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
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
Novira Therapeutics to Present at 2015 AASLD Meeting in San Francisco
Poster presentation: "Phase 1b Efficacy and Safety of NVR 3-778, a First-In-Class HBV Core Inhibitor, in HBeAg-Positive Patients with Chronic HBV Infection"
Poster presentation: "Encapsidation and secretion of HBV RNA can be inhibited by Core Inhibitors but not by Nucleoside Analogs"
Oral presentation: "Inhibition of Hepatitis B Virus Replication by the HBV Core Inhibitor NVR 3-778"
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DOYLESTOWN, Pa., Oct. 20, 2015 /PRNewswire/ -- Novira Therapeutics, Inc., a privately held, clinical-stage biopharmaceutical company developing novel therapies for curative treatment of chronic hepatitis B virus (HBV) infection, today announced that it will present two posters and one oral presentation for its core inhibitors, including its lead candidate, NVR 3-778, at the upcoming 2015 annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.
Late-breaking poster LB-10 on November 16 will describe the safety, pharmacokinetics and HBV DNA reduction efficacy of NVR 3-778 monotherapy in a 28 day Phase 1b clinical study.
Poster 2064 on November 17 will describe the inhibition of HBV RNA encapsidation and secretion by the core inhibitor NVR-3891.
Oral presentation 33 on November 15 at 3:30 PM will describe preclinical antiviral activity of NVR 3-778 against wild-type HBV, HBV nucleos(t)ide resistant variants and representative HBV strains from genotypes A to H.
About NVR 3-778
NVR 3-778 is a small molecule, direct acting antiviral, for oral administration in patients with Chronic Hepatitis B (CHB) that inhibits the HBV core or capsid protein. HBV core is a novel and promising drug target with multiple activities required for viral replication and persistence. Inhibition of the HBV core protein function by NVR 3-778 offers the potential for more efficient suppression of virus production and replication, leading to improved durable viral suppression and functional cure rates. NVR 3-778 completed a Phase 1a clinical trial in 2014 and is currently enrolling a Phase 1b clinical trial.
About HBV
Hepatitis B infection presents a significant unmet medical need with an estimated 350 million people worldwide living with chronic HBV infection. A significant number of patients with chronic infection incur a higher risk of developing cirrhosis and cancer. It is estimated that 60% of hepatocellular carcinoma (liver cancer) is a direct consequence of HBV infection. Current drugs approved for the management of CHB include PEG-Interferon and nucleot(s)ides which can effectively suppress virus replication, but rarely lead to a cure.
About Novira Therapeutics
Novira Therapeutics, Inc., is a privately held biopharmaceutical company focused on discovery and development of first-in-class antiviral drugs for the treatment of chronic HBV infection (CHB), a global disease with a high level of unmet medical need. The company is employing innovative chemistry and biology technologies to discover small molecule inhibitors of the HBV core or capsid protein as well as other drugs with novel mode of action. The company's novel antivirals will offer the potential to address the limitations of current CHB therapies when used either as mono-therapy or in combination with existing standards of care.