PB1152 - 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

Tuesday, July 12, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Savita Rangarajan, MD, FRCP, FRCPath

Associate Professor of Clinical Haematology
Faculty of Medicine, University of Southampton, Southampton, UK
Southampton, England, United Kingdom

Co-Author(s)

Alok Srivastava, MD, FRACP, FRCPA, FRCP

Professor of Medicine
Christian Medical College, Vellore, India
Vellore, Tamil Nadu, India
Bulent Bulent Zulfikar, MD

Prof. Dr. O. Bulent Zulfikar, Pediatric Hematology and Oncology
Istanbul University Oncology Institute
Istanbul, Istanbul, Turkey
EC

Erin Cockrell

Director
BayCare Medical Group, Pediatric Hematology Oncology at St. Jospeh’s Children’s Hospital, Tampa, Florida, USA
Tampa, Florida, United States
SK

Salim Kichou

Clinical study director
Sanofi Genzyme, Paris, France
Paris, Ile-de-France, France
ZQ

Zhiying Qiu

Biostatistics Project Leader, Associate Director
Sanofi, Bridgewater, NJ, USA
Bridgewater, New Jersey, United States
SA

Shauna Andersson

Global Clinical Lead
Sanofi
Cambridge, Massachusetts, United States
BM

Baisong Mei

Project head
Sanofi, Cambridge, MA, USA
Cambridge, Massachusetts, United States
Guy Young, MD

Director, Hemostasis and Thrombosis Center
Children's Hospital Los Angeles
Los Angeles, California, United States

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.