Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-24T13:36:14.825Z Has data issue: false hasContentIssue false

46 - Alzheimer ’s Disease Drug Discovery and the Evolution of Start-Up Biotechnology Companies: Cognition Therapeutics, Inc. as a Case Study

from Section 7 - Funding and Financing Alzheimer’s Disease Drug Development

Published online by Cambridge University Press:  03 March 2022

By
Susan Catalano
Edited by
Jeffrey Cummings ,
Jefferson Kinney  and
Howard Fillit
Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
Get access

Summary

This chapter tells the story of one start-up biotech company that discovered and developed CT1812, a disease-modifying therapeutic for Alzheimer’s dieases that is currently in clinical trials. The company overcame significant financial and scientific challenges to discover and develop a drug candidate that works by a novel mechanism of action: CT1812 removes the toxic Aβ oligomers thought to cause AD from the site on brain cells where they create damage. The company went from an idea to five Phase 2 clinical trials. This case study will hopefully encourage other entrepreneurs to take this journey.

Keywords

Sigma-2 receptoranti-Aβ targetAβ oligomersdisease-modifying drug candidatesnext generation anti-amyloid therapeutic
Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
 , pp. 513 - 523
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Patterson, C. World Alzheimer Report 2018. The state of the art of dementia research: new frontiers. Available at: www.alz.co.uk/research/WorldAlzheimerReport2018.pdf (accessed January 29, 2021).Google Scholar
Heron, M. Deaths: leading causes for 2016. Available at: www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_06.pdf (accessed January 29, 2021).Google Scholar
Grabrucker, A, Vaida, B, Bockmann, J, Boeckers, TM. Synaptogenesis of hippocampal neurons in primary cell culture. Cell Tissue Res 2009; 338: 333–41.CrossRefGoogle ScholarPubMed
Ramakers, GJA, Kloosterman, F, van Hulten, P, van Pelt, J, Corner, MA. Activity-dependent regulation of neuronal network excitability. In Neural Circuits and Networks, Torre, V, Nicholls, J (eds.). Berlin: Springer; 1998: 141–51.Google Scholar
Banker, G, Goslin, K. Types of nerve cell cultures, their advantages, and limitations. In Culturing Nerve Cells, Banker, G, Goslin, K (eds.). Cambridge, MA: MIT Press; 1998: 11–36.Google Scholar
Opitz, T, De Lima, AD, Voigt, T. Spontaneous development of synchronous oscillatory activity during maturation of cortical networks in vitro. J Neurophysiol 2002; 88: 2196–206.Google Scholar
Torre, V, Nicholls, J (eds.). Neural Circuits and Networks. Heidelberg: Springer; 1998.CrossRefGoogle Scholar
LaBarbera, KM, Limegrover, CM, Rehak, C, et al. Modeling the mature CNS: a predictive screening platform for neurodegenerative disease drug discovery. J Neurosci Methods 2021; 358: 109180.Google Scholar
Kamenetz, F, Tomita, T, Hsieh, H, et al. APP processing and synaptic function. Neuron 2003; 37: 925–37.CrossRefGoogle ScholarPubMed
Lacor, PN, Buniel, MC, Chang, L, et al. Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J Neurosci 2004; 24: 10191–200.Google Scholar
Reed, MN, Hofmeister, JJ, Jungbauer, L, et al. Cognitive effects of cell-derived and synthetically derived Aβ oligomers. Neurobiol Aging 2011; 32: 1784–94.CrossRefGoogle ScholarPubMed
Hsieh, H, Boehm, J, Sato, C, et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 2006; 52: 831–43.CrossRefGoogle ScholarPubMed
Hong, H-S, Maezawa, I, Yao, N, et al. Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Abeta oligomer-induced cytotoxicity. Brain Res 2007; 1130: 223–34.Google Scholar
Kreutzmann, P, Wolf, G, Kupsch, K. Minocycline recovers MTT-formazan exocytosis impaired by amyloid beta peptide. Cell Mol Neurobiol 2010; 30: 979–84.Google Scholar
Liu, Y, Schubert, D. Cytotoxic amyloid peptides inhibit cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction by enhancing MTT formazan exocytosis. J Neurochem 1997; 69: 2285–93.Google Scholar
Izzo, NJ, Staniszewski, A, To, L, et al. Alzheimer’s therapeutics targeting amyloid beta 1–42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 2014; 9: e111898.CrossRefGoogle ScholarPubMed
Izzo, NNJ, Xu, J, Zeng, C, et al. Alzheimer’s therapeutics targeting amyloid beta 1–42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 2014; 9: e111899.Google Scholar
Izzo, NJ, Yuede, CM, LaBarbera, KM, et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement 2021;DOI: https://doi.org/10.1002/alz.12302.CrossRefGoogle Scholar
Rishton, GM, Look, G, Ni, Z-J, et al. Negative allosteric modulators of the sigma-2 receptor: discovery of investigational drug CT1812 for Alzheimer’s Disease. ACS Med Chem Lett; DOI: https://doi.org/10.1021/acsmedchemlett.1c00048.Google Scholar
Rishton, GM. Reactive compounds and in vitro false positives in HTS. Drug Discov Today 1997; 2: 382–4.CrossRefGoogle Scholar
Rishton, GM. Nonleadlikeness and leadlikeness in biochemical screening. Drug Discov Today 2003; 8: 86–96.Google Scholar
