Randomized trial of verubecestat for mild-to-moderate Alzheimer's disease
Open accessAbstract
BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: 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. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).
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The first trial of population screening in the USA, screening 4005 primary care patients aged 65 years or older, found no clear benefit or harm in terms of quality of life, mood, or increasing diagnostic rates.
“The first trial of population screening took place in the USA, screening 4005 primary care patients aged 65 years or older. No clear benefit or harm in terms of quality of life, mood, or increasing diagnostic rates was found.197”
From Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (2020) · cites this paper as [197]
The Methods (Patient Population; page unavailable) describe a drug trial enrolling people aged 55–85 who already met criteria for probable Alzheimer’s dementia, not population screening of primary-care patients aged 65 or older. The Results (Patient Characteristics; page unavailable) report 1,958 patients assigned to verubecestat or placebo, rather than 4,005 patients screened. The reported screening outcomes are not addressed in these passages. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredAll BACE inhibitors tested in randomized clinical trials were discontinued for futility or safety reasons.
“All BACE inhibitors investigated in randomized clinical trials were discontinued for either futility or safety reasons.”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [96]
β-secretase inhibitors such as lanabecestat, verubecestat, and atabecestat target Bace-1 to decrease synthesis of amyloid beta.
“In order to decrease the synthesis of amyloid beta, β-secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8, Figure 5) [157,161,162], verubecestat (labeled as 9, Figure 5) [157,163,164], and atabecestat (labeled as 10, Figure 5) target the enzyme Bace-1 [157,165].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [163]
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“In order to decrease the synthesis of amyloid beta, β - secretase inhibitors (BACE inhibitors) such lanabecestat (labeled as 8 , Figure 5) [157,161,162], verubecestat (labeled as 9 , Figure 5) [157,163,164], and atabecestat (labeled as 10 , Figure 5) target the enzyme Bace-1 [157,165].”
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- Authors
- Egan, M. F., Kost, J., Tariot, P. N., Aisen, P. S., Cummings, J. L., Vellas, B., Sur, C., Mukai, Y., Voss, T., Furtek, C., Mahoney, E., Harper Mozley, L., Vandenberghe, R., Mo, Y., & Michelson, D.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Cleveland Clinic (US)
- University of Southern California (US)
- From Merck Research Laboratories, Merck, Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mukai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); Banner Alzheimer’s Institute, Phoenix, AZ (P.N.T.); University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Gerontopole, INSERM Unité 1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); and Leuven Institute of Neuroscience and Disease, Alzheimer...
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-05-03
- Volume
- 378
- Issue
- 18
- Pages
- 1691-1703
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6776074
- OpenAlex
- W2802659348
- Semantic Scholar
- 7d519aa90a797844d0e1f255dcd95d8458590aec
- Cited by
- 685
- References
- 32
- Citations by year
- 2026: 48 · 2025: 59 · 2024: 52 · 2023: 60 · 2022: 58 · 2021: 115 · 2020: 129 · 2019: 122 · 2018: 41
- FWCI
- 70.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Merck & Co., Inc.
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- verubecestat, Alzheimer's disease, BACE1 inhibitors, amyloid-beta, amyloid plaques, cognitive decline, activities of daily living, futility, early termination, dose comparison, ADAS-Cog, oral drug therapy, mild to moderate dementia, cerebrospinal fluid amyloid-beta, gamma-secretase inhibition
- MeSH terms
- Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Brain Chemistry, Cognition, Cyclic S-Oxides, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Thiadiazines, Biomarkers, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Treatment Failure, Amyloid Precursor Protein Secretases
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