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An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease

Lizama, B.N., North, H.A., Pandey, K., Williams, C., Duong, D., Cho, E., Di Caro, V., Ping, L., Blennow, K., Zetterberg, H., Lah, J., Levey, A.I., Grundman, M., Caggiano, A.O., Seyfried, N.T., Hamby, M.E.·2024·Neurobiology of Disease
DOI 10.1016/j.nbd.2024.106575

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Abstract

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abu…

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Metadata

Authors
Lizama, B. N., North, H. A., Pandey, K., Williams, C., Duong, D., Cho, E., Di Caro, V., Ping, L., Blennow, K., Zetterberg, H., Lah, J., Levey, A. I., Grundman, M., Caggiano, A. O., Seyfried, N. T., & Hamby, M. E.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2024-09
Volume
199
Pages
106575
ISSN
0969-9961
DOI
10.1016/j.nbd.2024.106575
Cited by
19
References
16
Language
en
Licence
Funders
  • ADDF
  • NIA

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