PB0157 - In vitro thrombin generation in the presence of emicizumab sequence identical analogue (emi-SIA) and concizumab

Background: Concizumab, an anti-tissue factor pathway inhibitor antibody, is under development as a once-daily subcutaneous prophylaxis for patients with hemophilia A/B (HA/HB) with/without inhibitors. In vitro thrombin generation (TG) data can help inform decisions regarding switching patients from other non-factor therapy to concizumab.

Aims: Evaluate TG potential of concizumab and/or emicizumab sequence identical analogue (emi SIA) in combination with hemostatic agents used to treat breakthrough bleeds.

Methods: TG assays initiated with a low tissue factor trigger were performed in an HA plasma pool in the presence of concizumab alone or with emi-SIA. Relevant concentrations of concizumab (4000 ng/mL) and emi-SIA (3, 10 and 30 µg/mL) were selected based on pharmacokinetic modelling and simulation. Concizumab/emi-SIA were combined with recombinant factor VIII (rFVIII, 1 IU/mL), recombinant activated FVII (rFVIIa, 25 nM), or activated prothrombin complex concentrate (aPCC, 0.5 and 1.0 U/mL). The effects of the compounds alone or combined were compared using analysis of variance (ANOVA).

Results: Separately, emi-SIA and concizumab led to concentration-dependent increases in thrombin peak. The combined effects of concizumab and emi-SIA were mainly additive with a small positive drug-drug interaction (DDI; +7% at 10 µg/mL emi-SIA; Figure 1). Addition of rFVIII to HA plasma increased thrombin peak. A small negative DDI (-17%) between emi-SIA and rFVIII was observed. Adding concizumab did not alter this effect. rFVIIa increased thrombin peak both in plasma with concizumab and emi-SIA. The effects of rFVIIa and concizumab plus emi-SIA were mainly additive with a small positive DDI (+16%). A positive DDI was observed between aPCC and emi-SIA (+331% with 1 U/mL aPCC, + 306% with 0.5 U/mL aPCC). This effect persisted in the presence of concizumab.

Conclusion(s): The effects of concizumab and emi-SIA were mainly additive. There were no unexpected DDI with hemostatic agents used to treat breakthrough bleeds when concizumab was added to plasma containing emi-SIA.