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HIGH ANTIVIRAL ACTIVITY OF THE HBV CORE INHIBITOR NVR 3-778 IN THE HUMANIZED UPA/SCID MOUSE MODEL
Klaus Klumpp* 1, Takashi Shimada2, Lena Allweiss3, Tassilo Volz3, Marc Luetgehetman3, 4, Osvaldo Flores1, George Hartman1, Angela Lam1, Maura Dandri3, 5
1Novira Therapeutics Inc., Doylestown, United States, 2PhoenixBio Co., Ltd. , Higashi-Hiroshima, Japan, 3Department of Internal Medicine, 4Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 5German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Hamburg, Germany
Corresponding author’s email: [email protected]
Background and Aims:
NVR 3-778 represents a new class of HBV core inhibitors and is in clinical development for the treatment of chronic hepatitis B. We determined the antiviral activity of NVR 3-778 alone or in combination with PEG-IFN or entecavir in the humanized uPA/SCID mouse model of HBV infection.
Methods:
Thirty six mice infected with HBV genotype C, with serum HBV viremia >106 copies/ml and human serum albumin levels >6 mg/ml were randomized into 6 treatment groups: (1) NVR 3-778, (2) vehicle, (3) entecavir, (4) PEG-IFN, (5) NVR 3-778 + entecavir and (6) NVR 3-778 + PEG-IFN. Virologic endpoints included serum and intrahepatic HBV DNA, HBV antigen, cccDNA and HBV RNA levels.
Results:
All 6 mice in the NVR 3-778 group showed >1.7 log serum viral load reduction from baseline at day 14 (mean (median) viral load reduction 1.9 (1.9) log). This effect was similar to that obtained with entecavir (p > 0.05) and larger than that obtained with PEG-IFN treatment (p < 0.05). The largest viremia reduction across all groups was obtained when NVR 3-778 was combined with PEG-IFN, resulting in a mean (median) viral load reduction of 2.4 (2.4) log at day 14, significantly larger than that obtained with either NVR 3-778 or PEG-IFN alone (p <0.05). The combination of NVR 3-778 and PEG-IFN also showed the largest reduction in intrahepatic HBV DNA loads (median 3.0 log; p< 0.005) as compared to other treatment groups (NVR 3-778 alone 2.0 log, entecavir 2.2 log and PEG-IFN 1.8 log). Intrahepatic HBV RNA loads were reduced significantly in the PEG-IFN groups only. As expected, serum levels of HBsAg were reduced most strongly in the PEG-IFN groups and were only minimally affected by NVR 3-778 alone. Levels of cccDNA were similar across treatment groups. Treatment with NVR 3-778 was not associated with any significant changes in the levels of human serum albumin, serum alanine aminotransferase (ALT) levels, or intrahepatic amounts of human β-globin, indicating that the number of human hepatocytes remained stable during the treatment period.
Conclusions:
The HBV core inhibitor NVR 3-778 demonstrated high intrinsic antiviral activity in HBV infected humanized mice. Serum HBV viral load reduction was larger than that obtained with PEG-IFN and similar to entecavir alone. The combination of NVR 3-778 and PEG-IFN showed higher antiviral activity as compared to NVR 3-778 or PEG-IFN alone, indicating a functionally beneficialinteraction between a core inhibitor and interferon alpha.
Disclosure of Interest: K. Klumpp: Employee: Novira Therapeutics, T. Shimada: Employee: PhoenixBio Co., Ltd. , L. Allweiss: Other: Novira Therapeutics, T. Volz: Other: Novira Therapeutics, M. Luetgehetman: Other: Novira Therapeutics, O. Flores: Employee: Novira Therapeutics, G. Hartman: Employee: Novira Therapeutics, A. Lam: Employee: Novira Therapeutics, M. Dandri: Other: Novira Therapeutics
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发表于 2015-4-13 18:07
