Mechanistic Modeling to Support Hemostatic Equivalency of Antithrombin Lowering in People with Hemophilia A or B

Fitusiran is an investigational siRNA therapeutic that lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia A (PwHA) or B (PwHB), irrespective of inhibitor status. Three completed phase 3 clinical studies [ATLAS A/B (NCT03417245), ATLAS INH (NCT03417102), and ATLAS PPX (NCT03549871)] have demonstrated that fitusiran prophylaxis significantly reduced bleeding events compared to on-demand or prior prophylaxis treatment with clotting factor concentrate (CFC) or bypassing agents (BPA) (Srivastava et al. Lancet Haematol 2023; Young et al. Lancet 2023; Kenet et al. Blood 2022). A quantitative systems pharmacology (QSP) model of the coagulation pathway was previously applied to support the hemostatic equivalency of fitusiran prophylaxis (i.e., AT lowering) in PwHA (Kaddi et al., 2022). Unlike prior models of the coagulation cascade, this QSP model considers the impact of α-2-macroglobulin, a key regulator of thrombin with increased influence at reduced AT levels, that is critical to understand the impact of fitusiran on thrombin generation (Kattula et al. Blood 2020). The prior analysis was informed by thrombin generation assay (TGA) data from donor-derived spiked plasma and clinical TGA metrics from the Ph1/2 clinical studies of fitusiran and predicted that the targeted therapeutic range of 15-35% AT resulted in a thrombin peak profile which was comparable to 20-40% supplemental FVIII activity in PwHA. The current analysis extends previous work by applying the validated QSP model to support hemostatic equivalency in both PwHA and PwHB, considering TGA metrics from completed phase 3 clinical studies of fitusiran in patients with inhibitors (ATLAS-INH) and without inhibitors (ATLAS-A/B). Virtual populations of untreated severe PwHA (<1% FVIII activity) and PwHB (<2% FIX activity) were used to simulate TGA metrics which were validated against clinical and literature data. Simulated TGA metrics from these virtual populations after AT lowering (15-35%) were compared to those treated with supplemental factor. Based on this analysis, the peak thrombin generated at 15-35% AT was predicted to be similar to peak thrombin from treatment with 20-40% supplemental FVIII activity for PwHA, and 20-40% supplemental FIX activity for PwHB. By considering the impact of α-2-macroglobulin, the QSP model provides a mechanistic representation of thrombin generation under conditions of AT lowering in PwHA and PwHB. This analysis predicted similar factor equivalency of 20-40% in both PwHA and PwHB for the target therapeutic range of fitusiran (15-35% AT). Clinical data on the efficacy and safety of treatment of breakthrough bleeds with reduced dosing of CFC/BPA further support these results.