Randomized Double Blind, Placebo Controlled, Parallel Group Trial to Evaluate the Safety and Efficacy of CT1812 in Early Alzheimer's Disease over 18 Months

Cognition Therapeutics, Inc. (CogRx) is developing CT1812, a disease-modifying drug for Alzheimer’s disease.
CT1812 is the first highly brain penetrant selective sigma-2 receptor antagonist small molecule. This drug
candidate selectively displaces amyloid-β oligomers bound to neuronal receptors at synapses and protects
synapses from toxic oligomer effects, clearing oligomers from the brain into the cerebrospinal fluid. When
administered once daily for 28 days to mild to moderate AD patients, CT1812 significantly increases CSF
concentration of AβOs, increases plasma concentrations of lipids and metabolites, and reduces concentrations
of synaptic degeneration markers in AD patient CSF, consistent with the disease-modifying and
synaptoprotective mechanism of action established in preclinical studies. No other therapeutic currently in
development selectively targets the most toxic form of the Aβ protein – oligomers (AβOs) and has
demonstrated selective clearance of AβO into CSF in AD patients. No other AD drug candidate has
demonstrated normalization of dysregulated protein and lipid/metabolite analytes in AD patient biofluids or
reported reduction of synaptic damage markers in AD patients as much, and as rapidly, as CT1812. We
hypothesize that the effects of oligomer displacement and clearance on cognitive function wil l be
detectable in symptomatic patients, and the effect on disease modification will be detectable in
presymptomatic patients. CogRx discovered CT1812, its mechanism of action and the role of the sigma-2
receptor complex in AD. No other group is pursuing this mechanism of action for Alzheimer’s disease treatment.
CT1812 has been demonstrated to be safe and well tolerated in healthy volunteers and mild-to moderate AD
patients in placebo-controlled Phase 1b/2a trials. Adverse events were predominantly mild and included
headache and GI disturbances. Two doses of CT1812 are currently being evaluated in follow-on safety trials in
mild to moderate AD patients (Q.D. for 6 months, MMSE 18-26). These same two doses will be tested in early
AD patients (MMSE 20-30) in the current trial, with treatment duration extended to 18 months. This project
proposes to conduct a randomized, double-blind, placebo-controlled, Phase 2 trial to evaluate the safety and
tolerability of two doses of CT1812 in patients with early AD (MMSE 20-30, corresponding to FDA late stage 2
to early stage 4) given q.d. over 18 months. This trial will determine whether CT1812 beneficially affects
cognition as measured by CDR-SB and other secondary cognitive measures, as well as measuring the impact
of CT1812 on biomarkers of target engagement (CSF concentrations of Aβ oligomers and synaptic
degeneration proteins) and disease modification (CSF concentrations of total tau and NfL, serum NfL as well
as hippocampal and whole brain volume change by MRI). Completion of this study in early AD patients will
inform the design and methods of the subsequent long term disease modification Phase 3 trials with CT1812.

Grant Number: 5R01AG065248-04
NIH Institute/Center: NIH
Principal Investigator: ANTHONY CAGGIANO