PO52 | MECHANISTIC POPULATION PHARMACOKINETIC/PHARMACODYNAMIC AND TIME-TO-EVENT MODELING SUPPORT SUSTAINED FACTOR XI INHIBITION AND SUPERIOR POST-OPERATIVE VENOUS THROMBOEMBOLISM PREVENTION WITH REGN7508CAT

O. Milberg¹, H. Abdallah¹, R.K. Lokken², R. Dingman¹, K.A. Meagher¹, P. Banerjee¹, M.E. Burczynski¹, E. Marin¹, A.P. Kithcart¹, D.E. Gutstein¹ | ¹Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; ²Allucent, Cary, NC, USA

Introduction. Although Factor XI (FXI) inhibition offers a novel anticoagulant approach, quantitative linkage between FXI suppression, pharmacodynamic (PD) biomarkers, and clinical efficacy is limited. Mechanistic modeling can bridge this gap and support translation from healthy volunteers (HVs) to patient populations.

Aim. Integrate HV and post-operative venous thromboembolism (VTE) prevention data using a joint population pharmacokinetic (PK)/PD and time-to-event (TTE) framework, and evaluate the relationship between REGN7508^CAT-mediated FXI inhibition and VTE risk reduction.

Materials and Methods. Data from a first-in-human HV study (NCT05603195) and a Phase 2 post-operative VTE prevention study (NCT06454630) were analyzed with a unified target-mediated drug disposition-based population PK/PD model describing REGN7508^CAT exposure, FXI activity suppression, and aPTT prolongation. TTE analyses for adjudicated deep vein thrombosis (DVT) were conducted during a prespecified 12-day post-operative assessment period using Kaplan–Meier estimation, log-rank testing, Cox proportional hazards modeling, and restricted mean survival time (RMST). Participants without confirmed DVT were censored at Day 12 or right before the last confirmed DVT-free assessment, consistent with the imaging-based endpoint definition.

Results. The joint model successfully linked REGN7508^CAT exposure to FXI inhibition and aPTT response in HVs and post-operative participants. A single intravenous REGN7508^CAT 250 mg dose resulted in rapid, sustained FXI suppression (>99%) and a 3-fold increase in median aPTT prolongation from baseline, with >95% of participants maintaining a 2.5-fold increase for ~≥2 weeks. In the VTE study, REGN7508^CAT improved DVT prevention relative to enoxaparin, with Kaplan–Meier curves separating in the post-operative period. TTE analyses showed a significant treatment effect favoring REGN7508^CAT, supported by RMST estimates over the 12-day assessment period. These findings support a clinically meaningful reduction in post-operative VTE risk.

Conclusions. Joint mechanistic PK/PD and TTE modeling demonstrated that sustained FXI inhibition with REGN7508^CAT results in improved post-operative VTE prevention versus standard-of-care anticoagulation. These results support REGN7508^CAT dose selection, validate mechanistic–clinical linkage, and provide a quantitative framework to evaluate thrombosis prevention and treatment in other populations, including patients with cancer.