- Email: [email protected]
SCID mouse model
ORAL PRESENTATIONS Conclusions: HLA DPB1 rs9277535 polymorphism strongly predicts IFN-induced HBsAg clearance in HBeAg-negative patients chronically infected by genotype D HBV. This genetic signature may help to select patients to IFN based regimen. O114 SERUM HBV-RNA LEVELS DECLINE SIGNIFICANTLY IN CHRONIC HEPATITIS B PATIENTS DOSED WITH THE NUCLEIC-ACID POLYMER REP2139-CA L. Jansen1,2 , A. Vaillant3 , F. Stelma1,2 , N.A. Kootstra2 , M. Bazinet3 , M. Al-Mahtab4 , H.W. Reesink1,2 . 1 Gastroenterology and Hepatology, 2 Experimental Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; 3 REPLICor Inc., Montreal, Canada; 4 Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh E-mail: [email protected] Background and Aims: Treatment of chronic hepatitis B (CHB) patients with the HBsAg release inhibitor REP2139-Ca may be a promising new option for achieving therapy-induced HBsAg loss (functional cure), however its effect on circulating hepatitis B pregenomic RNA (HBV-RNA) is not known. For this, we determined HBV-RNA levels during treatment with REP2139-Ca and compared these with HBV-DNA and HBsAg levels. Methods: 12 Patients with HBeAg positive CHB (mean HBV-DNA 8.21 logC/mL) participating in a phase 2 study were dosed with the nucleic-acid based amphipathic polymer REP2139-Ca for 20–38 weeks. Responders to REP2139 (defined as decline in serum HBsAg) were subsequently treated with add-on peginterferon alpha-2a and/or thymosin alpha-1. HBsAg (Architect), HBV-DNA, and HBVRNA levels were determined in baseline serum samples, after 20–24 weeks of REP2139-Ca monotherapy, and either during a treatmentfree follow-up (for responders) or during entecavir treatment (for non-responders). HBV-RNA isolated from 140 mL of plasma was quantified by RT-qPCR using HBV-specific primers. Lower limit of quantification of RNA was set at 3.00 logC/mL. Variables were evaluated with a paired T-test. Results: HBV-RNA was detectable in all 12 patients before treatment [mean 6.70 logC/mL (SD 0.83)], and was significantly associated with HBsAg (r2 0.33, p = 0.049) and HBV-DNA (r2 0.74, p < 0.001). After 20–24 weeks of REP2139-Ca treatment, mean HBVRNA, HBV-DNA, and HBsAg levels declined significantly compared to baseline (−2.54, −3.34, and −3.12 log C or IU/mL, respectively, all p < 0.001). At week 20–24, HBV-RNA was undetectable in 8/12 patients. In 7 of these 8 patients, HBV-RNA remained undetectable during the treatment-free follow-up period (mean 21.9 weeks, range 7–27). HBsAg loss and anti-HBs seroconversion was achieved in 4/8 patients during treatment-free follow-up (anti-HBs range 200–766 U/L). In contrast, 3/4 patients with detectable HBV-RNA at week 20–24 of REP2139-Ca treatment also showed no decline in HBV-DNA or HBsAg, after which entecavir therapy was initiated. After 21–32 weeks of entecavir treatment HBV-DNA had declined significantly (−4.39 logC/mL, p = 0.029), whereas HBV-RNA levels remained unchanged (+0.23 logC/mL, p = 0.188). Conclusions: Treatment of CHB patients with REP2139-Ca resulted in a pronounced decline of serum HBV-RNA, HBV-DNA and HBsAg in the majority of patients, and may be a promising new option for improving the chance of functional cure in CHB patients.
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O115 HIGH ANTIVIRAL ACTIVITY OF THE HBV CORE INHIBITOR NVR 3-778 IN THE HUMANIZED UPA/SCID MOUSE MODEL K. Klumpp1 , T. Shimada2 , L. Allweiss3 , T. Volz3 , M. Luetgehetman3,4 , O. Flores1 , G. Hartman1 , A. Lam1 , M. Dandri3,5 . 1 Novira Therapeutics Inc., Doylestown, United States; 2 PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan; 3 Department of Internal Medicine, 4 Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 5 German Center for Infection Research, Hamburg-L¨ ubeck-Borstel Partner Site, Hamburg, Germany E-mail: [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 PEGIFN treatment (p < 0.05). The largest viremia reduction across all groups was obtained when NVR 3-778 was combined with PEGIFN, 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 b-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.
Journal of Hepatology 2015 vol. 62 | S235–S262
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O115 HIGH ANTIVIRAL ACTIVITY OF THE HBV CORE INHIBITOR NVR 3-778 IN THE HUMANIZED UPA/SCID MOUSE MODEL K. Klumpp1 , T. Shimada2 , L. Allweiss3 , T. Volz3 , M. Luetgehetman3,4 , O. Flores1 , G. Hartman1 , A. Lam1 , M. Dandri3,5 . 1 Novira Therapeutics Inc., Doylestown, United States; 2 PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan; 3 Department of Internal Medicine, 4 Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 5 German Center for Infection Research, Hamburg-L¨ ubeck-Borstel Partner Site, Hamburg, Germany E-mail: [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 PEGIFN treatment (p < 0.05). The largest viremia reduction across all groups was obtained when NVR 3-778 was combined with PEGIFN, 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 b-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.
Journal of Hepatology 2015 vol. 62 | S235–S262