Scientific program

S32  SYMPOSIUM
SYMPOSIUM LATE BREAKING 1 - CLINICAL TRIALS IN AD, PD, AND PROGRESSIVE SUPRANUCLEAR PALSY

15-Mar-2018 10:00 12:00
 
 
Abstract:
EVIDENCE FOR CT1812 SYNAPTIC PROTECTION IN AD PATIENTS: PHASE 1B/2A TRIAL BIOMARKER ANALYSIS

Objectives: CT1812 is a therapeutic candidate for AD demonstrated to displace Aβ oligomers from synaptic receptor sites, clear oligomers from brain into CSF, and restore synapse number and cognitive performance in aged transgenic mouse models of AD. Neurogranin and synaptotagmin-1 are proteins that play a central role in synaptic function and their elevations in CSF are thought to be biomarkers of CNS synaptic damage. Preclinical studies indicate that CT1812 normalizes Aβ oligomer-induced dysregulation of these synaptic proteins in neurons in vitro. 

Methods: A multicenter, double-blind, placebo-controlled parallel group trial was performed with three doses of CT1812 (90, 280 and 560 mg) or placebo (N = 4 or 5 patients/group) given once daily for 28 days to Alzheimer’s patients (MMSE 18-26). Neurogranin and synaptotagmin concentrations were measured in CSF samples from patients at baseline and following treatment with CT1812 (ClinicalTrials.gov NCT02907567).
 
Results:  Neurogranin concentration was reduced by 33% in patients treated with 90 mg of CT1812, and 17.6% in all treated patients (pooled) compared to baseline (p=0.025 for 90mg dose vs. placebo, p=0.05 for pooled CT1812 dose group vs. placebo, utilizing ANCOVA with baseline value as a covariate and dose as a factor). CSF concentration of synaptotagmin-1 was reduced 27% at 90 mg, 22% at 560 mg and 19% in the pooled CT1812-treated patients compared to baseline (p=0.011 for pooled CT1812 dose group vs. placebo, utilizing a parametric, linear mixed model).

Conclusions:   The reductions of neurogranin and synaptotagmin are consistent with a positive effect on synapses in Alzheimer’s patients and with CT1812’s mechanism of action. This outcome was predicted by preclinical in vitro studies. Additional trials will examine the concentrations of these synaptic markers following longer term administration of CT1812 including a PET study to assess synaptic density after six months of daily treatment, and a Phase 2 trial.

 
Co-authors
S.M. Catalano1, L.S.. Schneider3, S. DeKosky4, R. Morgan5, C. Rehak1, C. Silky1, K. Mozzoni1, N.J. Izzo1, M. Grundman1,2, M. Schirm7, R. Guilbaud7, M. Watson7, D. Chelsky7, C. Davis8, H. Zetterberg9, K. Blennow9
1Cognition Therapeutics Inc., Pittsburgh, PA, USA
2Global R&D Partners, LLC, San Diego, California USA
3Keck School of Medicine of USC, Los Angeles, CA, USA
4McKnight Brain Institute, University of Florida, Gainesville, FL, USA
5MedSurgPI, LLC Raleigh, North Carolina, USA
6Aclairo Pharmaceutical Development Group, Inc, Vienna, VA, USA
7Caprion Biosciences, Inc., Montreal, Canada
8CSD Biostatistics, Inc., Arizona, USA
9University of Gothenburg, Sweden