Alzheimer’s Disease

Age-related Build-up 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 damage 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) removing Aβ using targeted monoclonal antibodies. None of these compounds selectively targeted Aβ oligomers and to date they have demonstrated limited effect.

Learn about the causes of Alzheimer's disease and our proposed mechanism of treatment

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 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.

Displaces oligomers from neurons (A) and from Alzheimer's patient neocortical tissue (B)

Development Status in Alzheimer's Disease

CT1812 has completed three Phase 1 trials and enrollment has concluded in two Phase 2 clinical trials with two additional physiology trials ongoing in patients with Alzheimer’s disease. Cognition has been awarded a $75.8M grant from the NIA to study CT1812 in a study of 540 Alzheimer’s disease patients. This study will be conducted collaboration with the distinguished Alzheimer’s Clinical Trial Consortium (ACTC) and is expected to commence in 2021.

Select Completed Studies

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.

Ongoing Studies

SNAP COG0104 study:
  • Assessing target engagement.
  • Expect topline results by YE 2021.
SPARC COG0105 study:
  • Assessing disease-modification as a measure of synapse density with PET imaging.
  • Expect topline results by YE 2021.
SHINE COG0201 study:
  • Double-blind, placebo-controlled study.
  • Enrollment complete.
  • 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 and treatment in Part B (n=38) continues.
SEQUEL COG0202 study:
  • Assessing disease-modification as a function of synapse function as measured by qualitative EEG.
  • Expect topline results in 2022.

Planned Studies

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 $75.8 million grant from the National Institute on Aging (NIA) of the National Institutes of Health (NIH).
  • Expected to commence in 2021.