Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Abstract

SUMMARYDespite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…Data taken from Löscher et al [14], Marescaux and Vergnes [154], Ebert et al [155], Hönack and Löscher [156], Barton et al [49], Bialer et al [157], Matagne and Klitgaard [158], Matagne et al [108], Bennett et al [130], Klitgaard et al [9], Löscher [159], Löscher et al [160], and unpublished experiments ADT after-discharge threshold, BRV brivaracetam, CBZ carbamazepine, CC 97 current inducing seizures in 97 % of mice, ED 50 median effective dose, GAERS genetic absence epilepsy rat from Strasbourg, GST generalized seizure threshold, LEV levetiracetam, LTG lamotrigine, MAD minimum active dose providing significant protection against the seizure endpoint, MES maximal electroshock seizure, NE not effective, PHT phenytoin, PTZ pentylenetetrazole, SEL seletracetam, SWDs spike-wave discharges, VPA valproate? indicates no data are available…”

“…Data taken from Löscher et al [14], Marescaux and Vergnes [154], Ebert et al [155], Hönack and Löscher [156], Barton et al [49], Bialer et al [157], Matagne and Klitgaard [158], Matagne et al [108], Bennett et al [130], Klitgaard et al [9], Löscher [159], Löscher et al [160], and unpublished experiments…”

“…Importantly, SV2A is the primary molecular target of the ASD levetiracetam [6, 7] and the selective SV2A ligand brivaracetam [8]. The latter was recently approved in Europe by the European Medicines Agency (EMA) and in the US by the Food and Drug Administration (FDA) as adjunctive treatment for drug refractory partial-onset seizures in patients with epilepsy aged 16 years and above [9]. These drugs have not only contributed a further understanding of the functions of SV2A but also constitute a new category of highly effective and well tolerated ASDs that have led to a paradigm shift in ASD discovery.…”

Overexpression of Synaptic Vesicle Protein 2A Inhibits Seizures and Amygdaloid Electroencephalogram Activity in Pilocarpine-induced Pharmacoresistant Epileptic Rats

“…LEV has only modest affinity for SV2A, but BRV is a selective, high-affinity SV2A ligand with promising antiepileptic properties and fast onset of action. BRV, which has rapid brain entry and fast brain SV2A occupancy [17], provides potent and complete seizure suppression in animal models of partial, generalized, and drug-resistant seizures [32].…”

Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam

“…[14][15][16][17][18][19][20][21][22] Its interesting pharmacokinetic properties together with its distinct chemical structure and mechanism of action make LEV unique among the marketed antiepileptic drugs. 9,11,23,24 For a better understanding of the pharmacodynamics of LEV, the characterization of its structure in solid and liquid state is crucial. Recently reported X-ray data show that etiracetam, the racemic mixture of R-and S-enantiomers, crystallizes in 3 different solid phases, that is, 2 polymorphs with monoclinic P2 1 /c symmetry and 1 hydrate phase of orthorhombic P1 symmetry, 4 whereas LEV crystallizes in a crystallographic form with monoclinic P2 1 symmetry.…”