icon-folder.gif   Conference Reports for NATAP  
  HEP DART 2003: Frontiers in drug development for Viral Hepatitis
December 14-18, 2003
Kauai, Hawaii
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NM 283 new HCV Inhibitor
  Reported by Jules Levin
December 14-18, 2003 in Kauai, Hawaii the HEP DART 2003 Frontiers In Drug Development For Viral Hepatitis Conference took place. You will receive a series of reports providing key highlights concerning new drug developments from the conference.
NM283 Has Potent Antiviral Activity against Chronic Hepatitis C Virus Genotype-1 in the Chimpanzee
DN Standring, Idenix Pharmaceuticals and colleagues.
Improved therapeutics are required for chronic hepatitis C with genotype 1 infection. A ribonucleoside analogue, NM107, was discovered as a potent and selective inhibitor of flavi- and pesti-virus replication in cell culture. NM283, a prodrug form of NM107 with improved oral bioavailibility, is currently being evaluated against HCV infection in human clinical trials. Other compounds related to NM107 are currently being investigated as additional therapeutic agents for HCV infection.
NM107 and related compounds were tested in a panel of antiviral assays and in vitro toxicity assays. NM107 was found o inhibit flavi- and pest-virus replication in cell culture. The prodrug form of NM107, NM283, has been evaluated in subchronic toxicity studies in animals as well as for activity against HCV-1 in chronically infected chimpanzees.
In cell culture, NM107 inhibited bovine viral diarrhea virus (BVDV) replication (EC50 0.67nM), eliminated persistent BVDV infection at nontoxic concentrations, and was synergistic in combination with interferon alpha 2b but not with ribavirin. NM107 triphosphate was a competitive inhibitor of purified BVDV RNA polymerase in vitro (Ki 160 nM). NM107/NM283 had a favorable profile with respect to in vitro mitochondrial and bone marrow toxicity, lack of incorporation into cellular DNA and RNA, and subchronic toxicology in rats and monkeys.
HCV-1 infected chimpanzeeswere given NM283 orally once daily for 1 week at 8.3 or 16.6 mg/kg (2 chimps/dose group). Serum HCV RNA titers, measured by the Roche HCV Cobas Amplicor assay, were stable in the pretreatment and placebo samples but dropped rapidly within 2 days of therapy in all 4 treated animals. Mean log10 viral load reductions of 1.05 and 0.83 seen at day 7 of therapy in the high and low dose groups were similar to reductions seen in patients after 7 days of treatment with PEG-interferon and ribavirin (Buti et al, Hepatology 2002).
NM283 is a promising antiviral agent for chronic HCV infection, including HCV 1, and is currently in human trials.