Evaluating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in adult males with severe hemophilia A, with or without inhibitors: SWITCH study, a trial in progress

Abstract Introduction As the treatment landscape of hemophilia non-factor therapies expands, there is a growing need to improve understanding of how to safely and effectively switch between therapeutics. Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A or B, with or without inhibitors. The SWITCH study was designed to investigate the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in people with severe hemophilia A, with or without inhibitors. Methods SWITCH is an exploratory, open-label, single-arm Phase 1 study (NCT06145373) investigating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in approximately 15–20 males aged ≥18 years with severe hemophilia A, with or without inhibitors. This study consists of a screening period of approximately 60 days, a 2-month pre-fitusiran treatment period to allow washout of emicizumab, and an 18-month fitusiran prophylaxis period. The washout strategy was developed based on a combination of modeling and simulation data to predict factor VIII-like activity equivalence. A population-pharmacokinetic model was used to directly link emicizumab exposure during the washout period to factor VIII-like activity (Retour S, et al. A. Clin Pharmacokinet. 2020; Schmitt C, et al. Thromb Haemost. 2021). Simulations of AT levels in participants receiving fitusiran were inputted into a quantitative systems pharmacology model to predict factor VIII-like activity in people with severe hemophilia A (Leiser et al. ASH. 2024; Kaddi et al. ASH. 2022). The total FVIII-like activity derived from emicizumab and fitusiran was assumed to be additive, suggesting that total factor VIII-like activity will remain below ~50% when fitusiran is administered ~2 months after the last dose of emicizumab. During the fitusiran prophylaxis period, breakthrough bleed management guidelines with reduced dose/frequency of CFC/BPAs and regular appropriate laboratory testing will be implemented. Participants start fitusiran treatment once every two months (Q2M), though the dose may be adjusted by escalation (monthly treatment) or de-escalation to a lower dose to target AT activity levels of 15–35% and maintain adequate bleed protection. The first 3 sentinel participants are treated in a stepwise fashion, requiring one participant to complete one month of fitusiran treatment before the subsequent participant may receive their first dose of fitusiran. Following the final fitusiran dose, AT activity levels will be monitored at monthly intervals during the 6-month AT follow-up period. The primary endpoint is incidence, severity, and seriousness of adverse events from Day 1 to Month 4 of fitusiran treatment. Secondary endpoints include: laboratory assessments (peak thrombin generation and AT levels) from Day 1 to Month 4 of fitusiran treatment; emicizumab plasma concentrations up to complete washout (~Month 4 of fitusiran treatment); incidence, severity and seriousness of adverse events from Day 1 to Month 18 of fitusiran treatment; health-related quality of life measures from baseline to the end of the study; change in participant joint health; and annualized bleeding rate during the 14-month extension period. Conclusion The SWITCH study will continue recruitment following evaluation of the 3 sentinel patients. This analysis will provide critical evidence to inform healthcare providers on how to safely transition patients from emicizumab to fitusiran, an important consideration in hemophilia clinical practice.