COMMENTARY

Brivaracetam: A New Epilepsy Drug for 2016

Andrew N. Wilner, MD

Disclosures

October 06, 2016

New Treatment, Familiar Mechanism of Action

On February 19, the US Food and Drug Administration (FDA) approved brivaracetam (Briviact®) for the adjunctive treatment of partial-onset seizures in patients 16 years and older.[1] Brivaracetam is the first antiepileptic drug (AED) for partial seizures approved by the FDA since the 2013 approval of eslicarbazepine (Aptiom®). It joins 16 other AEDs approved since 1993, most with indications for the treatment of partial seizures.

Brivaracetam has a high affinity for selectively binding to synaptic vesicle protein 2A (SV2A), which is the mechanism of action proposed for the familiar AED levetiracetam (Keppra®). SV2A, located in presynaptic membranes, regulates the calcium-dependent exocytosis of neurotransmitters into the synaptic cleft.[2] The AED binding of SV2A decreases the release of excitatory neurotransmitters and controls seizures by resetting the balance from excitation to inhibition. The affinity for its target is 15-30 times greater with brivaracetam than with levetiracetam, resulting in a dose approximately 10 times lower.

In a meta-analysis of six randomized, placebo-controlled, single- or double-blind trials, brivaracetam was administered to 1715 of 2399 participants.[3] The increase in 50% responders (patients with a decrease in seizures from baseline of at least 50%) was nearly twice as high with brivaracetam as with placebo (relative risk [RR], 1.79), and the increase in seizure-free patients was nearly five times as high (RR, 4.74). The most common adverse events were irritability, fatigue, somnolence, and dizziness. The effect of brivaracetam on seizure control was diminished in patients already taking levetiracetam (RR, 0.88) and in those already taking other AEDs (RR, 1.99). This decrease could be related to similarities in the mechanisms of action of brivaracetam and levetiracetam.

New vs Old

Both brivaracetam and levetiracetam have similar chemical structures and mechanisms of action, but their effects have not been compared in head-to-head trials. A meta-analysis and indirect comparison of the two drugs that involved 13 trials suggested that brivaracetam might not be superior to its older congener; the difference in efficacy was not significantly different between the two drugs, and the incidence of dizziness was higher with brivaracetam than levetiracetam.[2]

However, one small (n=29), open-label, prospective study suggested that, in patients who switched from levetiracetam to brivaracetam because of behavioral adverse events, quality of life improved and there was no loss of seizure control.[4] Because it is a new AED, the long-term efficacy and safety of brivaracetam are not known.[5]

Conclusions

A new drug for seizure control is always welcome. Brivaracetam is a second-generation SV2A ligand, modeled on the successful antiseizure drug levetiracetam. As with many new AEDs, it is unclear whether brivaracetam represents a therapeutic advance or simply a viable alternative for patients who do not achieve seizure control or who suffer intolerable effects with other treatments. It is unlikely that double-blind, randomized controlled trials of brivaracetam and levetiracetam will be conducted in the foreseeable future. Given that both drugs have similar mechanisms of action, their combination will probably not be advantageous. As experience with brivaracetam grows, close observation might reveal which patients are more likely to respond to brivaracetam and which are more likely to respond to levetiracetam in terms of efficacy, tolerability, or safety. A differential response could unveil subtle differences in mechanisms of action between brivaracetam and levetiracetam, and offer insight into the pathophysiology of each patient's epilepsy.

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