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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 With Inhibitors

1University of Southampton, Southhampton, England, United Kingdom, 2Christian Medical College, Vellore, India, Vellore, Tamil Nadu, India, 3Istanbul University Oncology Institute, Istanbul, Istanbul, Turkey, 4BayCare Medical Group, Pediatric Hematology Oncology at St. Jospeh’s Children’s Hospital, Tampa, Florida, USA, Tampa, Florida, United States, 5Sanofi Genzyme, Paris, France, Paris, Ile-de-France, France, 6Sanofi, Bridgewater, NJ, USA, Bridgewater, New Jersey, United States, 7Sanofi, Cambridge, MA, USA, Cambridge, Massachusetts, United States, 8Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA, Los Angeles, California, United States

Abstract Number: PB1152

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 A or B, irrespective of inhibitor status.

Aims: Longitudinal assessment of changes over time in antithrombin activity levels and TG in people with hemophilia A or B with inhbitors (PwHI) with fitusiran prophylaxis to prevent bleeding.

Methods: This analysis of a Phase 3, multinational, randomised, open-label study (NCT03417102) included males aged ≥12 years with severe hemophilia A or B with inhibitors, previously treated on-demand with bypassing agents (BPA). Participants were randomized 2:1 to receive once-monthly 80 mg subcutaneous fitusiran prophylaxis (fitusiran arm) or on-demand BPA (BPA arm) for 9 months. The primary endpoint was annualized bleeding rate (ABR). Exploratory endpoints included changes in antithrombin levels and TG over time.

Results: Overall, 60 participants were included in the exploratory analysis. On day 15, there was a 76.8% mean reduction from baseline in antithrombin activity levels in the fitusiran arm, with a further reduction to 84.1% on day 29 and maintained at 87.6%–89.9% from day 43 onwards (figure 1). There was a mean increase in Peak TG of 21.9 nM from baseline in the fitusiran arm on day 15, with a further increase to 30.8 nM on day 29 and maintained at 36.8–47.5 nM from day 43 onwards (figure 2). These results translated into a 90.8% reduction in estimated ABR with fitusiran prophylaxis vs on-demand BPA.

Conclusion(s): Fitusiran gradually reached target pharmacodynamic effect of antithrombin lowering and increased TG by day 29 and demonstrated a sustained effect over the duration of the study. These findings and the significant reduction in ABR suggest fitusiran has the potential to rebalance hemostasis and provide consistent bleed protection in PwHI.

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Figure 1: Mean percentage change in antithrombin activity level from baseline

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Figure 2: Mean change in peak thrombin generation from baseline

To cite this abstract in AMA style:

Rangarajan S, Srivastava A, Zulfikar O, Cockrell E, Kichou S, Qiu Z, Andersson S, Mei B, Young G. 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 With 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-with-inhibitors/. Accessed August 9, 2022.

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