Reduced Doses of Factor Concentrates and Bypassing Agents to Treat Breakthrough Bleeds in Patients with Hemophilia A and B on Fitusiran Antithrombin-Based Dosing Regimen: ATLAS-OLE
Authors: Pipe Steven W. , Kavakli Kaan , Matsushita Tadashi , Tran Huyen , Zulfikar Bulent , Menapace Laurel , Puurunen Marja , Hu Wenruo , Shen Yuqian , Kaddi Chanchala , Salinas Vanessa 
Published: December 2024

Introduction

Fitusiran, a subcutaneous investigational siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia A/B (PwHA/B), irrespective of inhibitor status. For PwHA/B receiving fitusiran, the bleed management guidelines (BMG) recommend reduced doses and frequencies of clotting factor concentrates (CFC) or bypassing agents (BPAs) to treat breakthrough bleeding. In three phase 3 trials of fitusiran, (ATLAS-INH [NCT03417102], ATLAS-A/B [NCT03417245], ATLAS-PPX [NCT03549871]), the majority of breakthrough bleeds were successfully managed with only one infusion of reduced dose CFC or BPA. This current analysis compared a subset of participants receiving the fitusiran antithrombin-based dosing regimen (AT-DR) in ATLAS-OLE (NCT03754790) to their previous CFC/BPA prophylaxis in the ATLAS-PPX study and reports on CFC/BPA utilization in this subgroup.

Methods

Analysis included males aged ≥12 years with severe hemophilia A or B, with or without inhibitors, who received ≥1 dose of fitusiran in ATLAS-PPX and then continued AT-DR in the ATLAS-OLE study. CFC/BPAs were used for the management of breakthrough bleeds during both periods and for SOC prophylaxis during the CFC/BPA period, with BPAs (activated prothrombin complex concentrate [aPCC] or recombinant activated factor VII [rFVIIa]) used to treat PwH with inhibitors, and FVIII and FIX CFC for PwH without inhibitors. Annualized weight-adjusted CFC/BPA consumption, number of treated bleeds, and infusions per bleed were assessed in the fitusiran efficacy period and in the CFC/BPA prophylaxis period.

Results

Data from 67 participants (PwHA, n=52; PwHB, n=15) receiving CFC/BPA prophylaxis and 69 participants (PwHA, n=52; PwHB, n=17) receiving fitusiran prophylaxis were included in the analysis. Overall in the participants receiving fitusiran prophylaxis, 33.3% of participants with inhibitors (Cohort A) and 66.7% without inhibitors (Cohort B) were enrolled. The AT-DR demonstrated a substantial reduction in mean annualized bleeding rate (ABR) versus BPA prophylaxis (70% reduction, p=0.0002) and was comparable with CFC prophylaxis (p=0.61). Annualized mean weight-adjusted consumption of CFCs and BPAs and number of infusions per breakthrough bleed were lower with fitusiran AT-DR versus CFC/BPA prophylaxis. The mean (SD) total weight-adjusted dose per bleed for participants without inhibitors and with inhibitors was reduced during fitusiran prophylaxis as compared to the CFC/BPA prophylaxis period (FVIII/FIX (45.3 [41.8] IU/kg and 73.6 [54.7] IU/kg, respectively) vs FVIII/FIX (12.0 [6.0] IU/kg and 22.3 [10.8] IU/kg, respectively) and aPCC/rFVIIa (207.8 [373.5] U/kg and 637.3 [1090.8] ug/kg, respectively during the BPA prophylaxis period versus 50.1 [32.2] U/kg and 86.5 [85.8] ug/kg. In order to treat a bleed while on fitusiran prophylaxis, participants without inhibitors required a median (Q1, Q3) of 1.0 (1.0, 1.0) infusions of reduced dose FVIII and FIX, whereas participants with inhibitors required 1.0 (1.0, 2.0) infusions of reduced dose aPCC and rFVIIa. Overall, participants required fewer infusions for the management of breakthrough bleeds with fitusiran AT-DR (with inhibitors=57, without inhibitors=148) versus those who received CFC (total=189) or BPA (total=465) prophylaxis.

Conclusion

Fitusiran prophylaxis was associated with a meaningful reduction in the number of infusions and substantially lower doses of CFCs/BPAs required to treat breakthrough bleeds as compared to SOC prophylaxis. Consumption was reduced on fitusiran based AT-DR. These results support the hemostatic capacity of fitusiran prophylaxis which led to a reduction in the number of bleeds and the amount of CFC/BPA required for the management of breakthrough bleeding events. These data further support the modeled factor equivalency of 20-40% in both PwHA and PwHB on fitusiran prophylaxis.