Posdinemab shows linear pharmacokinetics and predicted tau reduction in Phase 1 AD study

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).