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

Educational Objective
To investigate whether lanabecestat, a potent inhibitor of the β-site amyloid precursor protein–cleaving enzyme, slows the progression of early Alzheimer disease and dementia.

1 Credit CME

JAMA Neurology

February 1, 2020

Original Investigation

Article Information and Disclosures

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

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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.

Abstract

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

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Article Information

Accepted for Publication: October 3, 2019.

Published Online: November 25, 2019. doi:10.1001/jamaneurol.2019.3988

Correction: This article was corrected on July 13, 2020, to fix the mean data reported for lanabecestat 20 mg vs placebo in DAYBREAK-ALZ.

Corresponding Author: John R. Sims, MD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (sims_john_r@lilly.com).

Author Contributions: Drs Wessels and Tariot contributed equally to this work as co–first authors. Dr Sims had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wessels, Tariot, Zimmer, Downing, Willis, Shering, Sims.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wessels, Zimmer, Selzler, Willis.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Andersen, Landry, Willis, Barker, Schumi.

Administrative, technical, or material support: Wessels, Zimmer, Selzler, Bragg, Downing, Willis, Shering, Sims.

Supervision: Wessels, Tariot, Zimmer, Mullen, Shering, Matthews, Sims.

Conflict of Interest Disclosures: Drs Wessels, Zimmer, Selzler, Krull, Downing, Willis, Shcherbinin, Matthews, and Sims; Ms Bragg; and Messrs Andersen and Landry reported being full-time employees and minor shareholders of Eli Lilly and Company. Dr Tariot reported receiving personal fees from AbbVie, AC Immune, Acadia, Auspex, Boehringer Ingelheim, Chase Pharmaceuticals, Corium, Eisai, GliaCure, INSYS Therapeutics, Pfizer, and T3D; receiving grants and personal fees from AstraZeneca, Avanir, Biogen, Eli Lilly and Company, H. Lundbeck A/S, Merck and Company, Roche, and Takeda; receiving grants from Amgen, Avid, GE Healthcare, Genentech, Novartis, National Institute on Aging, and Arizona Department of Health Services; owning stock options in Adamas; and being a contributor on a patent owned by the University of Rochester. Drs Mullen, Barker, Schumi, and Shering reported being employees of AstraZeneca, which holds the intellectual property for lanabecestat, and being minor shareholders of AstraZeneca. Drs Barker, Schumi, and Shering reported having a lanabecestat patent held by AstraZeneca pending and issued. Dr Stern reported receiving personal fees from Eli Lilly and Company and Biogen, receiving grants from Avid Radiopharmaceuticals (a subsidiary of Eli Lilly and Company), and receiving royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. Dr Vellas reported being a member of scientific boards for Otsuka, Eli Lilly and Company, Nestlé, MSD, Biogen, Roche, Accera, and Arcadia and receiving research grants from AbbVie, Eli Lilly and Company, Lundbeck, MSD, AstraZeneca, Nestlé, and Novartis. Dr Cohen reported receiving grants from Eli Lilly and Company to her research site for execution of lanabecestat clinical trials, receiving consultancy payments from Eli Lilly and Company for her participation in the lanabecestat steering committee, and receiving grants from Merck. Dr Boada reported receiving fees or consulting compensation from Servier, Roche, Eli Lilly and Company, Avid, Bayer, Elan, Janssen, Neuroptix, and Sanofi; receiving fees for lectures from Eli Lilly and Company, Nutricia, Roche, Schwabe Farma Ibérica SLU, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal Imaging Limited, Pfizer-Wyett, and Servier; receiving fees for being part of the advisory board of Eli Lilly and Company and Schwabe Farma Ibérica SLU; and receiving grants or research funding from AbbVie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Eli Lilly and Company, Merck Sharp & Dohme, Merck Inc, Kyowa Hakko Kirin, Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma Ibérica SLU. No other disclosures were reported.

Funding/Support: Eli Lilly and Company and AstraZeneca provided the funding for the study.

Role of the Funder/Sponsor: Eli Lilly and Company was responsible for data collection, monitoring, and statistical analyses. AstraZeneca was responsible for manufacturing investigational product and matching placebo. AstraZeneca participated in the study designs, and both companies interpreted the data and reviewed the manuscript. All final content decisions were made by the authors.

Additional Contributions: Patricia Bennett, MS, a full-time employee of Eli Lilly and Company, contributed to the data analyses. Writing support was provided by Sriram Govindan, PhD, and Rohit Bhandari, PhD (both full-time employees of Eli Lilly Services India Private Limited). None were compensated for their contributions. We thank all patients, site employees, investigators, vendor partners, employees, and former employees of Eli Lilly and Company and AstraZeneca.

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

Error in the Biomarker Subsection

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease

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