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The ability to anticoagulate patients at elevated risk for thrombosis without inducing a bleeding diathesis remains an unmet need of patient care both in a hospital setting and at home. Traditional anticoagulants including warfarin and heparin effectively inhibit clotting, but incur a bleeding risk and require continued monitoring after a stable profile has been established. Current generation direct oral anticoagulants (DOACs) including dabigatran, rivaroxaban, and apixaban overcome many of the liabilities of warfarin and heparin (e.g. lack of target specificity and need for monitoring), but are still susceptible to bleeding diathesis. Thus there remains a need for novel anticoagulants that offer an improved therapeutic index. The recombinant human antibody JNJ-64179375 (JNJ-9375) is a novel thrombin inhibitor that binds to the exosite I region with high affinity and selectivity. In contrast to DOACs that inhibit the protease active site, JNJ-9375 inhibits the interaction of thrombin with its substrates including fibrinogen and PAR-1 while retaining active site and exosite II mediated interactions. This targeted and distinct mechanism of action which modulates the actions of thrombin offers the potential for efficacious anticoagulation with the potential for reduced risk of bleeding compared to active site-specific DOACs.

Introduction -

We have previously reported an improved therapeutic index (TI) for JNJ-9375 vs apixaban in rat and cynomolgus monkey models of venous thrombosis and bleeding. We have also reported that JNJ-9375 preferentially inhibited the fibrin component of the thrombus without significant impact on the platelet component under low and high shear conditions in a human translational model of thrombosis (Badimon chamber model). We hypothesized that the novel mode of action of JNJ-9375 which by selectively inhibiting exosite 1 substrates from binding to thrombin (such as fibrinogen and PAR-1) may allow for other thrombin interactions at the active site and exosite 2 including platelet activation by PAR-4 and GP1b.

The recyclable catalytic system can be used in up to four consecutive cycles with nearly constant activity and selectivity.

Shang: Merck: Employment. Wang:Merck: Employment. Feng:Merck: Employment. Wu:Merck: Employment. Wu:Merck: Employment. Chen:Merck Research Laboratories: Employment. Li:Merck: Employment. Kurowski:Merck: Employment. Chintala:Merck: Employment.

Venous thromboembolism (VTE) is common in patients with advanced cancer and may influence patient eligibility for clinical studies, quality of life, and survival. We reviewed the records of 220 consecutive patients seen in the Phase I Program at M. D. Anderson Cancer Center to determine the frequency of VTE, associated characteristics and clinical outcomes. Of 220 patients, 23 (10.5%) presented to the Phase I clinic with a history of VTE. Twenty-six patients (11.8%) subsequently developed a venous thromboembolic event, with a median follow-up of 8.4 months. These included 9 of 23 patients (39%) with and 17 of 197 (8.6%) without a history of VTE (p < 0.0001). The median time from the first visit to the Phase I clinic to a new thromboembolic episode in the 26 patients was 5.1 months (range, 0 to 27 months). The respective times to development of new thromboembolic events for patients with and without a history of thromboembolism were 3.1 months (n = 9) and 5.3 months (n = 17). Four (15%) of the 26 patients developed venous thromboembolism within one month after their first visit to the Phase I clinic. Among the remaining 22 patients, 18 (69%) developed venous thromboembolism within the first year following their initial visit to the Phase I clinic, and 4 patients developed it after 2.5 years. Fifteen patients developed DVT, seven pulmonary embolism (PE), and one patient each developed one of the following thromboembolic episodes: concurrent DVT and PE; right atrial thrombus; thrombus in the abdominal aorta and DVT; and isolated thrombus in an abdominal aortic aneurysm. The median survival in patients with and without a history of VTE were 4.7 and 10.9 months, respectively (p = 0.0002). Multivariate analysis demonstrated that a history of VTE (hazard ratio 6.2; 95% C.I. 2.6–14.7; p < 0.0001), diagnosis of pancreatic cancer (hazard ratio 4.0; 95% C.I. 1.5–11.2; p=0.007) and platelet count >440 × 109/L (hazard ratio 3.1; 95% C.I. 1.1–8.2; p = 0.026) predicted the development of new venous thromboembolic episodes. These three parameters were used to design a predictive model. Based on the relative risks of the independent covariates, the relative risk of a new thromboembolic episode could be characterized by summing the weighted number of risk factors present at first visit to the Phase I clinic. History of venous thromboembolism was given a score of 2 because the hazard ratio was 6.3, whereas the diagnosis of pancreatic cancer and elevated platelet counts had hazard ratios of 4.7 and 3.0, respectively, and were each given a score of 1. Therefore, patients could have a score ranging from 0 to 4 (no patients had a score of 4). Patients were assigned to one of three risk groups on the basis of their weighted number of presenting risk factors: 0, low risk; 1, medium risk; 2–3, high risk. At 6 months, the rates of a new thromboembolic episode were 3.5%, 12.5%, and 28% for patients with scores 0, 1, or 2–3, respectively (p<0.0001). The median time to a new thromboembolic episode was not reached for patients with a score 0 or 1, and it was 9.1 months for patients with a score of 2–3. In conclusion, a history of VTE or new development of VTE was noted in 40 (18%) of 220 patients seen in our Phase 1 clinic. Our study suggests the need to closely monitor individuals with advanced cancer for the development of venous thromboembolic events. The high risk of recurrent venous thromboembolism in patients with a prior history of venous thromboembolism, whose anticoagulation therapy was discontinued before clinic referral, supports long-term continued prophylaxis in these patients. A prognostic score to predict for time to and frequency of venous thromboembolic events is thereby proposed.

Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disease characterized by defects in trafficking of intracellular vesicles to lysosome-related organelles such as melanosomes, lung lamellar bodies and platelet dense granules. The ashen (rab27a) mouse coat color mutant maintained at Roswell Park Cancer Institute (ash-Roswell) has been proposed as an animal model of HPS based upon prolonged bleeding times, decreased platelet aggregation and greatly decreased platelet dense granule components, including serotonin and ADP. However, human patients with Rab27a deficiency (Griscelli Syndrome) and other isolates of mouse ashen mutants do not exhibit prolonged bleeding suggesting an additional mutation in a gene affecting platelets but not melanocytes in the ash-Roswell mouse. In order to identify this mutation, a backcross between ash-Roswell and the PWK control strain was analyzed. In 390 backcross progeny, deficient platelet serotonin and diluted coat color (Rab27a) phenotypes segregated independently and in the proportions expected for single gene traits. The gene for serotonin deficiency was narrowed to a 2.1Mb region of mouse chromosome 10 containing 15 genes. None of these genes have been implicated previously in platelet storage pool deficiency. These studies indicate this genomic region contains a gene which uniquely controls platelet dense granules and is a candidate gene for a new form of human HPS.

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