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

Abstract Aoligomers are considered the most toxic structural form of Amyloid betacausing synaptotoxic changes underlying cognitive decline in Alzheimer s diseaseCogRx 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 fluidCSFThis first in class drugCTallosterically modulates a key protein regulator of oligomer receptorsthe sigmaPGRMCprotein complexdestabilizing the oligomer binding siteincreasing the off rate of A Os and allowing rapid clearance into the CSFhowever the interactions between the receptor components and their role in downstream signaling pathways are unknownCTrestores synapse number and cognitive performance to normal in AD mouse modelsCThas been demonstrated to be safe and well tolerated in healthy volunteers dosed once daily fordays in a placebocontrolled Phasea trialand is currently being evaluated in a follow on placebo controlled safety trial in AD patientsThe study will provide critical information about the mechanism of action of this innovative differentiated and first in class compoundSuccessful commercialization of this drug will require partnership with a large pharmaceutical company to support Phaseandclinical trials and marketingand detailed understanding of the molecular mechanism of action of CThas been cited by potential development partners as being a critical requirement for engaging in such a partnershipCogRx has no other support available for elucidating the details of CTs mechanism of actionThis Fast Tract SBIR proposal will provide crucial details about this novel mechanism of action and will enable the application of the proprietary portfolio of sigmaligands at CogRx to other diseasesThis information will increase the chance for partnering opportunities necessary for the clinical development of CTfor AD patients and will expand the pipeline portfolio of CogRX into new clinical areas involving autophagy pathways Project Narrative Aoligomers are considered the most toxic structural form of Amyloid betacausing synaptotoxic changes underlying cognitive decline in Alzheimer s diseaseCogRx 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 fluidCSFThis first in class drugCTallosterically modulates a key protein regulator of oligomer receptorsthe sigmaPGRMCprotein complexdestabilizing the oligomer binding siteincreasing the off rate of A Os and allowing rapid clearance into the CSFhowever the interactions between the receptor components and their role in downstream signaling pathways are unknownThis project will inform our understanding of mechanism of action and thereby increase the chance for partnering opportunities necessary for the clinical development of CTfor AD patients and will expand the pipeline portfolio of CogRX into new clinical areas involving autophagy pathways