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.