TFPI Inhibition

Overview

Therapeutic strategy for hemophilia that inhibits tissue factor pathway inhibitor (TFPI), a three-Kunitz-domain anticoagulant, at the K2 domain to rebalance coagulation; mastacimab demonstrated 92% bleeding rate reduction in Phase 3; Novo Nordisk's higher-affinity anti-TFPI candidate requires daily dosing. TFPI is a three-Kunitz-domain protein (K1, K2, K3) where K2 interacts with factor Xa both in solution and on the cell surface, and K1 interacts with factor VIIa; blocking K2 prevents TFPI from inhibiting factor Xa, rebalancing coagulation toward clot formation in hemophilia. Mastacimab was selected to bind directly at the arginine in the K2 domain that projects into the factor Xa active site, completely inactivating TFPI; this was important because another candidate that only partially inactivated TFPI led to increased bleeding in development. (TFPI Biology (20:00-25:00))