Enhanced
Clinical Effects and Favorable Resistance Profile with Combination of Boceprevir
Plus HCV-796 The experimental HCV
NS3 protease inhibitor boceprevir (SCH-503034), in development by Schering Plough, and the experimental non-nucleoside
HCV polymerase inhibitor HCV-796 from Wyeth Phamaceuticals and ViroPharma have both shown significant
antiviral activity in early clinical studies. Researchers at Schering Plough, Wyeth, and ViroPharma have
evaluated the combined antiviral effects
of these 2 new agents in cell-culture replicon studies, which demonstrated that
genetic variants exhibiting reduced susceptibility can be selected from both compounds. The potential exists for enhanced antiviral responses in humans
when the 2 inhibitors are used in combination,
because boceprevir and HCV-796 target different HCV enzymes (protease and polymerase,
respectively). There is also the potential for delaying the emergence of clinically
resistant HCV when the 2 compounds
are combined. The current cell-culture replicon studies were undertaken
to assess whether these objectives could be achieved. The combined
antiviral effect of boceprevir and HCV-796 was evaluated using genotype 1b HCV
replicon cells. Each compound was individually
assessed for its ability to inhibit the activity of variant replicons exhibiting
reduced susceptibility to the other inhibitor. Results ·
The combination of boceprevir and HCV-796 notably enhanced
replicon inhibition in treated cells, in a dose-dependent manner, compared with either inhibitor used alone. ·
The antiviral effect
of the combination was at least additive.
·
No cytotoxicity was
observed. ·
Boceprevir exhibited
equivalent inhibitory activity against the wild-type replicon and replicon variants
expressing single polymerase amino acid substitutions that confer reduced susceptibility
to HCV-796. ·
The inhibitory effect
of HCV-796 against replicon variants with protease amino acid substitutions conferring
reduced susceptibility to the protease inhibitor was found to be identical to
that observed against the wild-type replicon. ·
The combination significantly reduced the frequency of
emergence of resistant colonies compared
to each inhibitor used alone. Conclusion In conclusion, the investigators wrote, “The
anti-replicon activity of the combination
of SCH-503034 [boceprevir] and HCV-796, as well as the activity of each compound against replicons with reduced susceptibility
to the other compound, strongly support
the combined use of these two inhibitors
in clinical trials.” They continue, “The cell-culture replicon
data suggest that the in vivo antiviral effects of the combination will be notably improved over the effects
seen to date with monotherapy.” Finally, they note, “Importantly, compared with monotherapy, the combination will likely impose a greater genetic barrier
to the selection of clinically resistant viral variants.” 05/22/07 Reference
R Ralston, A Y Howe, R Chase, and others.
Favorable Cross-Resistance Profile of HCV-796 and SCH-503034 and Enhanced Anti-Replicon
Activity Mediated By Combination Treatment. Digestive Disease Week 2007 (DDW 2007). Washington, DC. May 19-24, 2007. Abstract 364. Return
to to DDW 2007 Main Page
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