10 Apr Verubecestat Failed to Slow Progression of Early Alzheimer’s Disease
MedicalResearch.com: What is the background for this study?
Response: Alzheimer’s disease (AD) appears to be due to the gradual accumulation of amyloid over many years (the “amyloid hypothesis”). At some point, it is thought that amyloid triggers abnormalities in tau, which then forms deposits within neurons and leads to progressive neurodegeneration.
Amyloid is made up of a small, sticky peptide, Abeta, which is produced when the enzyme BACE cleaves a large protein called APP. In our trial, we tested whether a potent BACE inhibitor, verubecestat, could slow disease progression in subjects with early AD (or prodromal AD) by blocking formation of Abeta. A previous trial in subjects with dementia due to AD failed to find evidence of efficacy.
One possible reason for this failure is that subjects had too much amyloid in their brain already.
MedicalResearch.com: What are the main findings?
Response: The main finding from the prodromal Alzheimer’s disease trial is that verubecestat failed to slow clinical progression of the disease. Patients on the higher dose of verubecestat actually appeared to do worse clinically compared to subjects on placebo. Exploratory analyses suggested that verubecestat worsened cognition at early time points in the trial. This early worsening of cognition was also seen in another trial conducted by another group with a different BACE inhibitor. Their trial included subjects at an even earlier stage of AD (“preclinical AD”). The worsening of cognition in our trial was relatively small (small effect size). While experts had hoped that BACE inhibitors could be tested at very early stages of Alzheimer’s disease , these results suggest that BACE inhibitors may be associated with some risk.
MedicalResearch.com: What should readers take away from your report?
Response: BACE inhibition was a very promising approach for slowing or preventing AD, but not without uncertainty and risk. The results are clear in showing that this approach is not effective in subjects with prodromal Alzheimer’s disease .
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Given the challenges of anti amyloid approaches so far, shifting research focus to tau may be more attractive.
Disclosures: I am a full time employee of Merck (known as MSD outside the US).
Michael F. Egan, M.D., James Kost, Ph.D., Tiffini Voss, M.D., Yuki Mukai, M.D., Paul S. Aisen, M.D., Jeffrey L. Cummings, M.D., Sc.D., Pierre N. Tariot, M.D., Bruno Vellas, M.D., Ph.D., Christopher H. van Dyck, M.D., Merce Boada, M.D., Ying Zhang, Ph.D., Wen Li, Ph.D.,
April 11, 2019
N Engl J Med 2019; 380:1408-1420
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