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Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Published on Aug 25, 2015in Neurology8.69
· DOI :10.1212/WNL.0000000000001877
Enchi Liu14
Estimated H-index: 14
,
Mark Schmidt20
Estimated H-index: 20
+ 20 AuthorsH. Robert Brashear14
Estimated H-index: 14
Cite
Abstract
Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using 11 C-Pittsburgh compound B ( 11 C-PiB)-PET. Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE e4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an 11 C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in 11 C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. Conclusions: The 11 C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.
  • References (20)
  • Citations (65)
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References20
Newest
Published on Sep 1, 2015in Alzheimers & Dementia14.42
Mark Schmidt20
Estimated H-index: 20
(Janssen Pharmaceutica),
Ping Chiao2
Estimated H-index: 2
(Biogen Idec)
+ 11 AuthorsN. Scott Mason21
Estimated H-index: 21
(University of Pittsburgh)
Abstract In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image process...
Published on Jan 23, 2014in The New England Journal of Medicine70.67
Stephen Salloway55
Estimated H-index: 55
(Brown University),
Reisa A. Sperling87
Estimated H-index: 87
(Harvard University)
+ 21 AuthorsH. Robert Brashear14
Estimated H-index: 14
(Janssen Pharmaceutica)
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) e4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion ...
Published on Jan 23, 2014in The New England Journal of Medicine70.67
Rachelle S. Doody58
Estimated H-index: 58
(BCM: Baylor College of Medicine),
Ronald G. Thomas52
Estimated H-index: 52
(UCSD: University of California, San Diego)
+ 10 AuthorsPaul S. Aisen82
Estimated H-index: 82
(UCSD: University of California, San Diego)
BackgroundAlzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. MethodsIn two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (admin...
Published on Oct 1, 2013in Alzheimers & Dementia14.42
Keith Johnson86
Estimated H-index: 86
(Harvard University),
Reisa A. Sperling87
Estimated H-index: 87
(Harvard University)
+ 16 AuthorsAdam S. Fleisher51
Estimated H-index: 51
(UCSD: University of California, San Diego)
Abstract Objective To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy control subjects (HCs). Methods Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative. Results Florbetapir PET was rated v...
Published on Aug 1, 2012in JAMA Neurology12.32
Kaj Blennow118
Estimated H-index: 118
,
Henrik Zetterberg84
Estimated H-index: 84
+ 6 AuthorsInvestigators1
Estimated H-index: 1
Background Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti–β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms. Objective To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers r...
Published on Feb 1, 2012in JAMA Neurology12.32
Susanne Ostrowitzki13
Estimated H-index: 13
,
Dennis Deptula6
Estimated H-index: 6
+ 9 AuthorsZhi-Xin Xu1
Estimated H-index: 1
Background Gantenerumab is a fully human anti-Aβ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). Objectives To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to elucidate the mechanism of amyloid reduction. Design A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices fro...
Published on Jun 1, 2011in NeuroImage5.81
Manuel Jorge Cardoso29
Estimated H-index: 29
(UCL: University College London),
Matthew J. Clarkson19
Estimated H-index: 19
(UCL: University College London)
+ 3 AuthorsSebastien Ourselin55
Estimated H-index: 55
(UCL: University College London)
Abstract Thickness measurements of the cerebral cortex can aid diagnosis and provide valuable information about the temporal evolution of diseases such as Alzheimer's, Huntington's, and schizophrenia. Methods that measure the thickness of the cerebral cortex from in-vivo magnetic resonance (MR) images rely on an accurate segmentation of the MR data. However, segmenting the cortex in a robust and accurate way still poses a challenge due to the presence of noise, intensity non-uniformity, partial ...
Published on May 1, 2011in Lancet Neurology28.75
Henryk Barthel35
Estimated H-index: 35
(Leipzig University),
Hermann-Josef Gertz30
Estimated H-index: 30
(Leipzig University)
+ 8 AuthorsCornelia Reininger2
Estimated H-index: 2
(Bayer Schering Pharma AG)
Summary Background Imaging with amyloid-β PET can potentially aid the early and accurate diagnosis of Alzheimer's disease. Florbetaben ( 18 F) is a promising 18 F-labelled amyloid-β-targeted PET tracer in clinical development. We aimed to assess the sensitivity and specificity of florbetaben ( 18 F) PET in discriminating between patients with probable Alzheimer's disease and elderly healthy controls. Methods We did a multicentre, open-label, non-randomised phase 2 study in 18 centres in Australi...
Published on Nov 1, 2010in Biological Psychiatry11.50
Timo Grimmer31
Estimated H-index: 31
(LMU: Ludwig Maximilian University of Munich),
Susanne Tholen4
Estimated H-index: 4
(LMU: Ludwig Maximilian University of Munich)
+ 10 AuthorsRobert Perneczky41
Estimated H-index: 41
(LMU: Ludwig Maximilian University of Munich)
Background Pittsburgh Compound B ([ 11 C] PiB) is a specific positron emission tomography (PET) marker of cerebral amyloid deposits. Only few data have been published on in vivo longitudinal changes of amyloid load in Alzheimer's disease (AD) patients, with conflicting results. Therefore, little is known about the factors that influence these changes. Methods A group of 24 patients with probable AD diagnosed by combining established clinical criteria with an AD-typical pattern in [ 18 F] fluoro-...
