Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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    Original Investigation
    November 25, 2019

    Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials

    Author Affiliations
    • 1Eli Lilly and Company, Indianapolis, Indiana
    • 2Banner Alzheimer’s Institute, University of Arizona College of Medicine, Phoenix
    • 3AstraZeneca, Waltham, Massachusetts, and Gaithersburg, Maryland
    • 4Now retired
    • 5Alzheimer’s Disease Center, Boston University School of Medicine, Boston, Massachusetts
    • 6Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Unités Mixtes de Recherche Institut National de la Santé et de la Recherche Médicale 1027, Université Toulouse III–Paul Sabatier, Toulouse, France
    • 7Toronto Memory Program, Toronto, Ontario, Canada
    • 8Re:Cognition Health, London, United Kingdom
    • 9Research Center and Memory Clinic, Fundació Alzheimer Centre Educacional, Institut Català de Neurociències Aplicades, Barcelona–Universitat Internacional de Catalunya, Barcelona, Spain
    • 10Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
    JAMA Neurol. 2020;77(2):199-209. doi:10.1001/jamaneurol.2019.3988
    Key Points

    Question  Does lanabecestat, a potent inhibitor of the beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1), slow the progression of early Alzheimer disease (AD) and mild AD dementia?

    Findings  In 2 global randomized clinical trials (AMARANTH [n = 2218] and DAYBREAK-ALZ [n = 1722]), daily lanabecestat at both doses tested (20 mg and 50 mg) failed to slow cognitive or functional decline compared with placebo.

    Meaning  In patients with early AD or mild AD dementia, lanabecestat was generally well tolerated but did not slow cognitive or functional decline.


    Importance  Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression.

    Objective  To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia.

    Design, Setting, and Participants  AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study.

    Interventions  Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo.

    Main Outcomes and Measures  The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population.

    Results  Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo.

    Conclusions and Relevance  Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline.

    Trial Registration  ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573