Elsevier

The Lancet Neurology

Volume 9, Issue 4, April 2010, Pages 363-372
The Lancet Neurology

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11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study

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Summary

Background

Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease.

Methods

Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446.

Findings

28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was −0·09 (95% CI −0·16 to −0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was −0·24 (95% CI −0·39 to −0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema.

Interpretation

Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo.

Funding

Elan Pharmaceuticals and Wyeth Research.

Introduction

Alzheimer's disease is characterised neuropathologically by deposits of extracellular amyloid-β plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss.1 Antibodies directed against the N terminus of amyloid β reduce cerebral amyloid-β load in transgenic mice2, 3 and block the synaptotoxic effects of amyloid-β oligomers.4 Bapineuzumab, an antibody targeted against the N terminus of amyloid β, is a passive immunotherapy that is being tested in Alzheimer's disease.5 Bapineuzumab might bind to amyloid β in the brain and facilitate its clearance.2, 3

Amyloid-β load can be measured in patients with Alzheimer's disease by use of PET and the radiotracer carbon-11-labelled Pittsburgh compound B (11C-PiB).6, 7 PiB is a thioflavin analogue that binds with low nanomolar affinity to aggregated fibrillar deposits of the amyloid-β peptide, enters the brain at concentrations detectable by PET, and clears rapidly from normal brain tissue.6, 8 At the low nanomolar concentrations used in PET studies, PiB selectively binds to fibrillar amyloid-β deposits in post-mortem human brain.7, 9 Compared with healthy controls, patients with Alzheimer's disease have about two times greater retention of 11C-PiB in areas of the association cortex that are targeted by amyloid-β deposits.6, 10 11C-PiB retention is similar in patients with Alzheimer's disease and healthy controls in areas unaffected by amyloid-β deposition, such as the subcortical white matter, pons, and cerebellum.6

We aimed to investigate whether bapineuzumab-related changes in cortical amyloid-β load could be measured in vivo by use of 11C-PiB PET imaging.

Section snippets

Patients

We did a phase 2, multicentre, randomised, double-blind, placebo-controlled, ascending-dose study at three clinical sites (two in the UK and one in Finland) between August, 2005, and January, 2009.

Eligible patients were aged 50–80 years inclusive, met NINCDS-ADRDA criteria for probable Alzheimer's disease,11 and had amyloid-β loads in the range expected for patients with Alzheimer's disease, defined as 11C-PiB PET retention ratios relative to the cerebellum of 1·5 or more in at least three

Results

Of 53 screened patients, 28 were randomly assigned (20 bapineuzumab vs eight placebo; ten in the 0·5 mg/kg group, ten in the 1·0 mg/kg group, and eight in the 2·0 mg/kg group; figure 1). The sponsor stopped enrolment in the 2·0 mg/kg group after a greater frequency of patients with cerebral vasogenic oedema after treatment with this dose was reported from another study.5 Eight patients did not meet the inclusion criteria because of low 11C-PiB retention. 15 patients failed to meet other

Discussion

There was a significant difference in change from baseline in the 11C-PiB PET mean retention from six targeted regions of interest in patients in the bapineuzumab group compared with those in the placebo group. A reduction in 11C-PiB retention relative to baseline was noted for the bapineuzumab group, while an increase was observed in the placebo group. Other recent studies have also reported small increases in 11C-PiB retention over time in patients with Alzheimer's disease;29, 30 however,

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