- Email: [email protected]
1048 A NOVEL HUMAN MONOCLONAL ANTIBODY DIRECTED AGAINST THE E2 GLYCOPROTEIN OF HEPATITIS C VIRUS (HCV) PREVENTS INFECTION IN CHIMPANZEES
LATE-BREAKER POSTERS
LATE-BREAKER POSTERS
1048 A NOVEL HUMAN MONOCLONAL ANTIBODY DIRECTED AGAINST THE E2 GLYCOPROTEIN OF HEPATITIS C VIRUS (HCV) PREVENTS INFECTION IN CHIMPANZEES B.M. Blair1 , T.J. Broering1 , G.J. Babcock1 , G. Szabo2 , R.W. Finberg2 , P.S. Cheslock1 , M. Knauber1 , B.A. Leav1 , R. Lanford3 , R.H. Purcell4 , D.M. Ambrosino1 , D.C. Molrine1 . 1 MassBiologics, University of Massachusetts Medical School, Boston, MA, 2 University of Massachusetts Medical School, Worcester, MA, 3 Southwest Foundation for Biomedical Research, San Antonio, TX, 4 National Institute of Health, Bethesda, MD, USA E-mail: [email protected] Background: HCV infection is a leading cause of liver transplantation and there is an urgent need to develop therapy to reduce rates of re-infection of transplanted livers. Methods: Using transgenic mice (HuMAb, Medarex), we have developed a fully human monoclonal antibody to a linear epitope of HCV E2 glycoprotein MBL-HCV1 that neutralizes pseudoviruses from multiple HCV genotypes. We then tested the ability of MBL-HCV1 to neutralize infectious, replication competent HCV in a cell culture assay using HCVcc 2a strain JFH1/J6. Concentrated cell culture supernatants of JFH1/J6 virions were pre-incubated with MBL-HCV1, applied to Huh 7.5 cells and HCV RNA infection measured by qRT-PCR. MBL-HCV1 completely neutralized HCVcc at concentrations as low as 0.15mg/ml. Based on these in vitro results, the ability of MBL-HCV1 to prevent HCV infection in uninfected chimpanzees was assessed. Three chimpanzees received a single dose of 0 mg/kg, 50 mg/kg or 250 mg/kg of MBL-HCV1 intravenously before challenge with 32 CID of HCV 1a strain H77. Animals were followed for 20 weeks with weekly PCR based viral loads [Lower Limit of Quantification (LLQ) = 500 Genomes/mL (Ge/mL)] as well as clinical and safety laboratory assessments. Results: Infusion of MBL-HCV1 was safe and well tolerated. No HCV RNA was detected in the serum of the 250 mg/kg dosed chimp through week 20. A subset of samples through day 56 was also measured in a transcription-mediated amplification assay (LLQ = 50 Ge/mL) and none of these tested positive. In contrast, the 0 mg/kg and 50 mg/kg dosed chimps both became infected by Day 14. To investigate the impact of MBL-HCV1 on viral clearance, the 0 mg/kg dosed chimp was administered 250 mg/kg of MBL-HCV1 at day 42 when viral load measured 1.0×105 Ge/mL. At day 49, the viral load was undetectable before rebounding at day 56 to 2.8×104 Ge/mL. Conclusions: These findings suggest that a human monoclonal antibody directed to a conserved epitope of HCV E2 glycoprotein neutralizes infectious, replication competent HCV and prevents infection in the chimpanzee model of HCV disease. A phase I study is planned.
