Alzheimer's Disease
Age-related Buildup of Toxic Proteins
Several neurodegenerative disorders are characterized by an age-related build-up of toxic proteins in the brain, which bind to neuronal receptors and disrupt key cellular processes.
Alzheimer’s disease in particular 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.
A Unique Approach to Treating Alzheimer’s Disease
In Alzheimer’s disease, the preponderance of evidence suggests that Aβ oligomers are toxic when bound to neuronal synapses. The damage they inflict causes a cascade of injury to and eventual loss of synapses. Synapses are the communication points between neurons, facilitating signal transmission throughout the brain. Loss of these structures is directly correlated with cognitive decline in Alzheimer’s disease.
Previous therapeutic approaches have attempted to a) reduce the production of Aβ by inhibiting the enzymes that generate Aβ: γ-secretase or β-secretase; or b) remove Aβ using targeted monoclonal antibodies (mAbs). We believe a common issue with many mAb approaches is that they fail to discriminate between different forms of Aβ: fibrils, plaques, protofibrils and oligomers. Conversely, mAbs that target Aβ protofibrils/oligomers have shown promise in preventing synaptotoxicity. Our strategy of targeting the σ-2 receptor to prevent Aβ oligomer toxicity at the synapse is distinct from these immunotherapeutic approaches, but we believe may be complementary.
Restoring Damaged Cellular Processes
Cognition’s approach is unique in that its candidate, CT1812, is designed to restore damaged cellular processes such as autophagy, cholesterol synthesis and protein trafficking, which are dysregulated in neurodegenerative disorders. CT1812 binds to TMEM97, a protein component of the σ-2 receptor, a key regulator of the cellular damage response. In Alzheimer’s disease, this results in the displacement of Aβ oligomers, which are then cleared into the cerebrospinal fluid (CSF).
Preclinical studies have shown that by displacing Aβ oligomers and preventing further oligomer binding, the brain’s damage control mechanisms can be re-enabled. So long as the neurons remain viable, synaptic density and function can recover. This creates the opportunity to treat ongoing cognitive deficits in Alzheimer’s disease and prevent further deficits from occurring.
Click below to learn about the mechanism of action of Cognition’s lead candidate, CT1812 in Alzheimer’s disease
SEQUEL COG0202 study:
- Assessed disease-modification as a function of synapse function as measured by qualitative EEG.
- Topline results showed improvements in global measures of brain activity.
- For more information, please visit clinicatrials.gov and reference NCT04735536.
- Background information on qEEG and a summary of topline results maybe found here.
SNAP COG0104 study:
- Assessed target engagement vis-a-vis displacement of Aβ oligomers.
- For more information, please visit clinicaltrials.gov and reference NCT03522129.
SPARC COG0105 study:
- Assessed disease-modification as a measure of synapse density with PET imaging.
- For more information, please visit clinicaltrials.gov and reference NCT03493282.
Phase 1b/2a COG0102 study:
- CT1812 was generally safe and tolerated in patients with mild-to-moderate Alzheimer’s disease.
- All adverse events were mild or moderate; there were no serious adverse events.
- CT1812 achieved CSF concentrations greater than 80 percent estimated brain receptor occupancy, a level previously demonstrated in preclinical studies to be the minimum efficacious dose.
- Protein biomarkers associated with Alzheimer’s disease changed differentially in CT1812-treated vs. placebo patients.
- For more information, please visit clinicaltrials.gov and reference NCT02907567.
SHINE COG0201 study:
- Double-blind, placebo-controlled study.
- Top-line results from Part A (n=24) showed positive trend in cognitive function in favor of CT1812.
- Treatment-emergent adverse events were well balanced across all treatment groups in Part A.
- Enrollment expected to conclude 2023.
- For more information, please visit shineADstudy.com or clinicatrials.gov and reference NCT03507790.
START COG0203 study:
- 540-person Phase 2 study in early Alzheimer’s disease in collaboration with the Alzheimer’s Clinical Trials Consortium (ACTC).
- Supported by a $81 million grant from the National Institute on Aging (NIA) of the National Institutes of Health (NIH).
- For more information, please visit start-study.org or clinicatrials.gov and reference NCT05531656.