Why are BACE inhibitors failing clinical trials?

The β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) is an enzyme required for the production of β-amyloid (Aβ) in one of the main signalling pathways in Alzheimer’s disease (AD). Excessive production of this leads to Aβ plaque formation, a pathological hallmark of AD. As such, many institutes have been experimenting with blocking this production by producing BACE1 inhibitors.

However, over the years, these have proven unsuccessful due to a variety of reasons. Completely blocking the activity of an enzyme which produces amyloid plaques interferes in the regulation of new neurons generated in the adult hippocampus, according to a study of mice published in eNeuro. These new findings may also identify why the drugs are failing in clinical trials.

Several trials of BACE1 inhibitors have been suspended due to their inability to improve AD symptoms or because of adverse side effects, despite reducing Aβ plaque formation. Many scientists think that BACE inhibitors fail as they prevent amyloid production later in the course of illness and may be more effective if used earlier. Trials failing on safety issues may be due to the structure of the drug.

The recent Merck BACE inhibitor clinical trial failure may have been due to safety issues with BACE inhibition. Since the trial failures have not been attributed to a particular reason, the issue may stem from the understanding of BACE inhibition itself, and the role that BACE1 plays in a healthy brain.

Researchers are now looking to identify if BACE1 is involved in adult hippocampal neurogenesis; a process that may be responsible for the brains ability to repair itself.

The study revealed that although mice which do not express BACE1 had an increased production of neural stem cells, fewer of these cells reach maturity and may compromise brain function. Thus, AD patients treated with BACE1 inhibitors may be experiencing a similar scenario, and partial rather than complete BACE1 inhibition may be a reasonable alternative strategy to prevent plaque formation, while maintaining adult neurogenesis.