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 non-hemophilic levels of coagulation activity to people with hemophilia A (PwHA). 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 five 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 (AEs), and no thrombotic events or injection-site reactions were reported. One serious AE 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 (ADAs); 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 ADA-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.

Conclusions: 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 PwHA.