Details

Autor(en) / Beteiligte

• Madrasi, Kumpal
• Das, Raibatak
• Mohmmadabdul, Hafiz
• Lin, Lin
• Hyman, Bradley T.
• Lauffenburger, Douglas A.
• Albers, Mark W.
• Rissman, Robert A.
• Burke, John M.
• Apgar, Joshua F.
• Wille, Lucia
• Gruenbaum, Lore
• Hua, Fei

Titel

Systematic in silico analysis of clinically tested drugs for reducing amyloid‐beta plaque accumulation in Alzheimer's disease

Ist Teil von

• Alzheimer's & dementia, 2021-09, Vol.17 (9), p.1487-1498

Ort / Verlag

United States: John Wiley and Sons Inc

Erscheinungsjahr

2021

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• Introduction Despite strong evidence linking amyloid beta (Aβ) to Alzheimer's disease, most clinical trials have shown no clinical efficacy for reasons that remain unclear. To understand why, we developed a quantitative systems pharmacology (QSP) model for seven therapeutics: aducanumab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat. Methods Ordinary differential equations were used to model the production, transport, and aggregation of Aβ; pharmacology of the drugs; and their impact on plaque. Results The calibrated model predicts that endogenous plaque turnover is slow, with an estimated half‐life of 2.75 years. This is likely why beta‐secretase inhibitors have a smaller effect on plaque reduction. Of the mechanisms tested, the model predicts binding to plaque and inducing antibody‐dependent cellular phagocytosis is the best approach for plaque reduction. Discussion A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development.