S381
1049 PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED STUDY OF NITAZOXANIDE PLUS PEGINTERFERON AND RIBAVIRIN IN HCV GENOTYPE 1 PATIENTS: INTERIM ANALYSIS SHOWS INCREASE IN EVR B. Bacon1 , M. Shiffman2 , J. Lim3 , A. Berman4 , V. Rustgi5 , E. Keeffe6,7 . 1 Medicine/Gastroenterology, St. Louis University, St. Louis, MO, 2 Medicine/Hepatology, Virginia Commonwealth University Medical Center, Richmond, VA, 3 Medicine/Gastroenterology, Yale University Medical Center, New Haven, CT, 4 Florida Center for Gastroenterology, Largo, FL, 5 Medicine/Hepatology, Georgetown University Medical Center, Fairfax, VA, 6 Romark Institute for Medical Research, Romark Laboratories, Sausalito, CA, 7 Medicine/Gastroenterology, Stanford University Medical Center, Stanford, CA, USA E-mail: [email protected] Background and Aims: Nitazoxanide (NTZ) is undergoing study for treatment of chronic hepatitis C (CHC) and shows complete EVR (cEVR) rates of 68% to 86% and SVR rates of 79% and 80% in naive genotype 4 patients. The antiviral mechanism of action of NTZ appears to be induction of PKR, a mediator of cellular antiviral responses. The aim of this study is to determine the efficacy of NTZ in combination with peginterferon alfa2a (PegIFN) and ribavirin (RBV) in naive patients with CHC genotype 1; this is the first interim analysis of RVR, cEVR, and EVR rates. Methods: 112 treatment-naive patients with CHC genotype 1 underwent 2:1 randomization in 13 U.S. centers in this double-blind, placebocontrolled study to receive either NTZ (n = 75) or placebo (PBO) (n = 37) twice daily over a 4-week lead-in followed by continued NTZ or PBO plus PegINF 180 mcg weekly and weight-based RBV (1000 to 1200 mg/d) for 48 weeks. Serum HCV RNA was measured using the Roche Cobas Taqman assay. Discontinuation criteria include failure to achieve EVR or detectable HCV RNA after 24 weeks of combination therapy. Results: Mean ages (±SD) in the NTZ and PBO groups were 50±7 and 51±8 years, respectively, and 65% of patients were men in both groups. Median baseline HCV RNA was 6.4 log10 IU/mL in the NTZ group and 6.6 log10 IU/mL in the PBO group. Analysis of data was by intention-totreat. Treatment group
RVR
cEVR
EVR
NTZ + PegIFN + RBV (n = 75) PBO + PegIFN + RBV (n = 37)
9 (12%) 7 (19%)
45 (60%) 18 (49%)
60 (80%) 25 (68%)
In patients with HCV RNA levels >600,000 IU/mL, cEVR and EVR rates were higher in the NTZ (n = 67) vs. PBO (n = 31) groups (57% vs. 39%, and 79% vs. 61%, respectively). There were 21 SAEs and no significant differences in AEs between the two treatment groups. Conclusions: Interim results of this study in genotype 1 naive patients with CHC shows that the addition of NTZ increases EVR rates. Moreover, these findings are consistent with the previously observed EVR results in naive genotype 4 patients.
LATE-BREAKER POSTERS
1048 A NOVEL HUMAN MONOCLONAL ANTIBODY DIRECTED AGAINST THE E2 GLYCOPROTEIN OF HEPATITIS C VIRUS (HCV) PREVENTS INFECTION IN CHIMPANZEES B.M. Blair1 , T.J. Broering1 , G.J. Babcock1 , G. Szabo2 , R.W. Finberg2 , P.S. Cheslock1 , M. Knauber1 , B.A. Leav1 , R. Lanford3 , R.H. Purcell4 , D.M. Ambrosino1 , D.C. Molrine1 . 1 MassBiologics, University of Massachusetts Medical School, Boston, MA, 2 University of Massachusetts Medical School, Worcester, MA, 3 Southwest Foundation for Biomedical Research, San Antonio, TX, 4 National Institute of Health, Bethesda, MD, USA E-mail: [email protected] Background: HCV infection is a leading cause of liver transplantation and there is an urgent need to develop therapy to reduce rates of re-infection of transplanted livers. Methods: Using transgenic mice (HuMAb, Medarex), we have developed a fully human monoclonal antibody to a linear epitope of HCV E2 glycoprotein MBL-HCV1 that neutralizes pseudoviruses from multiple HCV genotypes. We then tested the ability of MBL-HCV1 to neutralize infectious, replication competent HCV in a cell culture assay using HCVcc 2a strain JFH1/J6. Concentrated cell culture supernatants of JFH1/J6 virions were pre-incubated with MBL-HCV1, applied to Huh 7.5 cells and HCV RNA infection measured by qRT-PCR. MBL-HCV1 completely neutralized HCVcc at concentrations as low as 0.15mg/ml. Based on these in vitro results, the ability of MBL-HCV1 to prevent HCV infection in uninfected chimpanzees was assessed. Three chimpanzees received a single dose of 0 mg/kg, 50 mg/kg or 250 mg/kg of MBL-HCV1 intravenously before challenge with 32 CID of HCV 1a strain H77. Animals were followed for 20 weeks with weekly PCR based viral loads [Lower Limit of Quantification (LLQ) = 500 Genomes/mL (Ge/mL)] as well as clinical and safety laboratory assessments. Results: Infusion of MBL-HCV1 was safe and well tolerated. No HCV RNA was detected in the serum of the 250 mg/kg dosed chimp through week 20. A subset of samples through day 56 was also measured in a transcription-mediated amplification assay (LLQ = 50 Ge/mL) and none of these tested positive. In contrast, the 0 mg/kg and 50 mg/kg dosed chimps both became infected by Day 14. To investigate the impact of MBL-HCV1 on viral clearance, the 0 mg/kg dosed chimp was administered 250 mg/kg of MBL-HCV1 at day 42 when viral load measured 1.0×105 Ge/mL. At day 49, the viral load was undetectable before rebounding at day 56 to 2.8×104 Ge/mL. Conclusions: These findings suggest that a human monoclonal antibody directed to a conserved epitope of HCV E2 glycoprotein neutralizes infectious, replication competent HCV and prevents infection in the chimpanzee model of HCV disease. A phase I study is planned.
