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In silico exploration of amyloid-related imaging abnormalities in the gantenerumab open-label extension trials using a semi-mechanistic model



. 2022 Jun 6;8(1):e12306.


doi: 10.1002/trc2.12306.


eCollection 2022.

Affiliations

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Roxana Aldea et al.


Alzheimers Dement (N Y).


.

Abstract


Introduction:

Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) are commonly observed with anti-amyloid therapies in Alzheimer’s disease. We developed a semi-mechanistic, in silico model to understand the time course of ARIA-E and its dose dependency.


Methods:

Dynamic and statistical analyses of data from 112 individuals that experienced ARIA-E in the open-label extension of SCarlet RoAD (a study of gantenerumab in participants with prodromal Alzheimer’s disease) and Marguerite RoAD (as study of Gantenerumab in participants with mild Alzheimer’s disease) studies were used for model building. Gantenerumab pharmacokinetics, local amyloid removal, disturbance and repair of the vascular wall, and ARIA-E magnitude were represented in the novel vascular wall disturbance (VWD) model of ARIA-E.


Results:

The modeled individual-level profiles provided a good representation of the observed pharmacokinetics and time course of ARIA-E magnitude. ARIA-E dynamics were shown to depend on the interplay between drug-mediated amyloid removal and intrinsic vascular repair processes.


Discussion:

Upon further refinement and validation, the VWD model could inform strategies for dosing and ARIA monitoring in individuals with an ARIA-E history.


Keywords:

Alzheimer’s disease; amyloid beta; amyloid‐related imaging abnormalities; gantenerumab; in silico; modeling; pathophysiology; semi‐mechanistic; vascular wall disturbance.

Conflict of interest statement

RA, HPG, CH, DL, SB, PD, GK, ML, and NAM are full‐time employees of F. Hoffmann‐La Roche. RG is a former employee of F. Hoffmann‐La Roche, currently acting as consultant for F. Hoffmann‐La Roche. HPG, RG, CH, DL, SB, PD, GK, ML, and NAM are shareholders of F. Hoffmann‐La Roche. FP and ROC are consultants for F. Hoffmann‐La Roche. FP is the Funding Member and Coordinator of the iCAβ international Network and the CAA study Group of the Italian Society of Neurology‐dementia (SINdem) and is a member of the European Alzheimer’s Disease Consortium (EADC) General Assembly. He is the inventor (without ownership) of a patent for a method and kit for anti‐Aβ autoantibody ultrasensitive detection of ARIA and CAA‐ri. He served as a consultant and he has been involved in Global Advisory Boards on Alzheimer’s disease immunotherapy and biomarkers done by Roche. He is the Principal Investigator of the ModelCAA Research Grant AARG‐18‐561699 funded by the Alzheimer’s Association. Author disclosures are available in the supporting information.



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