HRS-5965, a small-molecule factor B inhibitor, in healthy participants and participants with renal insufficiency: A first-in-human, phase 1 trial.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-05-12 DOI:10.1016/j.medj.2025.100698

Yi Xu, Fen Tian, Hong Ren, Xian Yu, Xiaoyu Chen, Kun Ye, Feifei Sun, Lin Fang, Yuan Li, Rongxin Ban, Xin Jiang, Chenjing Wang, Yaping Ma, Fu Kuang, Xin Li, Zhigao Zhang, Chaobaihui Ye, Min Hu, Feng He, Chang Shu, Yanfang Zou, Rong Huang, Kai Shen, Guangqun Xing, Yu Cao

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引用次数: 0

Abstract

Background: HRS-5965 is an oral selective small-molecule inhibitor of complement factor B, a key component of the alternative pathway. This study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of HRS-5965 in healthy participants and participants with renal insufficiency.

Methods: The first-in-human, phase 1 study consisted of 3 parts (ClinicalTrials.gov: NCT05505955). Part 1 was a single-ascending-dose, randomized, double-blind study with 5 dose groups preset, including a food effect evaluation. Part 2 was a multiple-ascending-dose, randomized, double-blind study with 9 dose groups preset. Part 3 was an open-label, single-dose study on severe renal insufficiency. The primary endpoints were safety and tolerability.

Findings: A total of 82 participants were enrolled and received either HRS-5965 or placebo (26 in part 1, 40 in part 2, and 16 in part 3). HRS-5965 was well tolerated. Treatment-emergent adverse events were comparable between the HRS-5965 groups and placebo groups in part 1 (17/20 [85.0%] vs. 6/6 [100.0%]) and part 2 (27/30 [90.0%] vs. 10/10 [100.0%]). No deaths were reported. HRS-5965 was absorbed rapidly, with a median time to reach peak concentration (T_max) ranging from 0.75 to 1.50 h in fasted states and 2.00 h in fed states. Pharmacokinetics was nonlinear, and food delayed the absorption of HRS-5965 but did not impact the exposure. Alternative pathway activity was inhibited by over 80% with HRS-5965, compared to less than 20% with placebo.

Conclusion: HRS-5965 demonstrated favorable safety and robust inhibition of alternative pathway activity, supporting further clinical development.

Funding: The study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

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HRS-5965，一种小分子因子B抑制剂，用于健康参与者和肾功能不全参与者：一项首次人体1期试验

背景：rs -5965是补体因子B的口服选择性小分子抑制剂，补体因子B是替代途径的关键组成部分。本研究评估了rs -5965在健康受试者和肾功能不全受试者中的安全性、耐受性、药代动力学和药效学。方法：第一项人体i期研究由3部分组成（ClinicalTrials.gov: NCT05505955）。第一部分为单剂量递增、随机、双盲研究，预设5个剂量组，包括食物效应评价。第二部分为多重递增剂量、随机、双盲研究，预设9个剂量组。第三部分是一项关于严重肾功能不全的开放标签单剂量研究。主要终点是安全性和耐受性。结果：共有82名参与者入组，接受了rs -5965或安慰剂（第1部分26人，第2部分40人，第3部分16人）。rs -5965耐受性良好。在第1部分（17/20 [85.0%]vs. 6/6[100.0%]）和第2部分（27/30 [90.0%]vs. 10/10[100.0%]）中，HRS-5965组和安慰剂组的治疗不良事件具有可比性。没有死亡报告。rs -5965吸收迅速，在禁食状态下达到峰浓度（Tmax）的中位时间为0.75 ~ 1.50 h，在进食状态下为2.00 h。药代动力学是非线性的，食物延迟了rs -5965的吸收，但不影响暴露。替代途径活性被hr -5965抑制了80%以上，而安慰剂的抑制率不到20%。结论：HRS-5965表现出良好的安全性和对替代途径活性的抑制作用，支持进一步的临床开发。经费：本研究由江苏恒瑞药业有限公司资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.