CERC-611 is a potent and selective Transmembrane AMPA Receptor Regulatory Proteins (“TARP”)-γ8-dependent AMPA receptor antagonist being developed as an adjunctive therapy for the treatment of partial-onset seizures in epilepsy with or without secondarily generalized seizures in patients with epilepsy. CERC-611 is a key addition to our pipeline and we expect to file an IND and commence Phase 1 development in 2017
AMPA receptors are glutamate sensitive ion channels on postsynaptic membranes of excitatory synapses in the central nervous system and are largely responsible for mediating fast neurotransmission across synaptic gaps. AMPA receptor antagonists are known anticonvulsant agents and their ability to down modulate excitatory neurotransmission is key to their anti-epileptic therapeutic potential. However, since AMPA receptor activity is so ubiquitous in the CNS, general antagonism affects most areas of the CNS resulting in undesired effects, such as ataxia, sedation, and/or dizziness, which are shared by all known non-selective AMPA receptor antagonists. Typically these non-selective, broad spectrum antagonists have a very narrow therapeutic dosing window, meaning that typically the doses needed to obtain anti-convulsant activity are close to or overlap with doses at which undesired effects are observed.
Transmembrane AMPA Receptor Regulatory Proteins (TARPs) are a fairly recently discovered family of proteins that have been found to associate with and modulate the activity of AMPA receptors. Several TARPS are fairly region specific in the brain, leading to physiological differentiation of the AMPA receptor activity. As for example, TARPγ2 (stargazing) dependent AMPA receptors are primarily localized in the cerebellum and cerebral cortex and TARP γ8 dependent AMPA receptors are localized primarily in the hippocampus, which region is particularly relevant to seizures origination and/or propagation. It has been theorized that targeting individual TARPS may enable selective modulation of specific brain circuits without globally affecting synaptic transmission.
CERC-611 (AMPA-TARP) is the first molecule to selectively target and functionally block regionally-specific AMPA receptors after oral dosing. This selectivity was engineered into CERC-611 using structure-activity relationship information to achieve selective blockade of the AMPA receptor regulator protein or TARP-γ8 (high density in hippocampus, a region of importance in partial epilepsies) while sparing AMPA receptors associated with TARP γ2 (high density in cerebellum regulating the ataxia and falling associated with perampanel-Fycompa™). CERC-611 is the first molecule to selectively target TARP-γ8-containing AMPA receptors.