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

Abstract

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.

Keywords:

• hemophilia
• RNAi
• siRNA
• fitusiran
• inhibitor
• ribonucleic acid interference
• small integral RNA

Disclosure

Dr Sara Boyce reports grants from Sangamo Therapeutics Ltd, personal fees, advisory board and speaker fees from CSL Behring, outside the submitted work. Dr Savita Rangarajan reports being a principal investigator in ongoing clinical Trials from Sanofi, during the conduct of the study; consultant from Reliance Life Sciences, advisory board from Pfizer, Sigilon, and Takeda, outside the submitted work. The authors report no other conflicts of interest in this work.