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Cited by 304Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials

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Vandenberghe, Rik, Rinne, Juha O., Boada, Mercè, Katayama, Sadao, Scheltens, Philip, Vellas, Bruno, Tuchman, Michael, Gass, Achim, Fiebach, Jochen B., Hill, Derek, Lobello, Kasia, Li, David, McRae, Tom, Lucas, Prisca, Evans, Iona, Booth, Kevin, Luscan, Gerald, Wyman, Bradley T., Hua, Lisa, Yang, Lingfeng, Brashear, H. Robert, Black, Ronald S., for the Bapineuzumab 3000 and 3001 Clinical Study Investigators·2016·Alzheimer's Research & Therapy
DOI 10.1186/s13195-016-0189-7PMC PMC4866415
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Abstract

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer’s disease (AD). Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale and the Disability Assessment for Dementia. Results: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. Conclusions: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. Trial registration: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143; registered 2 May 2008.

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Fig. 1 Disposition of patients with Alzheimer’s disease in the apolipoprotein E ε4 carrier and noncarrier studies. Recruitment and follow-up occurred between 28 May 2008 and 3 December 2012 for the carrier study and between 25 June 2008 and 27 November 2012 for the noncarrier study. ARIA-E, amyloid-related imaging abnormalities with edema or effusion; BAP, bapineuzumab; N/A, not applicable; PBO, placebo. aSubject participation status is unknown for five subjects (one in PBO group, four in BAP group) owing to missing conclusion of patient participation in study and/or conclusion of patient participation in treatment electronic case report form pages. Four of these subjects completed six infusions and the week 78 visit. One subject completed four infusions and the week 45 visit
Fig. 1 Disposition of patients with Alzheimer’s disease in the apolipoprotein E ε4 carrier and noncarrier studies. Recruitment and follow-up occurred between 28 May 2008 and 3 December 2012 for the carrier study and between 25 June 2008 and 27 November 2012 for the noncarrier study. ARIA-E, amyloid-related imaging abnormalities with edema or effusion; BAP, bapineuzumab; N/A, not applicable; PBO, placebo. aSubject participation status is unknown for five subjects (one in PBO group, four in BAP group) owing to missing conclusion of patient participation in study and/or conclusion of patient participation in treatment electronic case report form pages. Four of these subjects completed six infusions and the week 78 visit. One subject completed four infusions and the week 45 visitCC BY · PubMed Central
Fig. 2 Primary efficacy outcome analysis: change from baseline to week 78. a ADAS-Cog/11: total score range is 0 (least impairment) to 70 (most impairment). A positive change from baseline indicates worsening cognitive impairment. b DAD: total score range is 0 to 100, with higher scores indicating better function. A negative change from baseline indicates worsening function. Data shown are least squares means with standard error of the mean. ADAS-Cog/11, 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale; ApoE, apolipoprotein E; BAP, bapineuzumab; DAD, Disability Assessment for Dementia; LS, least squares
Fig. 2 Primary efficacy outcome analysis: change from baseline to week 78. a ADAS-Cog/11: total score range is 0 (least impairment) to 70 (most impairment). A positive change from baseline indicates worsening cognitive impairment. b DAD: total score range is 0 to 100, with higher scores indicating better function. A negative change from baseline indicates worsening function. Data shown are least squares means with standard error of the mean. ADAS-Cog/11, 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale; ApoE, apolipoprotein E; BAP, bapineuzumab; DAD, Disability Assessment for Dementia; LS, least squaresCC BY · PubMed Central
Fig. 3 Analysis of biomarkers and plasma Aβ: change from baseline to week 71. Data shown are least squares means with standard error of the mean. a PiB-PET analysis (b) CSF p-tau analysis (c) Volumetric analysis: An increase in BBSI on vMRI indicates a decrease in brain volume. d Plasma Aβ analysis. Aβ, amyloid β; ApoE, apolipoprotein E; BAP, bapineuzumab; BBSI, brain boundary shift integral; CSF, cerebrospinal fluid; LS, least squares; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; p-tau, phosphorylated tau protein; SUVr, standardized uptake value ratio; vMRI, volumetric magnetic resonance imaging. aExcludes nine patients who were PiB-PET-negative for Aβ at baseline
Fig. 3 Analysis of biomarkers and plasma Aβ: change from baseline to week 71. Data shown are least squares means with standard error of the mean. a PiB-PET analysis (b) CSF p-tau analysis (c) Volumetric analysis: An increase in BBSI on vMRI indicates a decrease in brain volume. d Plasma Aβ analysis. Aβ, amyloid β; ApoE, apolipoprotein E; BAP, bapineuzumab; BBSI, brain boundary shift integral; CSF, cerebrospinal fluid; LS, least squares; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; p-tau, phosphorylated tau protein; SUVr, standardized uptake value ratio; vMRI, volumetric magnetic resonance imaging. aExcludes nine patients who were PiB-PET-negative for Aβ at baselineCC BY · PubMed Central
Fig. 4 Individual patient baseline PiB-PET SUVr values (all PiB-PET population). ApoE, apolipoprotein E; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; SUVr, standardized uptake value ratio
Fig. 4 Individual patient baseline PiB-PET SUVr values (all PiB-PET population). ApoE, apolipoprotein E; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; SUVr, standardized uptake value ratioCC BY · PubMed Central

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Authors
Vandenberghe, R., Rinne, J. O., Boada, M., Katayama, S., Scheltens, P., Vellas, B., Tuchman, M., Gass, A., Fiebach, J. B., Hill, D., Lobello, K., Li, D., McRae, T., Lucas, P., Evans, I., Booth, K., Luscan, G., Wyman, B. T., Hua, L., Yang, L., Brashear, H. R., Black, R. S., & for the Bapineuzumab 3000 and 3001 Clinical Study Investigators
Affiliations
  • KU Leuven (BE)
  • University of Turku (FI)
  • Hiroshima University (JP)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Centre Hospitalier Universitaire de Toulouse (FR)
  • Palm Beach Neurological Center (US)
  • University Medical Centre Mannheim (DE)
  • Center for Stroke Research Berlin (DE)
  • Pfizer (United States) (US)
  • Pfizer (France) (FR)
  • Pfizer (United Kingdom) (GB)
  • Janssen Alzheimer Immunotherapy Research & Development (United States) (US)
Corresponding author
Vandenberghe, Rik
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2016-05-12
Volume
8
Issue
1
Pages
18-18
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-016-0189-7
PMC
PMC4866415
OpenAlex
W2385703614
Cited by
304
References
12
Citations by year
2026: 15 · 2025: 25 · 2024: 36 · 2023: 37 · 2022: 26 · 2021: 35 · 2020: 36 · 2019: 28 · 2018: 44 · 2017: 21 · 2016: 1
FWCI
25.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Pfizer Inc.
  • Janssen Research and Development
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
bapineuzumab, Alzheimer's disease, anti-amyloid therapy, amyloid-related imaging abnormalities, amyloid load, phosphorylated tau, cognitive decline, disability, drug safety, treatment efficacy
MeSH terms
Aged, Alzheimer Disease, Brain, Female, Humans, Male, Neuropsychological Tests, Severity of Illness Index, Biomarkers, Amyloid beta-Peptides, tau Proteins, Treatment Outcome, Positron-Emission Tomography, Apolipoprotein E4, Antibodies, Monoclonal, Humanized

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