Abstract 521: Pharmacological Profile of JNJ-64179375: a Novel, Long Acting Exosite-1 Thrombin Inhibitor

Abstract

Background: Thrombin is a key serine protease involved in hemostasis and thrombosis by mediating the conversion of soluble fibrinogen to insoluble fibrin that forms the meshwork of a clot. In addition, it is the most potent activator of platelets. Hence thrombin inhibition has been a target for the development of anticoagulant drugs. Recently, an IgA that binds to the exosite 1 region of thrombin was identified in a patient that was profoundly anticoagulated but without any abnormal bleeding episodes over a prolonged follow-up. JNJ-64179375 (JNJ-9375) is a monoclonal antibody derivative of the IgA which by selectively inhibiting exosite 1 may allow for some of thrombin functions mediated by exosite 2 and the active site which might be important for hemostasis. JNJ-9375 is being developed as a new long-acting anti-coagulant with a potential for better efficacy with a reduced bleeding liability. Objectives: To assess the in vitro effects of spiked JNJ-9375 on various clotting assays in human and animal plasma and to evaluate the antithrombotic activity in a rat A-V shunt model of thrombosis. Methods and results: JNJ-9375 produced a concentration-dependent prolongation of thrombin time (TT), ecarin clotting time (ECT), prothrombin time (PT), and activated partial thromboplastin time (aPTT) when added to normal human plasma. The concentrations required to prolong clotting time by twofold (EC2Xs) were 4.4, 12.4, 202.7, and 172.6 μg/ml for TT, ECT, aPTT, and PT respectively. Therefore, TT was the most sensitive assay to show pharmacodynamic activity of JNJ-9375. Similar effects were observed in other species studied including monkey, rat, and mouse. In the rat A-V shunt model of thrombosis, JNJ-9375 dose dependently inhibited thrombus weight with an efficacious dose of 0.3 mg/kg, which was accompanied by prolongation of TT, ECT, PT, and aPTT from ex vivo plasma samples. Conclusion: Results from these studies demonstrate that selective inhibition of exosite 1 on thrombin leads to robust anticoagulation and antithrombotic efficacy. JNJ-9375 is currently in early clinical development.