Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials

Abstract

Background: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD).

Methods: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale and the Disability Assessment for Dementia.

Results: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event.

Conclusions: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed.

Trial registration: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810 ; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143 ; registered 2 May 2008.

Keywords: ARIA-E; Alzheimer’s disease; Amyloid β; Bapineuzumab; Clinical trial; Immunotherapy; Vasogenic edema.

Figures

Fig. 1

Disposition of patients with Alzheimer’s disease in the apolipoprotein E ε4 carrier and noncarrier studies. Recruitment and follow-up occurred between 28 May 2008 and 3 December 2012 for the carrier study and between 25 June 2008 and 27 November 2012 for the noncarrier study. ARIA-E, amyloid-related imaging abnormalities with edema or effusion; BAP, bapineuzumab; N/A, not applicable; PBO, placebo. aSubject participation status is unknown for five subjects (one in PBO group, four in BAP group) owing to missing conclusion of patient participation in study and/or conclusion of patient participation in treatment electronic case report form pages. Four of these subjects completed six infusions and the week 78 visit. One subject completed four infusions and the week 45 visit

Fig. 2

Primary efficacy outcome analysis: change from baseline to week 78. a ADAS-Cog/11: total score range is 0 (least impairment) to 70 (most impairment). A positive change from baseline indicates worsening cognitive impairment. b DAD: total score range is 0 to 100, with higher scores indicating better function. A negative change from baseline indicates worsening function. Data shown are least squares means with standard error of the mean. ADAS-Cog/11, 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale; ApoE, apolipoprotein E; BAP, bapineuzumab; DAD, Disability Assessment for Dementia; LS, least squares

Fig. 3

Analysis of biomarkers and plasma Aβ: change from baseline to week 71. Data shown are least squares means with standard error of the mean. a PiB-PET analysis (b) CSF p-tau analysis (c) Volumetric analysis: An increase in BBSI on vMRI indicates a decrease in brain volume. d Plasma Aβ analysis. Aβ, amyloid β; ApoE, apolipoprotein E; BAP, bapineuzumab; BBSI, brain boundary shift integral; CSF, cerebrospinal fluid; LS, least squares; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; p-tau, phosphorylated tau protein; SUVr, standardized uptake value ratio; vMRI, volumetric magnetic resonance imaging. aExcludes nine patients who were PiB-PET-negative for Aβ at baseline

Fig. 4

Individual patient baseline PiB-PET SUVr values (all PiB-PET population). ApoE, apolipoprotein E; PiB-PET, 11C-Pittsburgh compound B positron emission tomography; SUVr, standardized uptake value ratio