Positive Results With Brivaracetam, Perampanel, in Epilepsy

Pauline Anderson

December 08, 2014

SEATTLE, Washington — Clinicians may soon have some new tools in their armamentarium to treat patients with epilepsy who haven't responded to currently available drug therapy.

Results of two separate and positive phase 3 clinical trials — one of a brand-new antiepileptic drug (AED) called brivaracetam (UCB Pharmaceuticals) and the other of a new indication for the already approved medication perampanel (Fycompa, Eisai Inc), were presented here at the American Epilepsy Association (AES) 68th Annual Meeting.

Analogue of Levetiracetam

The first trial was a double-blind, controlled study of the investigational agent brivaracetam in patients with partial-onset seizures who had responded to at least 2 prior epilepsy medications.

Brivaracetam is an analogue of the already available drug levetiracetam, which works by binding to a synaptic vesicle glycoprotein, thereby reducing neurotransmitter release. The new drug "binds to that protein with greater affinity than levetiracetam," explained Pavel Klein, MD, the study's principle investigator and director, Mid-Atlantic Epilepsy & Sleep Center, a private center in Bethesda, Maryland, at a press briefing.

The study, the largest of its kind to date according to Dr Klein, included 764 male and female patients aged 16 to 80 years from centers around the world who were randomly assigned to placebo or to brivaracetam, 100 mg/day or 200 mg/day, while continuing to take one or two other epilepsy medications.

After 12 weeks of treatment, patients were eligible for a 28-day follow-up period to monitor for efficacy and safety. Data from seizure diaries showed that both primary outcomes — reduction in seizure frequency and responder rate (50% or greater reduction in seizure frequency) — were clinically relevant and statistically significant (P < .001) for the two drug dose groups.

The percentage reduction over placebo was 22.8% for 100 mg and 23.2% for 200 mg. The responder rate was 21.6% for placebo, 38.9% for 100 mg of the drug, and 37.8% for 200 mg of the drug.

The secondary outcome of seizure freedom was achieved by 5.2% of patients in the 100-mg group, 4.0% in the 200-mg group, and 0.8% in the placebo group.

The medication was well tolerated and the rate of discontinuation was low for both drug doses. The main adverse effects were "relatively benign" and included somnolence, dizziness, and fatigue, said Dr Klein. "Across the 100-mg and 200-mg doses there wasn't really any significant difference in the efficacy or in the side effects."

Of note, the self-reported rate of irritability with this new drug was 2% for both drug doses vs 1% for placebo, which compares to as much as 10% for levetiracetam in some postmarketing studies.

Irritability and other psychiatric adverse effects, such as depression, anger, and even psychosis have been a "handicap" with levetiracetam, noted Dr Klein. "If brivaracetam turns out to be a friendlier version of levetiracetam, that would be a helpful thing," he said.

It's important to continue to broaden the choices of medication for patients with epilepsy because about a third of them still do not respond despite numerous new drugs being approved over the past 2 decades. "The proportion of patients who continue to not respond to medications has changed relatively little during the period of time that new medications have come onboard," said Dr Klein.

Novel Mechanism

The second study was a randomized, double-blind trial of perampanel (Fycompa, Eisai Inc), already approved for focal seizures, in the treatment of drug-resistant primary generalized tonic-clonic (PGTC) seizures among patients with idiopathic generalized epilepsy.

As an AMPA (a glutamate receptor) antagonist, perampanel has a novel mechanism of action, said the study's principal investigator, Jacqueline French, MD, professor, Neurology, NYU Langone Medical Center, New York.

"So many of the other drugs work on the inhibition side; but this one is suppressing excitatory mechanisms in the brain."

This is the first time that a drug with this mechanism has been tried in patients with PGTC, added Dr French. "We really didn't know if it would work."

Even though patients with primary generalized or idiopathic generalized epilepsy make up about 20% of the adult epilepsy population, only a handful of drugs are appropriate to treat them, including topiramate, lamotrigine, and levetiracetam, said Dr French. Nothing new has been approved to treat these patients "for quite a long time," she said.

"We treat patients with the available options and we very quickly run out of options, and have nowhere to go," she said. For that reason, "having another drug in that armamentarium to me is a very important addition."

The analysis included 162 patients at least 12 years of age from 78 sites in 16 countries who were receiving fixed doses of one to three concomitant AEDs for 30 or more days before baseline. They received up to 8 mg of perampanel per day or placebo.

