Page 71 - The Flying Publisher Guide to Hepatitis C Treatment

Searching for new antiviral therapies | 71

Nucleoside analogs target the catalytic sites of the enzyme by
competing with natural substrates and, once incorporated, act as
chain terminators stopping the further extension of viral RNA
nascent strand. This drug class is considered to have the
broadest genotypic coverage as well as a high resistance barrier.
This is due to the fact that mutations at the active site also affect
the viral polymerase fitness.
Several early developed compounds were discontinued because
of high toxicity (gastrointestinal or neutropenia related,
respectively).
The current most advanced compound in development is the
nucleoside analog mericitabine (R7128), an investigational
nucleoside inhibitor of NS5B HCV polymerase with antiviral
activity against HCV genotypes 1-6. The compound is a prodrug
of an oral cytidine nucleoside analog (PSI-6130). A phase IIb trial
in therapy-naive patients with genotype 1 or 4 HCV infection
demonstrated that a combination of mericitabine and
PegIFN/RBV achieves high rates of both rapid and complete
early virologic responses. Mericitabine has a safety profile
similar to SoC and, importantly, does not seem to be associated
with treatment-emergent viral breakthrough or resistance. The
combination of this NS5B polymerase inhibitor with an NS3
protease inhibitor (Danoprevir, R7227), administered without
additional PegIFN/RBV, for 14 days in treatment-naive, genotype
1-infected patients, demonstrated sustained viral suppression,
absence of PI resistant mutations and acceptable safety and
tolerability (INFORM 1 trial). The combination is associated with
a lower risk of relapse during SoC.
There are several others compounds in early stages of clinical
development, that are designed to achieve higher concentrations
of the active substance in the liver, reducing systemic exposure
and limiting the potential side effects.

The non-nucleoside polymerase inhibitors are a very
promising class of molecules, because they target multiple
distinct domains on the NS5B polymerase, acting through