Longitudinal Assessment of Thrombin Generation in Patients with Hemophilia Receiving Fitusiran Prophylaxis: Phase II Study Results

Introduction: Thrombin plays a central role in hemostasis: in the initiation, amplification, and propagation phases of coagulation and in the formation of a stable fibrin clot. Normal hemostatic function requires a balance between procoagulant and anticoagulant proteins that regulate thrombin generation (Negrier et al. Blood Reviews. 2019). Co-inheritance of antithrombin deficiency in people with hemophilia is associated with a milder bleeding phenotype (Shetty et al. Br J Haematol. 2007; Bolliger et al. Thromb Haemost. 2010), supporting the hypothesis that a reduction in antithrombin levels will increase thrombin generation and thus normalize hemostasis in people with hemophilia. Fitusiran is a subcutaneously administered investigational RNA interference therapeutic targeting antithrombin for prophylactic treatment of patients with hemophilia A and B, with or without inhibitors. In a completed Phase I study, monthly subcutaneous administration of fitusiran was found to lower antithrombin levels, increase thrombin generation, and was generally well tolerated (Pasi et al. Blood. 2016; Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe the longitudinal assessment of thrombin generation with fitusiran in the Phase I/II open-label extension study (NCT02554773). Methods: The fitusiran Phase I dose-escalation study (NCT02035605) was followed by the Phase II open-label extension study (NCT02554773), which included male patients, >18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors, who were eligible to continue dosing with monthly subcutaneous fixed doses of fitusiran 50 mg or 80 mg. Thrombin generation was assessed monthly for the first 2 years and every 6 months thereafter using the calibrated automated thrombogram (CAT) assay. Results: Thirty-four patients aged 19-61 with hemophilia A (n=27; 13 with inhibitors and 14 without inhibitors) or hemophilia B (n=7; 2 with inhibitors and 5 without inhibitors) were treated for up to 4.7 years with a median exposure of approximately 2.6 years at the time of the data cut (March 10, 2020). Peak thrombin generation was assessed over the length of the study for each patient. Once-monthly subcutaneous dosing of 50 mg or 80 mg fitusiran prophylaxis over a period of 48 months resulted in sustained antithrombin lowering (a reduction of between 85% to 72% from baseline), which led to peak thrombin levels and an endogenous thrombin potential approaching the normal range