Long-term Efficacy and Safety of Fitusiran in Participants with Hemophilia A and B: An Interim Analysis of the Phase 1/2 Open-Label Extension Study

Objective Hemophilia A (HA) and hemophilia B (HB) are caused by a deficiency in factors VIII and IX, respectively, leading to insufficient thrombin generation (TG) for clot formation. Fitusiran is a once-monthly subcutaneous (SC) prophylactic investigational siRNA therapeutic targeting antithrombin (AT) designed to restore sufficient TG and rebalance hemostasis in people with HA or HB, with or without inhibitors. The objective of this abstract is to present interim results on the safety and efficacy of fitusiran from the ongoing Phase 1/2 open-label extension (OLE) study (Sept 1, 2020 data cut).

Material and Methods The fitusiran Phase 1 study (NCT02035605) followed by the Phase 2 OLE study (NCT02554773) included male participants, ≥18 years of age, with moderate or severe HA or HB, with or without inhibitors. Participants received monthly SC prophylaxis with fixed doses of fitusiran, 50 mg or 80 mg. The observed annualized bleed rate (ABR) for participants with HA or HB, with or without inhibitors was calculated.

Results 34 participants were enrolled in the Phase 2 OLE study and treated with fitusiran for a median duration of 3.1 years and a maximum duration of 5 years. Serious treatment emergent adverse events were reported in 13 (38.2 %) participants and resulted in study drug discontinuation in 2 (5.9 %) participants (events of cerebral venous sinus thrombosis and increased liver transaminases). Once-monthly SC dosing of fitusiran prophylaxis resulted in sustained AT lowering in the participants (HA, n = 27 [13 with inhibitors and 14 without inhibitors]; HB, n = 7 [2 with inhibitors and 5 without inhibitors]), leading to thrombin generation levels approaching the lower end of the range seen in healthy volunteers. Overall, the observed median [interquartile range] ABR for treated bleeds in the efficacy period was 0.0 [0.0–3.8]. Factor replacement or bypassing agents were used during breakthrough bleeds, which were managed with the revised bleed management guidelines (BMG, 2017).

Conclusion Over a median treatment duration of 3.1 years, fitusiran prophylaxis was generally well tolerated and provided sustained AT lowering in people with hemophilia, resulting in a milder bleeding phenotype over an extended period. These data suggest that fitusiran has the potential to be used as a prophylactic treatment for people with HA or HB, regardless of inhibitor status.

Publication History

Article published online:
18 June 2021