Lanabecestat

Lanabecestat (previously known as AZD3293 and LY3314814) is a small molecule therapy candidate that was being developed by AstraZeneca and Eli Lilly (Lilly) for the treatment of early Alzheimer’s disease. However, the companies discontinued the development of lanabecestat in June 2018 after an analysis suggested that clinical trials would not meet their primary objectives.

How lanabecestat works

Alzheimer’s disease is characterized by a gradual buildup of beta-amyloid plaques in the brain. These plaques consist of insoluble misfolded protein fragments that are toxic to brain cells. They cause damage to nerve cells, resulting in a decline in memory and the ability to think and learn.

The formation of beta-amyloid plaques involves the action of multiple enzymes, including BACE1 (beta-secretase cleaving enzyme). Lanabecestat worked by inhibiting BACE1, blocking the formation of beta-amyloid. In this way, it was thought that lanabecestat could help prevent the formation of beta-amyloid plaques and slow or even stop the progression of the disease.

Lanabecestat in clinical trials

Several Phase 1 trials demonstrated that lanabecestat is well-tolerated across a range of doses and reduces the level of beta-amyloid in the fluid surrounding the brain and spinal cord (the cerebrospinal fluid), as well as in the blood. It was reported that the treatment could effectively suppress beta-amyloids with as little as a once-weekly dose. 

Based on these findings, a multicenter Phase 2/3 clinical trial (NCT02245737) was launched. The trial, called AMARANTH, compared two doses of lanabecestat with placebo in patients with early Alzheimer’s disease. The primary outcome of the study was to look at changes from the start of the study on the 13-item Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog13). Some additional outcomes measured were the change in the clinical dementia rating sum of boxes (CDR-SOB), a measure of the severity of dementia in Alzheimer’s disease, changes in clinical markers, and brain scan results. 

After positive interim results, AstraZeneca and Eli Lilly announced in April 2016 that the trial would continue to Phase 3.

A second Phase 3 trial (NCT02783573) called DAYBREAK-ALZ was conducted in patients with mild dementia caused by Alzheimer’s disease. The study was going to compare two once-daily doses of lanabecestat given for three years to two groups of participants.

However, both the AMARANTH and DAYBREAK-ALZ trials were terminated early after interim results showed that neither study was likely to meet its primary goals. Due to these results, AstraZeneca and Lilly decided to discontinue the investigation of lanabecestat.

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