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.
Keywords: aducanumab; amyloid beta pathway; amyloid plaque reduction; bapineuzumab; crenezumab; elenbecestat; model-informed drug development; quantitative systems pharmacology model; semagacestat; solanezumab; verubecestat.
© 2021 Applied BioMath. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.