Title | Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Salloway, S, Sperling, R, Fox, NC, Blennow, K, Klunk, W, Raskind, M, Sabbagh, M, Honig, LS, Porsteinsson, AP, Ferris, S, Reichert, M, Ketter, N, Nejadnik, B, Guenzler, V, Miloslavsky, M, Wang, D, Lu, Y, Lull, J, Tudor, ICristina, Liu, E, Grundman, M, Yuen, E, Black, R, H Brashear, R |
Corporate Authors | Bapineuzumab 301 and 302 Clinical Trial Investigators |
Journal | N Engl J Med |
Volume | 370 |
Issue | 4 |
Pagination | 322-33 |
Date Published | 2014 Jan 23 |
ISSN | 1533-4406 |
Keywords | Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Antibodies, Monoclonal, Humanized, Apolipoproteins E, Biomarkers, Brain, Cognition, Double-Blind Method, Edema, Female, Humans, Intention to Treat Analysis, Male, Middle Aged, Neuropsychological Tests, Phosphorylation, Positron-Emission Tomography, Severity of Illness Index, tau Proteins, Treatment Failure |
Abstract | 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.). |
DOI | 10.1056/NEJMoa1304839 |
Alternate Journal | N. Engl. J. Med. |
PubMed ID | 24450891 |
PubMed Central ID | PMC4159618 |
Grant List | K24 AG035007 / AG / NIA NIH HHS / United States MR/K013041/1 / / Medical Research Council / United Kingdom P30 AG008051 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States R01 NS080820 / NS / NINDS NIH HHS / United States |