Experimental Agent HCV-796 Shows Activity in Preclinical Studies By Liz Highleyman Two posters presented at the 46th ICAAC, held last week in San Francisco, provided further information on the investigational non-nucleoside HCV polymerase inhibitor HCV-796, being developed jointly by ViroPharma and Wyeth. Drug Discovery The first poster, by E. Amparo and colleagues, discussed the process of discovering the compound. Researchers sought to find an inhibitor of HCV RNA-dependent RNA polymerase (NS5B), which they said "could potentially be a mainstay of HCV therapy as in the case of non-nucleoside inhibitors of HIV [reverse transcriptase]." Evaluation of compounds for their ability to inhibit HCV genotype 1b NS5B polymerase resulted in the identification of a series of potent inhibitors known as benzofurans. Researchers synthesized over 400 candidate compounds, which were then tested at multiple concentrations to generate a standard inhibitory curve and corresponding IC50s (the concentration required to reduce viral replication by 50%). Subsequent testing using a HCV subgenomic replicon assay (a model system often used because HCV replicates poorly in vitro) was performed to provide information about potency in a cellular system. The most potent compounds were then tested for selectivity against a panel of human and unrelated viral polymerases. The small molecule HCV-796 was identified as a potent and selective inhibitor of HCV NS5B with an IC50 of 0.04 +/- 0.02 mcM, an EC50 of 8.6 +/- 4.0 nM, and no inhibitory activity against a panel of human and unrelated viral polymerases. The researchers concluded that, "In vitro, HCV-796 shows potent selective inhibitory activity in the biochemical and replicon assays. Based on its biological activity, HCV-796 is a promising antiviral agent currently in Phase 1 clinical development." Laboratory and Animal Studies A. Y. M. Howe and colleagues presented data from preclinical laboratory and animal studies of HCV-796. In vitro antiviral activity was evaluated in an HCV replicon models. In the HCV 1a replicon, HCV-796 reduced HCV RNA levels by 3-4 log HCV copies/mg (EC50 = 4.5nM). Pharmacokinetics and in vivo efficacy were then assessed using SCID-Alb/uPA mice carrying chimeric human livers infected with genotype 1a HCV. Mice with HCV titers of 104-107 IU/mL were treated with HCV-796, interferon alpha-2b, or both for 5-10 days. Results
Conclusion The researchers concluded that, "HCV-796 represents a potential antiviral for the treatment of HCV infection in humans." Results of a Phase Ib monotherapy trial of HCV-796 in humans were presented at the Digestive Disease Week 2006 meeting this past May. In August, ViroPharma and Wyeth announced that they had reached a developmental "proof of concept" milestone. Further studies of HCV-796 are currently underway. ViroPharma Inc., Exton, PA; Wyeth Research, Collegeville, PA; Wyeth Research, Pearl River, NY. Wyeth Research, Collegeville, PA; KMT Hepatech, Inc., Edmonton, Canada; University of Alberta, Edmonton, Canada; ViroPharma, Inc., Exton, PA. 10/03/06 References E Amparo, A Saha, C Young, and others. HCV-796: A Potent and Selective Non-Nucleoside Inhibitor of HCV NS5B. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract F1-1378. A Y M Howe, N M Kneteman, t Gao, and others. HCV-796 Displays Potent Antiviral Activity in Replicon and in Chimeric Mice Infected with Hepatitis C Virus (HCV). 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract F1-1379.
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At 8 hours after a single dose and after dosing for 5 days with 50 mg/kg HCV-796,
mean plasma concentrations were 5-fold and 12-fold, respectively, above replicon
EC50.
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