CT1812 biomarker signature from a meta-analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease

INTRODUCTION: CT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials. METHODS: Unbiased analysis of tandem-mass tag mass spectrometry (TMT-MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC cohort (NCT03493282). Comparative analyses and a meta-analysis with the interim SHINE cohort (NCT03507790; SHINE-A) followed by network analysis (weighted gene co-expression network analysis [WGCNA]) were used to understand the biological impact of CT1812. RESULTS: CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta-analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment-associated networks driven by S2R. DISCUSSION: Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development.