Author: He, William ; Levy, Gary A. ; Koscik, Cheryl ; Phillips, M. James ; Fung, Laisum ; Ghanekar, Anand ; Ng, Nancy F. ; Ma, Max Xuezhong ; Levy, Adam ; Gorczynski, Reginald ; Scrocchi, Louise A. ; Rowe, Andrea ; McGilvray, Ian D. ; Biessels, Pieter ; Bell, David ; Woods, Caroline ; Adamson, Gord ; Brookes, Steve

Side effects of interferon–ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin–ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) by macrophages. In vivo , untreated MHV-3–infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203–treated mice with a marked reduction in biochemical [ALTmax 964 ± 128 IU/L (ribavirin); 848 ± 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203–treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion , targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro . (Hepatology 2006;43:581–591.)

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C	Preclinical	CA	Therapure Innovations	-

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