Hemophilia A and B are inherited bleeding disorders arising from insufficient thrombin generation to prevent bleeding which is caused by deficiencies in coagulation factors VIII and IX, respectively. Without effective treatment, patients have recurrent bleeding, which can be life-threatening and lead to disability from chronic hemarthropathy.Current management is based on replacement therapy with concentrates of factor VIII or IX, when administered either on demand or prophylactically.The benefits of prophylaxis therapy have been established,but such treatment poses a substantial treatment burden.
Standard regimens require two or three intravenous infusions per week to maintain factor trough levels of more than 1 IU per deciliter, yet maintenance of higher levels may provide greater hemostatic protection.
The development of a new generation of factor concentrates with an extended half-life has reduced the frequency of administration, most notably for factor IX products.
Genetic studies have identified potential alternative strategies to address insufficient thrombin generation in hemophilia. Evidence suggests that the coinheritance of deficiency in natural anticoagulants may ameliorate the hemophilia phenotype.Reduced antithrombin levels are hypothesized to improve thrombin generation and promote hemostasis in hemophilia.
Researchers have now developed fitusiran (ALN-AT3SC), an investigational RNA interference (RNAi) therapy that specifically targets antithrombin messenger RNA (encoded by SERPINC1) to suppress the production of antithrombin in the liver, for the treatment of hemophilia.