Background & Aims

NVR3–778 is a capsid assembly modulator in clinical development. We determined the in vivo antiviral efficacy and effects on innate and endoplasmic reticulum (ER) stress responses of NVR3–778 alone or in combination with pegylated interferon alpha (peg-IFN) and compared with entecavir.

Methods

We performed 2 studies, with a total of 61 uPA/SCID mice with humanized livers. Mice were infected with a hepatitis B virus (HBV) genotype C preparation; we waited 8 weeks for persistent infection of the human hepatocytes in livers of mice. Mice were then randomly assigned to groups (5 or 6 per group) given vehicle (control), NVR3–778, entecavir, peg-IFN, NVR3–778 + entecavir, or NVR3–778 + peg-IFN for 6 weeks. We measured levels of HB surface antigen, HB e antigen, HBV RNA, alanine aminotransferase, and human serum albumin at different time points. Livers were collected and analyzed by immunohistochemistry; levels of HBV DNA, covalently closed circular DNA, and HBV RNA, along with markers of ER stress and IFN response, were quantified.

Results

Mice given NVR3–778 or entecavir alone for 6 weeks had reduced serum levels of HBV DNA compared with controls or mice given peg-IFN. The largest reduction was observed in mice given NVR3–778 + peg-IFN; in all mice in this group, the serum level of HBV DNA was below the limit of quantification. NVR3–778 and peg-IFN, but not entecavir, also reduced serum level of HBV RNA. The largest effect was obtained in the NVR3–778 + peg-IFN group, in which serum level of HBV RNA was below the limit of quantification. Levels of HB surface antigen and HB e antigen were reduced significantly in only the groups that received peg-IFN. Levels of covalently closed circular DNA did not differ significantly among groups. NVR3–778 was not associated with any significant changes in level of alanine aminotransferase, the ER stress response, or IFN-stimulated genes.

Conclusions

NVR3–778 has high antiviral activity in mice with humanized livers and stable HBV infection, reducing levels of serum HBV DNA and HBV RNA. Entecavir reduced levels of serum HBV DNA, but had no effect on HBV RNA. The combination of NVR3–778 and peg-IFN prevented viral replication and HBV RNA particle production to a greater extent than each compound alone or entecavir.

中文翻译：

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NVR 3-778（单独和与聚乙二醇化干扰素联合使用）与恩替卡韦相比对uPA / SCID小鼠人源化肝炎和HBV感染的疗效

背景与目标

NVR3-778是临床开发中的衣壳装配调节剂。我们确定了单独或与聚乙二醇化干扰素α（peg-IFN）组合使用的NVR3-778的体内抗病毒功效及其对先天和内质网（ER）应激反应的影响，并与恩替卡韦进行了比较。

方法

我们进行了2项研究，共对61只具有人源化肝脏的uPA / SCID小鼠进行了研究。小鼠感染了丙型肝炎病毒（HBV）基因型制剂；我们等待了8周，以持续感染小鼠肝脏中的人类肝细胞。然后将小鼠随机分配至各组（每组5或6个），分别给予赋形剂（对照组），NVR3-778，恩替卡韦，peg-IFN，NVR3-778 +恩替卡韦或NVR3-778 + peg-IFN，持续6周。我们在不同的时间点测量了HB表面抗原，HB e抗原，HBV RNA，丙氨酸转氨酶和人血清白蛋白的水平。收集肝脏并通过免疫组织化学分析；量化了HBV DNA，共价闭合环状DNA和HBV RNA的水平，以及ER应激和IFN反应的标志物。

结果

与对照组或接受PEG-IFN的小鼠相比，单独给予NVR3-778或恩替卡韦治疗6周的小鼠血清HBV DNA含量降低。在给予NVR3-778 + peg-IFN的小鼠中观察到最大的减少；在该组的所有小鼠中，HBV DNA的血清水平均低于定量限。NVR3-778和peg-IFN（但不包括恩替卡韦）也可降低HBV RNA的血清水平。在NVR3-778 + peg-IFN组中获得最大的效果，其中HBV RNA的血清水平低于定量限。仅在接受peg-IFN的组中，HB表面抗原和HBe抗原的水平显着降低。各组之间共价闭合环状DNA的水平没有显着差异。NVR3-778与丙氨酸转氨酶水平，ER应激反应或IFN刺激基因的任何显着变化无关。

结论

NVR3-778在人源化肝脏和稳定的HBV感染的小鼠中具有很高的抗病毒活性，从而降低了血清HBV DNA和HBV RNA的水平。恩替卡韦可降低血清HBV DNA水平，但对HBV RNA无影响。与单独使用每种化合物或恩替卡韦相比，NVR3-778和peg-IFN的结合在更大程度上阻止了病毒复制和HBV RNA颗粒的产生。