Next-generation FVIIIa-mimetic bispecific antibody NXT007: evaluation in preclinical models of hemostasis and thrombosis.

abstractNXT007 is a next-generation factor VIIIa (FVIIIa)-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. Both 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, achieving peak at lower concentrations and producing a 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; the maximum effect of NXT007 was greater than that of emicizumab and was 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, the administration of NXT007 and emicizumab at plasma concentrations of ∼20 to 200 μg/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 can substantially improve therapeutic efficacy for PwHA.