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Evaluating the Safety and Tolerability of Switching from Emicizumab to Fitusiran Prophylaxis in Males Aged ≥12 Years with Severe Hemophilia A, with and without Inhibitors: SWITCH Study Guy Young1, Ekta S Chhabra2, Shariq Ali2, Lila-Sabrina Fetita3, Marek Demissie2, Abhimanyu Yarramaneni2, Chanchala Kaddi2, Sheng C Chou4. 1Children’s Hospital Los Angeles, Los Angeles, CA, USA.2Sanofi, Cambridge, MA, USA.3Sanofi Genzyme, Paris, France.4Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

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 and B (HA/HB), with and without inhibitors. The SWITCH study was designed to investigate the safety and tolerability of switching from emicizumab to fitusiran in people with severe HA, with and without inhibitors. Methods SWITCH is an exploratory, open-label, single-arm Phase 4 study (NCT06145373) investigating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in ~15–20 males aged ≥12 years with severe HA, with and without inhibitors. This study consists of a screening period of ~60 days, a pre-fitusiran treatment period (allowing washout of emicizumab) of 2 months or shorter if emicizumab levels are <20 μg/mL, and an 18-month fitusiran prophylaxis period (Figure 1). The washout strategy was developed using a combination of modeling and simulation data to predict factor VIII (FVIII)-like activity. Total FVIII-like activity derived from emicizumab and fitusiran was assumed to be additive, suggesting that total FVIII-like activity will remain below ~50% when administering fitusiran ~2 months after the last emicizumab dose. Primary endpoint is incidence, severity, and seriousness of adverse events from Day 1 to Month 4 of fitusiran treatment. Key secondary endpoints are shown in Table 1. Results Two sentinel participants have been enrolled in the study, both of which had HA without inhibitors and received a biweekly emicizumab regimen. Emicizumab levels in the assessed sentinel participants were ~30–50 μg/mL at baseline, <15 μg/mL after 2 months of emicizumab washout and below the lower limit of quantification (5 μg/mL) by Month 5. Peak thrombin levels were lower than with 100% FVIII at all timepoints. Peak thrombin generation during fitusiran treatment was higher than in the pre-switch period (following the last emicizumab dose) across the majority of measurements in both participants. No serious adverse events (AEs) or new safety signals were reported in these participants. Increased alanine aminotransferase (three times the upper limit of normal) of moderate severity was reported in each participant; one event has resolved, and the second event is resolving without additional treatment. Conclusion Early results from two sentinel participants suggest that residual emicizumab in the presence of fitusiran does not substantially increase thrombin generation potential; therefore, patients can potentially switch from emicizumab to fitusiran with a much shorter washout period of ≤2 months. No serious AEs or new safety signals were reported after switching from emicizumab to fitusiran. Study recruitment is ongoing.

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