A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease
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 p...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-024-01382-2 |
| _version_ | 1797276716045959168 |
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| author | Christopher H. van Dyck Adam P. Mecca Ryan S. O’Dell Hugh H. Bartlett Nina G. Diepenbrock Yiyun Huang Mary E. Hamby Michael Grundman Susan M. Catalano Anthony O. Caggiano Richard E. Carson |
| author_facet | Christopher H. van Dyck Adam P. Mecca Ryan S. O’Dell Hugh H. Bartlett Nina G. Diepenbrock Yiyun Huang Mary E. Hamby Michael Grundman Susan M. Catalano Anthony O. Caggiano Richard E. Carson |
| author_sort | Christopher H. van Dyck |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-03-07T15:32:13Z |
| format | Article |
| id | doaj.art-f8737e4097cf48b39181feb795adf981 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-03-07T15:32:13Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-f8737e4097cf48b39181feb795adf9812024-03-05T16:22:06ZengBMCAlzheimer’s Research & Therapy1758-91932024-01-0116111410.1186/s13195-024-01382-2A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s diseaseChristopher H. van Dyck0Adam P. Mecca1Ryan S. O’Dell2Hugh H. Bartlett3Nina G. Diepenbrock4Yiyun Huang5Mary E. Hamby6Michael Grundman7Susan M. Catalano8Anthony O. Caggiano9Richard E. Carson10Alzheimer’s Disease Research Unit, Department of Psychiatry, Yale University School of MedicineAlzheimer’s Disease Research Unit, Department of Psychiatry, Yale University School of MedicineAlzheimer’s Disease Research Unit, Department of Psychiatry, Yale University School of MedicineAlzheimer’s Disease Research Unit, Department of Psychiatry, Yale University School of MedicineAlzheimer’s Disease Research Unit, Department of Psychiatry, Yale University School of MedicineDepartment of Radiology and Biomedical Imaging, Yale UniversityCognition Therapeutics Inc.Global R&D Partners, LLCCircle BiopharmaCognition Therapeutics Inc.Department of Radiology and Biomedical Imaging, Yale UniversityAbstract 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).https://doi.org/10.1186/s13195-024-01382-2Alzheimer’s diseaseSigma-2 receptorAmyloid beta oligomersSV2A PETFDG PETBiomarkers |
| spellingShingle | Christopher H. van Dyck Adam P. Mecca Ryan S. O’Dell Hugh H. Bartlett Nina G. Diepenbrock Yiyun Huang Mary E. Hamby Michael Grundman Susan M. Catalano Anthony O. Caggiano Richard E. Carson A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease Alzheimer’s Research & Therapy Alzheimer’s disease Sigma-2 receptor Amyloid beta oligomers SV2A PET FDG PET Biomarkers |
| title | A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease |
| title_full | A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease |
| title_fullStr | A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease |
| title_full_unstemmed | A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease |
| title_short | A pilot study to evaluate the effect of CT1812 treatment on synaptic density and other biomarkers in Alzheimer’s disease |
| title_sort | pilot study to evaluate the effect of ct1812 treatment on synaptic density and other biomarkers in alzheimer s disease |
| topic | Alzheimer’s disease Sigma-2 receptor Amyloid beta oligomers SV2A PET FDG PET Biomarkers |
| url | https://doi.org/10.1186/s13195-024-01382-2 |
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