Population PK/PD modelling of the anti-IL-33 antibody tozorakimab to predict pulmonary target engagement in patients with COPD

Background: Tozorakimab (MEDI3506) is a human monoclonal antibody targeting interleukin (IL)-33, an alarmin cytokine which plays a key role in inflammatory disease. Tozorakimab is in clinical development for several indications, including chronic obstructive pulmonary disease (COPD). Objective: To build a mechanistic population pharmacokinetic (PK)/pharmacodynamic (PD) model for tozorakimab, utilising phase 1 systemic target engagement biomarker data, to enable dose selection for future studies. Methods: Phase 1 tozorakimab PK data (NCT03096795) were collected following intravenous or subcutaneous dosing in healthy adults with a history of atopy, in adults with COPD and in healthy Japanese adults. Systemic target engagement data were utilised from all cohorts and were based on the measurement of the IL‑33:tozorakimab and IL-33:soluble ST2 (sST2) receptor complexes using ultrasensitive assays.¹ Results: A four-compartment PK/PD model reliably described measured tozorakimab concentrations, the formation of IL‑33:tozorakimab and the inhibition of IL-33:sST2 formation in serum. Tozorakimab dose-dependently increased levels of the IL‑33:tozorakimab complex and decreased levels of IL-33:sST2 complex. Inhibition of IL-33:sST2 formation in the lungs by tozorakimab was predicted and used to select tozorakimab doses expected to achieve desired levels of pulmonary IL‑33 inhibition in COPD. Conclusions: Our PK/PD model reliably predicts systemic target engagement by tozorakimab and can predict pulmonary target engagement. The model will help determine optimal tozorakimab dosing in future clinical trials. Reference 1. Scott IC et al. Eur Respir J 2019 54:PA4072.