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Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| Overview on Management of Breakthrough Bleeds and Major Surgeries Following Bleed Management Guidelines During the Fitusiran Clinical Program in People With Hemophilia Julian Zorrilla1, Kaan Kavakli2, László Nemes3, Tienan Zhu4, Stephanie P'ng5, Steven W Pipe6, Marek Demissie7, Abhimanyu Yarramaneni8, Yuqian Shen7, Umer Khan7, Guy Young9. 1Nemours Children’s Health, Division of Pediatric Hematology/Oncology, Jacksonville, FL, USA.2Division of Hematology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey.3National Haemophilia Center and Haemostasis Department, Center Hospital of Northern Pest - Military Hospital, Budapest, Hungary.4Peking Union Medical College Hospital, Beijing, China.5Fiona Stanley Hospital, Murdoch, Australia.6University of Michigan Medical Center, Department of Hemophilia and Coagulation Disorders, Ann Arbor, MI, USA.7Sanofi, Cambridge, MA, USA.8Sanofi, Morristown, NJ, USA.9Hemostasis and Thrombosis Center, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA |
Abstract
Introduction Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia (PwH) A/B, with or without inhibitors. Due to the synergistic effect on thrombin generation of concomitant fitusiran prophylaxis with clotting factor concentrates (CFC)/bypassing agents (BPA) (Figure 1), breakthrough bleed management guidelines (BMG) with reduced dose and frequency of CFC/BPA were therefore implemented for bleeding and perioperative management to minimize thrombotic risk (Table 1). 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. Here we present outcomes following incorporation of the BMG. Objective To compare CFC/BPA utilization to treat breakthrough bleeds in participants who received the fitusiran AT-DR in ATLAS-OLE [NCT03754790] to their previous CFC/BPA prophylaxis in ATLAS-PPX [NCT03549871]. Secondly, to evaluate hemostatic outcomes of major surgeries following BMG while on fitusiran prophylaxis in PwHA/B aged ≥12 years, regardless of inhibitor status across all studies within the fitusiran clinical program. Methods Analysis of consumption of CFC/BPA to treat breakthrough bleeds during fitusiran prophylaxis, as guided by BMG, included males aged ≥12 years with severe hemophilia A/B, with or without inhibitors, who received ≥1 dose of fitusiran in ATLAS-PPX and transitioned to fitusiran AT-DR in ATLAS‑OLE. All major surgeries in the fitusiran clinical development program until June 2023 were evaluated, including participants on the AT-DR and fixed 80 mg QM dose regimen. Procedures conducted during fitusiran prophylaxis and AT activity <60% were included. Investigators/surgeons assessed perioperative hemostatic control based on the ISTH 4-point response scale (excellent/good/moderate/poor). Results Data from 67 participants (PwHA, n=52; PwHB, n=15) who received CFC/BPA prophylaxis and 69 participants (PwHA, n=52; PwHB, n=17) who received fitusiran AT-DR prophylaxis were included in the analysis. Compliance with BMG for the treatment of breakthrough bleeds was >90%. Overall consumption of BPA/CFC required to treat bleeds was markedly reduced (64.2–98.4% reduction) during fitusiran AT-DR compared with standard of care (SoC) prophylaxis. Of sixty major surgeries performed in 44 participants during the clinical development program, reduced doses of CFC/BPA, at approximately 50% of conventional quantities, were used for perioperative management as per BMG in the majority (n=47, 78.3%) of surgeries. In participants with hemostatic assessment conducted, hemostatic control was rated as excellent/good in 36/38 (95%) major surgeries following BMG and in 8/8 (100%) major surgeries not following BMG. Four major surgeries were conducted without additional CFC/BPA. Postoperative thrombosis was observed exclusively in two participants whose dosing exceeded recommendations outlined by the BMG; no major treatment‐related safety concerns were identified perioperatively. Conclusions Following the implementation of the BMG in the ATLAS clinical trial program, fitusiran AT-DR prophylaxis was associated with a reduction in number of infusions and substantially lower doses of CFC/BPA required to sufficiently treat breakthrough bleeds vs CFC/BPA prophylaxis. Similarly, reduced doses of CFC/BPA were effectively used for perioperative management of 47 (78.3%) major surgeries, and four major surgeries were conducted without perioperative CFC/BPA.
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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.