Levene Rachel Emily, DeVincenzo John, Conery Annie L, Ahmad Alaa, Or Yat Sun, Rhodin Michael H J
Enanta Pharmaceuticals, Inc, Watertown, Massachusetts, USA.
J Infect Dis. 2025 Feb 20;231(2):e290-e298. doi: 10.1093/infdis/jiae471.
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.
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.
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.
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.
NCT03691623.
EDP-938是一种每日口服一次的呼吸道合胞病毒（RSV）核蛋白（N）抑制剂，具有强大的抗病毒活性。在一项人类RSV激发试验中，EDP-938显著降低了病毒载量和症状严重程度。在抗病毒药物研发过程中，了解耐药性产生的倾向至关重要。对EDP-938的体外研究表明，与RSV融合抑制剂相比，其耐药屏障更高。我们在一项人类激发试验中评估了对EDP-938的病毒耐药性发展情况。
从124名RSV感染参与者中选取一部分进行基因分析；对48名参与者的159份鼻腔冲洗样本进行RSV N基因的二代测序分析。在48名采样参与者中，37名来自接受EDP-938治疗的参与者，11名来自接受安慰剂治疗的参与者，分别占参与者总数的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。
在37名接受EDP-938治疗且样本进行了测序的参与者中，有两名出现了治疗中出现的突变：N:L139I和N:E11G。体外分析显示，N:L139I使对EDP-938的敏感性降低了约10倍，而N:E112G没有影响。然而，N:L139I与病毒适应性降低有关，这表明临床耐药性与适应性代价有关。这些变体均与病毒清除率降低无关。
在用EDP-938治疗的人类RSV感染中，对EDP-938敏感性降低的RSV变体仅在1名参与者中出现，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。
NCT03691623。
