BACKGROUND EDP-938 is an oral once-daily RSV nucleoprotein (N) inhibitor with potent antiviral activity. In a human RSV challenge trial, EDP-938 significantly reduced viral load and symptom severity. During antiviral development, it is critical to understand the propensity for resistance to develop. In vitro studies of EDP-938 suggest a higher barrier to resistance as compared to RSV fusion inhibitors. We evaluated the development of viral resistance to EDP-938 in a human challenge trial. METHODS A subset of the 124 participants with RSV infection were chosen for genetic analysis; 159 nasal wash samples from 48 participants were analyzed using next-generation sequencing of the N gene of RSV. Of the 48 participant sampled, 37 were from EDP-938-treated and 11 were placebo-treated participants, representing 45% and 26% of the participants, respectively. The effects of treatment-emergent mutations on viral load, EDP-938 efficacy, and viral fitness were evaluated. RESULTS Two of the 37 EDP-938-treated participants with samples sequenced had treatment-emergent mutations: N:L139I and N:E112G. From in vitro analysis, N:L139I reduced sensitivity to EDP-938 by approximately 10-fold, while N:E112G had no effect. However, N:L139I was associated with a reduction in viral fitness, suggesting clinical resistance is associated with fitness costs. Neither of these variants were associated with reduced viral clearance. CONCLUSIONS In human RSV infections treated with EDP-938, emergence of RSV variants with reduced sensitivity to EDP-938 occurred in only 1 participant and was associated with reduced viral fitness. EDP-938's high barrier to resistance highlights its robust mechanism of action. CLINICAL TRIALS REGISTRATION NCT03691623.

中文翻译：

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EDP-938 在实验性感染呼吸道合胞病毒的健康成人中具有很高的耐药性屏障。


背景EDP-938 是一种口服的每日一次 RSV 核蛋白 （N） 抑制剂，具有有效的抗病毒活性。在人类 RSV 攻击试验中，EDP-938 显著降低了病毒载量和症状严重程度。在抗病毒药物开发过程中，了解耐药性发展的倾向至关重要。EDP-938 的体外研究表明，与 RSV 融合抑制剂相比，具有更高的耐药屏障。我们在人体攻击试验中评估了病毒对 EDP-938 的耐药性的发展。方法 选择 124 名 RSV 感染参与者的子集进行基因分析;使用 RSV N 基因的下一代测序分析了来自 48 名参与者的 159 份洗鼻液样本。在抽样的 48 名参与者中，37 名来自 EDP-938 治疗，11 名是安慰剂治疗的参与者，分别占参与者的 45% 和 26%。评估治疗中出现的突变对病毒载量、 EDP-938 疗效和病毒适应性的影响。结果 37 名接受 EDP-938 治疗的参与者中有 2 名进行了样本测序，其中 2 名具有治疗中出现的突变： N：L139I 和 N：E112G。从体外分析来看，N：L139I 对 EDP-938 的敏感性降低了约 10 倍，而 N：E112G 没有影响。然而，N：L139I 与病毒适应性的降低有关，表明临床耐药性与适应性成本有关。这些变体均与病毒清除率降低无关。结论在用 EDP-938 治疗的人类 RSV 感染中，仅 1 名参与者出现对 EDP-938 敏感性降低的 RSV 变体，并且与病毒适应性降低有关。EDP-938 的高耐药屏障突出了其强大的作用机制。临床试验注册NCT03691623。