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Aim: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of hemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in in-vitro and in-vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of SKB336 in healthy subjects. Methods: In this randomized, single-blinded, placebo-controlled, and dose-escalation phase I study, 60 healthy subjects were allocated to six cohorts (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 4 mg/kg) and received SKB336 injection or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics, and immunogenicity were measured up to 85 days post-dose. Exploratory analysis consisted of FXI activity and APTT. Results: SKB336 was well tolerated in all six cohorts, without any hemorrhagic events, reported deaths, or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the Cmax and AUC were observed. The mean t1/2 was 21.3–33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all six cohorts reached 0, 17%, 28%, 48%, 54%, and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91-, and 2.00-fold, respectively. Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.
Xiang et al. (Mon,) studied this question.