首次在健康受试者中开展人体研究,评估因子 XI 单克隆抗体 SHR-2004 的安全性、耐受性、药代动力学和药效学。

IF 4.9 2区 医学 Q1 PHARMACOLOGY & PHARMACY Expert opinion on investigational drugs Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI:10.1080/13543784.2024.2391837
Tingting Ma, Zuyi Weng, Bei Cao, Yanli Dong, Chanjuan Deng, Lei Huang, Yuanxun Yang, Yuqi Wang, Chenxi Shen, Lei Wang, Kai Shen, Juan Li
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引用次数: 0

摘要

背景:抑制凝血因子 XI (FXI) 是预防和治疗血栓栓塞症的一种新策略,但不会影响外源性凝血途径。SHR-2004是一种选择性结合FXI和因子XIa(FXIa)的人源化单克隆抗体:这项随机、双盲、剂量递增、安慰剂对照研究评估了静脉注射(i.v. ;A 部分)或皮下注射(s.c. ;B 部分)SHR-2004。在 A 部分,24 名受试者接受了单次静脉注射 SHR-2004(0.1、0.3 或 1.0 毫克/千克)或安慰剂。在 B 部分中,40 名受试者接受单次静脉注射 SHR-2004(0.5、1.0、3.0 或 4.5 毫克/千克)或安慰剂:结果:SHR-2004 的耐受性良好。SHR-2004 的血浆暴露量呈剂量依赖性增加。几何平均半衰期为 11.6 至 13.0 天。静脉注射和皮下注射后,FXI 活性降低,活化部分凝血活酶时间(APTT)延长,且呈剂量和时间依赖性。静脉注射最高剂量后,FXI 活性几乎完全消失,平均 APTT 延长至基线的近三倍:结论:SHR-2004 是一种有希望进一步开发的抗凝药物,它能发挥有效的抗凝作用,同时将出血风险降到最低。临床试验注册:www.clinicaltrials.gov 识别码为 NCT05369767。
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The first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the factor XI monoclonal antibody SHR-2004 in healthy subjects.

Background: Inhibiting the coagulation factor XI (FXI) is a novel strategy for prevention and treatment of thromboembolism without affecting extrinsic coagulation pathways. SHR-2004 is a humanized monoclonal antibody that selectively binds to FXI and factor XIa (FXIa).

Research design & methods: This randomized, double-blind, dose-escalation, placebo-controlled study evaluated SHR-2004 administered either intravenously (i.v.; Part A) or subcutaneously (s.c.; Part B). In Part A, 24 subjects received a single i.v. dose of SHR-2004 (0.1, 0.3, or 1.0 mg/kg) or placebo. In Part B, 40 subjects received a single s.c. dose of SHR-2004 (0.5, 1.0, 3.0, or 4.5 mg/kg) or placebo.

Results: SHR-2004 was well tolerated. Plasma exposure to SHR-2004 increased in a dose-dependent manner. The geometric mean half-time ranged from 11.6 to 13.0 days. FXI activity decreased, and the activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. FXI activity was nearly completely abolished immediately after administering the highest i.v. dose, with the average APTT prolonged to nearly three times of baseline.

Conclusion: SHR-2004 is a promising candidate for further development as an anticoagulant drug that exerts effective anticoagulation with minimal risk of bleeding.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT05369767.

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来源期刊
CiteScore
10.00
自引率
0.00%
发文量
71
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Investigational Drugs (ISSN 1354-3784 [print], 1744-7658 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles and original papers on drugs in preclinical and early stage clinical development, providing expert opinion on the scope for future development. The Editors welcome: Reviews covering preclinical through to Phase II data on drugs or drug classes for specific indications, and their potential impact on future treatment strategies Drug Evaluations reviewing the clinical and pharmacological data on a particular drug Original Research papers reporting the results of clinical investigations on agents that are in Phase I and II clinical trials The audience consists of scientists, managers and decision-makers in the pharmaceutical industry, and others closely involved in R&D.
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