Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer’s Disease Trials of Bapineuzumab

Article type: Research Article

Authors: Russu, Alberto^{a; *} | Samtani, Mahesh N.^b | Xu, Steven^b | Adedokun, Omoniyi J.^c | Lu, Ming^c | Ito, Kaori^f | Corrigan, Brian^f | Raje, Sangeeta^g | Liu, Enchi^d | Brashear, H. Robert^e | Styren, Scot^f | Hu, Chuanpu^c

Affiliations: [a] Janssen Research & Development, LLC, Beerse, Belgium | [b] Janssen Research & Development, LLC, Raritan, NJ, USA | [c] Janssen Research & Development, LLC, Spring House, PA, USA | [d] Janssen Research & Development, LLC, San Diego, CA, USA | [e] Janssen Research & Development, LLC, Freemont, CA, USA | [f] Pfizer Inc., Groton, CT, USA | [g] Pfizer Inc., Collegeville, PA, USA

Correspondence: [*] Correspondence to: Dr. Alberto Russu, Janssen Research & Development, Clinical Pharmacology & Pharmacometrics, Turnhoutseweg 30, 2340 Beerse, Belgium. Tel.: +32 14 607948; Fax: +32 14 605834; E-mail: arussu@its.jnj.com.

Abstract: 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.

Keywords: Amyloid PET, APOE^*E4, bapineuzumab, brain volume, cerebrospinal fluid, disease severity, exposure-response modeling, p-tau

DOI: 10.3233/JAD-151065

Journal: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 535-546, 2016