A dose-finding population pharmacokinetic/pharmacodynamic model of ginisortamab, an anti-gremlin-1 monoclonal antibody, in patients with solid tumours.

AIMS: Ginisortamab, a first-in-class human monoclonal antibody for the treatment of advanced solid tumours, binds to gremlin-1 and restores bone morphogenetic protein signalling. We used pharmacokinetic/pharmacodynamic (PK/PD) modelling to characterize the relationship between ginisortamab dose and serum gremlin-1 binding, using model-based simulations to inform ginisortamab-dose selection for ongoing clinical development.

METHODS

Ginisortamab and total gremlin-1 serum concentration data were obtained from the monotherapy dose-escalation module of the ONC001 phase 1/2 multipart study in participants with solid tumours (NCT04393298). Population PK/PD models were generated using an iterative model-building process with nonlinear mixed effects.

RESULTS

A two-compartment PK model with first-order drug elimination adequately described dose-proportional exposure for ginisortamab 100-2000 mg (administered every 2 weeks via intravenous infusion). PK/PD modelling incorporating total gremlin-1 serum concentrations adequately described ginisortamab binding to serum gremlin-1. Body surface area significantly affected central (Vc, 1.3 [95% CI: 1.0-1.7]) and peripheral (Vp, 2.2 [95% CI: 1.6-3.0]) volume of distribution of ginisortamab, but no other tested covariates impacted ginisortamab-gremlin-1 binding kinetics. Estimated gremlin-1 turnover time was rapid (~23 [95% CI: ~18-32] min). The developed PK/PD model was used to simulate ginisortamab dosing regimens; 1000 mg once-weekly and 2000 mg every 2 weeks were predicted to maintain target suppression ≥90% over the dosing interval at steady state.

CONCLUSION

This population PK/PD model adequately described ginisortamab PK and binding to serum gremlin-1 in patients with advanced solid tumours. Dose simulations informed the level of gremlin-1 suppression and supported further clinical evaluation of several dosing regimens.