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New HCV Antivirals in the Pipeline
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excertped from new Hepatology textbook recently published.
From Jules: there are over 25 orally administered HCV antiviral drugs in development at this time that have been publicly presented at conferences. Many companies have multiple drugs in development. There are many potential combinations for regimens. Therapy for HCV will be like HIV consisting of a combination of the oral drugs. For now peginterferon plus ribavirin will be included in therapy until and if researchers can prove that an SVR, a cure, can be achieved without using peginterferon and ribavirin. Plus, there are a few new interferons in development that appear to be easier to tolerate. The first 2 HCV protease inhibitors telaprevir & boceprevir are now in the last stage of clinical studies in patients, phase 3, before FDA approval, which is expected next around Summer 2011, so they are expected to be available in the pharmacy by the Fall of 2011.
Table 1. Antivirals in the pipeline.
HCV life cycle and targets for STAT-C
HCV is a positive-sense single-stranded RNA virus of approximately 9600 nucleotides.
The HCV genome contains a single large open reading frame encoding for
a polyprotein of about 3100 amino acids. From this initially translated polyprotein,
the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the
six non-structural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are
processed by both viral and host proteases. The core protein forms the viral nucleocapsid carrying E1 and E2, which are receptors for viral attachment and host cell
entry. The non-structural proteins are mainly enzymes essential for the HCV life
cycle (Bartenschlager 2004; Pawlotsky 2007). P7 is a small hydrophobic protein
that oligomerises into a circular hexamer, most likely serving as an ion channel
through the viral lipid membrane (Carrere-Kremer 2002; Clarke 2006). The large
translated section of the HCV genome is flanked by the strongly conserved HCV
3' and 5' untranslated regions (UTR). The 5' UTR is comprised of four highly
structured domains forming the internal ribosome entry site (IRES), which plays an
important role in HCV replication (Figure 2).
Figure 9. Antiviral activity of NS3/4A protease inhibitors.
Resistance to NS3/4A inhibitors
Because of the high replication rate of HCV and the poor fidelity of its RNA-dependent
RNA polymerase, numerous variants (quasispecies) are continuously produced
during HCV replication. Among them, variants carrying mutations altering the conformation of the binding sites of STAT-C compounds can develop. During treatment
with specific antivirals, these drug-resistant variants have a fitness advantage and
can be selected to become the dominant viral quasispecies. Many of these resistant
mutants exhibit an attenuated replication with the result that, after stopping exposure
to specific antivirals, the wild type may displace the resistant variants (Tong
2006; Sarrazin 2007). Nevertheless, HCV quasispecies resistant to NS3/4A protease
inhibitors or non-nucleoside polymerase inhibitors can be detected at low levels in
some patients who were never treated with specific antivirals before (Gaudieri 2009;
Kuntzen 2008; Rodriguez-Frias 2009; Le Pogam 2008). The clinical relevance of
these pre-existing mutants is not completely understood, although there is evidence
that they may reduce the chance of achieving an SVR after treatment with STAT-C
compounds.
Table 5. Resistance mutations to HCV NS3 protease inhibitors.
* mutations associated with resistance in vitro but not described in patients.
Telaprevir
To date, mutations conferring telaprevir-resistance have been identified at four positions, V36A/M/L, T54A, R155K/M/S/T and A156S//T (Lin 2005; Lin 2007; Sarrazin 2007; Welsch 2008; Zhou 2008) (Table 5). The A156 mutation was revealed by in vitro analyses in the replicon while the other mutations were detected in vivo by a clonal sequencing approach during telaprevir administration in patients with chronic hepatitis C. A detailed kinetic analysis of telaprevir-resistant variants was performed in genotype 1 patients during 14 days of telaprevir monotherapy and combination therapy with PEG-IFN a-2a (Sarrazin 2007). Telaprevir monotherapy initially led to a rapid HCV RNA decline in all patients due to a strong reduction in wild type virus. In patients who developed a viral rebound during telaprevir monotherapy, mainly the single mutation variants R155K/T and A156T were uncovered by wild type reduction and became dominant after day 8. These single mutant variants were selected from preexisting quasispecies. During the viral rebound phase these variants typically were replaced by highly resistant double-mutation variants (e.g., V36M/A +R155K/T). The combination of telaprevir and PEG-IFN a-2a was sufficient to inhibit the breakthrough of resistant mutations in a 14-day study (Forestier 2007). It is important to note that after up to 3 years of telaprevir treatment low to medium levels of V36 and R155 variants were observed in single patients (Forestier 2008).
As shown also for other NS3/4A protease inhibitors (e.g., ITMN-191), the genetic barrier to telaprevir resistance differs significantly between HCV subtypes. In all clinical studies of telaprevir alone or in combination with PEG-IFN a and ribavirin, viral resistance and breakthrough occurred much more frequently in patients infected with HCV genotype 1a compared to genotype 1b. This difference was shown to result from nucleotide differences at position 155 in HCV subtype 1a (aga, encodes R) versus 1b (cga, also encodes R). The mutation most frequently associated with resistance to telaprevir is R155K; changing R to K at position 155 requires 1 nucleotide change in HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates (McCown 2009).
