featured at a clinical pharmacology platform session, and again in a poster presentation.

Perampanel is a highly selective, noncompetitive antagonist for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. It is currently being evaluated by the US Food and Drug Administration and the European Medicines Agency.

Dr. Steinhoff says he anticipates that perampanel will be available in Europe next year, and in the United States after that.

EXPLORE Clinical Trial Program

The new agent has already been evaluated in 3 clinical trials (studies 304, 305, and 306), all of which were part of the Examining Perampanel Observations from Research Experience (EXPLORE) program and previously reported by Medscape Medical News.

These new results use 2 subgroups of patients in study 305 with treatment-resistant epilepsy, including complex partial and secondary generalized seizures. The analysis includes 389 patients with uncontrolled epilepsy who continue to take between 1 and 3 other drugs.

The investigators report that their findings in treatment-resistant patients were consistent with previous efficacy findings for perampanel. Improvements were found even in patients with complex partial and secondary generalized seizures.

Table 1. Change in Complex Partial and Secondary Generalized Seizures

Outcome Placebo (n = 126) Perampanel 8 mg (n = 119) Perampanel 12 mg (n = 113)
Median change in seizure frequency (%) −8.1 −32.7 −21.9
Responder rate (%) 16.7 37.8 33.6

Improvements in seizure control observed using the actual last dose were also consistent with those seen in the randomized dose analysis.

Table 2. Median Change After Actual Last Perampanel Dose

Outcome Placebo (n = 111) 2 mg (n = 1) 4 mg (n = 3) 6 mg (n = 17) 8 mg (n = 91) 10 mg (n = 9) 12 mg (n = 64)
Median change in seizure frequency (%) −9.5 22.4 −31.8 −47.1 −31.8 −26.5 −14.8
Responder rate (%) 16.2 0 0 41.2 39.6 33.3 34.4

Analyses of both randomized dose groups and actual last dose of perampanel showed that once-daily perampanel 8 mg and 12 mg were both effective in complex partial and secondary generalized seizures.

Table 3. Change From Baseline per 28 Days

Outcome Placebo (n = 111) Perampanel 8 mg (n = 91) Perampanel 12 mg (n = 64)
Median change in seizure frequency (%) −9.5 −31.8 −14.8

Table 4. ≥50% Response per 28 Days by Last Actual Dose

Outcome Placebo (n = 111) Perampanel 8 mg (n = 91) Perampanel 12 mg (n = 64)
Responder rate (%) 16.2 39.6 34.4

At the 2011 International Epilepsy Congress in September, where the complete trial results for study 305 were reported, presenter Jacqueline French, MD, director of clinical trials at the New York University Comprehensive Epilepsy Center, said, "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."

Dr. Steinhoff told Medscape Medical News that perampanel's-once daily administration makes it an excellent add-on.

At the American Academy of Neurology 63rd Annual Meeting in April, many neurologists also expressed excitement about this novel compound. "Perampanel is approaching epilepsy from a new direction, and I think this will help open the door to other agents as well," said Joseph Sirven, MD, from the Mayo Clinic in Scottsdale, Arizona.

Marc Nuwer, MD, from the University of California, Los Angeles, said he agrees. "I'm really happy to see a new category of drugs. We've had a dozen new agents emerge over the last 20 years, but many of them have been slight tinkerings of already-established drugs. This is actually a new category and a step forward."

This study was supported by Eisai Neuroscience. Some of the authors are employees of the company.

American Epilepsy Society (AES) 65th Annual Meeting: Platform B.03. Presented December 5, 2011.

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