Perampanel Reduces Treatment-Resistant, Partial-Onset Seizures

HONOLULU—Perampanel, in doses of 8 and 12 mg, is an effective and safe add-on therapy for patients with refractory partial-onset seizures, according to the results of a multicountry phase III trial. Jacqueline A. French, MD, Director of the Clinical Trials Consortium at New York University’s Epilepsy Center, presented the findings at the 63rd Annual Meeting of the American Academy of Neurology.

“I’m happy to say that this study was successful,” Dr. French said. “Most of the epilepsy drugs we have available are either channel-acting drugs or have been working on the inhibitory side, increasing gamma-aminobutyric acid. This is the first of the antiepileptic drugs (AEDs) that actually blocks the excitatory side—it’s an AMPA antagonist. And my hope is that perhaps by blocking excess excitation, you might actually have the potential to decrease excitatory damage.”

Dr. French described the results of the Perampanel Phase III Program’s Study 304, which investigated the effects of daily perampanel 8 mg and 12 mg among 308 patients in the United States, Canada, and Central/South America. An identical trial, Study 305, investigated the effects of these dosages among patients in the US, Europe, South Africa, Israel, Russia, India, and Australia; its results will be presented this summer. A previous trial, Study 306, investigated the effects of daily perampanel 2 mg, 4 mg, and 8 mg among 706 patients in European and Asian-Pacific countries, finding that the 4-mg and 8-mg doses were significantly more effective than placebo.

Eisai, Inc (Woodcliff Lake, NJ) plans to ask the FDA and the European Medicines Agency (EMA) to approve perampanel for seizure treatment. “The third study is still necessary to back-analyze before submission,” Dr. French said. “But it’s likely that submission is not going to be delayed for long.”

Perampanel Versus Placebo
The current study was a randomized, double-blind, placebo-controlled, dose-escalation trial of participants who had uncontrolled partial seizures, had received at least two different AEDs previously, had epilepsy for at least two years, and were being treated with stable doses of one to three approved AEDs. Patients underwent a six-week baseline phase and a 19-week double-blind phase that included a six-week titration period and a 13-week maintenance period. For the double-blind phase, 121 patients were randomized to receive placebo, 133 received perampanel 8 mg, and 134 received perampanel 12 mg.

The study’s end point was the percent change in 28-day seizure frequency in baseline versus the double-blind period (titration plus maintenance), which is the FDA-preferred end point for AEDs. Its secondary end points were 50% responder rate, which is the EMA’s preferred end point, and percent change in baseline versus the double-blind period in 28-day frequency of complex partial plus secondarily generalized seizures.

A full intention-to-treat analysis indicated that the placebo group, the 8-mg group, and the 12-mg group had a 20.95%, 26.34%, and 34.5% reduced seizure frequency, respectively. The 50% responder rates in the placebo group, 8-mg group, and 12-mg group were 23.4%, 37.6%, and 36.1%, respectively. When only complex partial plus secondarily generalized seizures were considered, 50% responder rates for the placebo, 8-mg, and 12-mg groups were 17.88%, 33.03%, and 33.06%, respectively.

The drug also showed a favorable safety and tolerability profile, with treatment-emergent adverse events reported by 82.6%, 88.0%, and 91.8% of patients in the placebo, 8-mg, and 12-mg groups, respectively. Adverse events leading to study drug withdrawal were reported by 6.6%, 6.8%, and 19.4% of patients in the placebo, 8-mg, and 12-mg groups, respectively. The most common adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.

Regional Differences in Response
There were very strong regional differences in outcomes, Dr. French noted. Among North American participants alone, the responder rates for the placebo group, the 8-mg group, and the 12-mg group were 10%, 27%, and 39%, respectively. But among non–North American patients alone, the responder rates were 25% in the placebo group and lower than 25% in the treatment groups.

“There was a beautiful dose-response relationship if you look at the North American patients alone. However, if you look at the non–North American patients, the numbers went exactly in the opposite direction,” Dr. French said. “So you either have to believe that the drug, for some pharmacogenomic reason, doesn’t work outside of North America, which would be very unlikely and would not explain the very high placebo responder rate, or you have to believe that in the particular areas outside the US where the study was done, the selection of patients may have compromised the ability to see an effect.” She noted that the drug was effective among the European and Asian-Pacific patients included in Study 306.

“Obviously, we can’t know what the differences are between the North American and the non–North American groups,” Dr. French said. “But we can speculate. And in North America, with EEG monitoring, we can confirm that the patients actually have epilepsy before we enroll them in trials. In other areas, that’s less likely to happen. There may be different background drugs that are contributing to their seizures, etc. I think we have to be very careful about looking at who was involved in the trials so that we can get valid, interpretable data.”

