Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease

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.).

Figure 1. Primary Outcome

Panel A shows the estimated mean change from baseline to week 78 in 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 Panel B the estimated mean change from baseline to week 78 in the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment) among APOE ε4 carriers and noncarriers, according to study regimen. The P values that are shown are unadjusted. Bapi denotes bapineuzumab.

Figure 2. Key Biomarkers

Shown are the changes from baseline to week 71 in brain amyloid burden, as measured by the average standardized uptake value ratio (SUVR) of five cortical regions of interest (anterior cingulate cortex, posterior cingulate cortex or precuneus, frontal cortex, lateral temporal cortex, and parietal cortex), assessed by means of positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) (Panel A); cerebrospinal fluid (CSF) phosphorylated tau (phospho-tau) concentration (Panel B); and brain volume on MRI, calculated with the use of the brain boundary-shift-integral method (Panel C), among carriers of the apolipoprotein E (APOE) ε4 allele and noncarriers, according to study regimen. In the primary analysis of cerebrospinal fluid phospho-tau concentration among noncarriers, the 0.5-mg-per-kilogram and the 1.0-mg-per-kilogram bapineuzumab groups were pooled, and the difference in the reduction in cerebrospinal fluid phospho-tau concentration between the pooled results and placebo was not significant (P = 0.11) (Table S3b in the Supplementary Appendix). The P values that are shown are unadjusted.