Work

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

Year: 2026

Type: article

Abstract: 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 ( V c , 1.3 [95% CI: 1.0–1.7]) and peripheral ( V p , 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.

Source: British Journal of Clinical Pharmacology

DOI: 10.1002/bcp.70567