%0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. %A Novak, Gerald %A Fox, Nick %A Clegg, Shona %A Nielsen, Casper %A Einstein, Steven %A Lu, Yuan %A Tudor, Iulia Cristina %A Gregg, Keith %A Di, Jianing %A Collins, Peter %A Wyman, Bradley T %A Yuen, Eric %A Grundman, Michael %A Brashear, H Robert %A Liu, Enchi %K Aged %K Alzheimer Disease %K Antibodies, Monoclonal, Humanized %K Apolipoprotein E4 %K Brain %K Double-Blind Method %K Female %K Heterozygote %K Humans %K Least-Squares Analysis %K Magnetic Resonance Imaging %K Male %K Nootropic Agents %K Organ Size %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 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.

%B J Alzheimers Dis %V 49 %P 1123-34 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639957?dopt=Abstract %R 10.3233/JAD-150448 %0 Journal Article %J N Engl J Med %D 2014 %T Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. %A Salloway, Stephen %A Sperling, Reisa %A Fox, Nick C %A Blennow, Kaj %A Klunk, William %A Raskind, Murray %A Sabbagh, Marwan %A Honig, Lawrence S %A Porsteinsson, Anton P %A Ferris, Steven %A Reichert, Marcel %A Ketter, Nzeera %A Nejadnik, Bijan %A Guenzler, Volkmar %A Miloslavsky, Maja %A Wang, Daniel %A Lu, Yuan %A Lull, Julia %A Tudor, Iulia Cristina %A Liu, Enchi %A Grundman, Michael %A Yuen, Eric %A Black, Ronald %A Brashear, H Robert %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Antibodies, Monoclonal, Humanized %K Apolipoproteins E %K Biomarkers %K Brain %K Cognition %K Double-Blind Method %K Edema %K Female %K Humans %K Intention to Treat Analysis %K Male %K Middle Aged %K Neuropsychological Tests %K Phosphorylation %K Positron-Emission Tomography %K Severity of Illness Index %K tau Proteins %K Treatment Failure %X

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.).

%B N Engl J Med %V 370 %P 322-33 %8 2014 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24450891?dopt=Abstract %R 10.1056/NEJMoa1304839