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Home News Efficacy of NVR 3-778, Alone and in Combination With Pegylated Interferon, vs Entecavir in uPASCID Mice With Humanized Livers and HBV Infection

Efficacy of NVR 3-778, Alone and in Combination With Pegylated Interferon, vs Entecavir in uPASCID Mice With Humanized Livers and HBV Infection

Published:2017-11-08 | Source:Gastroenterology | Visited:14

Abstract

Background & Aims

NVR3-778 is a capsid assembly modulator in clinical development. We determined the in vivo anti-viral 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 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 (HBsAg), HB e antigen (HBeAg), HBV RNA, alanine aminotransferase (ALT), and human serum albumin at different time points. Livers were collected and analyzed by immunohistochemistry; levels of HBV DNA, covalently closed circular DNA (cccDNA), 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 HBsAg and HBeAg were reduced significantly in only the groups that received peg-IFN. Levels of cccDNA did not differ significantly among groups. NVR3-778 was not associated with any significant changes in level of ALT, the ER stress response, or interferon-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.