Announcement
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| Transaminase Elevations in the Fitusiran Clinical Development Program With the Antithrombin-Based Dose Regimen Sanjay Ahuja1, Savita Rangarajan2, 3, Chur-Woo You4, Bulent Zulfikar5, Abhimanyu Yarramaneni6, Laurel A Menapace6, Yuqian Shen6, Steven W Pipe7. 1Rainbow Hemostasis & Thrombosis Center, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA.2Advanced Centre for Oncology, Haematology and Rare Diseases, K.J.Somaiya Super Specialty Hospital, Mumbai, India.3Faculty of Medicine, University of Southampton, Southampton, United Kingdom.4Department of Pediatrics, Eulji University School of Medicine, Daejeon, South Korea.5Division of Pediatric Hematology-Oncology, Istanbul University Oncology Institute, Istanbul, Turkey.6Sanofi, Cambridge, MA, USA.7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA |
Abstract
Background Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A and B, with and without inhibitors. In the Phase 3 open-label extension study ATLAS-OLE (NCT03754790), the AT-based dose regimen (AT-DR; targeting AT levels of 15–35%) was well tolerated while maintaining clinically meaningful bleed protection. An integrated analysis pooled all safety data of participants receiving the AT-DR across the fitusiran clinical program, including events of transaminase elevations. Objectives To present an overview of events of transaminase elevations, including patient demographics and any reported clinical management from the integrated safety analyses in participants who received the fitusiran AT-DR. Methods The analysis included all males aged ≥12 years with moderate (≤5% residual factor VIII/IX level) or severe hemophilia A and B (<1% residual factor VIII/IX level), with and without inhibitors, who received the fitusiran AT-DR in ATLAS-PPX (NCT03549871), ATLAS-OLE (NCT03754790) and a Phase 1/2 open-label extension study (NCT02554773). Participants with significant liver disease were ineligible. Data collected during major surgery periods were excluded from the analysis. Alanine transaminase (ALT)/apartate transaminase (AST) elevations >3x upper limit of normal (ULN), analyzed by liver function tests, were pre-defined as adverse events of special interest. Informed consent and ethics committee approval were obtained for all studies. Results Overall, 286 participants were included, with 486.0 (≥12 months exposure n=237) total patient-years of exposure with the AT-DR (data cut-off 14 June 2023). Ten (3.5%) participants experienced a total of 14 treatment-emergent adverse events of special interest (TEAESI) of “any ALT/AST elevations >3x ULN”, corresponding to an exposure-adjusted incidence rate (EAIR) of 2.06 per 100 patient-years (Table 1). Alternative etiologies of five participants experiencing ALT/AST elevations >3x ULN included excessive exercise associated with consumption of protein powder, nonsteroidal anti-inflammatory drugs, and alcohol consumption. Medical history of liver conditions reported in participants experiencing ALT/AST elevations >3x ULN included gastritis (n=1), non-alcoholic steatohepatitis (n=1), and hepatic steatosis (n=3). All 14 events of ALT/AST elevations of >3x ULN were asymptomatic, transient, and resolved spontaneously by the data cutoff date. Median time to recovery (≤3x ULN) and normalization (ULN or less) for ALT/AST elevations were 50.3 and 68.3 days, respectively. Three (1.1%) of the ten participants had an ALT/AST value of >5x ULN. Hemophilia type and inhibitor status did not appear to have an effect on the incidence of ALT/AST elevations. No potential cases of the Hy’s law were identiļ¬ed in any participant with AT-DR. Conclusions Integrated safety analyses confirm that there were no cases of sever liver toxicity or liver failure with fitusiran AT-DR during the fitusiran clinical program. The majority of liver transaminase elevations >3x ULN were mild to moderate, transient, and resolved without treatment.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.