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Cognition Therapeutics is currently enrolling participants in Phase 2 clinical trials both in Alzheimer’s Disease and dementia with Lewy bodies. Both studies utilize Cognition’s proprietary lead product candidate, CT1812, an orally delivered, small molecule designed to penetrate the blood-brain barrier and bind selectively to the sigma-2 (σ-2) receptor complex, a key regulator of cellular damage and stress response. More information on these studies may be found on www.clinicaltrials.gov.
Alzheimer’s disease is caused by the age-related buildup of proteins including beta amyloid (Aβ). Under normal conditions, the cell removes these proteins from the brain before they are allowed to accumulate and aggregate into more toxic forms. However, in Alzheimer’s disease, the cellular damage response is disrupted, allowing the formation of toxic Aβ oligomers. These oligomeric forms of the Aβ protein bind to synapses where they cause a cascade of damage and eventual loss of neurons.
Dementia with Lewy bodies (DLB) involves a neurodegenerative, progressive decline in motor and cognitive dysfunction. DLB is associated with the accumulation of the protein α-synuclein, which aggregates into fibrils, the major constituent of the Lewy bodies that occur inside brain neurons.
Only a few symptomatic treatments are approved today for these patients.
Cognition Presentations and Publications
Analyses from clinical studies of CT1812 in patients with Alzheimer’s disease were presented at AD/PD™ 2022.
Cognition Therapeutics has several publications on the sigma-2 receptor, its role in neurological disorders such as Alzheimer’s disease and results of earlier studies.
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CT1812 for the Treatment of Alzheimer's Disease
Rishton GM, Look GC, Ni Z-J, et al. Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer’s Disease. ACS Med Chem Lett. 2021 Aug 9;12(9):1389-1395.
Grundman M, Morgan R, Lickliterd 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 Jan 23; 5:20-26
Izzo NJ, 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 Nov 12; 9(11):e111899
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 Nov 12; 9(11):e111898
BioMarker Studies and Findings
Izzo NJ, Yuede CM, LaBarbera KM, et al. Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer’s disease modification. Alzheimer’s Dement. 2021 Aug; 17(8):1365-1382
Colom-Cadena M, Spires-Jones T, Zetterberg H, et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alz Res Therapy 12, 21 (2020)
CT1812 for the Treatment of Synucleinopathies
Limegrover CS, LeVine H III, Izzo NJ, et al. Alzheimer’s Protection Effect of A673T Mutation May Be Driven by Lower Aβ Oligomer Binding Affinity. J Neurochem. 2020; 00: 1– 15. doi:10.1111/jnc.15212
Sigma-2 Receptor Biology
Colom-Cadena M, Tulloch J, Jackson RJ, et al. TMEM97 increases in synapses and is a potential synaptic Aβ binding partner in human Alzheimer’s disease. bioRxiv 2021.02.01.428238; doi.org/10.1101/2021.02.01.428238
Izzo NJ, Colom-Cadena M, Riad AA, et al. Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease. 7(6) ENEURO .0317-20.2020 1–7
Supportive Industry Publications
Sigma-2 Receptor Complex Biology and Role in Disease
Alon A, Schmidt HR, et al. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165
Riad A, Zeng C, 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 Nov 15;8(1):16845
Synaptotoxicity of Aβ Oligomers
Cline EN, Bicca MA, et al. The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis. 2018; 64(s1):S567-S610
Selkoe DJ, Hardy J. The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years. EMBO Molecular Medicine. 2016 Jun; 8(6):595-608
BioMarkers of Disease and Target Engagement
Schindler SE, Li Y, et al; Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2019 May;15(5):655-665
Dhiman K, Blennow K, et al. Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis. Cell Mol Life Sci. 2019 May;76(10):1833-1863
The sigma-2 (σ-2) receptor is expressed by multiple cell types, including neuronal synapses, and acts as a key regulator of cellular damage commonly associated with certain age-related degenerative diseases of the CNS and retina. The σ-2 complex is comprised of transmembrane protein 97 (TMEM97), a four-domain transmembrane protein that forms a complex with progesterone receptor membrane component 1 (PGRMC1).
The σ-2 complex is expressed in the CNS, the retina, as well as peripheral organs, including the pancreas, liver and kidney. Within the brain, the σ-2 complex is found in several areas, including the cerebellum, cortex, hippocampus and substantia nigra, and is enriched in neurons as compared to glial cells in the adult brain. In the retina, the σ-2 complex is expressed in several cell types including the RPE cells, photoreceptors and retinal ganglion cells.
We believe that targeting the σ-2 complex represents a mechanism that is functionally distinct from other current approaches in clinical development for the treatment of degenerative diseases.
