https://orcid.org/0000-0001-9239-5027
Key Points
Using a range of in vitro and in vivo preclinical models of hemostasis, we provide a direct comparison of NXT007 with emicizumab
NXT007 showed greater potency and higher maximum effect vs emicizumab, with no sign of hypercoagulation at supratherapeutic concentrations
NXT007 is a next-generation factor (F)VIIIa-mimetic bispecific antibody currently in Phase 1/2 trials. It was developed by optimizing the framework of emicizumab to achieve hemostatic normalization in people with hemophilia A (PwHA). Here, we provide a direct comparison of NXT007 with emicizumab, using a wide range of in vitro and in vivo preclinical models of hemostasis and thrombosis. NXT007 and emicizumab increased tissue factor (TF)-triggered peak height thrombin generation when spiked into HA-like (FVIII-neutralized) plasma, with NXT007 being more potent than emicizumab, peaking at lower concentrations and with higher maximum effect. NXT007 and emicizumab delayed fibrinolysis in a dose-dependent manner, with NXT007 having ~20-fold more potent antifibrinolytic effect. Both bispecific antibodies corrected clotting times and kinetics of HA-like blood, measured by rotational thromboelastometry, with NXT007 being ~23-fold more potent. In collagen/TF-coated flow chambers perfused with HA-like blood at arterial shear rates, NXT007 and emicizumab increased fibrin deposition without increasing platelet adherence; maximum effect of NXT007 was greater than emicizumab and achieved at lower concentration. Following tail vein transection in HA mice, NXT007 was more potent than emicizumab in controlling bleeding. In a ferric chloride carotid injury model, administration of NXT007 and emicizumab at plasma concentrations ~20-200µg/mL had no effect on maximum blood flow reduction, indicating that they do not present a prothrombotic profile in this model. Overall, our data support the ongoing clinical evaluation of NXT007 and suggest that it has potential to substantially improve therapeutic efficacy for PwHA.
