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Presentation Details
| Biliary Events in the Fitusiran Clinical Development Program With the Antithrombin-Based Dose Regimen Mindy Simpson1, Canan Albayrak2, Savita Rangarajan3, 4, Oleksandra Stasyshyn5, Jing Sun6, Chur-Woo You7, Abhimanyu Yarramaneni8, Laurel A.Menapace8, Yuqian Shen8, Kaan Kavakli9. 1Rush Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA.2Ondokuz Mayis University Faculty of Medicine, Department of Pediatric Hematology, Samsun, Turkey.3Advanced Centre for Oncology, Haematology and Rare Diseases, K.J.Somaiya Super Specialty Hospital, Mumbai, India.4Faculty of Medicine, University of Southampton, Southampton, United Kingdom.5Institute of Blood Pathology and Transfusion Medicine, Lviv.6Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.7Department of Pediatrics, Eulji University School of Medicine, Seoul, Korea.8Sanofi, Cambridge, MA.9Division of Hematology, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Turkey |
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 the events of cholecystitis/ cholelithiasis. Objectives To present an overview of events of cholecystitis/cholelithiasis, including patient demographics and any reported clinical management from the integrated safety analyses in participants who received the fitusiran AT-DR. Methods The analyses 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 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. 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). Eleven (3.8%) participants experienced a total of 16 treatment-emergent adverse event of special interest (TEAESI) of cholecystitis/cholelithiasis, corresponding to an exposure-adjusted incidence rate (EAIR) of 2.26 per 100 participant years (Table 1). TEAESIs included cholelithiasis (n=5 [1.8%]); cholecystitis (n=3 [1.0%], severity not specified); gallbladder polyp (n=3 [1.0%]); acute cholecystitis (n=2 [0.7%]); chronic cholecystitis (n=1 [0.3%]); cholangitis (n=1 [0.3%]); and gallbladder enlargement (n=1 [0.3%]). Three (1.0%) participants experienced a serious TEAESI of cholecystitis/cholelithiasis. These events included cholecystitis (n=2 [0.7%]) and cholangitis (n=1 [0.3%]). No participants discontinued fitusiran due to a TEAESI of cholecystitis/cholelithiasis. As of data cut-off, 12 events were assessed as related to fitusiran by investigator and 7 events were reported as recovered/resolved with no reports of fitusiran dose modification. Outside of the analysis, one participant receiving AT-DR experienced an event of cholecystitis during the study and underwent an open cholecystectomy. The event of cholesystitis was determined as related to fitusiran by investigator and recovered/resolved with no fitusiran dose modification required; treatment was ongoing at the time of the last available report. Conclusions Integrated safety analyses confirm that the fitusiran AT-DR was well tolerated. The majority of events of cholecystitis/cholelithiasis did not require fitusiran dose modification and no participants discontinued dosing with fitusiran. The pathophysiological mechanism for these events remains undetermined. Additional studies assessing the AT-DR with fitusiran are ongoing and planned.
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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.