A first-in-human study of NXT007, a next-generation, activated factor VIII-mimetic bispecific antibody, in healthy participants.

BACKGROUND

NXT007 is a bispecific antibody that mimics the cofactor function of activated factor (F)VIII and was engineered by modifying emicizumab. Nonclinical investigations suggested its potential to provide nonhemophilic concentrations of coagulation activity to people with hemophilia A. A first-in-human, single-ascending dose study of NXT007 was conducted in healthy Japanese male adults (part A of the NXTAGE study).

OBJECTIVES

To evaluate safety, immunogenicity, pharmacokinetics, and pharmacodynamics of NXT007.

METHODS

Forty participants were enrolled across 5 cohorts and randomized to receive a single subcutaneous injection of NXT007 (n = 6 per cohort; 0.0018, 0.0054, 0.018, 0.054, or 0.18 mg/kg) or placebo (n = 2 per cohort).

RESULTS

There were no dose-dependent increases in the incidence of adverse events, and no thrombotic events or injection-site reactions were reported. One serious adverse event of erythema was reported in a participant who received NXT007 0.0054 mg/kg, and its causality to NXT007 could not be ruled out. Nine participants developed anti-NXT007 antibodies; all were considered to be associated with faster clearance of NXT007 without impacting safety. NXT007 exposure increased dose-dependently but less than dose proportionally. The elimination half-life of NXT007 was approximately 10 weeks in antidrug antibody-negative participants. With ex vivo neutralization of endogenous FVIII in plasma samples, activated partial thromboplastin time was shortened, and thrombin generation was promoted in a dose-dependent manner.

CONCLUSION

A single subcutaneous injection of NXT007 was well tolerated without occurrence of thrombotic events. The long half-life, pharmacological effect, and safety profile supported study progression to the subsequent multiple ascending dose parts of the NXTAGE study in people with hemophilia A.