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.