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.
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
72 | Hepatitis C Treatment
allosteric inhibition. HCV polymerase has at least four allosteric
binding pockets for nonnucleosidic inhibitors, unlike the HIV
reverse transcriptase where there is only a single one. Therefore,
if patients do not respond to one non-nucleoside inhibitor, there
is enough differentiation between the binding sites to allow the
use of a different drug within the class. Several non-nucleoside
HCV polymerase inhibitors are in clinical development. Most of
these investigational agents are active only against HCV
genotypes 1a and 1b and show a relatively high rate of
resistance, as well as an increased frequency of specific sideeffects.
These observations suggest that their use could be
limited to combination with other DAAs (Table 4.2). Such an
approach was investigated for a low potent non-nucleoside
polymerase inhibitor (tegobuvir, formerly known as GS-9190) in
combination with a protease inhibitor (GS-9256) in treatmentnaive
G1 HCV patients. The combination alone, without SoC was
not effective due to virologic rebound and selection of dual
resistance mutations that existed before treatment. Addition of
RBV alone significantly reduced the virologic breakthrough
rates.
Table 4.2 – Combinations of DAAs tested with or without PegIFN/RBV
Company DAA combination Phase
Vertex Telaprevir (PI*) + VX-222 (NNI†) II
Boehringer Ingelheim BI 201335 (PI) + BI 207127 (NNI) IIb
Bristol-Myers-Squibb BMS-650032 (PI)
+ BMS-790052 (NS5A inhibitor) II
Gilead GS-9256 (PI) + GS-9190 (NNI) II
Hoffmann-La Roche Danoprevir (R7227) (PI) + R7128 (NI‡) I
* PI: protease inhibitor
† NNI: non-nucleoside (polymerase) inhibitor
‡ NI: nucleoside (polymerase) inhibitor