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

Alette M. Wessels, Pierre N. Tariot, Jennifer A. Zimmer, Katherine J. Selzler, Sonja M. Bragg, Scott W. Andersen, John Landry, James H. Krull, Anncatherine M. Downing, Brian A. Willis, Sergey Shcherbinin, Jamie Mullen, Peter Barker, Jennifer Schumi, Craig Shering, Brandy R. Matthews, Robert A. Stern, Bruno Vellas, Sharon Cohen, Emer MacsweeneyMercè Boada, John R. Sims

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJAMA Neurology
DOIs
StateAccepted/In press - Jan 1 2019
Externally publishedYes

Fingerprint

Alzheimer Disease
Randomized Controlled Trials
Safety
Therapeutics
Placebos
Activities of Daily Living
National Institute on Aging (U.S.)
Hair Color
Outcome Assessment (Health Care)
Medical Futility
Hypopigmentation
Equipment and Supplies
Amyloid Precursor Protein Secretases
Phase III Clinical Trials
Vitiligo
Amyloid beta-Protein Precursor
Double-Blind Method
Amyloid
Neurodegenerative Diseases
Population

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Wessels, A. M., Tariot, P. N., Zimmer, J. A., Selzler, K. J., Bragg, S. M., Andersen, S. W., ... Sims, J. R. (Accepted/In press). Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.3988

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease : The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. / Wessels, Alette M.; Tariot, Pierre N.; Zimmer, Jennifer A.; Selzler, Katherine J.; Bragg, Sonja M.; Andersen, Scott W.; Landry, John; Krull, James H.; Downing, Anncatherine M.; Willis, Brian A.; Shcherbinin, Sergey; Mullen, Jamie; Barker, Peter; Schumi, Jennifer; Shering, Craig; Matthews, Brandy R.; Stern, Robert A.; Vellas, Bruno; Cohen, Sharon; Macsweeney, Emer; Boada, Mercè; Sims, John R.

In: JAMA Neurology, 01.01.2019.

Research output: Contribution to journalArticle

Wessels, AM, Tariot, PN, Zimmer, JA, Selzler, KJ, Bragg, SM, Andersen, SW, Landry, J, Krull, JH, Downing, AM, Willis, BA, Shcherbinin, S, Mullen, J, Barker, P, Schumi, J, Shering, C, Matthews, BR, Stern, RA, Vellas, B, Cohen, S, Macsweeney, E, Boada, M & Sims, JR 2019, 'Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials', JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.3988
Wessels, Alette M. ; Tariot, Pierre N. ; Zimmer, Jennifer A. ; Selzler, Katherine J. ; Bragg, Sonja M. ; Andersen, Scott W. ; Landry, John ; Krull, James H. ; Downing, Anncatherine M. ; Willis, Brian A. ; Shcherbinin, Sergey ; Mullen, Jamie ; Barker, Peter ; Schumi, Jennifer ; Shering, Craig ; Matthews, Brandy R. ; Stern, Robert A. ; Vellas, Bruno ; Cohen, Sharon ; Macsweeney, Emer ; Boada, Mercè ; Sims, John R. / Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease : The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. In: JAMA Neurology. 2019.
@article{d1e4f5339ec9479dbd39f93d9cadbf05,
title = "Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials",
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.",
author = "Wessels, {Alette M.} and Tariot, {Pierre N.} and Zimmer, {Jennifer A.} and Selzler, {Katherine J.} and Bragg, {Sonja M.} and Andersen, {Scott W.} and John Landry and Krull, {James H.} and Downing, {Anncatherine M.} and Willis, {Brian A.} and Sergey Shcherbinin and Jamie Mullen and Peter Barker and Jennifer Schumi and Craig Shering and Matthews, {Brandy R.} and Stern, {Robert A.} and Bruno Vellas and Sharon Cohen and Emer Macsweeney and Merc{\`e} Boada and Sims, {John R.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1001/jamaneurol.2019.3988",
language = "English (US)",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",

}

TY - JOUR

T1 - Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease

T2 - The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials

AU - Wessels, Alette M.

AU - Tariot, Pierre N.

AU - Zimmer, Jennifer A.

AU - Selzler, Katherine J.

AU - Bragg, Sonja M.

AU - Andersen, Scott W.

AU - Landry, John

AU - Krull, James H.

AU - Downing, Anncatherine M.

AU - Willis, Brian A.

AU - Shcherbinin, Sergey

AU - Mullen, Jamie

AU - Barker, Peter

AU - Schumi, Jennifer

AU - Shering, Craig

AU - Matthews, Brandy R.

AU - Stern, Robert A.

AU - Vellas, Bruno

AU - Cohen, Sharon

AU - Macsweeney, Emer

AU - Boada, Mercè

AU - Sims, John R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075646614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075646614&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2019.3988

DO - 10.1001/jamaneurol.2019.3988

M3 - Article

C2 - 31764959

AN - SCOPUS:85075646614

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

ER -