Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab

Liu, Enchi; Wang, Dai; Sperling, Reisa A.; Salloway, Stephen; Fox, Nick C.; Blennow, Kaj; Scheltens, Philip; Schmidt, Mark E.; Streffer, Johannes; Novak, Gerald; Einstein, Steve; Booth, Kevin; Ketter, Nzeera; Brashear, H. Robert

doi:10.1212/wnl.0000000000005060

Cited by 29 publications

(29 citation statements)

References 25 publications

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“…Consequently, the gantenerumab data indicate that ARIA-E is not a prerequisite for large amyloid reductions. This result contrasts the data reported for bapineuzumab, in which there was a lack of change from baseline in the non-ARIA-E groups [36].…”

Section: Discussioncontrasting

confidence: 99%

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

et al. 2019

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BackgroundWe previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD).MethodsA subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale.ResultsSixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold.ConclusionResults from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.Trial registrationClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

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Section: Discussioncontrasting

confidence: 99%

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

et al. 2019

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“…1,15,23,24,39,41 When ARIA occur, 1) the severity of pre-existing underlying CAA pathology, 2) the displacement of Aβ from parenchymal plaques to the vessel walls, 3) the rapid disaggregation of Aβ at high doses of the drug, particularly in APOEε4 patients, may all play a key role in determining and/or sustaining the inflammatory and immune response. 19,23,[42][43][44] The contributing role of underlying CAA pathology finds further support in the acute and focal nature of WMHs in both CAA-ri and ARIA-E, 23,41 which present mainly in posterior occipital regions of the brain, where there is a likely higher CAA burden. 45,46 Of note, although ARIA-E presents in brain areas with extensive removal of Aβ on amyloid-PET, with a mechanism presumably involving microglial activation, 41 similar consistently large amyloid reductions have been observed also in patients without ARIA-E in open-label extension studies.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy–Related Inflammation

et al. 2021

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Background and Objectives:To investigate the natural history and outcomes following treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).Methods:A multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria, recruited through the iCAβ International Network, in the period January 2013 - March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, GRE-T2*, fluid-suppressed T2-weighted (FLAIR), and T1 post-gadolinium contrast-enhancement images aquired on 1.5T MRI, was employed at 3, 6, 12, 24-months follow-up. Centralized reads of MRI images were performed blinded to clinical, therapeutic, and time-points information. Main outcomes were survival, clinical and radiological recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri.Results:The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri), mean age 72.9 years, 43.4% female, 37.1% APOEε4 carriers. 36.3% had a history of Alzheimer’s disease, 33.6% of ICH. A history of ICH, as well as the occurrence of new ICH at follow-up, was more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%; p< 0.0001 and 19.3% vs 3.6%; p<0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% CI, 61.6-78.5) and 84.1% (95% CI, 76.2-90.6) clinically recovered within three and twelve months, followed by radiological recovery in 45.1% (95% CI, 36.4 - 54.8) and 77.4% (95% CI, 67.7 - 85.9), respectively. After clinicoradiological resolution of the first-ever episode, 38,3% (95% CI, 22.9 - 59.2) had at least one recurrence within the following 24 months. Recurrence was more likely if intravenous high dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering-off (Hazard Ratio 4.68; 95% CI, 1.57-13.93; p=0.006).Discussion:These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiological acute manifestations of the disease and the effectiveness of slow oral tapering-off after intravenous corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in Aβ-driven diseases, including treatment-related ARIA in Alzheimer’s disease patients exposed to immunotherapy drugs.

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“…Preclinical studies revealed that aducanumab enhanced recruitment of microglia to amyloid plaques via engagement of Fcγ receptors. In a recent study on bapineuzumab (epitope: N-terminus Aβ1-5, IgG1 isotype) the authors demonstrated that Alzheimer's Related Imaging Abnormality-Edema (ARIA-E) was associated with larger reductions in amyloid PET, suggesting that in treated cases ARIA-E might be related to increased Aβ efflux from the brain [29]. In addition, higher dose of gantenerumab (epitope: N-terminus Aβ1-10 and central region Aβ18-27, IgG1 isotype) reduced amyloid load as measured by amyloid PET, which was indicative of successful target engagement in the brain [39].…”

Section: Discussionmentioning

confidence: 99%

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation

Žilková

Nölle

Kováčech

et al. 2020

acta neuropathol commun

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Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro. Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies. The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.

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Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab

Cited by 29 publications

References 25 publications

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis

Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy–Related Inflammation

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation

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