OC 50.2 - 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

Tuesday, July 12, 2022

11:00 AM – 11:15 AM

Location: ExCel Center, ICC Auditorium

Presentation Format: In-Person

Presenting Author(s)

Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States

Co-Author(s)

Alok Srivastava, MD, FRACP, FRCPA, FRCP

Professor of Medicine
Christian Medical College, Vellore, India
Vellore, Tamil Nadu, India
Robert Klamroth, MD, PhD

Priv. Doz. Dr. med.
Vivantes Klinikum im Friedrichshain, Clinic for Internal Medicine Angiology and Haemostaseology
Berlin, Berlin, Germany
Gili Kenet, MD

Director
The National Hemophilia Center, and Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel
Yehud-Monosson, HaMerkaz, Israel
HT

Huyen Tran

Professor
Australian Centre for Blood Diseases, Monash University
Melbourne, Victoria, Australia
LF

Lila-Sabrina Fetita

Clinical research 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
Savita Rangarajan, MD, FRCP, FRCPath

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

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.