Modeling to Support Dose Justification for Anti-PD-L1 Clinical Candidate CK-301 in Oncology Patients

Collaboration with Checkpoint Therapeutics

Background

A semi-mechanistic pharmacokinetic/target-occupancy (PKTO) model was developed with in vitro, preclinical and clinical data to facilitate dose selection of CK-301 (also known as TG-1501, cosibelimab), an anti-PD-L1 monoclonal antibody (mAb), for ongoing and future clinical trials in oncology patients.
The model was used to compare the PK and tumor target occupancy (TO) at steady state under various dosing regimens with cosibelimab to those with three marketed anti-PD-L1 mAbs (ie. atezolizumab, durvalumab and avelumab)

Ø indicates degradation/elimination of the indicated species in the model.

Model Description

The main reactions included in model (in all three compartments unless otherwise indicated):

PD-L1, sPD-L1 and PD1 are constantly synthesized and degraded, and the equilibrium has been reached before dosing. • PD-1 binds to both PD-L1 and sPD-L1 reversibly.
Drug binds to both PD-L1 and sPD-L1 reversibly.
Drug-PD-L1 complex is degraded with the same rate constant as PD-L1.
Drug and drug-sPD-L1 complex are eliminated in central compartment.
Drug, sPD-L1 and drug-sPD-L1 complex transport across the compartments.

With cosibelimab (also known as CK-301) IV dosing of 800 and 1200 mg q2w or q3w, a >99% TO is expected throughout the dosing interval, comparable to TO achieved with atezolizumab at 1200 mg q3w, and durvalumab at 10 mg/kg q2w.
Relative to atezolizumab and durvalumab treatments, similar percentages of patients would possibly benefit from cosibelimab treatment, under the assumption that cosibelimab has similar PK variability