S301: consumption of factor concentrates and bypassing agents for management of breakthrough bleeds with fitusiran prophylaxis in people with haemophilia a or b: analysis of atlas-ppx

Background: Fitusiran, an investigational subcutaneous (SC) siRNA prophylactic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or B (PwHA/B), irrespective of inhibitor status. For PwHA/B receiving fitusiran, reduced doses of clotting factor concentrates (CFC) or bypassing agents (BPA) are recommended to treat breakthrough bleeds. Previous trials (ATLAS-A/B [NCT03417245], ATLAS-INH [NCT03417102]) reported reduced total CFC/BPA consumption as result of reduction in ABR, number of injections and CFC/BPA doses required to treat breakthrough bleeds. Aims: To explore CFC/BPA consumption with fitusiran prophylaxis vs CFC/BPA prophylaxis in PwHA/B, with or without inhibitors. Methods: This Phase 3, multicentre, multinational, open-label trial (ATLAS-PPX, NCT03549871) enrolled males aged ≥12 years with haemophilia A or B, with or without inhibitors, who had received prior CFC or BPA prophylaxis. Participants continued CFC/BPA prophylaxis for 6 months, before switching to once-monthly 80 mg SC fitusiran prophylaxis (1-month onset and 6 months efficacy period). CFC/BPAs were used for the management of breakthrough bleeds, 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. Primary endpoint was annualised bleeding rate (ABR). Annualised weight-adjusted CFC/BPA consumption, number of treated bleeds and infusions per bleed were assessed in the fitusiran efficacy period and the CFC/BPA prophylaxis period. Results: Overall, 80 participants were enrolled; 65 were eligible for efficacy analyses (19 with inhibitors [Cohort A] and 46 without inhibitors [Cohort B]). Estimated ABR was significantly reduced by 61.1% with fitusiran (2.9 [95% CI: 1.7, 4.9]) vs CFC/BPA (7.5 [95% CI: 5.5, 10.1]; p=0.0008), and 41 (63.1%) experienced zero treated bleeds with fitusiran versus 11 (16.9%) with CFC/BPA. Fewer participants required CFC/BPA for breakthrough bleed treatment after switching to fitusiran. A total of 18 participants in Cohort A and 36 participants in Cohort B had any treated bleed whilst on CFC/BPA prophylaxis. After switching to fitusiran, this reduced to 4 and 20 participants respectively. Total number of treated bleeds was lower with fitusiran (18 in Cohort A and 54 in Cohort B) vs CFC/BPA prophylaxis (96 in Cohort A and 126 in Cohort B). Mean total weight-adjusted dose per bleed of CFC (FVIII=13.4 IU/kg, SD: 5.5; FIX=26.2 IU/kg, SD: 0.0) and BPA (aPCC=34.1 U/kg, SD: 16.1; rFVIIa=38.2 µg/kg, SD: 17.0) were markedly reduced when participants received fitusiran vs CFC (FVIII=45.3 IU/kg, SD: 41.8; FIX=73.6 IU/kg, SD: 54.7) or BPA (aPCC= 199.8 U/kg, SD: 366.1; rFVIIa=709.9 µg/kg, SD: 1163.8) prophylaxis. Total mean consumption of FVIII/FIX or aPCC/rFVIIa for breakthrough bleeds was lower when patients received fitusiran vs CFC or BPA prophylaxis, respectively (Table 1). Participants required fewer injections (with inhibitors=26, without inhibitors=59) with fitusiran vs those who received CFC (total=189) or BPA (total=419) prophylaxis. Summary/Conclusion: Fitusiran prophylaxis significantly reduced bleeding versus CFC/BPA prophylaxis, and consumption endpoint results consistently favoured fitusiran prophylaxis over CFC/BPA prophylaxis. Fitusiran prophylaxis reduced total CFC/BPA consumption by reducing mean total weight-adjusted dose per bleed in PwHA/B with and without inhibitors, number of treated bleeds and number of injections, thereby reducing treatment burden.Keywords: Hemophilia