Scientists from the Cleveland Clinic Lerner Research Institute in the United States have found that gradually depleting an enzyme called BACE1 completely reverses formation of amyloid plaques.
MSD confirmed that it will discontinue the Phase III APECS study, assessing the investigational BACE1 inhibitor in people with prodromal Alzheimer's disease (AD), on the recommendation of an external Data Monitoring Committee.
"Our study provides genetic evidence that preformed amyloid deposition can be completely reversed after sequential and increased deletion of BACE1 in the adult".
Gradually depleting BACE1 cleared their brains of a toxic protein building block, beta-amyloid, that is a key hallmark of Alzheimer's.
The Cleveland Clinic team wanted to block BACE1 in mice, but couldn't do it too early, because the complete absence of the enzyme leads to developmental brain defects. The results were remarkably positive, with the reduction in BACE1 activity not only stalling the development of amyloid plaques in the mice, but actually removing the deposits that had already formed. So the team engineered a mouse model that gradually lost the enzyme as it grew older and then bred those mice with rodents that were engineered to develop amyloid plaques from an age of 75 days.
On Tuesday, executives were forced to admit defeat, dealing an ominous forewarning to the four other major pharmaceutical companies which have bet big on this inhibitor, BACE1, to treat the disease.
As Yan and colleagues explain in their paper, the enzyme in question helps to produce beta-amyloid peptide. However, when the researchers made electrophysiological recordings of neurons from these animals, they found that depletion of BACE1 only partially restored synaptic function, suggesting that BACE1 may be required for optimal synaptic activity and cognition. The controversial move involved several hundred layoffs and a significant reallocation of funds to other research areas.
The most promising clinical trial for an Alzheimer's drug has been pulled as a review showed it is unlikely to work.
Another major pharma player, Roche, canceled its BACE1 research back in 2013, but several large-scale trials for BACE1 inhibitors are still now in development or underway.
There have been previous attempts to develop drugs that inhibit BACE1, but these have mostly failed owing to unacceptable side-effects, such as liver toxicity and eye problems.
The O'Donnell Brain Institute is also leading a five-year national clinical trial aiming to establish how fitness levels and Alzheimer's disease are connected.