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

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

Alette M Wessels et al. JAMA Neurol.

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.

Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. CONSORT Diagrams of Study Flow
A and B, Most patients did not enter the delayed-start (DS) period because of early study termination. AD indicates Alzheimer disease; CONSORT, Consolidated Standards of Reporting Trials; PC, placebo-controlled. aIntent-to-treat population.
Figure 2.
Figure 2.. Change in Outcome Scores From Baseline in AMARANTH and DAYBREAK-ALZ
A-C, Results are presented as least squares (LS) mean (SE) change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog13) (higher scores indicate greater cognitive impairment), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL) (lower scores indicate greater functional impairment), and Clinical Dementia Rating–sum of boxes (CDR-SB) (higher scores indicate greater cognitive/functional impairment).

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