HONOLULU—Perampanel, in doses of 8 and 12 mg, is an effective and safe add-on therapy for patients with refractory partial-onset seizures, according to the results of a multicountry phase III trial. Jacqueline A. French, MD, Director of the Clinical Trials Consortium at New York University’s Epilepsy Center, presented the findings at the 63rd Annual Meeting of the American Academy of Neurology.

“I’m happy to say that this study was successful,” Dr. French said. “Most of the epilepsy drugs we have available are either channel-acting drugs or have been working on the inhibitory side, increasing gamma-aminobutyric acid. This is the first of the antiepileptic drugs (AEDs) that actually blocks the excitatory side—it’s an AMPA antagonist. And my hope is that perhaps by blocking excess excitation, you might actually have the potential to decrease excitatory damage.”

Dr. French described the results of the Perampanel Phase III Program’s Study 304, which investigated the effects of daily perampanel 8 mg and 12 mg among 308 patients in the United States, Canada, and Central/South America. An identical trial, Study 305, investigated the effects of these dosages among patients in the US, Europe, South Africa, Israel, Russia, India, and Australia; its results will be presented this summer. A previous trial, Study 306, investigated the effects of daily perampanel 2 mg, 4 mg, and 8 mg among 706 patients in European and Asian-Pacific countries, finding that the 4-mg and 8-mg doses were significantly more effective than placebo.

Eisai, Inc (Woodcliff Lake, NJ) plans to ask the FDA and the European Medicines Agency (EMA) to approve perampanel for seizure treatment. “The third study is still necessary to back-analyze before submission,” Dr. French said. “But it’s likely that submission is not going to be delayed for long.”

Perampanel Versus Placebo
The current study was a randomized, double-blind, placebo-controlled, dose-escalation trial of participants who had uncontrolled partial seizures, had received at least two different AEDs previously, had epilepsy for at least two years, and were being treated with stable doses of one to three approved AEDs. Patients underwent a six-week baseline phase and a 19-week double-blind phase that included a six-week titration period and a 13-week maintenance period. For the double-blind phase, 121 patients were randomized to receive placebo, 133 received perampanel 8 mg, and 134 received perampanel 12 mg.

The study’s end point was the percent change in 28-day seizure frequency in baseline versus the double-blind period (titration plus maintenance), which is the FDA-preferred end point for AEDs. Its secondary end points were 50% responder rate, which is the EMA’s preferred end point, and percent change in baseline versus the double-blind period in 28-day frequency of complex partial plus secondarily generalized seizures.

A full intention-to-treat analysis indicated that the placebo group, the 8-mg group, and the 12-mg group had a 20.95%, 26.34%, and 34.5% reduced seizure frequency, respectively. The 50% responder rates in the placebo group, 8-mg group, and 12-mg group were 23.4%, 37.6%, and 36.1%, respectively. When only complex partial plus secondarily generalized seizures were considered, 50% responder rates for the placebo, 8-mg, and 12-mg groups were 17.88%, 33.03%, and 33.06%, respectively.

The drug also showed a favorable safety and tolerability profile, with treatment-emergent adverse events reported by 82.6%, 88.0%, and 91.8% of patients in the placebo, 8-mg, and 12-mg groups, respectively. Adverse events leading to study drug withdrawal were reported by 6.6%, 6.8%, and 19.4% of patients in the placebo, 8-mg, and 12-mg groups, respectively. The most common adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.

Regional Differences in Response
There were very strong regional differences in outcomes, Dr. French noted. Among North American participants alone, the responder rates for the placebo group, the 8-mg group, and the 12-mg group were 10%, 27%, and 39%, respectively. But among non–North American patients alone, the responder rates were 25% in the placebo group and lower than 25% in the treatment groups.

“There was a beautiful dose-response relationship if you look at the North American patients alone. However, if you look at the non–North American patients, the numbers went exactly in the opposite direction,” Dr. French said. “So you either have to believe that the drug, for some pharmacogenomic reason, doesn’t work outside of North America, which would be very unlikely and would not explain the very high placebo responder rate, or you have to believe that in the particular areas outside the US where the study was done, the selection of patients may have compromised the ability to see an effect.” She noted that the drug was effective among the European and Asian-Pacific patients included in Study 306.

“Obviously, we can’t know what the differences are between the North American and the non–North American groups,” Dr. French said. “But we can speculate. And in North America, with EEG monitoring, we can confirm that the patients actually have epilepsy before we enroll them in trials. In other areas, that’s less likely to happen. There may be different background drugs that are contributing to their seizures, etc. I think we have to be very careful about looking at who was involved in the trials so that we can get valid, interpretable data.”

