Exposure‐response modeling to describe the change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease

Background Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease‐modifying treatment for early Alzheimer’s disease in two clinical studies (NCT01767311 and CLARITY‐AD, NCT03887455). As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid. Method A model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from Phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population PK model and correlated with amyloid PET using an indirect response model, with a lecanemab‐dependent increase in the degradation rate of amyloid, introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter‐subject variability was estimated for each of the model parameters. Covariates were included in the model using a forward‐inclusion (p