Perampanel as a Treatment for Secondarily Generalized Seizures

Trevor Resnick, MD

At the American Epilepsy Society’s (AES) 72^nd Annual Meeting in New Orleans, Louisiana, investigators presented data from Study 307 (NCT00735397) of perampanel. The data showed that participants ≥12 years with secondarily generalized seizures achieved seizure-free status either with perampanel during the 3 preceding phase 3 double-blind studies—304 (NCT00699972), 305 (NCT00699582), or 306 (NCT00700310)—or the open-label extension of Study 307.

The results of Study 307 indicated that patients who were previously seizure free sustained their seizure freedom during the open-label extension study, which further supports the long-term use of perampanel in patients with secondarily generalized seizures.

Eighty participants who received adjunctive perampanel ≤12 mg/day and achieved seizure-free status during one of the previous 3 trials, 94.9% of participants (74/78) remained seizure free for 6 months, 73.1% (57/78) for 12 months, 53.8% (42/78) for 24 months, and 34.9% (22/63) for 36 months. Of the participants treated with perampanel during the open-label extension, 44.6% achieved seizure freedom (202/453) for 6 months, 32% (145/453) for 12 months, 21.4% (96/448) for 24 months, and 13.9% (48/345) for 36 months. Seizure-free rates were similar regardless of prior treatment during the double-blind studies.

Trevor Resnick, MD, pediatric epileptologist at Nicklaus Children’s Hospital, spoke with NeurologyLive at the AES meeting to provide additional insight on perampanel and to discuss the study’s long-term seizure freedom data.

NeurologyLive: What are the main findings of Study 307?

The initial study looking at the effectiveness of perampanel (Fycompa) for secondarily generalized seizures demonstrated a gratifying response in terms of seizure control for that group of patients. In fact, a significant number of those patients were seizure free during the study. The big question was whether they were able to sustain that seizure freedom, and for that reason, there was a post hoc analysis study (Study 307) done looking specifically at that group of patients who had been seizure free during the study. Thankfully those patients who had been seizure free during the study sustained their seizure freedom during the open-label extension study which further supports the use of perampanel in patients with secondarily generalized seizures.

Are any of the results surprising?

No, just gratifying in the fact that the seizure freedom rate was sustained because the question is always asked well it's a relatively short study and secondarily generalized seizures are not that frequent, so how do we know the data is meaningful. I think the fact that it [seizure freedom] was sustained in the open-label extension study for those specific patients was maybe not surprising, but very gratifying.

Are there any side effects that clinicians should know about when prescribing perampanel?

The big issue with perampanel is the boxed warning, which are the behavioral side effects.

I think there are 2 statements to be made with that, the first is that the behavioral side effects are generally dose-related and generally related to the escalation of the drug when you're starting it. It's very important to counsel patients and families that as we're increasing the dose of the medication, especially as you get up to higher doses, that's when you tend to see the behavioral side effects occur and it’s preventable by being cognizant of it and preventable by recognizing it early so you can reduce the dose.

Second, in the more recent studies, it was demonstrated that in new onset epilepsy that perampanel has demonstrated effectiveness even at lower doses of 4 mg. The reason that's important is that if you're using perampanel early as a monotherapy, the fact that it's that effective at 4 mg and 4 mg did not separate from placebo in terms of behavioral side effects, in other words there was no difference in the behavioral side effects at 4 mg comparing to placebo. This sends a message that it works well, demonstrates sustained seizure freedom in generalized seizures and if you use it early, and not in patients with intractable really difficult to control seizures, but early as a choice in the treatment of seizures especially generalized seizures, you can use it at a lower dose and obviate the behavioral side effects.

The commonest cause of breakthrough seizures is non-compliance and because perampanel has such a long half-life, even if patients miss their does the blood level is maintained for a longer period of time so that if they then remember to take the medication, the effect of the blood level is mitigated and not as severe.

What is the clinical impact perampanel has on this patient population?

As far as the clinical impact is concerned, there are a number of different scenarios where that answer is pertinent. Perampanel both for secondarily generalized seizures and primary generalized seizures has a very important impact and we don't have as many antiepileptic drugs that are available for treatment for generalized seizures of that kind and having a drug that is now approved for monotherapy and also improved entire proved in childhood really creates a scenario where we have perampanel available for a far greater number of patients, especially those patients who have secondarily generalized and generalized seizures.

Now in the partial seizure group of secondary generalization perampanel is also effective, but there are more drugs to choose from and even though perampanel is an excellent choice for that group of patients, the list of drugs getting to perampanel is much higher.

REFERENCE

Krauss G, Perucca E, Kwan P, et al. Final safety, tolerability, and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open‐label extension of phase III randomized trials: Study 307. Epilepsia. 2018;59(4):866—876.

doi

: 10.1111/epi.14044.