BACKGROUND Bapineuzumab, a humanized anti–amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer’s disease. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer’s disease — one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were −0.2 (P = 0.80) and −1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS Bapineuzumab did not improve clinical outcomes in patients with Alzheimer’s disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.)

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Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

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Background Amyloid-related imaging abnormalities (ARIA) have been reported in Alzheimer’s disease (AD) patients treated with bapineuzumab, a humanized monoclonal antibody to amyloid-β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). A better understanding of the incidence and risk factors for ARIA may further the development of amyloid-modifying treatments for AD. Methods Two neuroradiologists independently reviewed (kappa=0.76) and then reached consensus reads on over 2500 FLAIR-MRIs from 262 participants in three phase 2 studies of bapineuzumab. Subjects (n=210) were included in risk analyses if they had no evidence of ARIA-E on pre-treatment MRI, received bapineuzumab, and had at least one post-treatment MRI. Findings 36/210 (17%) subjects developed ARIA-E during treatment; 28 of these 36 (78%) did not report associated symptoms. Adverse events reported in 8 symptomatic patients included headache, confusion, neuropsychiatric and gastrointestinal symptoms. 15/36 of the ARIA-E cases (42%) were detected only on central review. 13/15 received additional infusions while ARIA-E was present, without any associated symptoms reported. ARIA-E incidence increased with bapineuzumab dose (Hazard Ratio [HR] 2.24 per mg/kg increase in dose; p<0·001) and with APOE ε4 allele number (HR 2.55 per allele; p<0·001). Interpretation ARIA appears to represent a spectrum of imaging findings with variable clinical correlates, with some cases remaining asymptomatic even when treated through ARIA-E. The increased risk of ARIA with APOE ε4 and bapineuzumab dose, and the time course in relation to dosing, is consistent with alterations in vascular amyloid burden.