A First-in-human phase I study of an innovative selective inhibitor
targeting coagulation factor XI/XIa in healthy volunteers
Abstract
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.