Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab
| Autor: | Sangeeta Raje, Enchi Liu, Kaori Ito, Ming Lu, Brian Corrigan, Scot Styren, Alberto Russu, Omoniyi J. Adedokun, H. Robert Brashear, Steven Xu, Chuanpu Hu, Mahesh N. Samtani |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Apolipoprotein E Male medicine.medical_specialty Standardized uptake value tau Proteins Placebo Antibodies Monoclonal Humanized 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cerebrospinal fluid Apolipoproteins E Double-Blind Method Alzheimer Disease Internal medicine medicine Humans Immunologic Factors Bapineuzumab Aniline Compounds business.industry General Neuroscience General Medicine Mental Status and Dementia Tests Magnetic Resonance Imaging Psychiatry and Mental health Clinical Psychology Thiazoles 030104 developmental biology Treatment Outcome chemistry Pharmacodynamics Area Under Curve Positron-Emission Tomography Biomarker (medicine) Female Geriatrics and Gerontology Pittsburgh compound B business 030217 neurology & neurosurgery Biomarkers medicine.drug |
| Zdroj: | Journal of Alzheimer's disease : JAD. 53(2) |
| ISSN: | 1875-8908 |
| Popis: | Background Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients. Objective To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Methods Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Results Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Conclusions Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated. |
| Databáze: | OpenAIRE |
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