Page 70 - The Flying Publisher Guide to Hepatitis C Treatment

70 | Hepatitis C Treatment

reaching 83% in GT1 patients at once-daily dosages of 240 mg (in
combination with PegINF+RBV). BI 201335 is now in phase III
trials in combination with PegINF+RBV and in phase II as part of
the interferon-free combination with the polymerase inhibitor,
BI 207127, in genotype-1 HCV patients.
Other notable examples are MK-5172, a competitive inhibitor
of HCV NS3/4A protease that has demonstrated in vitro activity
against genotypes 1b, 2a, 2b, and 3a, and proved to be active in
vivo against genotypes 1 and 3; and TMC435 (that can also be
administered once-daily), active in therapy-naive patients with
HCV G4 infection. Moreover, TMC435 antiviral activity was
similar, irrespective of the IL28B genotype. Some compounds,
such as Danoprevir (formerly R7227/ITMN-191) are being
studied in combination with low-dose ritonavir (a pharmacologic
booster used for HIV protease inhibitors) in order to improve
pharmacokinetics, without increasing toxicity. Whether such
complex therapies have the potential to minimize the risk of
viral breakthrough and the selection of resistance mutations,
remains to be evaluated.

HCV polymerase inhibitors
The HCV NS5B enzyme is an RNA-dependent RNA polymerase
essential for viral replication. As the enzyme is highly conserved
across all HCV genotypes, the inhibitors are expected to have
pan-genotypic activity. The structure of NS5B, like many other
viral polymerases (HIV reverse transcriptase included),
resembles the shape of a hand consisting of finger, thumb and
palm domains. There are two major classes of polymerase
inhibitors: nucleoside analogs and non-nucleoside analogs. The
enzyme has a catalytic site for nucleoside binding and at least
four other sites to which a non-nucleoside molecule could bind
and cause allosteric alteration. Inhibitors of NS5B polymerase
have advanced to the phase II of clinical development. These
agents have demonstrated potent antiviral efficacy, achieving
multi-log reductions in HCV RNA with short-term treatment.