Perioperative Management in Patients with Hemophilia Receiving Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia

Introduction: Hemophilia is a bleeding disorder characterized by ineffective clot formation due to insufficient thrombin generation. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) as a means to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or B with and without inhibitors. Previously reported data have shown that monthly administration of fitusiran led to dose dependent AT lowering, improved thrombin generation and decreased bleeding frequency. (Pasi et al. Blood . 2016.; Pasi et al. New Engl J Med . 2017.) Data from an open-label extension study demonstrated an encouraging safety and tolerability profile, including when used in combination with factor or bypassing agents to treat breakthrough bleeds. (Pasi et al. Res Pract Thromb Haemost . 2017.) The management of operative procedures while on novel, non-factor therapies for hemophilia, such as fitusiran, is of clinical interest. The purpose of this abstract is to describe details as reported by study investigators on the perioperative hemostatic management during dental/surgical procedures in patients with hemophilia receiving fitusiran in a clinical trial.

Methods: The fitusiran Phase 1 study (NCT02035605) followed by the Phase 2 open-label extension (OLE) study (NCT02554773) included patients with hemophilia A or B with and without inhibitors. After the Phase 1 dose-escalation study, patients eligible to continue dosing in the Phase 2 OLE received monthly, fixed SC doses of fitusiran, 50 mg or 80 mg. Data on perioperative hemostatic treatment and hemostatic response were collected for patients undergoing dental/surgical procedures while AT was lowered on study.

Results: Four patients, ages 22-36, with severe hemophilia A (2 with inhibitors) underwent 5 surgical procedures: endoscopic cholecystectomy and septoplasty; thoracotomy/partial lung segmentectomy; molar teeth extraction; premolar tooth extraction. 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 (FVIII, rFVIIa, and/or aPCC) were administered for 4 of the 5 procedures. The duration of hemostatic treatment coverage varied depending on the type of procedure: 15 hours post-procedure (premolar tooth extraction), 7 days post-procedures (endoscopic cholecystectomy and septoplasty), and 13 days post-procedure (thoracotomy/partial lung segmentectomy). No thromboprophylaxis was used in any procedure. All procedures were rated by the respective investigator as resulting in minimal blood loss or blood loss similar to a patient without hemophilia. Further details on the perioperative treatment regimens and hemostatic responses will be presented.

Conclusion: Successful perioperative hemostatic management of patients in the context of AT lowering with fitusiran has been observed; the number of dental/surgical procedures is limited and additional data are needed to further define appropriate perioperative hemostatic management plans.