Type: Oral
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Beyond Efficacy of Hemostatic Agents in Hemophilia: Exploring Pharmacokinetics, Dosing Regimens, and Special Populations
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Translational Research, Hemophilia, Drug-drug interactions, Diseases, Treatment Considerations
Hemophilia A (HA) is a serious, X-linked bleeding disorder caused by a deficiency of clotting factor VIII (FVIII). Emicizumab, a bispecific monoclonal antibody that brings together activated factor IX and factor X, is currently the only non-factor prophylaxis approved for HA, with and without inhibitors, and is given subcutaneously every week, two weeks, or monthly. Despite the high degree of efficacy of emicizumab for bleed prevention, breakthrough bleeds still occur, requiring treatment by CFCs or bypassing agents. Fitusiran, a subcutaneous investigational siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia A/B (PwHA/B), irrespective of inhibitor status, and is given subcutaneously monthly or every 2 months. While demonstrating excellent efficacy, fitusiran has led to thrombotic events which were found to occur in patients with persistently low AT levels of <10%. As a result, a revised dosing strategy targeting AT levels of 15-35% (AT-DR) has been employed in the Phase 3 clinical trials to reduce the risk of thrombotic events. AT-DR has been successful in reducing the incidence rate of thrombosis while maintaining clinically meaningful bleed control. As fitusiran becomes available for HA, a safe transition from emicizumab to fitusiran or vice versa needs to be developed in which both the risk of thrombotic and of bleeding events is minimized. Given the long half-life of emicizumab and the prolonged suppression of AT production by fitusiran, the optimal switch strategy remains unknown. This study, the first of its kind, evaluates the combined effect of emicizumab ex vivo with fitusiran in vitro. We present preliminary data of 8 subjects.
The primary aims of this study are to evaluate the peak thrombin and endogenous thrombin potential (ETP) of plasma obtained from HA patients on emicizumab with varying levels of AT lowering to mimic the effects of concurrent fitusiran.
Methods
Plasma was obtained from PwHA with or without inhibitors who were on emicizumab for at least one month, between the age of 3 and 65 years of age, and who did not receive any bypassing agents within 48 hours or FVIII replacement within 14 days from the blood draw. These samples were then spiked with AT antibody at various concentrations to lower AT levels. Using thrombin generation assay (TGA), we calculated peak thrombin and ETP at each AT level, with emicizumab at patient steady state. Pooled normal plasma (PNP) was used as control. Emicizumab levels were measured using r2 Diagnostics emicizumab calibrator. AT levels were measured using HemosIL® reagents.
Results
Baseline emicizumab levels ranged from 11.6 ug/mL to 75.8 ug/mL and baseline AT levels ranged from 93% to 147%. Baseline ETP ranged from 97.14 to 278.4 nM*min and baseline peak thrombin ranged from 2.09 to 12.7 nM. In PNP, ETP ranged from 702.2 to 996.84 nM*min and peak ranged from 65.73 to 105.68 nM. Higher baseline ETP and peak were seen with higher concentrations of emicizumab.
At AT levels of 70-80%, ETP ranged from 173.84 to 514.37 nM*min and peak ranged from 7.06 to 19.6 nM. At AT levels of 50-65%, ETP ranged from 259.01 to 818.94 nM*min and peak ranged from 10.6 to 25.53 nM. At AT levels of 40-45% ETP ranged from 553.43 to 913.62 nM*min and peak ranged from 17.55 to 25.68 nM. At AT levels of 35%, ETP ranged from 405.92 to 828.01 nM*min and peak ranged from 15.83 to 27.45nM. At AT levels of 25-30%, ETP ranged from 614.64 to 2732.96 nM*min and peak ranged from 15.4 to 76.86 nM. At AT levels of 20%, ETP ranged from 506.74 to 3163.51 nM*min and peak ranged from 19.34 to 78.87 nM. At AT levels below 15%, ETP ranged from 667.15 to 3828.46 nM*min, peak was 23.01 to 125.97 nM, with one subject at AT levels of 10% showing TG that surpassed the maximum threshold of the assay. Of note, this latter patient had a baseline emicizumab level of 75.8 ug/mL.
Conclusion
From this early data, we show that AT lowering in the presence of emicizumab leads to an increase in peak thrombin and ETP and an optimal wash out period needs to be determined as patients are transitioned from emicizumab to fitusiran or vice versa. This also establishes a model for studying other combinations of non-factor therapies in hemophilia to inform transitions from one to the other.
Disclosures: Zaheer: Sanofi: Research Funding. Toh: Sanofi: Current Employment. Young: Hema Biologics: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; BioMarin: Consultancy, Speakers Bureau; CSL Behring: Consultancy; Sanofi: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Spark: Speakers Bureau; Takeda: Consultancy.
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