Mechanistic Population Pharmacokinetic–Pharmacodynamic Model of the Tau‐Targeted Antibody Posdinemab in Healthy Participants and Participants with Alzheimer’s Disease

Disrupted homeostasis and transneuronal spread of hyperphosphorylated Tau protein (pTau) are hypothesized to be key pathogenic drivers of Alzheimer's disease (AD). Posdinemab (JNJ-63733657), a humanized IgG1/kappa monoclonal antibody that targets phosphorylated Tau protein at amino acid 217 (p217+tau), is currently in clinical development for the treatment of AD. In a first-in-human Phase 1 study (NCT03375697), posdinemab was well tolerated at doses up to 60 mg/kg, demonstrated linear pharmacokinetics (PK) in serum, and induced dose-dependent reductions in p217+tau levels in cerebrospinal fluid (CSF). The objective of the current analysis was to develop a mechanism-based population pharmacokinetic-pharmacodynamic (popPK-PD) model to guide the Phase 2 (Auτonomy) dose selection of posdinemab in participants with AD using the Phase 1 data from 69 adults. A two-compartment model was selected, which successfully described the available clinical PK-PD data and demonstrated that posdinemab PK in serum is linear, dose-proportional, and time-independent. Suppression of free p217+tau in CSF was used to reflect free antibody available to bind tau seeds in interstitial fluid (ISF). The PK-PD model-based simulations for fixed intravenous doses of 1,000 mg and 3,000 mg every 4 weeks predicted >90% reduction in tau seeds in ISF by Day 391 and Day 154, respectively, following treatment initiation. This model provides a physiologically relevant simulation-framework to investigate the impact of various posdinemab dose levels on PK-PD profiles, thereby supporting the clinical trial design of the Auτonomy study (NCT04619420).