PB0242 - A phase I tiral evaluating safety and pharmacokinetics in human and an ex vivo pharmacodynamics study in hemophilia patients of KN057, the first anti–TFPI monoclonal antibody in China

Background: Currently, there are still huge unmet needs for effective prophylaxis for hemophilia patients in China. KN057 is the first anti–tissue factor pathway inhibitor monoclonal antibody developed in China. It is designed for prophylaxis for all types of hemophilia (hemophilia A without inhibitors [HA], hemophilia B without inhibitors [HB], hemophilia A with inhibitors [HAW], hemophilia B with inhibitors [HBW] and potentially other types).

Aims: To determine the safety and pharmacokinetic characteristics of KN057 in healthy volunteers and confirm the pharmacodynamics of KN057 in hemophilia patients (HA/HB/HAW/HBW) ex vivo.

Methods: The human safety and pharmacokinetic study was a single-dose escalation, randomized, double-blind, placebo-controlled phase I clinical study in healthy male volunteers. The ex vivo pharmacodynamics study utilized platelet-poor plasma samples from 10 HA, 6 HB, 6 HAW, and 3 HBW, and different concentrations of KN057 were added to these samples, then the thrombin generation assay was measured.

Results: In healthy subjects, a single subcutaneous administration of KN057 ranged from 0.05 to 2.5mg/kg demonstrated overall good safety profile, and no thromboembolic events were reported. In the 1.0mg/kg and 2.5mg/kg dose groups, Cmax was reached at 48 hours after administration, and half-life was approximately one week. KN057 exhibited typical non-linear metabolic characteristics, as shown in Figure 1. The ex vivo pharmacodynamics study demonstrated that KN057 increased the peak thrombin and endogenous thrombin potential (ETP) in a concentration-dependent manner, and the effect reached peak at the concentration of 28nM. The trends and effective concentration ranges of KN057 were consistent in plasma samples from patients with different types of hemophilia, as shown in Figure 2.

Conclusion(s): KN057 exhibits favorable safety profile and half-life. The convenient administration (subcutaneous, once-a-week) of KN057 has the potential to improve treatment compliance of patients. KN057 can increase ex vivo thrombin generation in all hemophilia types, indicating its potential of prophylaxis for all hemophilia patients.