Background:
Hemophilia is an inherited bleeding disorder caused by an impairment in the body’s ability to accomplish the natural clotting process. People with hemophilia experience bleeds because there is an inadequate amount of thrombin due to a deficiency in factor VIII or IX. Thrombin is critical to clotting and sealing the wound by converting fibrinogen into fibrin, reinforcing the primary platelet plug. Thrombin activity is regulated by antithrombin.
Fitusiran is a subcutaneously administered investigational RNA interference (RNAi) therapeutic targeting antithrombin with the goal of improving thrombin generation to promote clotting in people with hemophilia A or B with and without inhibitors. Fitusiran is currently being evaluated as a prophylactic agent for hemophilia A and B with and without inhibitors in an ongoing Phase 2 extension study. Breakthrough bleeds on the study are being managed using replacement factors (non-inhibitor patients) or bypassing agents (BPAs; inhibitor patients). The use of replacement factors or BPAs in the background of fitusiran treatment is of clinical interest and will be described.
Methods:
The Phase 2 extension study (NCT02554773) includes people with hemophilia A or B with and without inhibitors, previously dosed in the Phase 1 (NCT02035605) study. Participants receive monthly, fixed subcutaneous doses of fitusiran, 50 mg or 80 mg. Data on breakthrough bleeds and how they were treated were collected by patient diary.
Results:
As of May 2017, 33 participants were enrolled in the study. Previously reported data demonstrated that fitusiran was generally well tolerated and led to dose-dependent antithrombin lowering, thrombin generation increase, and decrease in bleeding frequency in participants with hemophilia A and B with or without inhibitors. Among those achieving target antithrombin lowering of >75%, few bleed events occurred during the observation period. Bleed events were treated with factor concentrates (FVIII or FIX) or bypassing agents (rFVIIa or aPCC), respectively, in doses according to or lower than recommended by the WFH guidelines. Detailed analyses of the frequency and management of bleed events in the Phase 2 study will be presented.
Conclusions:
Clinical data suggest that fitusiran may be a promising investigational prophylactic therapy to promote appropriate clotting and reduce the frequency of bleeding in people with hemophilia A or B with and without inhibitors. Further, the initial limited experience in treating breakthrough bleeds with replacement factor or BPAs has been encouraging, demonstrating good treatment effect in the absence of identified safety concerns.