Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management in people with hemophilia A or B.

Fitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here we present the results of the completed Phase 2 open-label extension study, which evaluated the long-term safety and efficacy of fitusiran in participants with moderate or severe hemophilia A or B, with or without inhibitors. Male participants who had completed the Phase 1 study (NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 mg or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, following which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15-35%. Thirty-four participants (hemophilia A [n=27]; hemophilia B [n=7]) were enrolled in the Phase 2 study and treated with fitusiran for a median exposure of 4.1 years. Adverse events reported on the original and the AT-based dose regimen were consistent with the identified risks of fitusiran. Following implementation of the AT-based dose regimen, no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events were reported. The observed median annualized bleeding rate (ABR) on the AT-based dose regimen (0.87) was comparable to the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared to baseline and provided successful hemostatic control during surgical procedures and invasive interventions. Overall, fitusiran was well tolerated and effective bleeding control was maintained on an AT-based dose regimen. This trial was registered at www.clinicaltrials.gov as #NCT02554773.