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Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

ABSTRACT: Alzheimer's Disease (AD) is a leading cause of morbidity. Management of AD has traditionally been aimed at symptom relief rather than disease modification. Recently, AD research has begun to shift focus towards disease-modifying therapies that can alter the progression of AD. In this context, a class of immunotherapy agents known as monoclonal antibodies target diverse cerebral amyloid-beta (Aβ) epitopes to inhibit disease progression. Aducanumab was authorized by the US Food and Drug Administration (FDA) to treat AD on June 7, 2021. Aducanumab has shown promising clinical and biomarker efficacy but is associated with amyloid-related imaging abnormalities (ARIA). Neuroradiologists play a critical role in diagnosing ARIA, necessitating familiarity with this condition. This pictorial review will appraise the radiologic presentation of ARIA in patients on aducanumab.

SUBMITTER: Sotoudeh H

PROVIDER: S-EPMC10796528 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

Sotoudeh Houman H Alizadeh Mohammadreza M Shahidi Ramin R Shobeiri Parnian P Saadatpour Zahra Z Wheeler C Austin CA Natelson Love Marissa M Tanwar Manoj M

Frontiers in radiology 20240105

Alzheimer's Disease (AD) is a leading cause of morbidity. Management of AD has traditionally been aimed at symptom relief rather than disease modification. Recently, AD research has begun to shift focus towards disease-modifying therapies that can alter the progression of AD. In this context, a class of immunotherapy agents known as monoclonal antibodies target diverse cerebral amyloid-beta (Aβ) epitopes to inhibit disease progression. Aducanumab was authorized by the US Food and Drug Administra ...[more]

PMID: 38249159

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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.

Project description:ImportanceData from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae.ObjectivesTo describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E).Design, setting, and participantsSecondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023.InterventionsGRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk.Main outcomes and measuresPostbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments.ResultsThe safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases.Conclusions and relevanceThese results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended.Trial registrationsClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

Project description:BackgroundAnti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aβ peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aβ immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies.MethodsTo address these limitations, we have engineered SAR228810, a humanized monoclonal antibody (mAb) with limited Fc effector functions that binds specifically to soluble protofibrillar and fibrillar forms of Aβ peptide and we tested it together with its murine precursor SAR255952 in vitro and in vivo.ResultsUnlike gantenerumab and BAN2401, SAR228810 and SAR255952 do not bind to Aβ monomers, low molecular weight Aβ oligomers or, in human brain sections, to Aβ diffuse deposits which are not specific of AD pathology. Both antibodies prevent Aβ42 oligomer neurotoxicity in primary neuronal cultures. In vivo, SAR255952, a mouse aglycosylated IgG1, dose-dependently prevented brain amyloid plaque formation and plaque-related inflammation with a minimal active dose of 3 mg/kg/week by the intraperitoneal route. No increase in plasma Aβ levels was observed with SAR255952 treatment, in line with its lack of affinity for monomeric Aβ. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. Brain penetration and decoration of cerebral amyloid plaques was documented in live animals and postmortem. SAR255952 (up to 50 mg/kg/week intravenously) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice while 3D6, the murine version of bapineuzumab, did. In immunotolerized mice, the clinical candidate SAR228810 demonstrated the same level of efficacy as the murine SAR255952.ConclusionBased on the improved efficacy/safety profile in non-clinical models of SAR228810, a first-in-man single and multiple dose administration clinical study has been initiated in AD patients.

Dataset Information

Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

Publications

Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

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