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

BACKGROUND

Concomitant administration of activated prothrombin complex concentrate (APCC) at doses >100 U/kg/d 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.

OBJECTIVES

This study aimed to investigate the in vitro effects of recombinant factor (rF)VIII, rFVIIa, and APCC during NXT007 treatment and estimate tolerable doses with reference to emicizumab.

METHODS

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

RESULTS

A single dose of NXT007 at ≥10.0 μg/mL (plasma) achieved a nonhemophiliac coagulation potential. The concomitant addition of rFVIII, rFVIIa, and APCC each boosted various parameters following NXT007 levels at 0.1 to 50.0 μg/mL. In the copresence of NXT007 at 15.0 μg/mL (blood) and APCC at 0.13 U/mL, with the blood level immediately following the administration of 10.0 U/kg, the rotational thromboelastometry parameters were comparable with those observed with clinical emicizumab level and APCC at 0.63 U/mL, corresponding to the blood level immediately after administrating 50.0 U/kg (recommended initial dose).

CONCLUSION

Concomitant addition of coagulation agents increased coagulation potentials in vitro in the presence of NXT007. A dose of 10.0 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of APCC at plasma NXT007 levels of ∼30.0 μg/mL. Importantly, plasma NXT007 at ≥10.0 μg/mL demonstrated non-hemophiliac coagulation potentials in vitro.