S381
1049 PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED STUDY OF NITAZOXANIDE PLUS PEGINTERFERON AND RIBAVIRIN IN HCV GENOTYPE 1 PATIENTS: INTERIM ANALYSIS SHOWS INCREASE IN EVR B. Bacon1 , M. Shiffman2 , J. Lim3 , A. Berman4 , V. Rustgi5 , E. Keeffe6,7 . 1 Medicine/Gastroenterology, St. Louis University, St. Louis, MO, 2 Medicine/Hepatology, Virginia Commonwealth University Medical Center, Richmond, VA, 3 Medicine/Gastroenterology, Yale University Medical Center, New Haven, CT, 4 Florida Center for Gastroenterology, Largo, FL, 5 Medicine/Hepatology, Georgetown University Medical Center, Fairfax, VA, 6 Romark Institute for Medical Research, Romark Laboratories, Sausalito, CA, 7 Medicine/Gastroenterology, Stanford University Medical Center, Stanford, CA, USA E-mail: [email protected] Background and Aims: Nitazoxanide (NTZ) is undergoing study for treatment of chronic hepatitis C (CHC) and shows complete EVR (cEVR) rates of 68% to 86% and SVR rates of 79% and 80% in naive genotype 4 patients. The antiviral mechanism of action of NTZ appears to be induction of PKR, a mediator of cellular antiviral responses. The aim of this study is to determine the efficacy of NTZ in combination with peginterferon alfa2a (PegIFN) and ribavirin (RBV) in naive patients with CHC genotype 1; this is the first interim analysis of RVR, cEVR, and EVR rates. Methods: 112 treatment-naive patients with CHC genotype 1 underwent 2:1 randomization in 13 U.S. centers in this double-blind, placebocontrolled study to receive either NTZ (n = 75) or placebo (PBO) (n = 37) twice daily over a 4-week lead-in followed by continued NTZ or PBO plus PegINF 180 mcg weekly and weight-based RBV (1000 to 1200 mg/d) for 48 weeks. Serum HCV RNA was measured using the Roche Cobas Taqman assay. Discontinuation criteria include failure to achieve EVR or detectable HCV RNA after 24 weeks of combination therapy. Results: Mean ages (±SD) in the NTZ and PBO groups were 50±7 and 51±8 years, respectively, and 65% of patients were men in both groups. Median baseline HCV RNA was 6.4 log10 IU/mL in the NTZ group and 6.6 log10 IU/mL in the PBO group. Analysis of data was by intention-totreat. Treatment group
RVR
cEVR
EVR
NTZ + PegIFN + RBV (n = 75) PBO + PegIFN + RBV (n = 37)
9 (12%) 7 (19%)
45 (60%) 18 (49%)
60 (80%) 25 (68%)
In patients with HCV RNA levels >600,000 IU/mL, cEVR and EVR rates were higher in the NTZ (n = 67) vs. PBO (n = 31) groups (57% vs. 39%, and 79% vs. 61%, respectively). There were 21 SAEs and no significant differences in AEs between the two treatment groups. Conclusions: Interim results of this study in genotype 1 naive patients with CHC shows that the addition of NTZ increases EVR rates. Moreover, these findings are consistent with the previously observed EVR results in naive genotype 4 patients.