八项临床研究的汇总分析表明流感样症状与Toll-Like受体-7激动剂Vesatolimod的药效学之间存在联系

IF 4.7 3区 医学 Q1 INFECTIOUS DISEASES
Sharon A. Riddler, Constance A. Benson, Cynthia Brinson, Steven G. Deeks, Edwin DeJesus, Anthony Mills, Michael F. Para, Moti N. Ramgopal, Yanhui Cai, Yanan Zheng, Liao Zhang, Wendy Jiang, Xiaopeng Liu, Donovan Verrill, Daina Lim, Christiaan R. de Vries, Jeffrey J. Wallin, Elena Vendrame, Devi SenGupta
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引用次数: 0

摘要

导言:维沙托莫德是一种Toll样受体-7(TLR7)激动剂,目前正处于临床开发阶段,是治疗人类免疫缺陷病毒(HIV)的联合疗法的一部分。在维沙托莫德的临床试验中,出现了与 TLR7 介导的免疫激活相关的流感样症状。因此,更广泛地了解维沙托莫德的安全性概况以及与剂量和作用机制的关联将有助于为未来的临床研究提供依据。在这项分析中,汇总了八项临床研究中有关流感样不良事件(AEIs)的数据,在这些研究中,606名参与者接受了单剂量或多剂量的维沙托莫德(0.3-12 mg;n = 505)或安慰剂(n = 101)。结果维沙托莫德与安慰剂相比,流感样 AEI 的发生率更高(19% [96/505] vs. 8% [8/101]),并且随着维沙托莫德剂量和暴露量的增加而增加。使用维沙莫德后,大多数流感样AEI为1级或2级严重程度(55% [96例中的53例] 1级;35% [96例中的34例] 2级),主要在首次和第二次用药后发病。第 1-3 剂后出现的流感样 AEI 可预测以后剂量的再次发生。在流感样 AEI 患者中观察到的药效学生物标志物(干扰素刺激基因 15、2′-5′-寡腺苷酸合成酶 1、肌病毒抗性-1、干扰素-α、白细胞介素-1 受体拮抗剂、干扰素-γ 诱导蛋白 10、干扰素诱导的 T 细胞-α 趋化吸引子)的剂量依赖性升高表明与韦沙托莫德的作用机制有关。结论与服用维沙托莫德相关的流感样AEI通常比较轻微,但会随着暴露量的增加而增加,这可以通过对初始剂量的反应来预测。这些数据表明,在未来的维沙托莫德临床试验中,适应性临床监测有助于最大限度地提高药效学反应并平衡不良事件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod

A Pooled Analysis of Eight Clinical Studies Suggests a Link Between Influenza-Like Symptoms and Pharmacodynamics of the Toll-Like Receptor-7 Agonist Vesatolimod

Introduction

Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies.

Methods

In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3–12 mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed.

Results

The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19% [96/505] vs. 8% [8/101]) and increased with vesatolimod dose and exposure. Most flu-like AEIs with vesatolimod were grade 1 or 2 severity (55% [53 of 96] grade 1; 35% [34 of 96] grade 2) with onset primarily after the first and second dose. Occurrence of flu-like AEIs after doses 1–3 was predictive of reoccurrence after later doses. Dose-dependent elevations of pharmacodynamic biomarkers (interferon-stimulated gene 15, 2′-5′-oligoadenylate synthetase 1, myxovirus resistance-1, interferon-α, interleukin-1 receptor antagonist, interferon-γ-induced protein 10, interferon-inducible T-cell-α chemoattractant) observed in participants with flu-like AEIs suggest a link with vesatolimod mechanism of action.

Conclusions

Flu-like AEIs associated with vesatolimod administration were typically mild but increased with exposure, which may be predicted by the response to initial doses. The data suggest that adaptive clinical monitoring could help maximize pharmacodynamic responses and balance adverse events in future clinical trials of vesatolimod.

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来源期刊
Infectious Diseases and Therapy
Infectious Diseases and Therapy Medicine-Microbiology (medical)
CiteScore
8.60
自引率
1.90%
发文量
136
审稿时长
6 weeks
期刊介绍: Infectious Diseases and Therapy is an international, open access, peer-reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of infectious disease therapies and interventions, including vaccines and devices. Studies relating to diagnostic products and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. Areas of focus include, but are not limited to, bacterial and fungal infections, viral infections (including HIV/AIDS and hepatitis), parasitological diseases, tuberculosis and other mycobacterial diseases, vaccinations and other interventions, and drug-resistance, chronic infections, epidemiology and tropical, emergent, pediatric, dermal and sexually-transmitted diseases.
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