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Authors: Brashear, H. Robert | Ketter, Nzeera | Bogert, Jennifer | Di, Jianing | Salloway, Stephen P. | Sperling, Reisa

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer’s disease in bapineuzumab phase III studies. Objectives: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. Methods: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ɛ 4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. Results: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ɛ 4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, …and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. Conclusions: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function. Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302) Show more

Keywords: Amyloid-related imaging abnormality, bapineuzumab, clinical evaluation

DOI: 10.3233/JAD-180675

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1409-1424, 2018

Authors: Prins, Niels D. | van der Flier, Wiesje M. | Brashear, H. Robert | Knol, Dirk L. | van de Pol, Laura A. | Barkhof, Frederik | Scheltens, Philip

Article Type: Research Article

Abstract: We studied the predictive value of cognitive performance, vascular risk factors, apolipoprotein E (APOE) genotype, and structural brain changes on MRI, on progression to dementia in post hoc analyses of 426 placebo patients (mean age 71 years; 55% women) with mild cognitive impairment (MCI) who participated in a previously published large multi-center clinical trial (Gal-Int-11). The ADAS-cog/MCI test, the New York University Paragraph Recall Test, and the Digit Symbol Coding Test were available at baseline, as were vascular risk factors and APOE genotype. Medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH) and lacunes were assessed on MRI. Over two …years of follow-up, 81 patients (19%) converted to dementia, while 345 patients (81%) remained stable. Results of Cox proportional-hazards regression analysis showed that higher age, worse cognitive test performance, presence of an APOE ε4 allele, and higher MTA scores on MRI increased the risk of progression to dementia in univariate analyses. Vascular risk factors, and WMH and lacunes on MRI, were not associated with progression to dementia. Lower performance on the ADAS-cog/MCI test (HR 1.08 per point increase; 95% CI 1.06–1.10) and Delayed recall test (HR 0.76 per point increase; 95% CI 0.68–0.85), as well as higher MTA scores on MRI (HR 1.33 per point increase; 95% CI 1.00–1.77) were independent predictors of progression to dementia in a step-wise Cox proportional-hazards model with age and gender forced into the model. We conclude that global cognitive function, episodic memory performance, and MTA on MRI independently predict progression to dementia in patients with MCI. Show more

Keywords: Alzheimer's disease, apolipoprotein E, brain infarction, clinical trial, dementia, hippocampus, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-122233

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 79-85, 2013

Authors: Brody, Mark | Liu, Enchi | Di, Jianing | Lu, Ming | Margolin, Richard A. | Werth, John L. | Booth, Kevin | Shadman, Anna | Brashear, H. Robert | Novak, Gerald

Article Type: Research Article

Abstract: Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42 ) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities–edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. Methods: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led …to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). Results: Florbetapir PET SUVR decreased significantly (p  = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. Conclusion: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab. Show more

Keywords: Alzheimer’s disease, amyloid burden, bapineuzumab, biomarker, pharmacokinetics

DOI: 10.3233/JAD-160369

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1509-1519, 2016

Authors: Russu, Alberto | Samtani, Mahesh N. | Xu, Steven | Adedokun, Omoniyi J. | Lu, Ming | Ito, Kaori | Corrigan, Brian | Raje, Sangeeta | Liu, Enchi | Brashear, H. Robert | Styren, Scot | Hu, Chuanpu

Article Type: Research Article

Abstract: Background: Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer’s disease (AD) patients. Objective: To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Methods: Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11 C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance …imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE* E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Results: Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE* E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Conclusions: Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated. Show more

Keywords: Amyloid PET, APOE*E4, bapineuzumab, brain volume, cerebrospinal fluid, disease severity, exposure-response modeling, p-tau

DOI: 10.3233/JAD-151065

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 535-546, 2016

Authors: Ketter, Nzeera | Brashear, H. Robert | Bogert, Jennifer | Di, Jianing | Miaux, Yves | Gass, Achim | Purcell, Derk D. | Barkhof, Frederik | Arrighi, H. Michael

Article Type: Research Article

Abstract: Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ 4 allele carriers or noncarriers). Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ 4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. Results: In the Final …Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ 4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. Conclusion: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study. Show more

Keywords: Alzheimer’s disease, bapineuzumab, brain amyloid-related imaging abnormality, magnetic resonance imaging Registration: NCT00574132 (Bapineuzumab-301), NCT00575055 (Bapineuzumab-302)

DOI: 10.3233/JAD-160216

Citation: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 557-573, 2017

Authors: Novak, Gerald | Fox, Nick | Clegg, Shona | Nielsen, Casper | Einstein, Steven | Lu, Yuan | Tudor, Iulia Cristina | Gregg, Keith | Di, Jianing | Collins, Peter | Wyman, Bradley T. | Yuen, Eric | Grundman, Michael | Brashear, H. Robert | Liu, Enchi

Article Type: Research Article

Abstract: Background: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE* ɛ 4 carriers and noncarriers, respectively, with Alzheimer’s disease. Objectives: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. Methods: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. Results: For BBSI and HBSI, there were no significant treatment-related …differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. Conclusions: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences. Show more

Keywords: Alzheimer’s disease, bapineuzumab, brain boundary shift integral, brain volume, hippocampal boundary shift integral, magnetic resonance imaging, randomized controlled trial, ventricular boundary shift integral, ventricular volume

DOI: 10.3233/JAD-150448

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1123-1134, 2016

Authors: Salloway, Stephen P. | Sperling, Reisa | Fox, Nick C. | Sabbagh, Marwan N. | Honig, Lawrence S. | Porsteinsson, Anton P. | Rofael, Hany | Ketter, Nzeera | Wang, Daniel | Liu, Enchi | Carr, Stephen | Black, Ronald S. | Brashear, H. Robert

Article Type: Research Article

Abstract: Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer’s disease dementia (apolipoprotein (APOE ) ɛ 4 carriers and noncarriers) is summarized. Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the …parent studies. Results: A total of 1,462 (688 were APOE ɛ 4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies. Show more

Keywords: Alzheimer’s disease, amyloid-related imaging abnormality with edema/effusions, bapineuzumab, long-term safety

DOI: 10.3233/JAD-171157

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 689-707, 2018