Failure of the IV immunoglobulin trial highlighted a key issue in immunotherapy: identification of optimal drug dosing and timing in order to maximize efficacy while reducing the occurrence of amyloid-related imaging abnormalities (ARIA) side effects. [1] A phase 1b study with aducanumab pointed out this issue: a reduction in brain-deposited A-beta and cognitive decline was accompanied by high occurrences of ARIA in 55% of apoE4 carriers treated at the higher, most effective, dose. [2] These findings open theoretical criticisms and practical implications. According to "The ARIA paradox" etiologic model, high concentration of antibodies are necessary to efficiently remove the cerebrovascular-deposited A-beta. Nevertheless, rapid and uncontrolled increases of antibodies might induce a massive mobilization of A-beta, leading to transient increases of cerebral amyloid angiopathy and susceptibility to ARIA. [3,4] Understanding the mechanisms and significance of ARIA is a game changer for trials, marking a shift in the ability to treat patients. The future question is: what is the accepted risk between optimizing positive effects and reducing ARIA incidence and severity? [5] Addressing this question might impact the design of more effective clinical trials; not only from a safety perspective, but also by providing greater understanding of why and how immunotherapy drugs work

Piazza, F. (2018). Reader response: A phase 3 trial of IV immunoglobulin for Alzheimer disease. NEUROLOGY, 90(3), 144-145 [10.1212/WNL.0000000000004824].

Reader response: A phase 3 trial of IV immunoglobulin for Alzheimer disease

Piazza, F
2018

Abstract

Failure of the IV immunoglobulin trial highlighted a key issue in immunotherapy: identification of optimal drug dosing and timing in order to maximize efficacy while reducing the occurrence of amyloid-related imaging abnormalities (ARIA) side effects. [1] A phase 1b study with aducanumab pointed out this issue: a reduction in brain-deposited A-beta and cognitive decline was accompanied by high occurrences of ARIA in 55% of apoE4 carriers treated at the higher, most effective, dose. [2] These findings open theoretical criticisms and practical implications. According to "The ARIA paradox" etiologic model, high concentration of antibodies are necessary to efficiently remove the cerebrovascular-deposited A-beta. Nevertheless, rapid and uncontrolled increases of antibodies might induce a massive mobilization of A-beta, leading to transient increases of cerebral amyloid angiopathy and susceptibility to ARIA. [3,4] Understanding the mechanisms and significance of ARIA is a game changer for trials, marking a shift in the ability to treat patients. The future question is: what is the accepted risk between optimizing positive effects and reducing ARIA incidence and severity? [5] Addressing this question might impact the design of more effective clinical trials; not only from a safety perspective, but also by providing greater understanding of why and how immunotherapy drugs work
Articolo in rivista - Articolo scientifico
Alzheimer's disease, ARIA, IV Immunoglobulin, clinical trial
English
16-gen-2018
2018
90
3
144
145
none
Piazza, F. (2018). Reader response: A phase 3 trial of IV immunoglobulin for Alzheimer disease. NEUROLOGY, 90(3), 144-145 [10.1212/WNL.0000000000004824].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/159717
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