title: Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer's Disease Trials of Bapineuzumab.
abstract: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients.
  
  
  
  To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Janssen Research & Development, LLC, Beerse, Belgium.
authors.forename: Alberto
authors.initials: A
authors.lastname: Russu
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Xu
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Omoniyi J
authors.initials: OJ
authors.lastname: Adedokun
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Ito
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Corrigan
authors.affiliation: Pfizer Inc., Collegeville, PA, USA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Raje
authors.affiliation: Janssen Research & Development, LLC, San Diego, CA, USA.
authors.forename: Enchi
authors.initials: E
authors.lastname: Liu
authors.affiliation: Janssen Research & Development, LLC, Freemont, CA, USA.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Brashear
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Styren
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D000814:Aniline Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics; D019540:Area Under Curve; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D000073216:Mental Status and Dementia Tests; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000378:metabolism / Q000493:pharmacokinetics; D016896:Treatment Outcome; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D061067:Antibodies, Monoclonal, Humanized; D001057:Apolipoproteins E; D015415:Biomarkers; D007155:Immunologic Factors; D013844:Thiazoles; D016875:tau Proteins; C545458:bapineuzumab
keywords: APOE*E4; Amyloid PET; bapineuzumab; brain volume; cerebrospinal fluid; disease severity; exposure-response modeling; p-tau