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

• Published in: Alzheimer's & dementia Vol. 20; no. 10; pp. 6860 - 6880
• Main Authors: Lizama, Britney N., Williams, Claire, North, Hilary A., Pandey, Kiran, Duong, Duc, Di Caro, Valentina, Mecca, Adam P., Blennow, Kaj, Zetterberg, Henrik, Levey, Allan I., Grundman, Michael, Dyck, Christopher H., Caggiano, Anthony O., Seyfried, Nicholas T., Hamby, Mary E.
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01-10-2024
• Subjects: A beta oligomers; Alzheimer's disease; Aβ oligomers; clinical trial; CSF pharmacodynamic biomarkers; CT1812; investigational therapeutic; Neurosciences; Neurovetenskaper; TMT-MS proteomics; clinical trial; CT1812; CSF pharmacodynamic biomarkers; investigational therapeutic; Alzheimer's disease; TMT‐MS proteomics; Aβ oligomers
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14152

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.
Highlights
This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282)
Comparative analyses identified biomarkers replicating across trials/cohorts
Two independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE‐A]) were used in a meta‐analysis
Amyloid beta (Aβ) & synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment‐related correlates emerge
Network analyses revealed sigma‐2 receptor (S2R)‐interacting proteins that may be “drivers” of changes