Insights from in vitro global assays on possible doses of concomitant hemostatic agents in the presence of NXT007 in hemophilia A.

Introduction: Concomitant administration of activated prothrombin complex concentrate (aPCC) at doses >100 U/kg/day is associated with thrombotic risk under emicizumab prophylaxis. In vitro global assay data on the effects of concomitant coagulation-factor-agents in the presence of NXT007, an emicizumab-based engineered bispecific antibody under clinical development, may serve as a basis for addressing this potential risk.

Aim: To investigate the in vitro effects of rFVIII, rFVIIa, and aPCC during NXT007 treatment and estimate tolerable doses with reference to emicizumab.

Methods: Thrombin generation assays, clot waveform analysis, and rotational thromboelastometry (ROTEM) were performed using hemophilia A plasma and blood samples spiked with NXT007 and others.

Results: A single dose of NXT007 at ≥10 μg/mL (plasma) achieved a non-hemophiliac coagulation potential. The concomitant addition of rFVIII, rFVIIa, and aPCC each boosted various parameters following NXT007 levels at 0.1-50 μg/mL. In the co-presence of NXT007 at 15 μg/mL (blood) and aPCC at 0.13 U/mL, with the blood level immediately following the administration of 10 U/kg, the ROTEM parameters were comparable to those observed with clinical emicizumab level and aPCC at 0.63 U/mL, corresponding to the blood level immediately after administrating 50 U/kg (recommended initial dose).

Conclusions: Concomitant addition of coagulation agents increased coagulation potentials in vitro in the presence of NXT007. A dose of 10 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of aPCC at plasma NXT007 levels of approximately 30 μg/mL. Importantly, plasma NXT007 at ≥10 μg/mL demonstrated non-hemophiliac coagulation potentials in vitro.