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Quantitative Systems Pharmacology Model of the Amyloid Pathway in Alzheimer's Disease: Insights into the Therapeutic Mechanisms of Clinical Candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing beta-amyloid (Aβ) pathophysiology in AD. The model included mechanisms of Aβ monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the 3 compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti-Aβ monoclonal antibodies aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 non-carrier. Results indicate that the model is consistent with data on clinical Aβ accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aβ load accurately. This model may be employed to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aβ load at different dose levels for monoclonal antibodies with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.