Collaboration with CytomX Therapeutics - Published in Clinical Pharmacology & Therapeutics
CX‑072 is an anti‑PD‑L1 (programmed death ligand 1) Probody therapeutic (Pb‐Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model‐informed drug development of CX‐072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb‐Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation.
The QSP model predicted that a trough level of masked CX‐072 (intact CX‐072) of 13–99 nM would correspond to a targeted, 95% receptor occupancy in the tumor. The QSP model predictions appeared consistent with preliminary human single‑dose pharmacokinetic (PK) data following CX‐072 0.03–30.0 mg/kg as monotherapy: CX‑072 circulated predominantly as intact CX‐072 with minimal evidence of target‐mediated drug disposition.
A preliminary population PK (POPPK) analysis based upon 130 subjects receiving 0.03–30.0 mg/kg as monotherapy included a provision for a putative time‐dependent and dose‐dependent antidrug antibody (ADA) effect on clearance (CL) with a mixture model. Preliminary POPPK estimates for intact CX‐072 time‐invariant CL and volume of distribution were 0.306 L/day and 4.84 L, respectively. Exposure–response analyses did not identify statistically significant relationships with best change from baseline sum of measurements and either adverse events of grade ≥ 3 or of special interest.
Simulations suggested that > 95% of patients receiving CX‐072 10 mg/kg every two weeks would exceed the targeted trough level regardless of ADA, and that dose adjustment by body weight was not necessary, supporting a fixed 800 mg dose for evaluation in phase II.
Mark Stroh, Michelle Green, Bjorn L. Millard, Joshua F. Apgar, John M. Burke, Will Garner, Hong Lu, Susan K. Lyman, Luc R. Desnoyers, Jennifer Richardson, Alison Hannah and W. Michael Kavanaugh