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Hemophilia

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.

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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.

Please read the latest press releases and data presentations for fitusiran here.

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Interim Data from Ongoing Phase 1 Trial with Fitusiran for the Treatment of Hemophilia and Rare Bleeding Disorders

Interim Data from Ongoing Phase 1 Trial with Fitusiran for the Treatment of Hemophilia and Rare Bleeding Disorders

We reported new data from Parts C and D of our Phase 1 study with fitusiran, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders, at the World Federation of Hemophilia (WFH) World Congress, held July 24-28, 2016 in Orlando, Florida.



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Positive Data with Monthly Dosing Cohorts from Ongoing Phase 1 Trial with Fitusiran (ALN-AT3) for the Treatment of Hemophilia and Rare Bleeding Disorders

Positive Data with Monthly Dosing Cohorts from Ongoing Phase 1 Trial with Fitusiran (ALN-AT3) for the Treatment of Hemophilia and Rare Bleeding Disorders

We reported new data from our Phase 1 study with the newly named fitusiran (ALN-AT3), an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Interim results – presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8, 2015 – showed that monthly, subcutaneous administration of fitusiran achieved potent and dose-dependent lowering of AT of up to 88% in patients with hemophilia. This AT lowering was associated with statistically significant increases in thrombin generation and an 85% reduction in estimated median annualized bleeding rates (ABR) in all evaluable cohorts. The observed bleeding rates are comparable to those reported for prophylactic intravenous infusions of replacement factors in patients with hemophilia. Fitusiran was found to be generally well tolerated to date, including no thromboembolic events or clinically significant increases in D-dimer, a biomarker of excessive clot formation.



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Positive Interim Clinical Results from Ongoing Phase 1 Trial of ALN-AT3 for the Treatment of Hemophilia and Rare Bleeding Disorders

Positive Interim Clinical Results from Ongoing Phase 1 Trial of ALN-AT3 for the Treatment of Hemophilia and Rare Bleeding Disorders

We presented positive interim clinical data from our ongoing Phase 1 study for ALN-AT3, a subcutaneously administered, investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders. Data were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress held June 20 – 25, 2015. New clinical results from 12 subjects with severe hemophilia show that subcutaneous administration of ALN-AT3 achieved potent and dose-dependent knockdown of AT of up to 86%. AT knockdown was highly durable, with effects lasting over two months after the last dose, supporting further evaluation of a once-monthly subcutaneous dose regimen. In addition, AT knockdown was associated with statistically significant increases in thrombin generation with a mean increase of up to 350% and marked improvements in whole blood clotting; these results demonstrate a re-balancing of hemostasis in severe hemophilia subjects. Furthermore, in an exploratory post-hoc analysis, a reduced frequency of bleeding was observed at higher AT knockdown levels with a maximum bleed-free interval of 114 days. Very importantly, ALN-AT3 continues to be generally well tolerated.



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