Randomized trial of verubecestat for prodromal Alzheimer's disease
Open accessAbstract
BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).
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Whether non-prescribing of cholinesterase inhibitors will help patients by removing an intervention with known benefit or be detrimental to them is unknown.
“Whether non-prescribing of this drug will help patients by removing an intervention with known benefit or be detrimental to them is unknown.201”
From Dementia prevention, intervention, and care: 2020 report of the Lancet Commission (2020) · cites this paper as [201]
The Methods (Patients; page unavailable) say participants could continue a stable dose of an acetylcholinesterase inhibitor, but do not examine non-prescribing or withdrawal. The Discussion concerns verubecestat, not whether withholding cholinesterase inhibitors helps or harms patients. Searches for non-prescribing, discontinuation, and withdrawal found no passage addressing that question. (LLM, conf=0.76)
Experimental — accuracy not yet measuredInadequate efficacy and/or severe side effects in clinical trials with BACE1 inhibitors such as Verubecestat and Atabecestat have been reported.
“Similarly, inadequate efficacy and/or severe side effects in clinical trials with BACE1 inhibitors such as Verubecestat and Atabecestat [638–640] have also been reported.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [638]
The lanabecestat phase 3 investigation was halted due to a lack of efficacy, and the verubecestat and atabecestat trials were halted owing to inefficacy and safety concerns, respectively.
“The lanabecestat phase 3 investigation was halted due to a lack of efficacy, and the verubecestat and atabecestat trials were halted as well owing to inefficacy and safety concerns, respectively.”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Egan et al., 2019
All BACE inhibitor treatments reduced cerebrospinal fluid Aβ42 in a dose-dependent manner, but without providing any cognitive or functional benefits, and several were inadequately tolerated and ineffective in subjects with prodromal Alzheimer's disease.
“All the treatments reduced cerebrospinal fluid (CSF) Aβ42 in a dose-dependent manner, but without providing any cognitive or functional benefits, and several of them were inadequately tolerated and ineffective in subjects with prodromal AD.”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Egan et al., 2019
Clinical studies with BACE inhibitors such as lanabecestat, verubecestat, and atabecestat have lately been terminated due to unanticipated challenges.
“Due to unanticipated challenges, clinical studies with BACE inhibitors such as lanabecestat, verubecestat, and atabecestat have lately been terminated (Egan et al., 2019, Henley et al., 2019).”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Egan et al., 2019
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 [164]
Clinical trials with the BACE inhibitors lanabecestat, verubecestat, and atabecestat have been recently discontinued due to unexpected difficulties.
“However, the clinical trials with the BACE inhibitors lanabecestat,32 verubecestat,33 and atabecestat34 have been recently discontinued due to unexpected difficulties.”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [33]
The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness and safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).
“The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).10,32-34”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [33]
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Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention
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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].”
BackgroundArtificial intelligence for dementia drug discovery and trials optimization
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RetractedA Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer’s Disease
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- Authors
- Egan, M. F., Kost, J., Voss, T., Mukai, Y., Aisen, P. S., Cummings, J. L., Tariot, P. N., Vellas, B., van Dyck, C. H., Boada, M., Zhang, Y., Li, W., Furtek, C., Mahoney, E., Harper Mozley, L., Mo, Y., Sur, C., & Michelson, D.
- Affiliations
- University of Southern California (US)
- From Merck, Kenilworth, NJ (M.F.E., J.K., T.V., Y. Mukai, Y.Z., W.L., C.F., E.M., L.H.M., Y. Mo, C.S., D.M.); the University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Banner Alzheimer’s Institute, Phoenix, AZ (P.N.T.); Gerontopole, INSERM Unité 1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); Yale University School of Medicine, New Haven, CT (C.H.D.); and the...
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-04-11
- Volume
- 380
- Issue
- 15
- Pages
- 1408-1420
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6776078
- OpenAlex
- W2937097483
- Cited by
- 545
- References
- 38
- Citations by year
- 2026: 29 · 2025: 53 · 2024: 62 · 2023: 47 · 2022: 79 · 2021: 112 · 2020: 108 · 2019: 54
- FWCI
- 60.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- 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, prodromal Alzheimer's disease, BACE1 inhibitors, amyloid-beta, amyloid deposition, memory impairment, conversion to dementia, futility, dose comparison, cognitive decline, daily functioning, Alzheimer's disease prevention, drug safety, adverse events, trial termination
- MeSH terms
- Aged, Alzheimer Disease, Brain Chemistry, Cyclic S-Oxides, Double-Blind Method, Enzyme Inhibitors, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Organ Size, Thiadiazines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Treatment Failure, Disease Progression, Positron-Emission Tomography, Intention to Treat Analysis, Plaque, Amyloid, Cognitive Dysfunction, Prodromal Symptoms
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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