Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
Clin Infect Dis. 2021 Jun 1;72(11):e815-e824. doi: 10.1093/cid/ciaa1534.
Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1.
In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives.
A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values.
Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV.
NCT02858401.
在与包膜抗体或治疗性疫苗联合使用时，一种研究性口服 Toll 样受体 7（TLR7）激动剂维斯他汀可使部分非人类灵长类动物持续缓解病毒。我们报告了一项 Ib 期研究的结果，该研究评估了维斯他汀在接受抗逆转录病毒治疗且筛查时血浆 HIV-1 RNA 水平<50 拷贝/ml 的 HIV-1 感染者中的安全性、药代动力学和药效学。
在这项双盲、多中心、安慰剂对照试验中，接受抗逆转录病毒治疗且筛查时血浆 HIV-1 RNA 水平<50 拷贝/ml 的参与者按 6:2 比例随机（随机分组）接受维斯他汀（1-12 mg）或匹配安慰剂口服，每两周一次，共 6-10 个剂量，在递增剂量队列中进行连续给药。主要研究目的包括确定维斯他汀的安全性和病毒学效应（从基线到血浆 HIV-1 RNA 的变化）。药代动力学和药效学/免疫活性评估为次要目的。
共有 48 名参与者被随机分配至维斯他汀（n=36）或安慰剂（n=12）组。维斯他汀总体耐受性良好，无研究药物相关严重不良事件或导致研究药物停药的不良事件。与安慰剂相比，维斯他汀组的血浆 HIV-1 RNA 从基线水平无统计学意义的变化。维斯他汀的血浆暴露量与剂量成比例增加；与 4mg 以上剂量水平相比，观察到细胞因子、干扰素刺激基因表达和淋巴细胞激活的一致反应。与基线值相比，接受 6mg 剂量后 24 小时达到的峰值升高超过 3.9 倍，干扰素γ诱导蛋白 10（IP-10）、白细胞介素-1 受体拮抗剂（IL-1RA）和干扰素诱导的 T 细胞α趋化因子（ITAC）。
维斯他汀在 1-12mg 剂量范围内耐受良好。在 4mg 以上剂量时观察到免疫刺激，为未来在 HIV 感染者中进行联合试验提供了依据。
NCT02858401。
