SURGICAL EXPERIENCE IN PEOPLE WITH HEMOPHILIA A OR B WITH AND WITHOUT INHIBITORS RECEIVING FITUSIRAN

Background: Fitusiran, a subcutaneous, investigational siRNA therapeutic lowers antithrombin to rebalance hemostasis and enhance thrombin generation in People with Hemophilia (PwH) A or B, regardless of inhibitor status. For the management of perioperative hemostasis, Bleed Management Guidelines (BMG) with reduced dose and/or frequency of Clotting Factor Concentrates (CFC), or Bypassing Agents (BPA) were implemented. Aims: To describe hemostatic outcomes of major surgeries conducted while on fitusiran prophylaxis in PwHA/B aged ≥12-years, regardless of inhibitor status. Methods: All major surgeries in the fitusiran clinical development program until June 2023 were evaluated, including participants on the 80 mg QM and revised antithrombin-based dose regimen. Informed consent and ethics committee approval were obtained for all studies. Procedures conducted during fitusiran prophylaxis and AT activity < 60% were included. Major surgeries included: opening into a major body cavity, operation on a joint, removal of an organ, operative alteration of normal anatomy, crossing of a mesenchymal barrier, dental extraction of molar teeth or ≥3 nonmolar teeth, or tooth implantation. Investigators/surgeon assessed peri-operative hemostatic control based on the ISTH 4-point response scale (excellent/good/moderate/poor). Results and discussion: Sixty major surgeries (24 in inhibitor patients) were performed. In 47 (78.3%) major surgeries, BMG were followed, and reduced doses were used as perioperative prophylaxis. Four major surgeries were conducted without additional CFC/BPA. Hemostatic control on the day of the surgery was rated excellent/good in 30/31 (97%) cases following BMG and 9/10 (90%) cases not following BMG. ATIII concentrate was used to reverse the pharmacodynamic effect of fitusiran in 7 surgeries with an excellent/good hemostatic outcome. No major treatmentrelated safety concerns were identified perioperatively. Postoperative thrombosis occurred only when dosing exceeded BMG recommendations in 2 participants. Conclusions: Major surgeries can be safely and effectively conducted during fitusiran prophylaxis when BMG are followed, irrespective of inhibitor status. Reversal of lowered AT is not necessary.