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使用RBD4059抑制凝血因子XI：一种具有强效和持久抗血栓作用的新型GalNAc-siRNA

Inhibition of Factor XI Using RBD4059: A Novel GalNAc-siRNA With Potent and Durable Antithrombotic Effects.

作者信息

Liang Junshi, Nilsson Sofia, Wikström Johannes, Cao Huiqing, Zheng Shuquan, Xu Qian, Yan Xu, Ueckert Sebastian, Sun Qi, Guo Chun, Zhang Hongyan, Liang Zicai, Gao Shan, Gan Li-Ming

机构信息

Suzhou Ribo Life Science Co Ltd, Kunshan City, Jiangsu, China.

Ribocure Pharmaceuticals AB, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

出版信息

JACC Basic Transl Sci. 2025 Jun;10(6):786-797. doi: 10.1016/j.jacbts.2024.12.005. Epub 2025 Feb 19.

DOI:10.1016/j.jacbts.2024.12.005
PMID:40562491
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12230477/
Abstract

Coagulation factor XI (FXI) is an attractive target for novel antithrombotic drugs because of its minor role in hemostasis, which may address the current unmet medical need regarding a powerful anticoagulant with low bleeding risk. Here, we present RBD4059, the first FXI-targeting GalNAc-siRNA molecule to reach the clinical stage of development. In this study, RBD4059 demonstrated potent FXI inhibition with long duration in mice and monkeys, antithrombotic effects in mouse thrombosis models, and no prolonged bleeding in a mouse tail bleeding model. These findings make RBD4059 a promising candidate for the development of a safe and efficient antithrombotic drug.

摘要

凝血因子XI（FXI）是新型抗血栓药物的一个有吸引力的靶点，因为它在止血中作用较小，这可能满足目前对于具有低出血风险的强效抗凝剂的未满足医疗需求。在此，我们介绍RBD4059，首个进入临床开发阶段的靶向FXI的GalNAc-siRNA分子。在本研究中，RBD4059在小鼠和猴子中表现出强效且持久的FXI抑制作用，在小鼠血栓形成模型中具有抗血栓作用，并且在小鼠尾部出血模型中不会导致出血时间延长。这些发现使RBD4059成为开发安全有效的抗血栓药物的一个有前景的候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/1d0d0023364b/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/168385838c66/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/028400a3da44/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/77ca27a2b9e6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/f983b3b0aff8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/c56535c8349d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/52570fa9a7ee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/1d0d0023364b/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/168385838c66/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/028400a3da44/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/77ca27a2b9e6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/f983b3b0aff8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/c56535c8349d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/52570fa9a7ee/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d347/12230477/1d0d0023364b/gr6.jpg

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本文引用的文献

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Am J Health Syst Pharm. 2024 Dec 5;81(24):1222-1229. doi: 10.1093/ajhp/zxae182.
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A new strategy for anticoagulation: The factor XI inhibitors.一种新的抗凝策略：因子 XI 抑制剂。
Eur J Intern Med. 2023 Oct;116:8-15. doi: 10.1016/j.ejim.2023.08.001. Epub 2023 Aug 4.
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Pharmacology and Clinical Development of Factor XI Inhibitors.因子 XI 抑制剂的药理学和临床开发。
Circulation. 2023 Mar 14;147(11):897-913. doi: 10.1161/CIRCULATIONAHA.122.062353. Epub 2023 Mar 13.
4
Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial.急性非心源性缺血性脑卒中后用 asundexian 抑制因子 XIa（PACIFIC-Stroke）：一项国际、随机、双盲、安慰剂对照、2b 期试验。
Lancet. 2022 Sep 24;400(10357):997-1007. doi: 10.1016/S0140-6736(22)01588-4. Epub 2022 Sep 2.
5
A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction.一项多中心、2期、随机、安慰剂对照、双盲、平行组、剂量探索性试验，旨在研究口服凝血因子XIa抑制剂阿孙德西安预防急性心肌梗死后不良心血管事件的效果。
Circulation. 2022 Oct 18;146(16):1196-1206. doi: 10.1161/CIRCULATIONAHA.122.061612. Epub 2022 Aug 27.
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