At Thursday’s DOACs and Beyond – Translational Aspects Oral Session, Madhu Chintala, Ph.D. presented results from his study of JNJ-375, an investigational antithrombotic drug, in animal models. He reported that:
- JNJ-375 binds to the exosite-1 region on thrombin and does not inhibit the active site.
- In rat and monkey animal models, it was as effective as apixaban in preventing thrombosis but had a more favorable therapeutic index.
- This agent is dosed once monthly, which may be advantageous over existing antithrombotic agents dosed daily or BID.
An antibody (Ab) against thrombin exosite-1 was identified from a 54 year-old female who presented at a hospital in Cambridge, UK with a traumatic subacute subdural hematoma and markedly prolonged coagulation tests. The patient made a complete recovery without intervention and had no abnormal bleeding during 8-years of follow-up, despite persistent prolongation of standard coagulation assays. The Ab was characterized by scientists at Cambridge University and was licensed to XO1 Limited, a small biotech company that was later acquired by Janssen Pharmaceuticals, Inc. JNJ-375 is a human IgG4 antibody designed to mimic the patient’s IgA antibody, with the same binding properties. JNJ-375 specifically binds to the exosite-1 region on thrombin and does not inhibit the active site. In this study, the antithrombotic efficacy and bleeding risk (therapeutic index, TI) of JNJ-375 and apixaban, a marketed factor Xa inhibitor, were compared.
In the rat AV-shunt model of thrombosis, JNJ-375 inhibited thrombosis (50%) at 0.3 mg/kg and the positive control apixaban (58%) at 1 mg/kg. In the rat tail transection model, JNJ-375 and apixaban significantly increased bleeding at 10 (TI=33) and 3 mg/kg (TI=3), respectively. In the FeCl3 model of venous thrombosis in cynomolgus monkeys, JNJ-375 and apixaban inhibited thrombosis (>80%) at 1 and 0.1 mg/kg, respectively. In the cynomolgus monkey liver laceration bleeding model, JNJ-375 and apixaban significantly increased the bleeding time at 40 (TI=40) and 1 mg/kg (TI=10), respectively.
These animal studies demonstrate a favorable TI for JNJ-375 compared to apixaban. In addition to the potential for a decreased bleeding risk, JNJ-375, with a projected once monthly dosing regimen (vs. BID for apixaban), may also provide more consistent anticoagulation during the dosing interval. JNJ-375 is currently being investigated in early clinical studies.