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A phase 1 clinical trial of the sigma‐2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease
Abstract
Background: Elayta (CT1812) is a novel allosteric antagonist of the sigma‐2 receptor complex that prevents and displaces binding of Aβ oligomers to neurons. By stopping a key initiating event in Alzheimer's disease, this first‐in–class drug candidate mitigates downstream synaptotoxicity and restores cognitive function in aged transgenic mouse models of Alzheimer's disease. Methods: A phase 1, two‐part single and multiple ascending dose study was conducted in 7 and 4 cohorts of healthy human subjects, respectively. In part A, healthy, young subjects (<65 years old) received CT1812 doses ranging from 10 to 1120 mg (6:2 active to placebo [A:P] per cohort). In part B, subjects were administered 280, 560, and 840 mg once daily for 14 days (8:2 A:P per cohort). An elderly cohort, aged 65‐75 years, was dosed at 560 mg once daily for 14 days (7:2 A:P). Serum concentrations of CT1812 in part B were measured on day 3 and 14 and cerebrospinal fluid concentrations on day 7 or 9. Cognitive testing was performed in the healthy elderly cohort at baseline and at day 14 of treatment. Results: Treatment with CT1812 was well tolerated in all cohorts. Adverse events were mild to moderate in severity and included headache and GI tract symptoms. Plasma concentrations of drug were dose proportional across two orders of magnitude with minimal accumulation over 14 days. Cognitive scores in the healthy elderly cohort were similar before and after treatment. Conclusions: CT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.
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Those findings and the fact that TMEM97 modulators are pharmacologically well studied, have brought the use of TMEM97 modulators into Phase II clinical trials for Alzheimer's treatment.
“Those findings and the fact that TMEM97 modulators are pharmacologically well studied, have brought the use of TMEM97 modulators into Phase II clinical trials for Alzheimer’s treatment [11, 21].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [21]
A Sigma-2 modulator, CT1812, is in clinical development in Phase 2 trials for Alzheimer's disease and dementia with Lewy bodies.
“Sigma-2 receptors have been studied for more than four decades and are drug targets for several conditions including cancer, pain and diverse CNS disorders [22, 58]; and most notably, a Sigma-2 modulator, CT1812, is in clinical development in Phase 2 trials for Alzheimer’s disease and dementia with Lewy bodies [11, 21].”
From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [21]
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Cites
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The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
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“Symptomatic treatments that are available for AD only transiently slow cognitive decline [8], and prior clinical investigation of small molecule inhibitors and modulators of the g-secretase and b-secretase enzymes that cut Ab from its full-length precursor have not shown significant clinical efficacy [9–11].”
BackgroundTwo Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960
Self-citation2018 Alzheimer's disease facts and figures
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Research works printed but not linked: 6
- 10.1097/00002093-200110000-00002 · DOI · Paper page
- 10.1371/journal.pone.0111899 · DOI · Paper page
- 10.1146/annurev-pharmtox-010814-124309 · DOI · Paper page
- 10.1155/2014/431858 · DOI
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the Synaptic Health Endpoints Working Group, Colom-Cadena, M., Spires-Jones, T., Zetterberg, H., Blennow, K., Caggiano, A., DeKosky, S. T., Fillit, H., Harrison, J. E., Schneider, L. S., et al. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00588-4 · Cited by 328
Self-citationJeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306
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Huang, L.-K., Kuan, Y.-C., Lin, H.-W., & Hu, C.-J. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00976-6 · Cited by 252
“CT1812 is a ligand that targets the component 1 subunit of the sigma2/progesterone membrane receptor.”
BackgroundStructures of the σ2 receptor enable docking for bioactive ligand discovery
Alon, A., Lyu, J., Braz, J. M., Tummino, T. A., Craik, V., O’Meara, M. J., Webb, C. M., Radchenko, D. S., Moroz, Y. S., Huang, X.-P., et al. (2021) · Nature · doi:10.1038/s41586-021-04175-x · Cited by 211
Lizama, B. N., Kahle, J., Catalano, S. M., Caggiano, A. O., Grundman, M., & Hamby, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076251 · Cited by 54
Self-citationMorató, X., Pytel, V., Jofresa, S., Ruiz, A., & Boada, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169305 · Cited by 53
Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease
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Self-citationA Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer’s Disease
Ettcheto, M., Busquets, O., Espinosa-Jiménez, T., Verdaguer, E., Auladell, C., & Camins, A. (2020) · Current Pharmaceutical Design · doi:10.2174/1381612826666200211121416 · Cited by 13
Metadata
- Authors
- Grundman, M., Morgan, R., Lickliter, J. D., Schneider, L. S., DeKosky, S., Izzo, N. J., Guttendorf, R., Higgin, M., Pribyl, J., Mozzoni, K., Safferstein, H., & Catalano, S. M.
- Affiliations
- Global R&D Partners San Diego CA USA
- MedSurgPI, LLC Raleigh NC USA
- Nucleus Network Melbourne Victoria Australia
- Keck School of Medicine of USC Los Angeles CA USA
- McKnight Brain Institute, University of Florida Gainesville FL USA
- Cognition Therapeutics Inc. Pittsburgh PA USA
- Aclairo Pharmaceutical Development Group Vienna VA USA
- PharmaDirections, Inc. Cary NC USA
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2018-12-18
- Volume
- 5
- Issue
- 1
- Pages
- 20-26
- ISSN
- 2352-8737
- PMC
- PMC6352291
- Cited by
- 96
- References
- 8
- Language
- en
- Funders
- National Institute on Aging (AG051593, AG037337)
- National Institute of Neurological Disorders and Stroke (NS083175)
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