PB1317 - Assessment of the Combined Effects of Emicizumab and Fitusiran with in vitro Spiking of Emicizumab and Simulated Fitusiran into Factor VIII Deficient Plasma using Thrombin Generation Assay

Background: Emicizumab and fitusiran are novel agents for persons with hemophilia A (HA). Future use of these agents may involve temporary overlap when switching from one to another or the purposeful use of both together to either enhance efficacy or reduce toxicity by using lower doses of each together. While emicizumab can be spiked into plasma to exert its effect, fitusiran pharmacodynamics can be simulated by utilizing an anti-antithrombin (AT) antibody. This study, the first of its kind, evaluates the combined effect of emicizumab and fitusiran in vitro.

Aims: To identify combinations of concentrations of emicizumab and AT lowering that result in normal peak thrombin and endogenous thrombin potential (ETP).

Methods: Utilizing thrombin generation (TG), we calculated peak thrombin and ETP in commercially available pooled FVIII deficient plasma spiked with varying concentrations of emicizumab and with varying levels of AT achieved using a sheep anti-human AT antibody. AT assays were performed using a functional chromogenic assay. Pooled normal plasma (PNP) served as control. See row 1 and column 1 in table for concentrations of emicizumab and AT levels, respectively.

Results: Normal ETP was noted at the following combinations: 45% AT levels and 10 mcg/ml of emicizumab, 65% AT levels and 20 mcg/ml of emicizumab, 80% AT levels and 50 mcg/ml (therapeutic concentration) emicizumab. For full results see table and figure.

Conclusion(s): These results demonstrate that emicizumab with lower AT levels leads to an increase in TG. Normal TG can be achieved with certain combinations, including lower than therapeutic emicizumab concentrations along with low AT levels. These initial data can guide future studies in the use of combination therapy in the treatment of HA. Furthermore, understanding TG effects of different concentrations of emicizumab and different AT levels may also assist in transitioning patients from emicizumab to fitusiran or vice versa.