CLINICAL BIOMARKER EVIDENCE FOR TARGET ENGAGEMENT, REDUCTION OF SYNAPTIC DAMAGE AND DISEASE MODIFICATION IN ALZHEIMER’S PATIENTS TREATED WITH CT1812

CT1812 is a novel, clinical stage, experimental Alzheimer's therapeutic that displaces Abeta oligomers from their receptors to protect and restore synapses. By binding to the sigma-2 receptor complex, CT1812 allosterically modulates the oligomer receptor complex, destabilizing its binding site and increasing the off-rate of oligomers from neurons. Displaced oligomers are measured in interstitial and cerebrospinal fluid. This displacement reduces the oligomer-induced toxic effects and results in normalized synapse function and improved cognitive deficits in transgenic mouse AD models. CT1812 demonstrated a favorable clinical safety profile in healthy volunteers. A 28 day, multicenter, double-blind, placebo-controlled trial was performed with once daily CT1812 (90, 280 or 560 mg) or placebo (N = 4 or 5 group) p.o.to AD patients (MMSE 18-26). Patients were followed for safety. Plasma and CSF protein, lipid and metabolite values were measured at baseline and 28 days via ELISA or tandem mass spectroscopy. CSF Abeta oligomer concentrations were increased at day 28 relative to baseline in CT1812-treated compared with placebo-treated patients. Concentrations of 30 CSF proteins and 91 plasma proteins and lipids known to be dysregulated in AD changed in a therapeutic direction in CT1812-treated vs. placebo-treated patients. Synaptic protein fragments neurogranin and synaptotagmin were decreased in CSF at day 28 relative to baseline in CT1812-treated compared to the placebo group. AEs were similar between placebo and CT1812 in the 90 and 280mg dose groups. Sporadic elevations in liver enzymes and lymphopenia were observed at 560mg. These clinical data support CT1812’s mechanism of action of displacing Abeta oligomers, and provide evidence of target engagement, reduction of synaptic damage, and disease-modification. Ongoing trials include PET assessment of synaptic density, measures of synapse damage markers, and cognitive assessments.