Polymerase Inhibitor NM107 and Protease Inhibitor Boceprevir Show Enhanced Anti-HCV Activity When Used in Combination

By Liz Highleymanz

As is the case with therapy for HIV, experts expect that combining directly targeted small-molecule antiviral agents for the treatment of hepatitis C will lead to better outcomes and reduced emergence of drug resistance.

In a study presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007), researchers assessed the combined effect of 2 experimental agents directed at different HCV molecular targets:

• NS5B polymerase inhibitor NM107 (the active form of valopicitabine, or NM238)

• NS3 protease inhibitor boceprevir (formerly SCH 503034).

Both valopicitabine and boceprevir have demonstrated anti-HCV activity when used as monotherapy in clinical trials.

The investigators used a genotype 1b HCV replicon in laboratory cell cultures to assess the combined antiviral activity of the 2 drugs. Potential cross-resistance was evaluated using replicon variants carrying single protease inhibitor resistance mutations (T54A, A156S, V170A, A156T) or a known polymerase inhibitor resistance mutation (S282T). The selection of resistant cell colonies was carried out for 3-4 weeks in the presence of various concentrations of one or both drugs.

Results

• The combination of NM107 and boceprevir led to dose-dependent enhancement of HCV replicon inhibition, compared with the effect of either drug alone.

• The combination demonstrated no cross-resistance and the suppression of treatment-emergent resistance, as compared to monotherapy with either drug.

• In cross-resistance studies, NM107 showed similar antiviral activity (EC50 1.5-2 mcM) against wild-type and boceprevir-resistant replicons.

• Boceprevir showed similar activity (EC50 0.3-0.4 mcM) against wild-type and NM107-resistant replicons.

• When tested against HCV with known resistance mutations, each compound showed a 5-fold to 125-fold decrease in susceptibility.

• In selection experiments, the combination of NM107 and boceprevir significantly reduced the frequency of drug-resistant colonies in a dose-dependent manner, compared with either agent used alone.

Conclusion

"In these in vitro studies, the combination of the polymerase and protease inhibitors showed enhanced anti-replicon activity with no cross-resistance and a greater genetic barrier to resistance," the investigators concluded.

They added that, "These results support clinical evaluation of this combination in patients with chronic hepatitis C."

Idenix Pharmaceuticals, Cambridge, MA; Schering-Plough Research Institute, Kenilworth, NJ.

12/07/07

Reference
DN Standring, V Bichko, R Chase, and others. HCV Polymerase (NM107) and Protease (boceprevir) Inhibitors in Combination Show Enhanced Activity and Suppression of Resistance in the Replicon System. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, November 2-6, 2007. Abstract 1391.