Published on Jun 1, 2010in Computer Methods and Programs in Biomedicine3.42
Marc Modat31
Estimated H-index: 31
(UCL: University College London),
Gerard R. Ridgway39
Estimated H-index: 39
(UCL Institute of Neurology)
+ 5 AuthorsSebastien Ourselin55
Estimated H-index: 55
(UCL Institute of Neurology)
A large number of algorithms have been developed to perform non-rigid registration and it is a tool commonly used in medical image analysis. The free-form deformation algorithm is a well-established technique, but is extremely time consuming. In this paper we present a parallel-friendly formulation of the algorithm suitable for graphics processing unit execution. Using our approach we perform registration of T1-weighted MR images in less than 1min and show the same level of accuracy as a classic...
Cited By65
Newest
Published on Dec 1, 2019in Alzheimer's Research & Therapy
Jeffrey L. Cummings132
Estimated H-index: 132
(Cleveland Clinic),
Howard Feldman67
Estimated H-index: 67
(UCSD: University of California, San Diego),
Philip Scheltens108
Estimated H-index: 108
(UvA: University of Amsterdam)
There is a high rate of failure in Alzheimer’s disease (AD) drug development with 99% of trials showing no drug-placebo difference. This low rate of success delays new treatments for patients and discourages investment in AD drug development. Studies across drug development programs in multiple disorders have identified important strategies for decreasing the risk and increasing the likelihood of success in drug development programs. These experiences provide guidance for the optimization of AD ...
Published on Sep 5, 2019in Journal of Alzheimer's Disease3.70
Zongjun Guo (Qingdao University), Xing Peng4
Estimated H-index: 4
(CAS: Chinese Academy of Sciences)
+ 9 AuthorsYan-Jiang Wang24
Estimated H-index: 24
(Third Military Medical University)
Published on Aug 1, 2019in American Journal of Geriatric Psychiatry3.49
Christopher Randolph1
Estimated H-index: 1
(Loyola University Medical Center)
Abstract Correctly diagnosing early symptomatic Alzheimer's disease in the context of multinational clinical trials poses a significant challenge. Subjective complaints of memory ae fairly ubiquitous in an older population, and establishing the presence of definitive cognitive decline from clinical assessments is difficult. Most such trials have adopted the use of standardized episodic memory measures as an inclusion criterion, typically setting the cutoff at one standard deviation below age nor...
Published on Jul 4, 2019in Frontiers in Immunology4.72
Yannick Chantran1
Estimated H-index: 1
,
Jean Capron2
Estimated H-index: 2
+ 1 AuthorsPierre Aucouturier31
Estimated H-index: 31
Published on Apr 4, 2019in Brain11.81
Seth Love54
Estimated H-index: 54
(UoB: University of Bristol),
James A. R. Nicoll57
Estimated H-index: 57
+ 6 AuthorsClive Holmes55
Estimated H-index: 55
Published on Jun 1, 2019in Bioorganic Chemistry3.93
Anupamjeet Kaur1
Estimated H-index: 1
(Sri Guru Granth Sahib World University),
Sukhmani Mann2
Estimated H-index: 2
(Sri Guru Granth Sahib World University)
+ 4 AuthorsDeepti Goyal4
Estimated H-index: 4
(Sri Guru Granth Sahib World University)
Abstract A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aβ aggregation, metal-induced Aβ aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o -CF 3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC 50 ...
Published on May 7, 2019in Journal of Alzheimer's Disease3.70
Wei-Wei Li4
Estimated H-index: 4
(Third Military Medical University),
Ying-Ying Shen1
Estimated H-index: 1
(Third Military Medical University)
+ 15 AuthorsDong-Wan Chen1
Estimated H-index: 1
(Third Military Medical University)
Published on Apr 1, 2019in Immunity21.52
Timothy G. Hammond39
Estimated H-index: 39
(Broad Institute),
Samuel E. Marsh7
Estimated H-index: 7
(Broad Institute),
Beth Stevens38
Estimated H-index: 38
Neurodegenerative diseases of the central nervous system progressively rob patients of their memory, motor function, and ability to perform daily tasks. Advances in genetics and animal models are beginning to unearth an unexpected role of the immune system in disease onset and pathogenesis; however, the role of cytokines, growth factors, and other immune signaling pathways in disease pathogenesis is still being examined. Here we review recent genetic risk and genome-wide association studies and ...
Published on Apr 1, 2019in Seminars in Neurology1.47
Nicolas Villain12
Estimated H-index: 12
(University of Paris),
Bruno Dubois104
Estimated H-index: 104
Alzheimer's disease (AD) is the commonest neurodegenerative disease and the most frequent cause of dementia. It affects 30 million people worldwide. Current research criteria focus on biomarkers' status for amyloid and tau using positron emission tomography and cerebrospinal fluid analysis, independent of clinical status. Current epidemiological data, which mostly rely on biomarker-undetermined AD cases, have highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant mutations a...
Published on Feb 1, 2019in Clinical Pharmacology & Therapeutics6.34
Takaaki Ishida1
Estimated H-index: 1
(UTokyo: University of Tokyo),
Keita Tokuda1
Estimated H-index: 1
(UTokyo: University of Tokyo)
+ 6 AuthorsHiroshi Suzuki2
Estimated H-index: 2
(UTokyo: University of Tokyo)
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