Cognition Therapeutics, Inc., a clinical stage neuroscience company, provided its comments and perspective on the phase 3 clinical trial data of Eli Lilly’s Alzheimer’s disease medicine, solanezumab.

“These results, while disappointing for the Alzheimer’s disease patient community, still provide scientific insights into the pathological basis of Alzheimer’s disease,” said Susan Catalano, Ph.D., founder and chief science officer of Cognition Therapeutics.  “We view the statement that the responses in the trial directionally favored solanezumab as support for the amyloid hypothesis. This hypothesis has significantly evolved since solanezumab started clinical development, with clear evidence supporting the oligomeric form of the amyloid protein as the culprit that sets Alzheimer’s disease in motion.”

As the only therapeutic currently in clinical trials that potently engages the toxic oligomeric form of the beta amyloid protein, Cognition believes that CT1812, the company’s lead orally delivered small molecule, has a potentially important role in the future AD therapeutic armamentarium.

CT1812 has a unique mechanism of action that potently targets beta amyloid oligomers, acting to both displace bound oligomers from synaptic receptors and prevent oligomer rebinding. These discoveries are described in two companion papers published in 2014 [Izzo et.al] regarding the sigma2/PGRMC-1 receptor complex.  Over time, beta amyloid protein builds up in the brain and changes shape, forming oligomers (many beta amyloid proteins that are self-associated). These oligomers bind specifically to receptors on the surface of brain cells, triggering changes that result in the loss of synapses, the points of electrical communication between brains cells. When enough synapses are lost, the process of new memory formation fails, the earliest sign of Alzheimer’s disease.

Evidence that oligomeric forms of the beta amyloid protein are the most toxic shape of this protein makes them an ideal therapeutic target in Alzheimer’s disease.  The monoclonal antibodies currently in development bind only weakly to oligomers but bind strongly to other shapes of beta amyloid protein – monomers (a single beta amyloid protein molecule, which is the case with solanezumab) or fibrils (polymers of millions of beta amyloid proteins, which is the case with other monoclonal antibodies currently in the clinic).  Because oligomers exist in significantly smaller brain concentrations than other beta amyloid shapes, experts believe that modest efficacy seen by current beta amyloid-targeting antibodies is due to an inability to potently target oligomers.  Additionally, monoclonal antibodies do not achieve significant brain concentrations, averaging only 0.01% of injected antibodies crossing the blood-brain barrier.  Cognition’s CT1812, an orally available small molecule, readily crosses the blood-brain barrier and achieves high brain concentrations. Once there, CT1812 protects synapses from being lost by removing the toxic protein that causes them to malfunction, a much more efficient approach to oligomer targeting.

Cognition Therapeutics clinical programme has an ongoing phase 1b clinical trial of CT1812 in mild to moderate Alzheimer’s disease. In the phase 1b Study COG0102, patients with mild to moderate Alzheimer’s disease are being randomized to one of two doses of CT1812 (280mg patients or 560mg) or placebo, and dosed for 28 days to help evaluate the safety, tolerability and pharmacokinetic profile of CT1812.  Cognition previously conducted Phase 1a single and multiple ascending dose studies in 94 healthy volunteers, 74 of whom received CT1812.  CT1812 was safe and well tolerated at 14 days QD dosing at levels up to 20x the estimated Minimum Efficacious Dose in healthy young and elderly volunteers. The newly initiated Phase 1b Study COG0102 (https://clinicaltrials.gov/show/NCT02907567) is supported in part under Award Number RF1AG054176 from the National Institute on Aging of the National Institutes of Health.

Cognition Therapeutics (CogRx) is a privately held biopharmaceutical company whose disease-relevant screening and novel chemistry platforms have produced a pipeline of disease modifying small molecule drug candidates which are being developed to treat Alzheimer’s disease and potentially other neurocognitive disorders.