Authors: Brody, Mark | Liu, Enchi | Di, Jianing | Lu, Ming | Margolin, Richard A. | Werth, John L. | Booth, Kevin | Shadman, Anna | Brashear, H. Robert | Novak, Gerald
Article Type: Research Article
Abstract: Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42 ) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities–edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. Methods: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led …to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). Results: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. Conclusion: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab. Show more
Keywords: Alzheimer’s disease, amyloid burden, bapineuzumab, biomarker, pharmacokinetics
DOI: 10.3233/JAD-160369
Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1509-1519, 2016
Authors: Russu, Alberto | Samtani, Mahesh N. | Xu, Steven | Adedokun, Omoniyi J. | Lu, Ming | Ito, Kaori | Corrigan, Brian | Raje, Sangeeta | Liu, Enchi | Brashear, H. Robert | Styren, Scot | Hu, Chuanpu
Article Type: Research Article
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 11 C-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. Show more
Keywords: Amyloid PET, APOE*E4, bapineuzumab, brain volume, cerebrospinal fluid, disease severity, exposure-response modeling, p-tau
DOI: 10.3233/JAD-151065
Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 535-546, 2016
Authors: Salloway, Stephen P. | Sperling, Reisa | Fox, Nick C. | Sabbagh, Marwan N. | Honig, Lawrence S. | Porsteinsson, Anton P. | Rofael, Hany | Ketter, Nzeera | Wang, Daniel | Liu, Enchi | Carr, Stephen | Black, Ronald S. | Brashear, H. Robert
Article Type: Research Article
Abstract: Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer’s disease dementia (apolipoprotein (APOE ) ɛ 4 carriers and noncarriers) is summarized. Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the …parent studies. Results: A total of 1,462 (688 were APOE ɛ 4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies. Show more
Keywords: Alzheimer’s disease, amyloid-related imaging abnormality with edema/effusions, bapineuzumab, long-term safety
DOI: 10.3233/JAD-171157
Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 689-707, 2018
Authors: Pasquier, Florence | Sadowsky, Carl | Holstein, Ann | Leterme, Ghislaine Le Prince | Peng, Yahong | Jackson, Nicholas | Fox, Nick C. | Ketter, Nzeera | Liu, Enchi | Ryan, J. Michael | for the ACC-001 (QS-21) Study Team
Article Type: Research Article
Abstract: Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer’s disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party–unblinded, placebo-controlled, multiple ascending–dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic …resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx–40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16–56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD. Show more
Keywords: Active immunization, Alzheimer’s disease, amyloid-β peptides, amyloid-β protein, amyloid plaques, clinical trial, immunotherapy
DOI: 10.3233/JAD-150376
Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1131-1143, 2016
Authors: Novak, Gerald | Fox, Nick | Clegg, Shona | Nielsen, Casper | Einstein, Steven | Lu, Yuan | Tudor, Iulia Cristina | Gregg, Keith | Di, Jianing | Collins, Peter | Wyman, Bradley T. | Yuen, Eric | Grundman, Michael | Brashear, H. Robert | Liu, Enchi
Article Type: Research Article
Abstract: Background: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE* ɛ 4 carriers and noncarriers, respectively, with Alzheimer’s disease. Objectives: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. Methods: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. Results: For BBSI and HBSI, there were no significant treatment-related …differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. Conclusions: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences. Show more
Keywords: Alzheimer’s disease, bapineuzumab, brain boundary shift integral, brain volume, hippocampal boundary shift integral, magnetic resonance imaging, randomized controlled trial, ventricular boundary shift integral, ventricular volume
DOI: 10.3233/JAD-150448
Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1123-1134, 2016
