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Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin: Analysis of Antithrombin Levels and Thrombin Generation from a Phase 3 Study in People with Hemophilia A or B Without inhibitors

1University of Michigan, Ann Arbor, Michigan, United States, 2Christian Medical College, Vellore, India, Vellore, Tamil Nadu, India, 3Vivantes Klinikum im Friedrichshain, Berlin, Berlin, Germany, 4The National Haemophilia Centre, The Amalia Biron Thrombosis Research Institute, Sheba Medical Centre, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel, Tel Aviv, Tel Aviv, Israel, 5Department of Clinical Hematology, The Alfred Hospital, Melbourne, Australia AND Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia, Melbourne, Victoria, Australia, 6Sanofi Genzyme, Paris, France, Paris, Ile-de-France, France, 7Sanofi, Bridgewater, NJ, USA, Bridgewater, New Jersey, United States, 8Sanofi, Cambridge, MA, USA, Cambridge, Massachusetts, United States, 9University of Southampton, Southhampton, England, United Kingdom

Abstract Number: OC 50.2

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Hemophilia is characterized by deficiency of FVIII or FIX resulting in impaired thrombin generation (TG) and ineffective clot formation. Fitusiran is an investigational siRNA therapeutic which targets antithrombin to enhance TG and rebalance hemostasis in people with hemophilia (PwH) A or B, irrespective of inhibitor status.

Aims: Longitudinal assessment of changes in antithrombin levels and TG over time in PwH A or B without inhibitors with fitusiran prophylaxis.

Methods: This analysis of a Phase 3, multinational, randomised, open-label study (NCT03417245) included males aged ≥12 years with severe hemophilia A or B without inhibitors, previously treated on-demand. Participants were randomised 2:1 to receive once-monthly 80 mg subcutaneous fitusiran prophylaxis (fitusiran arm) or on-demand factor concentrates (OD arm) for 9 months. The primary endpoint was annualized bleeding rate (ABR). Exploratory endpoints included changes in antithrombin levels and mean peak height assessed by TG over time.

Results: Overall, 120 participants were randomised; 79 (98.8%) in the fitusiran arm and 37 (92.5%) in the OD arm completed the study. On day 15, there was a 71.6% mean reduction from baseline in antithrombin levels in the fitusiran arm, with a further reduction to 79.8% on day 29 and maintained at 85.3%–88.6% from day 43 onwards (figure 1). There was a mean increase in TG of 17.1 nM from baseline in the fitusiran arm on day 15, increasing to 24.4 nM on day 29 and maintained at 29.8.1–43.1 nM from day 43 onwards (figure 2). These results corresponded with an 89.9% reduction in estimated ABR with fitusiran vs OD factor concentrates.

Conclusion(s): Fitusiran reached target pharmacodynamic effect of antithrombin lowering and increased TG by day 29 and demonstrated a consistent effect throughout the study. These findings and a reduction in ABR suggest fitusiran has the potential to rebalance hemostasis in PwH A or B without inhibitors.

To cite this abstract in AMA style:

Pipe S, Srivastava A, Klamroth R, Kenet G, Tran H, Fetita L, Qiu Z, Andersson S, Mei B, Rangarajan S. Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin: Analysis of Antithrombin Levels and Thrombin Generation from a Phase 3 Study in People with Hemophilia A or B Without inhibitors [abstract]. https://abstracts.isth.org/abstract/fitusiran-an-investigational-sirna-therapeutic-targeting-antithrombin-analysis-of-antithrombin-levels-and-thrombin-generation-from-a-phase-3-study-in-people-with-hemophilia-a-or-b-without-inhibitors/. Accessed November 30, 2023.

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