OC 40.3 - Hepatobiliary events in the fitusiran clinical development program with the revised AT-based dose regimen

Monday, June 24, 2024

15:15 – 15:30 ICT

Room: Plenary Hall

Presenting Author(s)

Steven W. Pipe, MD

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

Co-Author(s)

Alok Srivastava

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

Paul Watkins

Howard Q. Ferguson Distinguished Professor; Director, Institute for Drug Safety Sciences
Eshelman School of Pharmacy, Univeristy of North Carolina
Chapel Hill, North Carolina, 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
Flora Peyvandi, MD, PhD

Full Professor
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Department of Pathophysiology and Transplantation
Milan, Lombardia, Italy

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

Aims: To describe hepatobiliary events in participants who received the fitusiran AT-DR.

Methods: Integrated safety analysis included all males aged ≥12 years with moderate or severe hemophilia A or B, with or without inhibitors who received the fitusiran AT-DR in the following studies: ATLAS-PPX (NCT03549871), ATLAS-OLE (NCT03754790) and a Phase I/II OLE (NCT02554773). Fitusiran dose was individually adjusted to achieve target AT levels of 15–35%. Participants with significant liver disease were ineligible. Informed consent and ethics committee approval were obtained for all studies.

Results: Overall, 286 participants were included in the analysis, with total patient-years of exposure of 486.0 (≥12 months exposure n=237) with the AT-DR. A total of 8/286 (2.8%) and 6/286 (2.1%) participants experienced ALT or AST elevations >3x upper limit of normal (ULN) with the AT-DR, respectively. The mean (SD) time to elevation was 241 (204.6), and 255 (240.6) days, respectively. All initial ALT/AST elevations >3xULN resolved spontaneously; mean (SD) time to resolution was 55 (26.3) and 45 (11.2) days. One event of asymptomatic transaminase elevation resulted in fitusiran discontinuation at physician discretion. There were no cases of severe liver toxicity or liver failure. Overall, 11/286 (3.8%) participants experienced events of cholecystitis/cholelithiasis, and one participant underwent cholecystectomy. No events of cholecystitis/cholelithiasis resulted in discontinuation of fitusiran.

Conclusion(s): Liver transaminase elevations were infrequent and transient with the fitusiran AT-DR. Events of cholecystitis/cholelithiasis resolved without clinical sequalae and participants continued dosing with fitusiran. The pathophysiological mechanism for these events require further elucidation and are under investigation.

Funding: Sanofi.