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CT1812 biomarker signature from a meta‐analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease
Abstract
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
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Previously, only CSF proteomics analyses have been reported to assess the biological impact of zervimesine in AD participants.
“Previously, only CSF proteomics analyses have been reported to assess the biological impact of zervimesine in AD participants [5, 6, 26].”
Reduction of plasma GFAP in zervimesine-treated participants compared to control is consistent with the potential effects of zervimesine in modulating inflammatory or immune response pathways.
“Reduction of plasma GFAP in zervimesine-treated participants compared to control is consistent with the potential effects of zervimesine in modulating inflammatory or immune response pathways”
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“54 Given that microglia can respond to and impact changes in synaptic activity, it is interesting to speculate whether there may be a non-cell-autonomous role of CT1812, thoughneuronalS2R,thatmayleadtoaneffectonmicrogliatofurther regulate synaptic activity and synaptic density.”
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Di Caro, V., Cho, E., Thiel, J., Lizama, B. N., Koel-Simmelink, M. J. A., Pandey, K., Duong, D., Seyfried, N. T., Grundman, M., Teunissen, C. E., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-02025-4 · Cited by 1
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Metadata
- Authors
- Lizama, B. N., Williams, C., North, H. A., Pandey, K., Duong, D., Di Caro, V., Mecca, A. P., Blennow, K., Zetterberg, H., Levey, A. I., Grundman, M., van Dyck, C. H., Caggiano, A. O., Seyfried, N. T., & Hamby, M. E.
- Affiliations
- Cognition Therapeutics Pittsburgh Pennsylvania USA
- Emtherapro Inc Systems Biology Atlanta Georgia USA
- Emory University School of Medicine, Biochemistry Atlanta Georgia USA
- Department of Psychiatry Alzheimer's Disease Research Unit Yale University School of Medicine New Haven Connecticut USA
- Paris Brain Institute ICM Pitié‐Salpêtrière Hospital Sorbonne University Paris France
- Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg, Mölndal Göteborg Sweden
- Emory University School of Medicine, Neurology Atlanta Georgia USA
- Global R&D Partners LLC San Diego California USA
- ORCID
- Hamby, Mary E.
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-08-21
- Volume
- 20
- Issue
- 10
- Pages
- 6860-6880
- ISSN
- 1552-5260
- 1552-5279
- PMC
- PMC11485314
- Cited by
- 8
- References
- 17
- Language
- en
- Funders
- National Institute on Aging (RF1AG057553, 1R01AG058660‐01)
- Alzheimer's Drug Discovery Foundation
- Vetenskapsrådet (#2023‐00356, #2022‐01018, #2019‐02397)
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