Presenter of 1 Presentation
QUANTITATIVE SYSTEMS PHARMACOLOGY (QSP) AMYLOID PLATFORM : MULTISCALE COMPUTATIONAL MODELING OF ABETA BIOLOGY AND ITS INTERACTION WITH LECANEMAB PHARMACOLOGY
Abstract
Aims
A QSP Platform was developed integrating the known features of amyloid beta (Aβ) aggregation and microglia biology with the pharmacology of lecanemab to evaluate the dynamics of the modulation of Aβ aggregation cascade by the unique binding properties of lecanemab targeting aggregated Aβ species for the treatment of Alzheimer’s Disease (AD).
Methods
A reduced physiological based pharmacokinetic (PBPK) model for lecanemab interstitial fluid concentrations was coupled with a mathematical model of the Aβ aggregation based on elongation, primary and secondary nucleation, and fragmentation. Removal of Aβ peptides was modeled by microglia-dependent clearance through phagocytosis of the antibody-Aβ-complexes and modulated by selective binding affinity of lecanemab. Activation of immune cells by antibody-bound plaques in a perivascular compartment was assumed to drive ARIA-E liability.
Results
The QSP Aβ Platform predicts well the observed lifetime trajectory of Aβ species (monomers, oligomers, protofibrils, and plaque), including the effect of APOE genotype. It was qualified against observed clinical PK and biomarker (Plasma Aβ, CSF Aβ, and PET SUVr) data for lecanemab. The model characterized the temporal changes of the clinical biomarkers during lecanemab treatment, its ARIA-E incidence, and the dynamics of SUVr after termination of treatment.
Conclusions
A QSP Aβ Platform was developed and qualified using existing clinical PK and PD data from lecanemab. The model describes the lecanemab PK and the time course of Aβ species in plasma, CSF, and ISF. It is a valuable tool to explore the impact of patient baseline characteristics and treatments on amyloid dynamics.