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A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease

van Dyck, Christopher H., Mecca, Adam P., O’Dell, Ryan S., Bartlett, Hugh H., Diepenbrock, Nina G., Huang, Yiyun, Hamby, Mary E., Grundman, Michael, Catalano, Susan M., Caggiano, Anthony O., Carson, Richard E.·2024·Alzheimer's Research & Therapy
DOI 10.1186/s13195-024-01382-2PMC PMC10809445
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Abstract

Background: Effective, disease-modifying therapeutics for the treatment of Alzheimer’s disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among the most toxic forms of Aβ. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aβ oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aβ oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients. Methods: The present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration. Results: No treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated. Conclusions: The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development. Trial registration: The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).

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  1. Cummings J, Lee G, Nahed P, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimer’s Dement. 2022;8:e12295. https://doi.org/10.1002/trc2.12295. · DOI · Paper page
  2. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. https://doi.org/10.15252/emmm.201606210. · DOI · Paper page
  3. Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–42. https://doi.org/10.1038/nm1782. · DOI · Paper page
  4. Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–9. https://doi.org/10.1038/416535a. · DOI · Paper page
  5. Van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol Psychiatry. 2018;83(4):311–9. · DOI · Paper page
  6. Izzo NJ, et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement. 2021;17(8):1365–82. · DOI · Paper page
  7. LaBarbera KM, Sheline YI, Izzo NJ, et al. A phase 1b randomized clinical trial of CT1812 to measure Aβ oligomer displacement in Alzheimer’s disease using an indwelling CSF catheter. Transl Neurodegener. 2023;12:24. https://doi.org/10.1186/s40035-023-00358-w. · DOI · Paper page
  8. 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. Alzheimer’s Dement (New York, N Y). 2019;5:20–6. https://doi.org/10.1016/j.trci.2018.11.001. · DOI · Paper page
  9. Bajjalieh SM, Peterson K, Linial M, Scheller RH. Brain contains two forms of synaptic vesicle protein 2. Proc Natl Acad Sci U S A. 1993;90:2150–4. · DOI
  10. Chen MK, Mecca AP, Naganawa M, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75(10):1215–24. https://doi.org/10.1001/jamaneurol.2018.1836. PMID:30014145;PMCID:PMC6233853. · DOI · Paper page
  11. Mecca AP, Chen MK, O’Dell RS, et al. In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET. Alzheimers Dement. 2020;16(7):974–82. · DOI · Paper page
  12. Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale that broaden its scope. The Alzheimer’s disease cooperative study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S13-21. · DOI
  13. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s disease cooperative study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S33-9. · DOI
  14. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98. · DOI · Paper page
  15. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–4. · DOI · Paper page
  16. de Jong HW, van Velden FH, Kloet RW, et al. Performance evaluation of the ECAT HRRT: an LSO-LYSO double layer high resolution, high sensitivity scanner. Phys Med Biol. 2007;52(5):1505–26. · DOI
  17. Carson R, Barker W, Liow J, et al. Design of a motion-compensation OSEM list-mode algorithm for resolution-recovery reconstruction of the HRRT. Portland: IEEE Nuclear Sciences Symposium; 2003.
  18. Jin X, Mulnix T, Gallezot JD, Carson RE. Evaluation of motion correction methods in human brain PET imaging—a simulation study based on human motion data. Med Phys. 2013;40(10):102503. · DOI
  19. Mecca AP, Barcelos NM, Wang S, et al. Cortical beta-amyloid burden, gray matter, and memory in adults at varying APOE epsilon4 risk for Alzheimer’s disease. Neurobiol Aging. 2018;61:207–14. · DOI
  20. Mecca AP, McDonald JW, Michalak HR, Godek TA, Harris JE, Pugh EA, et al. PET imaging of mGluR5 in Alzheimer’s disease. Alzheimer’s Res Ther. 2020;12(1):15. · DOI
  21. Chen MK, Mecca AP, Naganawa M, et al. Comparison of [11C]UCB-J and [18]FDG PET in Alzheimer’s disease: a tracer kinetic model study. J Cereb Blood Flow Metab. 2021;41(9):2395–409. · DOI
  22. Wu Y, Carson RE. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab. 2002;22(12):1440–52. · DOI
