Hemophilias are hereditary bleeding disorders characterized by an underlying defect in the ability to generate adequate levels of thrombin needed for effective clotting, thereby resulting in recurrent bleeds into joints, muscles, and other major internal organs.
There are approximately 200,000 persons worldwide with hemophilia A and hemophilia B. Hemophilia A is defined by loss-of-function mutations in factor VIII and hemophilia B is defined by a loss of function mutations in factor IX.
Deficiencies in these factors results in an inability to generate adequate levels of thrombin, the key enzyme of the clotting system responsible for clot formation, ultimately leading to recurrent bleeding characteristic of hemophilia. Standard treatment for people with hemophilia involves replacement of the deficient clotting factor either as prophylaxis or “on-demand” therapy which can lead to a temporary restoration of thrombin generation capacity. However, as many as one third of people with severe hemophilia A will develop a neutralizing antibody to their replacement factor – a very serious complication; individuals with ‘inhibitors’ become refractory to standard replacement factor therapy, and therefore, are significantly more complicated to manage and have poorer clinical outcomes. There are approximately 2,000 people with inhibitors in major markets and up to 6,000 worldwide. In addition, there are other Rare Bleeding Disorders (RBDs) defined by congenital deficiencies of other blood coagulation factors (e.g., factors II, V, VII, X, and XI), and there are an estimated 1,000 RBD people worldwide with a severe bleeding phenotype.
Fitusiran (ALN-AT3) for the Treatment of Hemophilia and Rare Bleeding Disorders
We are developing fitusiran, an investigational, subcutaneously administered RNAi therapeutic for the treatment of hemophilia and RBDs. Fitusiran is aimed at lowering the levels of plasma antithrombin (AT) – an endogenous inactivator of thrombin – as a means to improve nd increase levels of thrombin needed to restore hemostasis in people with hemophilia. This innovative approach, based on a Nobel Prize-winning scientific discovery, is supported by observations that people with hemophilia who have co-inherited prothrombotic traits – including AT deficiency – are characterized with a milder bleeding phenotype. Fitusiran utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, which enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. We believe the availability of a therapeutic option with a subcutaneous route of administration, long duration of action, and applicability to persons with hemophilia who have inhibitors would represent a marked improvement over currently available approaches for the treatment of hemophilia.Fitusiran is currently in clinical development for people with moderate-to-severe hemophilia, with and without inhibitors.