The study showed that the median percentage change in PGTC seizure frequency over 28 days was greater for patients receiving perampanel than those receiving placebo (–76.5% vs –38.4%; P < .0001). The 50% PGTC responder rate was also higher with the drug than placebo (64.2% vs 39.5%; P = .0019).

"About a third of patients who had very treatment-resistant seizures going into this study had no seizures during the maintenance phase of this study, so it was quite effective for them," commented Dr French.

The drug was effective in both males and females and for all ages (however, for study inclusion, a patient's epilepsy must have started after age 3 years and before age 30 years).

No Surprises

The adverse effect profile was "pretty consistent" with what was seen in patients with focal epilepsy and already included in the product package insert. "There were no surprises," said Dr French.

Treatment-emergent adverse events occurred in 82.7% of the treatment group and 72.0% in the placebo group. Dizziness, fatigue, headache, somnolence, and irritability were the most common adverse effects.

Having another drug to treat generalized tonic-clonic convulsions is all the more important now that these seizures have been "very highly associated" with sudden unexpected death in epilepsy, said Dr French.

This seizure type is difficult to classify, even for neurologists, something that became clear during the study when organizers had to exclude one third of patients being referred by neurologists for the study. "We have to work hard in the community to make sure people understand what this entity is," said Dr French.

She commented that perampanel could be an effective monotherapy although, like all AEDs, it has to be approved as an "add-on."

In her view, the distinction between monotherapy and add-on therapy for epilepsy drugs is "artificial" and "absurd" and doesn't exist for other areas of neurology, said Dr French.

The AES and the International League Against Epilepsy are together assembling a white paper to try to get this distinction removed, she said. "There is no evidence to support that a drug that works when you add it on wouldn't work by itself."

Medscape Medical News invited Timothy Welty, PharmD, professor, pharmacy practice, Drake University, Des Moines, Iowa, to comment on these new phase 3 study results.

Brivaracetam has an advantage over levetiracetam in that it gets into the brain "much more quickly," which means that "it could be used for status epilepticus, or acute seizures that cluster, or prolonged seizures," according to Dr Welty.

However, whether there's a substantial enough difference between these drugs to warrant the new one replacing the older one isn't clear, he said.

"That's my question and I don't think it's been answered," he said.

While brivaracetam may have less risk for psychiatric adverse effects, "you have to weigh whether the additional cost counterbalances that," he said.

As for perampanel, this agent is a "very complex drug" that has a very long half-life and requires adjustments for drug interactions, Dr Welty said. "You have to adhere to a very rigorous titration schedule; if you go outside that, you run into problems."

But probably the biggest drawback to perampanel is that it carries a black box warning about homicidal ideation. "You’re talking not just suicidal ideation, but it's well documented that the drug can lead to homicidal ideation, so you don't want to use it in anyone who has a psychiatric history," stressed Dr Welty. "At best, this is a third- or fourth-line drug."

He and his colleagues typically reserve perampanel for the treatment of adolescents or young adults who have cognitive delay and for severe seizures that have not responded to anything else.

The brivaracetam trial was supported by UCB Pharmaceuticals. Dr Klein has been on advisory boards of Accorda, Esai, UCB, Sunovion, and Lundbeck; has served on the speakers bureau for Esai, Sunovion, and UCB Pharma; and has received research funding for investigator-initiated studies from Lundbeck. The perampanel study was supported by Esai Inc. Dr French is president of the Epilepsy Study Consortium and the NYU Comprehensive Epilepsy Center receives salary support from the consortium; has acted as a consultant for Acorda, Alexza, Bio Pharm Solutions, Biotie Therapies, Brabant Pharma, Eisai Medical Research, Georgia Regents University, GlaxoSmithKline, GW Pharma Ltd, Marinus, Novartis, Pfizer, Pfizer-Neusentis, Sage, SK Life Science, Sunovion, Supernus Pharmaceuticals, Takeda, UCB Inc/Schwarz Pharma, Ultragenyx, Upsher Smith (all consulting is done on behalf of the Epilepsy Study Consortium, and fees are paid to the consortium); has been an investigator for clinical trials funded by Acorda, Alexza, Eisai, Novartis, Supernus Pharmaceuticals, Upsher-Smith, Vertex, and LCGH; has received grants from Eisai, Lundbeck, Pfizer, UCB, the Epilepsy Therapy Project, the Epilepsy Research Foundation, and the Epilepsy Study Consortium.

American Epilepsy Society (AES) 68th Annual Meeting. Poster 2.389, 2.417. Presented December 7, 2014.

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