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Mechanistic population PK/PD modelling of REGN7508CAT supports dose selection for sustained FXI suppression and aPTT response in healthy volunteers and post-surgical VTE-prevention participants Oleg Milberg1, Hisham Abdallah1, Rachel Kudgus Lokken2, Robert Dingman1, Karoline A.Meagher1, Poulabi Banerjee1, Michael E.Burczynski1, Ethan Marin1, Aaron Kithcart1, David E.Gutstein1. 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.2Allucent, Cary, NC, USA

Abstract

Background: Venous thromboembolism (VTE) remains a leading cause of morbidity and mortality post-surgery. Standard-of-care anticoagulants reduce VTE risk but increase bleeding. REGN7508^CAT, a high-affinity human monoclonal antibody targeting the catalytic domain of Factor XI (FXI) is designed to suppress FXI activity, potentially lowering bleeding risk. Pharmacokinetic/pharmacodynamic (PK/PD) modeling allows quantitative characterization of FXI suppression and activated partial thromboplastin time (aPTT) prolongation, enabling evidence-driven dose selection for post-operative VTE prevention.  Objectives: (1) Develop a joint target-mediated drug disposition (TMDD) model describing REGN7508^CAT PK and PD in healthy volunteers (HVs) and post-operative VTE-prevention study participants; (2) identify covariates explaining inter-individual and inter-population differences; (3) predict the magnitude and duration of FXI inhibition and aPTT prolongation following a single 250 mg IV dose administered post-surgery.  Methods: Data from two clinical trials were integrated: a first-in-human HV study (NCT05603195; 80 participants; 3:1 REGN7508^CAT; placebo; 5–250 mg IV; 125–600 mg subcutaneous) and a Phase 2 post-operative VTE-prevention study (NCT06454630; 120 participants on REGN7508^CAT; 250mg IV). The joint population TMDD model described total and functional drug concentrations, total FXI concentrations, FXI activity, and aPTT. FXI activity was modeled as a direct response to functional drug (free + single arm-bound antibody) concentrations, and aPTT as a direct function of FXI activity relative to baseline. PK incorporated allometric scaling on body weight. Age effects on EC₅₀ for FXI activity were evaluated and not retained in the final joint model. Covariate selection used the COSSAC procedure (COnditional Sampling use for Stepwise Approach based on Correlation). Model development used Monolix 2024R1; simulations were performed in Simulx/RsSimulx (R 4.2.2).  Results: The joint model successfully linked REGN7508^CAT exposure, FXI activity, and aPTT in both HV and post-operative participants (Figure 1). In post-operative participants receiving 250 mg IV, the model reproduced the full PK/PD time course of FXI activity suppression and aPTT elevation. Simulations predicted that >95% of post-operative participants would maintain near-maximal aPTT prolongation and sustained FXI suppression for ≥2 weeks post-dose (Figure 2), supporting the intended coverage interval for VTE prophylaxis. Covariate analyses identified higher FXI synthesis (+20%) and degradation (+30%) rates and lower baseline aPTT (−11%) and maximum achievable effect (Emax; −13%) in post-operative participants compared with HVs. Despite these shifts, the magnitude of aPTT fold-change from baseline was similar between populations, consistent with robust PD target engagement across a broad exposure range. The model accurately characterized PD effects relevant to anticoagulation – FXI inhibition and aPTT prolongation – and quantitatively supported the selection of a single 250 mg IV dose for postoperative VTE prevention.  Conclusions: A mechanistic joint PK/PD TMDD model successfully integrated data from HVs and post-surgical VTE-prevention participants and quantitatively linked REGN7508^CAT exposure with FXI activity suppression and aPTT response. Model-based simulations demonstrated that a single 250 mg IV dose provides sustained FXI inhibition and near-maximal PD effect for ≥2 weeks in most post-operative individuals. Covariate effects on FXI turnover, aPTT baseline, and Emax explained modest PD differences between populations. These results support dose selection, clinical translation, and Phase 3 evaluation of REGN7508^CAT for post-operative VTE prevention. 

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