CHMP Recommends EU Approval for Brivaracetam

Pauline Anderson

Disclosures

November 20, 2015

The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending marketing approval for brivaracetam (Briviact, UCB Pharma SA) as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization in adult and adolescent patients 16 years of age and older with epilepsy.

Brivaracetam will be available as 10-mg, 25-mg, 50-mg, 75-mg, and 100-mg film-coated tablets; a 10-mg/mL oral solution; and a 10-mg/mL solution for injection/infusion, a statement from EMA today notes.

"The benefits with Briviact are its ability to reduce the frequency of partial-onset seizures in epilepsy patients when added to an existing regimen of antiepileptic medicines," the EMA statement said. "The most common side effects are somnolence, dizziness and fatigue."

Detailed recommendations for the use of this product will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages after the European Commission grants marketing authorization.

Brivaracetam is thought to work by binding to synaptic vesicle glycoprotein 2A, thereby reducing neurotransmitter release.

The CHMP opinion was based on pooled data from three pivotal phase 3 studies in patients with pharmacoresistant partial-onset seizures (POS), UCB Pharma notes in a press release of its own.

One study included 768 patients with pharmacoresistant POS aged 16 to 80 years at 206 sites in countries across North and South America, Europe, and Asia, which made it the largest interventional study of its kind to date. These results were presented at the American Academy of Neurology 67th Annual Meeting and reported by Medscape Medical News at that time.

Participants in that study had to have at least two partial-onset seizures with or without secondary generalization per month during the 3 months before screening and to have at least eight partial-onset seizures during an 8-week baseline period.

Patients were randomly assigned to one of three groups: placebo (n = 263), brivaracetam at 100 mg/day (n = 254), or brivaracetam at 200 mg/day (n = 251).

In addition to the 8 weeks of baseline, the study consisted of 12 weeks of treatment (started at full dose — 100 or 200 mg/day — with no up-titration), followed by a 4-week down-titration period or entry into an open-label follow-up study.

Most patients completed the study and went on to enroll in the extension study. In the placebo group, 93.5% completed the study and 90.1% entered the follow-up study. In the 100-mg group, these percentages were 88.6% and 86.2%; in the 200-mg group, they were 89.6% and 87.6%.

The main reason for discontinuation was adverse events, which affected 3.8% of those in the placebo group, 8.3% in the 100-mg group, and 6.8% in the 200-mg group.

For both doses of the drug, the co-primary efficacy outcomes were statistically significant (P < .001) compared with placebo. The percentage reduction over placebo in the 28-day adjusted POS frequency was 22.8% for the 100-mg group and 23.2% for the 200-mg group.

The other co-primary outcome — a 50% or greater responder rate for POS frequency — is required in Europe for approval. The study showed that this rate was 21.6% for placebo, which according to Dr Klein is "very much in the ballpark" of recent phase 3 studies of other anticonvulsants; 38.9% for the 100-mg group (P < .001); and 37.8% for the 200-mg group (P < .001).

Pooled Data

According to the pooled results of this and the other studies, brivaracetam demonstrated statistically significant reductions over placebo in POS frequency per 28 days (19.5%, 24.4%, and 24.0% for brivaracetam 50, 100, and 200 mg/day, respectively; P < .01), the UCB press release notes.

The proportion of patients showing a 50% or greater reduction in POS frequency was 34.2% (50 mg/day), 39.5% (100 mg/day), and 37.8% (200 mg/day) vs 20.3% for placebo (P < .01 for all groups).

Brivaracetam was generally well tolerated by patients, and the most commonly reported adverse events were somnolence (15.2%), dizziness (11.2%), headache (9.6%), and fatigue (8.7%).

Brivaracetam is also under review in other countries, including the United States, Australia, Canada, and Switzerland.

The agent is an analogue of the antiepileptic drug levetiracetam, which is already available in the United States. But according to one of the study's principal investigators, Pavel Klein, MD, director, Mid-Atlantic Epilepsy & Sleep Center, a private center in Bethesda, Maryland, who presented the large trial at AAN in May 2015, the new drug binds to the synaptic vesicle glycoprotein with greater affinity than does levetiracetam.

Dr Klein told Medscape Medical News at that time that the new agent appears to have a much lower self-reported rate of irritability than the up to 10% for levetiracetam that has been observed in some 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 don't respond despite the approval of numerous new drugs over the past two 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," Dr Klein said.

"This CHMP positive opinion for brivaracetam represents a significant step forward to providing a new treatment option for epilepsy patients who cannot control their seizures with current antiepileptic drugs," said Jean-Christophe Tellier, chief executive officer, UCB, in the company release.

"We look forward to the European Commission's decision and are hopeful that we are able to make brivaracetam available to patients as soon as possible to help improve the lives of those with epilepsy."

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