  23. Mertens N, Maguire RP, Serdons K, et al. Validation of parametric methods for [(11)C]UCB-J PET imaging using subcortical white matter as reference tissue. Mol Imag Biol. 2020;22(2):444–52. · DOI
  24. Rossano S, Toyonaga T, Finnema SJ, et al. Assessment of a white matter reference region for (11)C-UCB-J PET quantification. J Cereb Blood Flow Metab. 2020;40(9):1890–901. · DOI · Paper page
  25. O’Dell RS, Mecca AP, Chen MK, et al. Association of AB depositon and regional synaptic density in early Alzheimer’s disease: a PET imaging study with [11C]UCB-J. Alzheimer’s Res Ther. 2021;13(1):11. · DOI
  26. Fischl B. FreeSurfer. Neuroimage. 2012;62(2):774–81. https://doi.org/10.1016/j.neuroimage.2012.01.021. · DOI · Paper page
  27. Desikan RS, Segonne F, Fischl B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31(3):968–80. · DOI · Paper page
  28. Buckner RL, Head D, Parker J, et al. A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage. 2004;23:724–38. · DOI
  29. Masliah E, Terry RD, Alford M, DeTeresa R, Hansen LA. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol. 1991;138(1):235–46.
  30. Rao JS, Rapoport SI, Kim HW. Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer’s disease brain. Transl Psychiatry. 2011;1(8):e31. https://doi.org/10.1038/tp.2011.27. Retraction in: Transl Psychiatry. 2017 May 9;7(5):e1127. PMID: 22832605; PMCID: PMC3309508. · DOI
  31. Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry. 2001;71(5):589–95. · DOI
  32. Feldman HH, Lane R, Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2007;78(10):1056–63. · DOI
  33. Kehoe PG, Turner N, Howden B, et al. Losartan to slow the progression of mild-to-moderate Alzheimer’s disease through angiotensin targeting: the RADAR RCT. Southampton: NIHR Journals Library; 2021. PMID: 34748298.
  34. Lang FM, Mo Y, Sabbagh M, et al. Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer’s disease: a randomized, placebo-controlled, phase 3 clinical trial (MINDSET). Alzheimers Dement. 2021;7(1):e12136. · DOI · Paper page
  35. Nirogi R, Ieni J, Goyal VK, et al. Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer’s disease: a randomized, double-blind, phase 2, proof-of-concept study. Alzheimers Dement (N Y). 2022;8(1):e12307. · DOI · Paper page
  36. Teng E, Manser PT, Sanabria Bohorquez S, et al. Baseline [18F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer’s disease. Alz Res Therapy. 2021;13:196. · DOI
  37. Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging. 2006;27:1372–84. · DOI · Paper page
  38. Toyonaga T, Smith LM, Finnema SJ, Gallezot JD, Naganawa M, Bini J, Mulnix T, Cai Z, Ropchan J, Huang Y, Strittmatter SM, Carson RE. In vivo synaptic density imaging with 11C-UCB-J detects treatment effects of Saracatinib in a mouse model of Alzheimer disease. J Nucl Med. 2019;60(12):1780–6. · DOI · Paper page
  39. Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Pérez-Cañamás A, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Cai Z, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci Transl Med. 2022;14(647):eabi593. https://doi.org/10.1126/scitranslmed.abi8593. · DOI · Paper page
  40. Trujillo-Estrada L, Vanderklish PW, Nguyen MM, et al. SPG302 Reverses synaptic and cognitive deficits without altering amyloid or tau pathology in a transgenic model of Alzheimer’s disease. Neurotherapeutics. 2021:1–6. · DOI
  41. Nygaard HB, Wagner AF, Bowen GS, et al. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease. Alz Res Therapy. 2015;7:35. https://doi.org/10.1186/s13195-015-0119-0. · DOI
  42. Van Dyck CH, Nygaard HB, Chen K, et al. Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurology. 2019;76(10):1219–29. · DOI
  43. Fox NC, Scahill RI, Crum WR, Rossor MN. Correlation between rates of brain atrophy and cognitive decline in AD. Neurology. 1999;52(8):1687. · DOI
  44. Silbert LC, Quinn JF, Moore MM, et al. Changes in premorbid brain volume predict Alzheimer’s disease pathology. Neurology. 2003;61(4):487–92. · DOI
  45. Reuter M, Schmansky NJ, Rosas HD, Fischl B. Within-subject template estimation for unbiased longitudinal image analysis. Neuroimage. 2012;61(4):1402–18. https://doi.org/10.1016/j.neuroimage.2012.02.084. · DOI · Paper page

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Metadata

Authors
van Dyck, C. H., Mecca, A. P., O’Dell, R. S., Bartlett, H. H., Diepenbrock, N. G., Huang, Y., Hamby, M. E., Grundman, M., Catalano, S. M., Caggiano, A. O., & Carson, R. E.
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-01-25
Volume
16
Issue
1
ISSN
1758-9193
DOI
10.1186/s13195-024-01382-2
PMC
PMC10809445
Cited by
29
References
11
Language
en
Licence
Funders
  • National Institute on Aging (AG057553)
  • Cognition Therapeutics

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