Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer’s Disease

By S. Salloway, Reisa A. Sperling, Nick C Fox, Kaj Blennow, William E. Klunk, M. Raskind, M. Sabbagh, L. Honig, A. Porsteinsson, S. Ferris and 14 more. New England Journal of Medicine, 2014

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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.)

Subfields: Physiology, Psychiatry and Mental health

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Citations in the corpus

Alzheimer’s disease: experimental models and reality (2017, background): “In the ongoing passive immunization AD clinical trials a major complication has been vasogenic edema (or encephalitis) with/or without hemorrhage (termed amyloid-related imaging abnormalities with edema (ARIAE) or with hemorrhage (ARIA-H) [116, 132, 133, 171, 172].”
CSF biomarkers of Alzheimer’s disease concord with amyloid-β PETand predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts (2018, background): “It is well established, from combined clinical and neuropathologic studies [5,6], and clinical trials using amyloid-b PET scans [7], that the accuracy of clinical criteria is suboptimal.”
Defining imaging biomarker cut points for brain aging and Alzheimer's disease (2017, neutral): “Of individuals with clinically diagnosed AD dementia, 10%–30% do not have AD at autopsy [18] or have no biomarker evidence of amyloidosis [19,20].”
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “This antibody was tested in two parallel phase 3 trials in mild-to-moderate AD patients and had no effect on cognition or ADL at the doses tested (Salloway et al., 2014).”
Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. (2016, background): “has shown potential as a surrogate outcome measure in clinical trials tailored to reduce cerebral amyloid-b plaque burden (Salloway et al., 2014; Liu et al., 2015).”
Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease (2017, background): “, 2003) and the reduction of plaque load in the brain in therapeutic trials has not thus far yielded cognitive benefit in Alzheimer’s disease patients (Salloway et al., 2014).”