NXT007: The Next Step in Emicizumab Evolution - An Engineered Bispecific Antibody with Enhanced Pharmacological Profile

Emicizumab, a bispecific antibody, is used to prevent bleeding in hemophilia A patients through subcutaneous injections. A next-generation version, the engineered NXT series, was developed with a focus on maintaining hemostatic potential and a more convenient dosing schedule. NXT007 was chosen as a clinical candidate and was evaluated for its in vitro and in vivo properties.

In vitro tests using a thrombin generation assay showed that NXT007 at a concentration of 30 μg/mL could elevate the peak height in FVIII-deficient plasma to levels comparable to that of recombinant human FVIII. In vivo studies in a cyno model indicated that NXT007 could alleviate bleeding symptoms to a similar extent as recombinant porcine FVIII when administered intravenously.

Enzymatic kinetics analysis revealed that NXT007 significantly increased the turnover rate of FIXa-catalyzed FX activation, similar to emicizumab. Surface plasmon resonance analysis demonstrated NXT007's strong binding affinity to FX/FXa and comparable affinity to FIX/FIXa. This suggests that NXT007 is capable of forming a more effective ternary complex than emicizumab.

The estimated concentration of the ternary complex in plasma at 30 μg/mL of NXT007 was approximately 10 times higher than that of emicizumab, correlating with their respective thrombin generation activities. Prothrombin time tests indicated that NXT007 had minimal impact on FX function.

In vivo pharmacokinetic studies in cynos showed that NXT007 had a half-life of 19.6 to 24.4 days and a subcutaneous bioavailability of 84.4%. No significant changes in plasma FIX or FX levels were observed post-administration.

The conclusion drawn from these nonclinical results is that NXT007, administered every four weeks subcutaneously, can maintain a non-hemophilic range of thrombin generation in hemophilia A patients. Its improved cofactor activity, attributed to efficient ternary complex formation and maintained turnover rate with minimal impact on FX function, is a promising advancement over emicizumab. A phase 1/2 clinical study of NXT007 is currently underway.