Verubecestat: Another one bites the dust?

by Joshua Grill, PhD February 15, 2017

Merck announced on Tuesday, February 14, that yet another clinical trial of a promising Alzheimer’s disease drug had failed. The trial was testing the safety and efficacy of verubecestat, an oral therapy that, at some doses, can reduce amyloid beta production by as much as 90% (Kennedy et al., Science 2016). The trial was being conducted in patients with mild-to-moderate dementia and was stopped because it was determined early that there was essentially no chance of showing a clinical benefit of the drug, compared to placebo. Perhaps importantly, based on the limited available information at this time, safety did not appear to play a role in the decision and the press release from Merck states that the safety signal in the trial did not indicate a need to halt this or other studies. It is the “other studies,” much like other studies we’ve written about in previous blogs, where one can derive a glimmer of hope. Merck will continue a trial of verubecestat in prodromal Alzheimer’s disease (people with memory problems but who remain functionally independent).

The verubecestat study adds to a growing list of trials in which intervention at the stage of dementia was inadequate. One possible explanation is that treatment simply was not early enough. Indeed, we refer to the “amyloid cascade hypothesis” and cascade may be a critical component. Putting up a dam at the bottom of the waterfall may not be helpful. One of the strongest pieces of evidence to support the amyloid hypothesis is the observation that people with a very rare genetic mutation that causes them to produce about 40% less amyloid are five times more likely to live out their older years free of dementia (Jonsson et al., Nature 2012). This reduction in amyloid is far slighter than that caused by drugs like verubecestat, but it is present for mutation carriers’ whole lives. Thus, the question may not be how much do we need to reduce amyloid, but rather, how early do we need to do so?