Rishton, GM. Aggregator compounds confound amyloid fibrillization assay. Nat Chem Biol 2008; 4: 159–60.Google Scholar
Arai, H, Beierle, K, Fullenwider, C, Kaj, Z. Chemically conditioned extracts of ginger oil: leadlike “alkaloidal” compounds derived from natural extracts via reductive amination. American Chemical Society Western Regional Meeting, Anaheim, CA, Jan 22, 2006. Available at: http://acs.confex.com/acs/werm05/techprogram/S2455.HTM.Google Scholar
Grundman, M, Morgan, R, Lickliter, JD, et al. A Phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y) 2019; 5: 20–6.Google ScholarPubMed
Limegrover, CS, LeVine, H, Izzo, NJ, et al. Alzheimer’s protection effect of A673 T mutation may be driven by lower Aβ oligomer binding affinity. J Neurochem 2021; 157: 1316–30.Google Scholar
Masliah, E, Terry, RD, Alford, M, DeTeresa, R, Hansen, L. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 1991; 138: 235–46.Google ScholarPubMed
DeKosky, ST, Scheff, SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 1990; 27: 457–64.Google Scholar
Scheff, SW, Price, DA. Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 2003; 24: 1029–46.Google Scholar
Colom-Cadena, M, Spires-Jones, T, Zetterberg, H, et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res Ther 2020; 12: 21.Google Scholar
Riad, A, Zeng, C, Weng, C-CC, et al. Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 2018; 8: 16845.CrossRefGoogle ScholarPubMed
Riad, A, Lengyel-Zhand, Z, Zeng, C, et al. The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates. Mol Neurobiol 2020; 57: 3803–13.Google Scholar
Xu, J, Zeng, C, Chu, W, et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun 2011; 2: 380.Google Scholar
Alon, A, Schmidt, HR, Wood, MD, et al. Identification of the gene that codes for the σ 2 receptor. Proc Natl Acad Sci USA 2017; 114: 7160–5.CrossRefGoogle ScholarPubMed
Behrends, C, Sowa, ME, Gygi, SP, Harper, JW. Network organization of the human autophagy system. Nature 2010; 466: 68–76.CrossRefGoogle ScholarPubMed
Mir, SU, Schwarze, SR, Jin, L, et al. Progesterone receptor membrane component 1/sigma-2 receptor associates with MAP1LC3B and promotes autophagy. Autophagy 2013; 9: 1566–78.Google Scholar
Ahmed, IS, Rohe, HJ, Twist, KE, Craven, RJ. PGRMC1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J Biol Chem 2010; 285: 24775–82.Google Scholar
Thomas, P, Pang, Y, Dong, J. Enhancement of cell surface expression and receptor functions of membrane progestin receptor α (mPRα) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology 2014; 155: 1107–19.Google Scholar
Zhang, M, Robitaille, M, Showalter, AD, et al. Progesterone receptor membrane component 1 is a functional part of the GLP-1 receptor complex in pancreatic beta cells. Mol Cell Proteomics 2014; 1: 3049–62.Google Scholar
Runko, E, Kaprielian, Z. Caenorhabditis elegans VEM-1, a novel membrane protein, regulates the guidance of ventral nerve cord-associated axons. J Neurosci 2004; 24: 9015–26.Google Scholar
Hampton, KK, Anderson, K, Frazier, H, Thibault, O, Craven, RJ. Insulin receptor plasma membrane levels increased by the progesterone receptor membrane component 1. Mol Pharmacol 2018; 94: 665–73.CrossRefGoogle ScholarPubMed
Mansouri, MR, Schuster, J, Badhai, J, et al. Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Hum Mol Genet 2008; 17: 3776–83.Google Scholar
Sanchez-Pulido, L, Ponting, CP. TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Front Genet 2014; 5: 1–9.CrossRefGoogle ScholarPubMed
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 300205:11/20/2019. Available at: https://omim.org/.Google Scholar
Ebrahimi-Fakhari, D, Wahlster, L, Bartz, F, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann–Pick type C1 disease cells. Hum Mol Genet 2015; 25: 3588–99.Google Scholar
Intlekofer, KA, Clements, K, Woods, H, et al. Progesterone receptor membrane component 1 inhibits tumor necrosis factor alpha induction of gene expression in neural cells. PLoS One 2019; 14: e0215389.CrossRefGoogle ScholarPubMed
Rohe, HJ, Ahmed, IS, Twist, KE, Craven, RJ. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacol Ther 2009; 121: 14–19.Google Scholar
Suchanek, M, Radzikowska, A, Thiele, C. Photo-leucine and photo-methionine allow identification of protein–protein interactions in living cells. Nat Methods 2005; 2: 261–7.Google Scholar
Hughes, AL, Powell, DW, Bard, M, et al. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab 2007; 5: 143–9.Google Scholar
Limegrover, CS, Yurko, R, Izzo, NJ, et al. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain-derived α-synuclein. J Neurosci Res 2021; 99: 1161–76.Google Scholar
Izzo, NJ, Colom-Cadena, M, Riad, AA, et al. Proceedings from the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease. eNeuro 2020; 7: 1–7. Available at: http://eneuro.org/lookup/doi/10.1523/ENEURO.0317-20.2020.CrossRefGoogle ScholarPubMed
Frautschy, SA, Cole, GM. Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 2010; 41: 392–409.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×