Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy

Abstract

One third of patients with epilepsy will continue to have uncontrolled seizures despite treatment with antiseizure medications (ASMs). There is therefore a need to develop novel ASMs. Brivaracetam (BRV) is an ASM that was developed in a major drug discovery program aimed at identifying selective, high-affinity synaptic vesicle protein 2A (SV2A) ligands, the target molecule of levetiracetam. BRV binds to SV2A with 15- to 30-fold higher affinity and greater selectivity than levetiracetam. BRV has broad-spectrum antiseizure activity in animal models of epilepsy, a favorable pharmacokinetic profile, few clinically relevant drug-drug interactions, and rapid brain penetration. BRV is available in oral and intravenous formulations and can be initiated at target dose without titration. Efficacy and safety of adjunctive BRV (50-200 mg/day) treatment of focal-onset seizures was demonstrated in three pivotal phase III trials (NCT00490035/NCT00464269/NCT01261325), including in patients who had previously failed levetiracetam. Efficacy and safety of adjunctive BRV were also demonstrated in adult Asian patients with focal-onset seizures (NCT03083665). In several open-label trials (NCT00150800/NCT00175916/NCT01339559), long-term safety and tolerability of adjunctive BRV was established, with efficacy maintained for up to 14 years, with high retention rates. Evidence from daily clinical practice highlights BRV effectiveness and tolerability in specific epilepsy patient populations with high unmet needs: the elderly (≥ 65 years of age), children (< 16 years of age), patients with cognitive impairment, patients with psychiatric comorbid conditions, and patients with acquired epilepsy of specific etiologies (post-stroke epilepsy/brain tumor related epilepsy/traumatic brain injury-related epilepsy). Here, we review the preclinical profile and clinical benefits of BRV from pivotal trials and recently published evidence from daily clinical practice.

Keywords: Antiseizure medication; Comorbidities; Drug-drug interactions; Effectiveness; Elderly; Fast response; Focal-onset seizures; Real-world evidence; SV2A; Tolerability.

Fig. 1

Mechanism of action of clinically approved ASMs. Drugs marked with asterisks indicate that these compounds act by multiple mechanisms (not all mechanisms shown here). AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ASM antiseizure medication, GABA gamma-aminobutyric acid, GABA-T GABA aminotransferase, GAT GABA transporter, KCNQ a family of voltage-gated potassium channels (also known as the Kv7 family), NMDA N-methyl-D-aspartate, SV2A synaptic vesicle protein 2A. Reproduced with small modifications from Fig. 1 of Löscher et al. [69], licensed under CC BY-NC 4.0

Fig. 2

Overview of drug discovery efforts at UCB based on modulation of the pyrrolidone-acetamide scaffold (a), properties of BRV and LEV (b), and proposed mechanism of action of BRV and LEV (C). AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, BRV brivaracetam, GABA gamma-aminobutyric acid, GAD 65 glutamate decarboxylase 65, HVA high-voltage-activated, IC₅₀ inhibitory half maximal concentration, Ki equilibrium constant, LEV levetiracetam, MES maximal electroshock seizure test, PTZ subcutaneous pentylenetetrazole seizure test, SV2A synaptic vesicle protein 2A. a Reproduced from Fig. 1 of Klitgaard et al. [7], licensed under CC BY-NC-ND 4.0. b Reproduced from Table 31.2 of D’Souza et al. [70], with permission from John Wiley & Sons, Ltd. Panel C: Reproduced with small modifications from Fig. 1 of Feyissa [71], licensed under CC BY-NC 4.0

Fig. 3

Overview of BRV metabolism. BRV brivaracetam, CYP cytochrome P450. Reproduced from Fig. 1 of Moseley et al. [17], licensed under CC BY-NC-ND 4.0

Fig. 4

Median percent reduction in POS frequency from baseline (a) and ≥ 50% responder rates (b). BRV brivaracetam, POS partial-onset seizure (focal-onset seizure). Reproduced from Fig.3a and 2B of Ben-Menachem et al. [31], licensed under CC BY-NC-ND 4.0

Fig. 5

Greater than 50% responder rates in patients treated with BRV, with or without previous LEV exposure (a), percent reduction over PBO in 28-day adjusted POS frequency during the treatment period according to reason for previous discontinuation of LEV (b), and ≥ 50% responder rates for POS frequency from baseline to the end of treatment period according to reason for previous discontinuation of LEV (c). p values are derived from a logistic regression model with effects for treatment, study, and log-transformed baseline focal seizure frequency as a continuous covariate. All p values are exploratory. BRV brivaracetam, LEV levetiracetam, PBO placebo, POS partial-onset seizure (focal-onset seizure). Panel A: Reproduced from Fig. 1A of Asadi-Pooya et al. [32], licensed under CC BY-NC-ND 4.0. Panel B and C: Reproduced from Fig. 4C and D of Klein et al. [30], licensed under CC BY-NC-ND 4.0

Fig. 6

Time to PPR elimination in patients with photosensitive epilepsy (a) and proportion of patients with PPR elimination on EEG at designated timepoints (b). Part 1: IV infusion over 15 min (n = 8); part 2: IV infusion over 15 min (n = 8); parts 1 and 2 combined (n = 16). ^aRange when excluding patient NNN (non-responder in Part 1): 1–5; ^bPatient OOO completed part 1, but patient PPP participated in part 2. BRV brivaracetam, EEG electroencephalogram, IV intravenous, LEV levetiracetam, PPR photoparoxysmal response. Adapted from Table 1 and 3 of Reed et al. [50], licensed under CC BY-NC 4.0