Background/Objective:
Hemophilia is a bleeding disorder caused by the body’s inability 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; it converts fibrinogen into fibrin, establishing a network to help more platelets accumulate. 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. Interim data from the Phase 1 study showed fitusiran was generally well tolerated and administration of monthly fitusiran led to dose-dependent antithrombin lowering, improvement in thrombin generation, and decrease in bleeding frequency. We will report interim safety, pharmacodynamics, and clinical activity of fitusiran from the Phase 2 extension study.
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. Primary endpoints include safety and tolerability; secondary endpoints include antithrombin activity, thrombin generation and exploratory evaluation of bleed events.
Summary of Results:
As of May 2017, 33 participants were enrolled in the study and had received continuous dosing of up to 14 months. Previously reported data showed that fitusiran was generally well tolerated, with no serious adverse events related to study drug and no thromboembolic events. Once-monthly subcutaneous dosing achieved dose-dependent antithrombin lowering of ~80% and thrombin generation levels approaching levels similar to participants without hemophilia. Exploratory post-hoc analysis of bleed events showed median annualized bleed rate (ABR)=1 in participants without inhibitors and median ABR=0 in participants with inhibitors. Bleed events were successfully managed with either replacement factors or bypassing agents. Updated safety, tolerability and clinical activity will be presented.
Conclusions:
Emerging 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.