BACKGROUND & AIMS

Hepatitis E virus (HEV) constitutes a substantial public health burden with ∼20 million human infections annually, including 3.3 million symptomatic cases. Appropriate treatment options for, in particular, HEV-infected immunocompromised patients and pregnant women are lacking, underscoring the urgent need for potent and safe antiviral drugs.

METHODS

HEV subgenomic replicon systems were used to screen a small library of pre-selected nucleoside analogues, originally developed in a hepatitis C virus (HCV) antiviral program. Antiviral activity of the selected hit on HEV infection was evaluated in a variety of cell culture systems; the efficacy of the compound was assessed in the athymic nude rat HEV infection model.

RESULTS

Compound JNJ-9117 exerts pan-genotype antiviral activity against HEV in different cell types as well as in primary human hepatocytes. A high level of conservation is observed between three crucial motifs in the catalytic domain of the HCV and HEV polymerases. This suggests a mechanism of action that is identical to that of the molecule against HCV, whereby the 5’-triphosphate of JNJ-9117 acts as a chain terminator during viral RNA synthesis. JNJ-9117 has a favorable pharmacokinetic and safety profile in rats and results in a pronounced antiviral effect in a chronic rat HEV infection model, both in a prophylactic and therapeutic setting. The combination of JNJ-9117 and ribavirin (each at an intentionally selected suboptimal/inactive dose) was in infected rats highly effective in lowering viral RNA load in liver and feces to (almost) undetectable levels.

CONCLUSIONS

JNJ-9117 has a profile that holds promise for the treatment of life-threatening HEV infections in humans. Phase 1 studies with JNJ-9117 have been initiated in healthy human volunteers.

中文翻译：

---

一种在大鼠感染模型中具有高效效力的泛基因型戊型肝炎病毒复制抑制剂

 背景和目标

戊型肝炎病毒 （HEV） 构成了巨大的公共卫生负担，每年约有 2000 万人感染，其中包括 330 万例有症状病例。特别是对于 HEV 感染的免疫功能低下患者和孕妇，缺乏适当的治疗选择，这凸显了对有效和安全的抗病毒药物的迫切需求。

 方法

HEV 亚基因组复制子系统用于筛选一个小型预选核苷类似物库，这些核苷类似物最初是在丙型肝炎病毒 （HCV） 抗病毒计划中开发的。在各种细胞培养系统中评估所选命中对 HEV 感染的抗病毒活性;在无胸腺裸鼠 HEV 感染模型中评估了该化合物的疗效。

 结果

化合物 JNJ-9117 在不同细胞类型以及原代人肝细胞中对 HEV 发挥泛基因型抗病毒活性。在 HCV 和 HEV 聚合酶的催化结构域中观察到三个关键基序之间的高度保守性。这表明其作用机制与分子对抗 HCV 的作用机制相同，其中 JNJ-9117 的 5'-三磷酸在病毒 RNA 合成过程中充当链终止子。JNJ-9117 在大鼠中具有良好的药代动力学和安全性，并在慢性大鼠 HEV 感染模型中产生显着的抗病毒作用，无论是在预防还是治疗环境中。JNJ-9117 和利巴韦林的组合 （各自以有意选择的次优/非活性剂量） 在感染大鼠中非常有效地将肝脏和粪便中的病毒 RNA 载量降低到（几乎）检测不到的水平。

 结论

JNJ-9117 的概况有望治疗危及生命的人类 HEV 感染。JNJ-9117 的 1 期研究已在健康人类志愿者中启动。