LY3202626 was an investigational maintenance therapy for Alzheimer’s disease being developed by Eli Lilly. However, clinical trials testing the treatment have been discontinued, and it is no longer under development.
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 disease by accumulating and forming plaques in the brain.
The idea is that BACE1 inhibitors 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 was thought that LY3202626 could be used to keep the brains of Alzheimer’s disease patients free of beta-amyloid accumulation, after other therapies, such as immunotherapy or antibody therapies, have cleared out existing beta-amyloid plaques.
LY3202626 was thought to be superior to other BACE1 inhibitors because it was reported to be 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 disease patients after two weeks of treatment.
LY3202626 in clinical trials
Eli Lilly conducted a Phase 1 clinical trial (NCT02323334) in four sequential parts between December 2014 and February 2016 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 disease patients.
Results of the trial were presented at the Alzheimer’s Association International Conference in 2016 and showed that healthy volunteers tolerated LY3202626 well at all doses, without adverse events for up to 42 days after the last dose. The medication also reached the brain effectively and reduced beta-amyloid in the blood and CSF of Alzheimer’s patients. These findings were also subsequently published in the journal Alzheimer’s and Dementia in 2016.
In September 2015, a second Phase 1 trial (NCT02555449) was launched to evaluate the pharmacokinetics (how the therapy moves through the body) of 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 recruited participants with mild Alzheimer’s dementia in the U.S., Australia, Canada, and Japan. Participants were assigned either one of two doses of LY3202626 or a placebo once daily for a year and were evaluated with tau PET scans for their neurofibrillar pathology burden (the presence of protein “tangles” characteristic in the brains of Alzheimer’s patients) at the beginning of the study and after one year. Secondary outcomes included cognitive testing and scores on the integrated Alzheimer’s disease rating scale (iADRS), a measure of cognition or the ability to think and make decisions, and the ability to function.
The trial was terminated in July 2018 after recruiting 316 participants due to a lack of significant results as well as a slight decline in cognition in patients who had been taking the medication longest.
A Phase 2 trial (NCT03367403), called TRAILBLAZER-ALZ, was to test the immunotherapy LY3002813 alone or in combination with LY3202626 in patients with early symptomatic Alzheimer’s disease. In October 2018, Lilly decided to continue the trial but without the addition of LY3202626. However, after the results of the NAVIGATE-AD trial and similar results from other BACE1 inhibitors, Lilly has also discontinued the development of LY3002813.
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