Mechanism of action of oligomer-displacing Alzheimer investigation drug, CT1812:Receptor interactions and signaling pathways

Aβ oligomers are considered the most toxic structural form of Amyloid beta, causing synaptotoxic changes underlying cognitive decline in Alzheimer’s disease. CogRx has developed the world’s first highly brain penetrant drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). This first-in-class drug, CT1812, allosterically modulates a key protein regulator of oligomer receptors (the sigma-2/PGRMC1 protein complex), destabilizing the oligomer binding site, increasing the off-rate of AβOs and allowing rapid clearance into the CSF, however the interactions between the receptor components and their role in downstream signaling pathways are unknown. CT1812 restores synapse number and cognitive performance to normal in AD mouse models. CT1812 has been demonstrated to be safe and well-tolerated in healthy volunteers dosed once daily for 14 days in a placebocontrolled Phase 1a trial, and is currently being evaluated in a follow-on placebo-controlled safety trial in AD patients. The study will provide critical information about the mechanism of action of this innovative differentiated and first in class compound. Successful commercialization of this drug will require partnership with a large pharmaceutical company to support Phase 2 and 3 clinical trials and marketing, and detailed understanding of the molecular mechanism of action of CT1812 has been cited by potential development partners as being a critical requirement for engaging in such a partnership. CogRx has no other support available for elucidating the details of CT1812’s mechanism of action. This Fast-Tract SBIR proposal will provide crucial details about this novel mechanism of action and will enable the application of the proprietary portfolio of sigma-2 ligands at CogRx to other diseases. This information will increase the chance for partnering opportunities necessary for the clinical development of CT1812 for AD patients and will expand the pipeline portfolio of CogRX into new clinical areas involving autophagy pathways.Aβ oligomers are considered the most toxic structural form of Amyloid beta, causing synaptotoxic changes underlying cognitive decline in Alzheimer’s disease. CogRx has developed the world’s first highly brain penetrant drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). This first-in-class drug, CT1812, allosterically modulates a key protein regulator of oligomer receptors (the sigma-2/PGRMC1 protein complex), destabilizing the oligomer binding site, increasing the off-rate of AβOs and allowing rapid clearance into the CSF, however the interactions between the receptor components and their role in downstream signaling pathways are unknown. This project will inform our understanding of mechanism of action and thereby increase the chance for partnering opportunities necessary for the clinical development of CT1812 for AD patients and will expand the pipeline portfolio of CogRX into new clinical areas involving autophagy pathways.