Target Engagement Biomarkers for Alzheimer's Therapeutics

Abstract Project Summary Cognition Therapeutics Inc CogRx has discovered CT a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells By stopping the initiating event in the Abeta oligomer cascade this first in class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimerandapos s disease CT displaces receptor bound Abeta oligomers by allosterically antagonizing the sigma PGRMC receptor Izzo et al a b CT thus represents the first disease modifying therapeutic that will test the oligomer hypothesis of Alzheimerandapos s disease Such a drug candidate would significantly impact the lives of the million patients worldwide suffering from AD and MCI for whom no disease modifying treatment exists This proposal seeks to identify biomarkers of CT functional target engagement The project proposes measuring changes in expression levels of proteins regulated by sigma PGRMC in the presence of Abeta oligomers that are blocked by CogRxandapos s sigma PGRMC antagonists in neurons and determining if such changes are observed in the brains CSF or serum of transgenic mice treated with CT The proposed studies will also conduct unbiased proteomic investigations on biofluids from wild type and transgenic AD mice treated with CT or vehicle to identify patterns of altered protein expression associated with drug engagement with target in settings of disease With this data we propose to construct a pathway from CT target engagement to peripherally available biomarker using targeted reaction monitoring MRM proteomics data The successful outcome of this project is the development of an assay to measure candidate biomarkers in humans for exploratory investigation in the clinic Project Narrative Cognition Therapeutics Inc has discovered a drug candidate that promises to stop and even reverse the memory loss in Alzheimerandapos s disease This drug canddi ate CT works by a completely novel mechanism to stop the binding of toxic proteins that build up in the brains of Alzheimerandapos s patients known as Abetaoligomers We are requesting funding support to identify and develop a target engagement biomarker through determination of precise measurements of biomarker proteins in biofluids such as CSF and plasma Such biomarkers would be invaluable for exploratory investigation of target engagement in the clinic of drug candidates in Alzheimerandapos s patients and would be a ot ol in the development of therapeutics which could significantly impact the lives of the million patients worldwide suffering from Alzheimerandapos s diseaseand Mild Cognitive Impairment for whom no disease modifying treatment exists