Does Verubecestat Signal the End of the Amyloid Hypothesis?

02/15/2017

Pharmaceutical giant Merck has announced that it is ending a late-stage clinical trial of its drug verubecestat in patients with mild to moderate Alzheimer’s disease after an interim data analysis found it was unlikely to have a positive “clinical effect.”

What does this mean for patients and for other Alzheimer’s drugs? In a recent article, I examined the anti-amyloid drugs for Alzheimer’s, including verubecestat, and stated that results from the late-stage trials would provide an answer on the “amyloid hypothesis.” This hypothesis posits that beta-amyloid proteins, which clump into plaques, are a primary cause of Alzheimer’s disease and removing beta-amyloid or blocking its accumulation will slow or stop the disease’s progression. Today’s announcement from Merck is a serious blow to that hypothesis.

Merck’s drug is a BACE inhibitor, which attempts to reduce the production of beta-amyloid in the brain before it forms plaques. Earlier data released from Merck showed that the drug “worked” as intended, meaning it did lower levels of beta-amyloid. The data is significant because it reveals that reducing production of beta-amyloid has no significant effect on the progression of Alzheimer’s disease in these patients. (Merck is continuing a different trial of verubecestat in patients in an earlier stage of Alzheimer’s.) The Merck results—along with the failure of Lilly’s solanezumab and other anti-amyloid drugs—raises questions for the remaining anti-amyloid drugs, including Biogen’s aducanumab, which targets beta-amyloid after it has formed plaques.

The Alzheimer’s Drug Discovery Foundation made the strategic decision to halt funding for anti-amyloid drugs back in 2010. The pharmaceutical industry was investing billions in these programs, and we chose to focus our efforts on advancing innovative and diverse drug targets that seemed more likely to be contributing factors to the disease. As we age, a host of biological processes occur that can damage our neurons, leading to Alzheimer’s and other dementias. As Alzheimer’s disease progresses, inflammation increases, our brain’s ability to use energy decreases, vascular issues can worsen, and epigenetic changes accrue.  The ADDF is funding multiple drugs that target each of these processes. In fact, the largest percentage of our portfolio is devoted to neuroprotective drugs, which protect brain cells from many of the potential sources of damage.  

While the verubecestat results are disheartening, they don’t derail any of the drug programs we are funding. The ADDF understands that a diverse pipeline of drug targets is critical, and we remain the only charity solely focused on funding drugs to prevent and treat Alzheimer’s disease.  

By Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF

Image: Betty Lee

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