Presentation Details
| Long-Term Safety and Efficacy of Fitusiran Prophylaxis in a Phase 1/2 Open-label Extension Study in People with Moderate or Severe Hemophilia A or B Steven W.Pipe1, Toshko Lissitchkov2, Sarah Mangles3, Pencho Georgiev4, Erin Feng5, Laurel A.Menapace6, Salim Kichou7, Shauna Andersson6, Marek Demissie6, Margaret Ragni8. 1University of Michigan, Ann Arbor, MI, USA.2Clinic Specialized Hospital for Active Treatment of Haematological Diseases, Sofia, Bulgaria.3Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, United Kingdom.4University Multiprofile Hospital for Active Treatment, Plovdiv, Bulgaria.5Sanofi, Shanghai, China.6Sanofi, Cambridge, MA, USA.7Sanofi, Paris, France.8University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA |
Abstract
Background: Fitusiran is a subcutaneous investigational siRNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia A or B, regardless of inhibitor status. Objectives: To evaluate the long-term safety and efficacy of fitusiran prophylaxis in people with hemophilia A or B, with or without inhibitors, in a Phase 1/2 open-label extension study (NCT02554773). Methods: This Phase 1/2, single-arm, open-label extension study included males aged ≥18 years with moderate or severe hemophilia A or B, with or without inhibitors, who had completed the Phase 1 study (NCT02035605). Participants initially received once-monthly subcutaneous fitusiran 50 or 80 mg (original dose regimen [ODR]). Following a voluntary dosing pause in 2020 after reports of non-fatal thrombotic events, a revised AT-based dosing regimen was implemented, with dose adjustments based on individual participant responses, targeting AT levels between 15–35% to mitigate thrombotic risk. Primary and secondary endpoints were safety and annualized bleeding rate, respectively. Results: Overall, 34 participants initiated the ODR (hemophilia A inhibitor/non-inhibitor, n=13/14; hemophilia B inhibitor/non-inhibitor: n=2/5). Following the voluntary dosing pause, 18 participants restarted on the revised AT-based dosing regimen (hemophilia A inhibitor/non-inhibitor, n=6/6; hemophilia B inhibitor/non-inhibitor, n=2/4), and 12 completed the study (Figure 1). Of those that restarted on the revised AT-based dosing regimen, 2 participants received 80 mg once-monthly (QM), 5 received 50 mg QM and 11 received 50 mg every other month (Q2M). One participant escalated from 50 mg Q2M to 50 mg QM following the restart as per investigator decision. AT levels were maintained in target range of 15–35% with the revised AT-based dosing regimen. Median (min–max) exposure was 1135 (28–1700) days on the ODR and 568 (227–625) days on the revised AT-based dosing regimen. No thrombotic events occurred in participants with the revised AT-based dosing regimen; thrombotic events occurred in 2/34 (5.9%) participants with the ODR. Alanine transaminase/aspartate aminotransferase (ALT/AST) elevations >3× upper limit of normal occurred in 6/34 (17.6%) participants with the ODR and 1/18 (5.6%) participants with the revised AT-based dosing regimen. Cholecystitis and/or cholelithiasis occurred in 4/34 (11.8%) participants with the ODR and 0/18 participants with the revised AT-based dosing regimen. Fitusiran prophylaxis maintained effective bleed protection over a 6-year period; observed median annualized bleeding rate was 0.70 with ODR and 0.87 with the revised AT-based dosing regimen (Figure 2). Conclusions: Following implementation of the fitusiran revised AT-based dosing regimen, no thrombotic events and no cholecystitis and/or cholelithiasis were reported. ALT/AST elevation occurred in one subject. AT-based dose individualization may improve the safety profile of fitusiran, while maintaining effective bleed protection. The revised AT-based dosing regimen is under evaluation in ongoing clinical studies.
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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.