Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)

Abstract

BackgroundWe investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD).MethodsThis double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18–26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment.ResultsFrom August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n = 26) or placebo (n = 13); high-dose IV cohort: crenezumab (n = 36) or placebo (n = 16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF Aβ(1–42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20–26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed.ConclusionThe primary endpoint was not met. Exploratory findings suggest potential Aβ target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing.Trial registrationClinicalTrials.gov, NCT01397578. Registered on 18 July 2011.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0424-5) contains supplementary material, which is available to authorized users.

Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid

“…The study design has been described, 7,8 and the administration regimens and patients contributing to this study are summarized in Figure 1, with demographic information in Tables 1 and 2, and a biomarker overview in Table 3. The study design has been described, 7,8 and the administration regimens and patients contributing to this study are summarized in Figure 1, with demographic information in Tables 1 and 2, and a biomarker overview in Table 3.…”

“…7,8 Both ABBY and BLAZE were sequentially enrolled, starting with the subcutaneous (SC) arm and then the intravenous (IV) arm in each trial. Patient ages (50-80 years), sex, and Mini-Mental State Examination (MMSE) scores were closely similar to those of the overall ABBY and BLAZE populations.…”

“…Patient ages (50-80 years), sex, and Mini-Mental State Examination (MMSE) scores were closely similar to those of the overall ABBY and BLAZE populations. 8 Samples (500μl) were thawed on the day of assay; 470μl of CSF was removed to a fresh tube, and 150μl of Standard Diluent (CAT# 02-0485-00; Millipore, Billerica, MA) was added to each. AD patients received 300mg crenezumab or placebo by SC injection every 2 weeks or 15mg/kg crenezumab or placebo by IV infusion every 4 weeks.…”

“…5,6 Crenezumab is hypothesized to be neuroprotective by blocking the interaction of Aβ oligomers with neurons and promoting the removal of oligomers via microglial phagocytosis. 7 Based on these findings, the safety profile of this agent, 7,8 and the emerging recognition that anti-Aβ therapy will likely work best through early intervention, 9,10 crenezumab is currently being evaluated presymptomatically as part of the Alzheimer's Prevention Initiative in autosomal dominant presenilin mutation carriers. In the ABBY trial, the primary and secondary endpoints (change in Alzheimer's Disease Assessment Scale-Cognitive Subscale and Clinical Dementia Rating-Sum of Boxes, respectively) were not met, but prespecified exploratory analyses suggested a potential treatment effect in patients with mild AD treated with high-dose crenezumab.…”

“…Specifically, there was a reduction in decline on the ADAS-Cog12, and the separation from placebo on this test was greatest in patients with the mildest clinical manifestations of AD. 7,8 Given the pathogenic importance of oAβ in AD and the demonstrated preference of crenezumab for aggregated forms of Aβ, we asked whether crenezumab could target and alter oAβ levels in the CSF of subjects in the ABBY and BLAZE trials. 11 In living humans, soluble Aβ monomers and oligomers can only be measured in CSF, not directly in the brain.…”