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SPLTRAK Abstract Submission
Perioperative Management of Patients With Hemophilia Receiving Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia
K. John Pasi1, Claude Négrier2, Margaret V. Ragni3, Pencho Georgiev4, Vasily Mamonov5, Toshko Lissitchkov 6, Kichou Salim7, Baisong Mei7, Shauna Andersson7
1Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, London, United Kingdom/2Unité d’Hémostase Clinique, Centre Régional de Traitement de l’Hémophilie, Hôpital Louis Pradel, Lyon, France/3Department of Medicine and Hemophilia Center of Western Pennsylvania, University of Pittsburgh, Pittsburgh, PA, United States/4University Multiprofile Hospital for Active Treatment Sveti Georgi and Medical University Plovdiv, Plovdiv, Bulgaria/5National Research Center for Hematology, Moscow, Russia/6 Specialized Hospital for Active Treatment of Hematological Diseases, Sofia, Bulgaria/7Sanofi, Cambridge, MA, United States

Background: Fitusiran is a once-monthly subcutaneously administered investigational RNA interference (RNAi) therapeutic that targets antithrombin (AT) to enhance thrombin generation and rebalance hemostasis for people with hemophilia A (HA) or hemophilia B (HB), with or without inhibitors. Clinical management of patients with hemophilia who are undergoing surgical procedures while receiving novel therapies such as fitusiran is of great interest. Objective: To describe the hemostatic management of patients with hemophilia A or B who underwent surgical procedures while receiving therapy with fitusiran. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a continuation phase 2 open-label extension (OLE) study (NCT02554773) that included patients with hemophilia A or B, with or without inhibitors. Patients who were eligible to continue in the phase 2 OLE study received monthly fixed subcutaneous doses of fitusiran 50 mg or 80 mg. Data on perioperative hemostatic therapies and hemostatic response were collected for patients undergoing surgical procedures who had lowered AT levels during the study. Results: Five patients, aged 27 to 53 years, with severe hemophilia A (3 with inhibitors) underwent a total of 6 procedures: endoscopic cholecystectomy and septoplasty, thoracotomy/partial lung segmentectomy, molar tooth extraction, premolar tooth extraction, and total knee joint replacement. Prior to the procedures, the AT level for each of these patients was <20% (range, 10.7%-19%) relative to baseline. At the investigators’ discretion, perioperative hemostatic treatments (factor VIII, activated recombinant factor VII, and/or activated prothrombin complex concentrate) were administered for 5 of 6 procedures. Duration of hemostatic treatment provided post procedure varied depending on type of procedure: 15 hours for premolar tooth extraction, 7 days for endoscopic cholecystectomy and septoplasty, 9 days for total knee joint replacement, and 13 days for thoracotomy/partial lung segmentectomy. Thromboprophylaxis was used in only 1 procedure (total knee joint replacement). All procedures were rated by the respective investigators as resulting in minimal blood loss or blood loss similar to a patient without hemophilia. Further details on perioperative treatment regimens and hemostatic responses as well as updated data with any additional surgical procedures, as applicable, will be presented at the congress. Conclusions: Successful perioperative hemostatic management of patients in the context of AT lowering with fitusiran has been observed in a variety of surgical procedures, including a thoracotomy/partial lung segmentectomy and a total knee joint replacement, which are major operations in patients with hemophilia. The number of surgical procedures observed to date is limited, and additional data are needed to further define appropriate perioperative hemostatic management plans.