Boceprevir
In the replicon system, mutations have been seen at three positions that confer boceprevir
resistance (Table 5). T54A, A156S and V170A confer low level resistance to
boceprevir whereas A156T, which also confers telaprevir and ciluprevir resistance,
exhibits greater levels of resistance (Tong 2006). In patients with chronic hepatitis
C three additional mutations were detected during boceprevir monotherapy (V36G/
M/A, V55A, R155K) (Susser 2009). In a number of these patients at one year and in
single patients at even 4 years after stopping boceprevir treatment resistant variants
could still be detected in the HCV quasispecies by clonal sequence analysis (Susser
2009). However, another study revealed that the antiviral activity of boceprevir was
not different in people whether they had or had not been previously treated with
PEG-IFN a (Vermehren 2009).
Compounds targeting HCV replication
NS5B polymerase inhibitors
NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851 or IDX184 mimic the natural substrates of the polymerase and are incorporated into the growing RNA chain, thus causing direct chain termination by blocking the active site of NS5B (Koch 2006; Koch 2007). Because the active centre of NS5B is a highly conserved region of the HCV genome, NIs are potentially effective against different genotypes. Single amino acid substitutions in every position of the active centre may result in loss of function. Thus, there is a relatively high genetic barrier in the development
of resistances to NIs.
In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs)
achieves NS5B inhibition by binding to different allosteric enzyme sites, which results in conformational protein change before the elongation complex is formed (Beaulieu 2007). For allosteric NS5B inhibition high chemical affinity is required. NS5B is structurally organized in a characteristic Òright hand motifÓ, containing finger, palm and thumb domains, and offers at least four NNI binding sites, a benzimidazole-(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm 2)-binding site (Lesburg 1999; Beaulieu 2007) (Figure 12). Because of their distinct binding sites, different polymerase inhibitors can theoretically be used in combination
or in sequence to manage the development of resistance. Because NNIs bind distantly to the active centre of NS5B, their application may rapidly lead to the development of resistant mutants in vitro and in vivo. Moreover, mutations at the NNI binding sites do not necessarily lead to impaired function of the enzyme.
Figure 13. Antiviral activity of nucleoside analogue NS5B polymerase inhibitors.
Non-nucleoside analogs
At least 4 different allosteric binding sites have been identified for the inhibition of the NS5B polymerase by non-nucleoside inhibitors. An overview of the antiviral activities of non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 14.
NNI site 1 inhibitors (thumb 1 / benzimidazole site)
BILB1941, BI207127 and MK-3281 are NNI site 1 inhibitors investigated in phase I clinical trials and have shown little to modest antiviral activity (Erhard 2009; Shi 2009; Sarrazin 2009). No viral breakthrough via selection of resistant variants was seen after 5 days of treatment with BILB1941 or BI207127.
NNI site 2 inhibitors (thumb 2 / thiophene site)
Filibuvir (PF-00868554) is a NNI site 2 inhibitor with modest antiviral activity in a
phase I study. In a subsequent triple therapy trial with filibuvir, pegylated interferon a-2a and ribavirin for 4 weeks viral breakthrough was observed in 5/26 patients.
VCH-759, VCH-916 and VCH-222 are three other NNI site 2 inhibitors with
antiviral activity in monotherapy studies (Cooper 2009; Sarrazin 2009). For VCH-759 as well as VCH-916 viral breakthroughs via selection of resistant variants were observed.
NNI site 3 inhibitors (palm 1 / benzothiadiazine site)
ANA598 is a NNI site 3 inhibitor that displayed antiviral activity during treatment of genotype 1 infected patients. Viral breakthrough was not observed during this short monotherapy trial.
NNI site 4 inhibitors (palm 2 / benzofuran site)
Monotherapy with the NNI site 4 inhibitor HCV-796 showed low antiviral activity
in genotype 1 infected patients (Kneteman 2009; Villano 2007). Viral breakthrough was associated with selection of resistant variants conferring a medium to high level of phenotypic resistance. For GS-9190 low antiviral activity was observed in a clinical study and variants conferring resistance were identified in the beta-hairpin of the polymerase. ABT-333, another palm site inhibitor, demonstrated antiviral activity in patients with genotype 1 infection and from in vitro replicon as well as clinical studies specific variants were observed as main resistance mutations.
Figure 14. Antiviral activity of non-nucleoside analogue NS5B polymerase inhibitors.
NS5A inhibitor
In a single ascending dose study it was shown that inhibition of the NS5A protein with BMS-790052 leads to a sharp initial decline of HCV RNA concentrations (Nettles 2008). BMS-790052 is the first NS5A inhibitor binding to domain I of the NS5A protein, which was shown to be important for regulation of HCV replication. No clinical data on resistance to this class of drugs have been presented yet and results of multiple dose studies are eagerly anticipated. (from Jules: clinical data, in patients was presented at the EASL meeting in April 2010 and previously at AASLD 2 years ago)
links:
Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In Treatment-naïve HCV-genotype 1 Subjects: Phase 2a Trial - Bristol-Myers Squibb Study AI444014 - (04/20/10)
BMS-790052 is a First-in-class Potent Hepatitis C Virus (HCV) NS5A ...
Nov 1, 2008 ... This new class of drug, the BMS NS5A inhibitor, attracted quite a lot of discussion because of it potent viral load reduction of -3.6 logs, ...
www.natap.org/2008/AASLD/AASLD_06.htm
The Most recent data updates on new HCV antivirals and new interferons were reported at the recent EASL:
EASL 45th Annual Meeting
(European Association for the Study of the Liver)
April 14-18, 2010
Vienna, Austria
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