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Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis.

ABSTRACT: BACKGROUND:Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid ?. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS:Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient's treatment, APOE ?4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS:210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ?4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION:ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ?4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING:Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.

SUBMITTER: Sperling R

PROVIDER: S-EPMC4063417 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis.

Sperling Reisa R Salloway Stephen S Brooks David J DJ Tampieri Donatella D Barakos Jerome J Fox Nick C NC Raskind Murray M Sabbagh Marwan M Honig Lawrence S LS Porsteinsson Anton P AP Lieberburg Ivan I Arrighi H Michael HM Morris Kristen A KA Lu Yuan Y Liu Enchi E Gregg Keith M KM Brashear H Robert HR Kinney Gene G GG Black Ronald R Grundman Michael M

The Lancet. Neurology 20120203 3

<h4>Background</h4>Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors.<h4>Methods</h4>Two neu ...[more]

PMID: 22305802

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Project description:BACKGROUND:Amyloid-related imaging abnormalities due to haemosiderin deposition (ARIA-H) occur in patients with mild to moderate dementia due to Alzheimer's disease (AD) and have been reported with increased incidence in clinical trials of amyloid-lowering therapies under development for AD. OBJECTIVE:Our objective was to explore the relationship between the incidences of ARIA-H during treatment with placebo and different doses of bapineuzumab, a humanised monoclonal antibody directed against amyloid ?. METHODS:Two neuroradiologists independently reviewed 2572 GRE/T2* MRI sequences from 262 participants in two phase two clinical trials of bapineuzumab and an open-label extension study. Readers were blinded to the participant's therapy, APOE ?4 genotype and medical history. RESULTS:Several risk factors for small ARIA-H <10?mm (microhaemorrhages) were identified: APOE ?4, bapineuzumab treatment, pre-existing small ARIA-H and use of antithrombotics. The HR (95%CI) for incident ARIA-H <10?mm associated with the number of APOE ?4 alleles was 11.9 (3.3 to 42.5) for 2 versus no alleles and 3.5 (1.0 to 12.0) for 1 versus no allele. The HR for bapineuzumab therapy was 3.5 (1.0 to 12.0); for the presence of baseline ARIA-H <10?mm, it was 3.5 (1.6 to 7.8), and for the use of antithrombotic agents it was 2.2 (1.0 to 4.8). The incidence rate for ARIA-H <10?mm was elevated only in the initial 6?months of active treatment and declined after this interval to a rate similar to that observed in the group treated with placebo. CONCLUSIONS:ARIA-H represents a spectrum of MRI findings due to haemosiderin deposition that appears to be related to impaired vascular integrity. The increased risk for ARIA-H associated with APOE ?4 allele frequency, pre-existing ARIA-H, treatment with bapineuzumab and use of antithrombotic agents provides additional support for this hypothesis of loss of integrity of cerebral vessels due to amyloid burden. TRIAL REGISTRATION:NCT00112073 and NCT00606476.

Project description:ImportanceThe EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia.ObjectiveTo describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE.Design, setting, and participantsSecondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021.InterventionsParticipants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy.Main outcomes and measuresBrain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events.ResultsOf 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively.Conclusions and relevanceIn this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache.Trial registrationsClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.

Dataset Information

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis.

Publications

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis.

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