Fitusiran, an RNAi Therapeutic Targeting Antithrombin to Restore Hemostatic Balance in Patients with Hemophilia a or B with or without Inhibitors: Management of Acute Bleeding Events

Background Fitusiran is a once-monthly subcutaneously administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) to enhance thrombin generation (TG) and rebalance hemostasis in patients with hemophilia A (HA) or hemophilia B (HB) with or without inhibitors. Phase 1 and 2 data show dose-dependent lowering of AT, increased TG, and a decrease in the frequency of spontaneous and traumatic bleeds on fitusiran. Given AT knockdown with fitusiran, bleed management guidelines supporting the use of low-dose and reduced-frequency factor or bypassing agent (BPA) were developed and implemented to manage breakthrough bleeds in subjects participating in clinical trials of fitusiran (Table 1). Aim To report the available results on the management of breakthrough bleeding events in subjects on prophylactic therapy with fitusiran using low-dose and reduced-frequency factor or BPA. Methods The ongoing Phase 2 study includes subjects with HA or HB with or without inhibitors who were previously exposed to fitusiran in the Phase 1 study. Subjects received monthly fixed doses of fitusiran 50 mg or 80 mg subcutaneously. To assess the effectiveness of the bleed management guidelines, analyses of 11 months of available data on breakthrough bleeds and treatment after the implementation of the guidelines were performed. Presented are data from an interim ad hoc analysis of a Phase 2 open-label extension study. Results Of the 26 subjects included in this study population, 20 have HA (with inhibitors, n=10; without inhibitors, n=10) and 6 have HB (with inhibitors, n=2; without inhibitors, n=4). Fifteen subjects had ≥1 bleed and 12 subjects (80%) were compliant with the bleed management guidelines. A total of 107 bleeding events evaluable for compliance with the guidelines at the time of data cutoff in 14 subjects required treatment with factor or BPA. A single reduced dose of factor or BPA was sufficient to manage 62 of 107 bleeds (60%) requiring treatment (HA with inhibitors, 21 of 27 bleeds [78%]; HA without inhibitors, 23 of 25 bleeds [92%]; HB with inhibitors, 17 of 51 bleeds [33%]; HB without inhibitors, 1 of 4 bleeds [25%]). Of the 28 bleeds in 5 subjects requiring repeat dosing, 15 (54%) were treated according to the recommended dose and frequency of factor or BPA (HA with inhibitors, 1 of 5 bleeds [20%]; HA without inhibitors, 2 of 2 bleeds [100%]; HB with inhibitors, 9 of 18 bleeds [50%]; HB without inhibitors, 3 of 3 bleeds [100%]). Updated d