HONOLULU—Perampanel, in doses of 8 and 12 mg, is an effective and safe add-on therapy for patients with refractory partial-onset seizures, according to the results of a multicountry phase III trial. Jacqueline A. French, MD, Director of the Clinical Trials Consortium at New York University’s Epilepsy Center, presented the findings at the 63rd Annual Meeting of the American Academy of Neurology.

“I’m happy to say that this study was successful,” Dr. French said. “Most of the epilepsy drugs we have available are either channel-acting drugs or have been working on the inhibitory side, increasing gamma-aminobutyric acid. This is the first of the antiepileptic drugs (AEDs) that actually blocks the excitatory side—it’s an AMPA antagonist. And my hope is that perhaps by blocking excess excitation, you might actually have the potential to decrease excitatory damage.”

Dr. French described the results of the Perampanel Phase III Program’s Study 304, which investigated the effects of daily perampanel 8 mg and 12 mg among 308 patients in the United States, Canada, and Central/South America. An identical trial, Study 305, investigated the effects of these dosages among patients in the US, Europe, South Africa, Israel, Russia, India, and Australia; its results will be presented this summer. A previous trial, Study 306, investigated the effects of daily perampanel 2 mg, 4 mg, and 8 mg among 706 patients in European and Asian-Pacific countries, finding that the 4-mg and 8-mg doses were significantly more effective than placebo.

Eisai, Inc (Woodcliff Lake, NJ) plans to ask the FDA and the European Medicines Agency (EMA) to approve perampanel for seizure treatment. “The third study is still necessary to back-analyze before submission,” Dr. French said. “But it’s likely that submission is not going to be delayed for long.”

Perampanel Versus Placebo
The current study was a randomized, double-blind, placebo-controlled, dose-escalation trial of participants who had uncontrolled partial seizures, had received at least two different AEDs previously, had epilepsy for at least two years, and were being treated with stable doses of one to three approved AEDs. Patients underwent a six-week baseline phase and a 19-week double-blind phase that included a six-week titration period and a 13-week maintenance period. For the double-blind phase, 121 patients were randomized to receive placebo, 133 received perampanel 8 mg, and 134 received perampanel 12 mg.

The study’s end point was the percent change in 28-day seizure frequency in baseline versus the double-blind period (titration plus maintenance), which is the FDA-preferred end point for AEDs. Its secondary end points were 50% responder rate, which is the EMA’s preferred end point, and percent change in baseline versus the double-blind period in 28-day frequency of complex partial plus secondarily generalized seizures.

A full intention-to-treat analysis indicated that the placebo group, the 8-mg group, and the 12-mg group had a 20.95%, 26.34%, and 34.5% reduced seizure frequency, respectively. The 50% responder rates in the placebo group, 8-mg group, and 12-mg group were 23.4%, 37.6%, and 36.1%, respectively. When only complex partial plus secondarily generalized seizures were considered, 50% responder rates for the placebo, 8-mg, and 12-mg groups were 17.88%, 33.03%, and 33.06%, respectively.

The drug also showed a favorable safety and tolerability profile, with treatment-emergent adverse events reported by 82.6%, 88.0%, and 91.8% of patients in the placebo, 8-mg, and 12-mg groups, respectively. Adverse events leading to study drug withdrawal were reported by 6.6%, 6.8%, and 19.4% of patients in the placebo, 8-mg, and 12-mg groups, respectively. The most common adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.

Regional Differences in Response
There were very strong regional differences in outcomes, Dr. French noted. Among North American participants alone, the responder rates for the placebo group, the 8-mg group, and the 12-mg group were 10%, 27%, and 39%, respectively. But among non–North American patients alone, the responder rates were 25% in the placebo group and lower than 25% in the treatment groups.

“There was a beautiful dose-response relationship if you look at the North American patients alone. However, if you look at the non–North American patients, the numbers went exactly in the opposite direction,” Dr. French said. “So you either have to believe that the drug, for some pharmacogenomic reason, doesn’t work outside of North America, which would be very unlikely and would not explain the very high placebo responder rate, or you have to believe that in the particular areas outside the US where the study was done, the selection of patients may have compromised the ability to see an effect.” She noted that the drug was effective among the European and Asian-Pacific patients included in Study 306.

“Obviously, we can’t know what the differences are between the North American and the non–North American groups,” Dr. French said. “But we can speculate. And in North America, with EEG monitoring, we can confirm that the patients actually have epilepsy before we enroll them in trials. In other areas, that’s less likely to happen. There may be different background drugs that are contributing to their seizures, etc. I think we have to be very careful about looking at who was involved in the trials so that we can get valid, interpretable data.”