ASSOCIATION OF ANTITHROMBIN LEVELS WITH EFFICACY OF FITUSIRAN PROPHYLAXIS IN PEOPLE WITH HEMOPHILIA A OR B, WITH AND WITHOUT INHIBITORS: A PREDICTIVE MODELING APPROACH

Fitusiran is a United States Food and Drug Administration-approved Antithrombin (AT) lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A or B, with or without inhibitors. The AT-based Dose Regimen (AT-DR) targeting AT levels between 15%–35% was implemented to mitigate the risk of thrombosis and enhance the benefit-risk profile of fitusiran. To quantitatively characterize the relationship between AT levels and Annualized Bleeding Rate (ABR) during fitusiran prophylaxis, using a predictive modeling approach. To assess the relationship between AT levels and ABR, an Andersen-Gill model with frailty was used, utilizing data from patients who received ≥1 dose of fitusiran during the steady-state period of three completed Phase 3 trials (ATLAS-INH, ATLAS-A/B, ATLAS-PPX), ongoing Phase 3 extension study (ATLAS-OLE), and a subset of 34 patients from a Phase 2 trial. All available data of participants who received the 80 mg once-monthly Original Dose Regimen (ODR) and the AT-DR were included in the analysis. Data from 254 patients spanning 552.9 patient-years of observation were used. Individual mean (interquartile range) AT levels were 23.2% (20.7%–25.8%) with the AT-DR and 11.5% (10.4–13.3%) with the ODR. A monotonic increasing relationship between ABR and AT levels was confirmed by modeling and simulation, with a median (95% Confidence Interval) ABR of 0.73 (0.48, 1.05) at 10% AT activity levels, 2.31 (1.69, 3.18) at 15%, and 4.58 (3.55, 6.30) at 35%. This analysis demonstrates that lower AT levels are associated with decreased bleeding rates. Based on these results, fitusiran prophylaxis can be individualized to patient needs within the 15%–35% AT range to enhance treatment efficacy. The ability to measure AT activity levels is an advantage of fitusiran prophylaxis. Sanofi.