Alzheimer Study: New Drug Did Not Reduce Cognitive Decline Interview with:
Dr. Michael F. Egan MD

Merck & Co.
North Wales, PA 19454 What is the background for this study? What are the main findings?

Response: A leading theory of Alzheimer’s Disease is that it is caused by the buildup of amyloid plaques in the brain. Amyloid is composed of a sticky peptide called Abeta.  Abeta production can be blocked by Inhibiting an enzyme called BACE.  In animal models, BACE inhibtion prevent amyloid accumulation.  We aimed to see if a potent BACE inhibitor would slow clinical decline in Alzheimer’s Disease.

EPOCH was a Phase 2/3 randomized, placebo-controlled, parallel-group, double-blind study evaluating efficacy and safety of two oral doses of verubecestat an investigational BACE inhibitor, administered once-daily versus placebo in patients with mild-to-moderate AD currently using standard of care treatment. The primary efficacy outcomes of the study are the change from baseline in cognition (assessed using the Alzheimer’s Disease Assessment Scale Cognitive Subscale, or ADAS-Cog),  as well as the change from baseline in function (assessed using the Alzheimer’s Disease Cooperative Study – Activities of Daily Living, or ADCS-ADL)  after 78 weeks of treatment.

Following the recommendation of the external Data Monitoring Committee (eDMC), which assessed overall benefit/risk during  the trial,  the study was stopped early, as there was “virtually no chance of finding a positive clinical effect.”

Verubecestat did not reduce cognitive or functional decline in patients with mild-to moderate Alzheimer’s disease and was associated with treatment-related adverse events. What should clinicians and patients take away from your report?

Response: Our trial showed that near-maximal reduction of Abeta in cerebrospinal fluid and a significant reduction in brain amyloid load by means of BACE inhibition for 78 weeks was not effective in slowing the clinical progression of mild-to-moderate Alzheimer’s disease.

This suggests that once dementia is present, disease progression may be independent of Abeta production or, alternatively, that the amyloid hypothesis of Alzheimer’s disease may not be correct.

Because Abeta deposition takes place years before clinical symptoms become apparent, it has been proposed that treatments targeting amyloid should be implemented early in the disease process, before the onset of clinical symptoms. What recommendations do you have for future research as a result of this study?

Response: Future research evaluating treatments targeting amyloid should be implemented early in the disease process, before the onset of clinical symptoms. Is there anything else you would like to add?

Response: Since the discontinuation of the EPOCH study, Merck also discontinued a Phase 3 study evaluating verubecestat in patients with prodromal Alzheimer’s disease (see here).

I am an employee of Merck & Co., Inc., Kenilworth, NJ USA Thank you for your contribution to the community.


Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease
Michael F. Egan, M.D., James Kost, Ph.D., Pierre N. Tariot, M.D., Paul S. Aisen, M.D., Jeffrey L. Cummings, M.D., Sc.D., Bruno Vellas, M.D., Ph.D., Cyrille Sur, Ph.D., Yuki Mukai, M.D., Tiffini Voss, M.D., Christine Furtek, B.S., Erin Mahoney, B.A., Lyn Harper Mozley, Ph.D., 

May 3, 2018
N Engl J Med 2018; 378:1691-1703
DOI: 10.1056/NEJMoa1706441

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on May 2, 2018 by Marie Benz MD FAAD