OC 40.2 - Incidence of thrombotic events in the fitusiran clinical development program

Monday, June 24, 2024

15:00 – 15:15 ICT

Room: Plenary Hall

Presenting Author(s)

Guy Young, MD

Director, Hemostasis and Thrombosis Program
Children's Hospital of Los Angeles, Los Angeles, USA
Los Angeles, California, United States

Co-Author(s)

Davide Matino

Assistant Professor
Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Ontario, Canada
Hamilton, Ontario, Canada
Steven W. Pipe, MD

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

Laurel A. Menapace

Lead Global Safety Officer, Rare Blood Disorders
Sanofi, Cambridge, MA, United States
Cambridge, Massachusetts, United States
YS

Yuqian Shen

Associate Statistical Project Leader
Sanofi, Bridgewater, NJ, United States
Bridgewater, New Jersey, United States
ZQ

Zhiying Qiu

Senior Biostatistics Project Leader
Sanofi, Bridgewater, NJ, United States
Bridgewater, New Jersey, United States
MP

Marja Puurunen

Senior Clinical Research Director
Sanofi, Cambridge, MA, United States
Cambridge, Massachusetts, United States
SA

Shauna Andersson

Global Clinical Lead
Sanofi, Cambridge, MA, United States
Cambridge, Massachusetts, United States
MD

Marek Demissie

Global Project Head, Rare Diseases and Rare Blood Disorders Clinical Development
Sanofi, Cambridge, MA, United States
Cambridge, Massachusetts, United States
Alok Srivastava

Professor of Medicine
Christian Medical College, Department of Haematology, Vellore, Tamil Nadu, India
Vellore, Tamil Nadu, India

Background: Fitusiran, a subcutaneous, investigational siRNA therapeutic lowers antithrombin (AT) with the goal of increasing thrombin generation and rebalancing hemostasis in people with hemophilia (PwH) A or B, regardless of inhibitor status. A revised AT-based dose regimen (AT-DR) targeting AT levels between 15–35% was implemented to mitigate thrombotic risk during clinical development.

Aims: To describe thrombotic events in the fitusiran clinical program that occurred on the AT-DR and the original dose regimen (ODR).

Methods: Analysis included males aged ≥12 years with moderate or severe hemophilia A or B, with or without inhibitors who participated in fitusiran studies ATLAS-INH (NCT03417102), ATLAS-A/B (NCT03417245) and ATLAS-PPX (NCT03549871), ATLAS-OLE (NCT03754790), or Phase I/II OLE (NCT02554773). Integrated safety analysis compared the exposure-adjusted incidence rate (EAIR) of thrombotic events in participants exposed to the fitusiran AT-DR versus the ODR. Informed consent and ethics committee approval were obtained for all studies.

Results: Overall, 286 participants were exposed to fitusiran AT-DR (n=221 hemophilia A [HA]; n=65 hemophilia B [HB]) and 270 were exposed to ODR (n=211 HA; n=59 HB). Three participants had moderate hemophilia; all other participants had severe hemophilia. Total patient-years of exposure were 486.0 (≥12 months exposure n=237) with the AT-DR and 306.8 (≥12 months exposure n=101) with the ODR. There were nine thrombotic events reported in seven participants with the ODR (Table 1), and four events in four participants with the AT-DR (Table 2). Overall, only one thrombotic event, with the ODR, did not have any provoking or significant predisposing risk factors. The EAIR of thrombotic events per 100 patient-years was numerically lower with the AT-DR (0.82) versus the ODR (2.28).

Conclusion(s): The fitusiran AT-DR mitigated the risk of thrombotic events in PwH A or B, irrespective of inhibitor status, compared with the ODR.

Funding: Sanofi.