Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease
- Michael F Egan 1, James Kost 1, Tiffini Voss 1, Yuki Mukai 1, Paul S Aisen 1, Jeffrey L Cummings 1, Pierre N Tariot 1, Bruno Vellas 1, Christopher H van Dyck 1, Merce Boada 1, Ying Zhang 1, Wen Li 1, Christine Furtek 1, Erin Mahoney 1, Lyn Harper Mozley 1, Yi Mo 1, Cyrille Sur 1, David Michelson 1
- Michael F Egan 1, James Kost 1, Tiffini Voss 1
- 1From 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 Research Center and Memory Clínic, Fundació Alzheimer Centre Educacional, Institut Català de Neurociènces Aplicades-Universitat Internacional de Catalunya, Barcelona, and the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid - both in Spain (M.B.).
- 0From 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 Research Center and Memory Clínic, Fundació Alzheimer Centre Educacional, Institut Català de Neurociènces Aplicades-Universitat Internacional de Catalunya, Barcelona, and the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid - both in Spain (M.B.).
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View abstract on PubMed
Summary
This summary is machine-generated.Verubecestat, an investigational drug for prodromal Alzheimer's disease, failed to show clinical benefits and worsened outcomes in some measures. This BACE-1 inhibitor did not prevent dementia progression in patients with early signs of Alzheimer's.
Area Of Science
- Neuroscience
- Pharmacology
- Clinical Trials
Background
- Prodromal Alzheimer's disease (AD) presents a critical window for therapeutic intervention before dementia onset.
- Amyloid-beta (Aβ) deposition is a key pathological hallmark targeted by disease-modifying drugs.
- Verubecestat, a β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor, was developed to reduce Aβ production.
Purpose Of The Study
- To evaluate the efficacy and safety of verubecestat in patients with prodromal Alzheimer's disease.
- To assess the impact of verubecestat on cognitive and functional decline over 104 weeks.
- To determine if BACE-1 inhibition can prevent or delay the progression to dementia.
Main Methods
- A randomized, double-blind, placebo-controlled trial involving 1454 patients with memory impairment and elevated brain amyloid.
- Patients received verubecestat (12 mg or 40 mg daily) or placebo for 104 weeks.
- Primary outcome: change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score; secondary outcomes included cognitive and functional assessments.
Main Results
- The trial was terminated early due to futility.
- Verubecestat did not significantly improve CDR-SB scores compared to placebo (P=0.67 for 12 mg).
- The 40 mg dose showed a trend towards worse outcomes (P=0.01) and increased dementia progression (HR 1.38), with more adverse events.
Conclusions
- Verubecestat failed to demonstrate efficacy in patients with prodromal Alzheimer's disease.
- Higher doses of verubecestat were associated with potential worsening of cognitive and functional status.
- The study highlights the challenges in targeting amyloid production for early AD intervention.
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