Biotech Values

[DewDiligence]

HCV combination treatment with VX-950,
ACH-806 (GILD/ACHN), and NM107 (IDIX).

NM107 is the drug into which the NM283 prodrug is
metabolized. ACH-806 is also known as GS9132.

http://www.easl.ch/liver-meeting/Program/ViewAbstract.asp

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In Vitro Evaluation of Combination Treatment of ACH-806 With Interferon; VX-950 and NM107

M. Huang, W. Yang, J. Fabrycki, X. Nie, A. Phadke, M. Deshpande

Achillion Pharmaceuticals, New Haven, CT, USA

Background and Aim: Current therapy of HCV consists of pegylated interferon (IFN) in combination with ribavirin. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM107) are in clinical development for treatment of chronic HCV. Due to the high mutation rate of HCV, combination of drugs with complimentary mechanisms of action may be needed to suppress emergence of viral resistance. Short term and long term in vitro antiviral activity of ACH-806, a replicase inhibitor, was evaluated in combination with interferon; VX-950, a protease inhibitor; and NM 107, a polymerase inhibitor.

Methods: HCV 1b-Con-1 replicon-containing cells were utilized for evaluation of combination treatment. For short-term combination assays, serial dilutions of ACH-806 were combined with serial dilutions of IFN, VX-950, or NM107 in a checker board manner. Three days after addition of compounds, the level of HCV RNA replication was quantified with luciferase reporter assay. For long-term combination assays, replicon-containing cells were grown for 7~10 days in the presence of ACH-806 or ACH-806 plus one of the three above mentioned drugs. To examine the proportion of cells in which HCV replicon RNA was still present (not cured) after 7 to10-day exposure, replicon cells were plated in an equal densities and were treated with G418 until formation of colonies became visible.

Results: Combination of ACH-806 with VX-950, NM107, or IFN was not antagonistic over a range of concentrations. More importantly, ACH-806 was synergistic in combination with VX-950 and NM107 at or below drug concentrations corresponding to the EC90 values for each drug. Furthermore, the benefit of combination treatment was sustained over time such that only a minor fraction of cells were left uncured following 7~10 days of combination treatment.

Conclusion: Our results suggest that ACH-806 has the potential to be used effectively in combination with different classes of HCV inhibitors for the treatment of HCV infection.
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