BackgroundOur objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer’s disease (AD).MethodsTwo 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.ResultsA 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.ConclusionsThese 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 registrationNoncarriers (3000) ClinicalTrials.gov identifier NCT00667810; registered 24 Apr 2008.Carriers (3001) ClinicalTrials.gov identifier NCT00676143; registered 2 May 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0189-7) contains supplementary material, which is available to authorized users.

Objective: To evaluate the effects of bapineuzumab on brain b-amyloid (Ab) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET.Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers,were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Ab monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Ab over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Bapineuzumab, a humanized monoclonal antibody targeting the N-terminus of b-amyloid (Ab), was recently evaluated in phase 3 trials for the treatment of mild to moderate Alzheimer disease (AD) dementia. As part of those investigations, brain volumetric MRI, brain amyloid PET imaging, and CSF sampling were performed in biomarker substudies. The primary aim of the substudies was to assess the pharmacologic effects of bapineuzumab on AD CNS biomarkers. The PET substudy used 11 C-Pittsburgh compound B ( 11 C-PiB)-PET as a measure of brain fibrillar Ab.1 Differences in the incidence of amyloid-related imaging abnormalities (ARIA) and potential efficacy signals had been seen between participants treated with bapineuzumab who were APOE e4 carriers and noncarriers in phase 2 studies 2-4 ; therefore, separate clinical trials for APOE e4 carriers (Study 302) and noncarriers (Study 301) were conducted in phase 3. The primary clinical and biomarker endpoint results of these trials were recently All authors contributed equally to this work.

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.

BackgroundImmunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer’s disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.MethodsThe long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses.ResultsBecause of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7 % of the patients who originally received placebo and 66.9 % of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1 % and 67.6 % of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7 % and 64.3 % of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11 % of placebo + bapineuzumab and 4 % of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study.ConclusionsIn these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials.Trial registrationNoncarriers (Study 3002): ClinicalTrials.gov NCT00996918. Registered 14 October 2009.Carriers (Study 3003): ClinicalTrials.gov NCT00998764. Registered 16 October 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0193-y) contains supplementary material, which is available to authorized users.

Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.