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

abstractFitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here, we present the results of a 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 (ClinicalTrials.gov identifier: NCT02035605) were enrolled. Participants received monthly subcutaneous fitusiran (50 or 80 mg) under the original dose regimen until a voluntary dosing pause in 2020, after which the AT-based dose regimen was introduced, targeting the recommended AT activity levels of 15% to 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. After implementation of the AT-based dose regimen, there were no thrombotic events, and a reduction in the incidence of elevated transaminases and biliary events was reported. The observed median annualized bleed rate (ABR) on the AT-based dose regimen (0.87) was comparable with the ABR under the original dose regimen (0.70). Furthermore, fitusiran prophylaxis was associated with improved health-related quality of life compared with 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.