RNAi for the Treatment of People with Hemophilia: Current Evidence and Patient Selection.

Severe hemophilia is associated with spontaneous, prolonged and recurrent bleeding. Inadequate prevention and treatment of bleeding can lead to serious morbidity and mortality. Due to the limitations of intravenous clotting factor replacement, including the risk of inhibitory antibodies, innovative novel therapies have been developed that have dramatically changed the landscape of hemophilia therapy. Ribonucleic acid interference (RNAi) has brought the opportunity for multiple strategies to manipulate the hemostatic system and ameliorate the bleeding phenotype in severe bleeding disorders. Fitusiran is a RNAi therapeutic that inhibits the expression of the natural anticoagulant serpin antithrombin. Reduction in antithrombin is known to cause thrombosis if coagulation parameters are otherwise normal and can rebalance hemostasis in severe hemophilia. Reports from late stage clinical trials of fitusiran in hemophilia A and B participants, with and without inhibitory antibodies to exogenous clotting factor, have demonstrated efficacy in preventing bleeding events showing promise for a future "universal" prophylactic treatment of individuals with moderate-severe hemophilia.