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A First-in-human phase I study of an innovative selective inhibitor targeting coagulation factor XI/XIa in healthy volunteers
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  • Qian Xiang,
  • Zhiyan Liu,
  • Qiu-fen Xie ,
  • nan Zhao,
  • Shuang Zhou,
  • Linyu Cao,
  • Xia Zhao,
  • Yaling Li,
  • Jing Si,
  • Qingmei Wu,
  • Junyou Ge,
  • Yi Min Cui
Qian Xiang
Peking University First Hospital
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Zhiyan Liu
Peking University First Hospital
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Qiu-fen Xie
Peking University First Hospital
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nan Zhao
Peking University First Hospital
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Shuang Zhou
Peking University First Hospital
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Linyu Cao
Peking University First Hospital
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Xia Zhao
Peking University First Hospital
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Yaling Li
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
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Jing Si
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
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Qingmei Wu
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
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Junyou Ge
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
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Yi Min Cui
Peking University First Hospital

Corresponding Author:cui.pharm@pkufh.com

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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.
26 Jul 2024Submitted to British Journal of Clinical Pharmacology
26 Jul 2024Submission Checks Completed
26 Jul 2024Assigned to Editor
26 Jul 2024Review(s) Completed, Editorial Evaluation Pending
28 Jul 2024Reviewer(s) Assigned
15 Sep 2024Editorial Decision: Revise Major
06 Nov 20241st Revision Received
08 Nov 2024Submission Checks Completed
08 Nov 2024Assigned to Editor
08 Nov 2024Review(s) Completed, Editorial Evaluation Pending