How LY3202626 works
LY3202626 is a potent small-molecule inhibitor of beta-secretase 1 (BACE1), the enzyme that cuts the amyloid precursor protein (APP) into fragments, ultimately producing beta-amyloid, which is thought to contribute to the symptoms of Alzheimer’s by accumulating in the brain and forming plaques.
The idea of BACE1 inhibitors is that they will block the production of beta-amyloid at an early stage in what is known as the amyloid cascade, or before APP is cut into the smaller pieces that include beta-amyloid.
It is thought that LY3202626 could be used to keep the brains of Alzheimer’s patients free of beta-amyloid accumulation, after other therapies, such as immunization or antibody therapies, have cleared out existing beta-amyloid plaques.
LY3202626 may be superior to other BACE1 inhibitors because it is reported to have been highly effective in reducing levels of beta-amyloid in the cerebrospinal fluid (CSF, the fluid that bathes the brain and the spinal cord) of two Alzheimer’s patients after two weeks of treatment. The reduction in beta-amyloid in the CSF may indicate that less beta-amyloid is being produced in the brain.
LY3202626 in clinical trials
Between December 2014 and February 2016, Eli Lilly conducted a Phase 1 clinical trial (NCT02323334) in four sequential parts to evaluate the safety, pharmacodynamics (how the medication is metabolized in the body), and the effect of multiple doses of LY3202626 in healthy volunteers and Alzheimer’s patients.
At the Alzheimer’s Association International Conference 2016, volunteers were reported to have tolerated LY3202626 well at all doses, without adverse events up to 42 days after the last dose. The medication reached the brain effectively and reduced beta-amyloid in the blood and CSF.
In September 2015, a second Phase 1 trial (NCT02555449) was initiated to evaluate the pharmacokinetic (how the drug moves through the body) of labeled LY3202626 in eight healthy volunteers. The trial was completed in November 2015 but no results were posted.
In June 2016, Lilly started a Phase 2 trial (NCT02791191) called NAVIGATE-AD that is currently recruiting participants with mild Alzheimer’s dementia in the U.S., Australia, Canada, and Japan. Participants will be assigned either one of two doses of LY3202626 or placebo once daily for a year, and will be evaluated with tau PET scans for their neurofibrillar pathology burden (the presence of “tangles” of proteins characteristic in the brains of Alzheimer’s patients) at the beginning of the study and after one year.
The tangles are thought to be produced partly by an immune response to amyloid plaques in addition to the protein called tau. Secondary outcomes include cognitive testing and scores on the integrated Alzheimer’s disease rating scale (iADRS), a measure of cognition (the ability to think and make decisions) and ability to function. The trial is expected to be completed by summer 2018.
A Phase 2 trial (NCT03367403) testing the immunotherapy LY3002813 alone or in combination with LY3202626 in patients with early symptomatic Alzheimer’s disease is currently recruiting participants in the U.S. and Canada.
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