Background Livmoniplimab is an IgG4 that targets the glycoprotein-A repetitions predominant-transforming growth factor (GARP-TGF)-β complex, blocking release of active TGF-β1 and facilitating anti-tumor immune response. It is being investigated in combination with budigalimab (anti-PD-1) in patients with solid tumors. To address Project Optimus, we characterized the pharmacokinetics and preclinical and clinical PK/PD relationships to identify doses for further development of livmoniplimab.

Methods A population-PK model characterizing the PK of livmoniplimab in subjects with solid tumors was developed using data from the FIH study of livmoniplimab (NCT03821935) that tested livmoniplimab at doses ranging from 3 to 1500 mg Q2W. Two complementary approaches were employed to identify minimal livmoniplimab concentration that would be needed in the tumor microenvironment (TME) to engage GARP-TGF-β1 and inhibit TGF-β1 release and signaling. Clinical GARP-TGF-β1 target engagement and PK data were utilized to generate clinical PK/PD model to identify livmoniplimab EC₉₅ for GARP/TGF-β1 engagement in circulation. In addition, an in-vitro GARP-TGF-β1 cell-based assay was utilized to determine livmoniplimab concentrations that would achieve maximal inhibition of TGF-β1 release and signaling in the TME. The developed livmoniplimab population-PK model was then used to simulate livmoniplimab exposures and guide dose selection.

Results A two-compartment PK model with linear and Michaelis–Menten elimination mechanisms described livmoniplimab PK (N=159). Clinical PK/PD modeling of peripheral target engagement data on circulating platelets (N=51) were described by a direct response sigmoidal E_max model and used to determine livmoniplimab EC₉₅ of 0.319 µg/mL for GARP-TGF-β1 complex. The in-vitro GARP-TGF-β1 cell-based assay demonstrated that a minimum livmoniplimab concentration of 0.8 ug/mL results in maximal inhibition of TGF-β1 release and signaling. The PK model was used to determine doses that would achieve effective livmoniplimab concentrations within the TME starting Cycle 1. A dose of 400 mg Q3W is the minimal dose achieving complete target engagement with >90% of subjects achieving sufficient concentration at TME to achieve blockade of TGF-β1 release. Top dose of 1200 mg Q3W enables exposures at TME needed for 100% of subjects to achieve complete target engagement and inhibition of active TGF-β1 release and signaling. These dose levels are below MAD of 1500 mg Q2W.

Conclusions PK/PD modeling leveraging clinical and pre-clinical data identified 400 mg Q3W and 1200 mg Q3W as minimal doses required to achieve maximal target engagement and TGF-β1 inhibition in the TME. Livmoniplimab 400 mg Q3W and 1200 mg Q3W are being explored in multiple Phase 2 studies.