Advances in antiepileptic drugs targeting synaptic vesicular protein 2A(SV2A)

Levetiracetam’s (Keppra®) binding site and its subsequent identification as the synaptic vesicle protein 2A (SV2A) has opened a new and successful avenue for drug discovery programs at UCB. A number of structurally diverse, selective high affinity SV2A ligands have been identified in binding assays and displayed potent, broad spectrum activity in animal models of epilepsy. Promising preclinical data enabled the identification of brivaracetam as an antiepileptic drug (AED) candidate now in Phase III development for epilepsy. In parallel, intensive research efforts have also been undertaken to further understand the mechanism of action of levetiracetam and other SV2A ligands. A strong correlation between SV2A binding affinity and anticonvulsant potency, initially observed in the audiogenic seizure model, has now been extended to other models of generalized and partial epilepsy. Furthermore, the anticonvulsant efficacy of levetiracetam was significantly reduced in SV2A deficient mice. Several research groups have been working to elucidate the role of SV2A in synaptic vesicle release and cycling, but despite many efforts its function still remains elusive. Recent studies report reduced SV2A expression in brain tissue obtained from both experimental epilepsy models and patients with epilepsy. These observations appear to correlate with the data from SV2A deficient animals which display increased vulnerability to seizures. Furthermore, SV2A deficient mice show rapid development of kindling suggesting accelerated epileptogenesis. SV2A represents an important novel target for AED discovery that is now well validated in a large number of both preclinical and clinical studies.

Background:

Levetiracetam’s (Keppra®) binding site and its subsequent identification as the synaptic vesicle protein 2A (SV2A) has opened a new and successful avenue for drug discovery programs at UCB.

Methods:

A number of structurally diverse, selective high affinity SV2A ligands have been identified in binding assays and displayed potent, broad spectrum activity in animal models of epilepsy. Promising preclinical data enabled the identification of brivaracetam as an antiepileptic drug (AED) candidate now in Phase III development for epilepsy. In parallel, intensive research efforts have also been undertaken to further understand the mechanism of action of levetiracetam and other SV2A ligands.

Results:

A strong correlation between SV2A binding affinity and anticonvulsant potency, initially observed in the audiogenic seizure model, has now been extended to other models of generalized and partial epilepsy. Furthermore, the anticonvulsant efficacy of levetiracetam was significantly reduced in SV2A deficient mice. Recent studies report reduced SV2A expression in brain tissue obtained from both experimental epilepsy models and patients with epilepsy. These observations appear to correlate with the data from SV2A deficient animals which display increased vulnerability to seizures. Furthermore, SV2A deficient mice show rapid development of kindling suggesting accelerated epileptogenesis.

Data Summary:

A strong correlation between SV2A binding affinity and anticonvulsant potency, initially observed in the audiogenic seizure model, has now been extended to other models of generalized and partial epilepsy. The anticonvulsant efficacy of levetiracetam was significantly reduced in SV2A deficient mice. SV2A deficient mice show rapid development of kindling suggesting accelerated epileptogenesis.

Conclusions:

SV2A represents an important novel target for AED discovery that is now well validated in a large number of both preclinical and clinical studies.

Practical Significance:

A number of structurally diverse, selective high affinity SV2A ligands have been identified in binding assays and displayed potent, broad spectrum activity in animal models of epilepsy. Promising preclinical data enabled the identification of brivaracetam as an antiepileptic drug (AED) candidate now in Phase III development for epilepsy.