HCV Drug Discovery Aimed at Viral Eradication

R. F. Schinazi; L. Bassit; C. Gavegnano

Disclosures

J Viral Hepat. 2010;17(2):77-90. 

In This Article

Polymerase Inhibitors

Inhibitors of HCV NS5B RdRp are divided into two classes, namely the nucleoside and non-nucleoside inhibitors (NI and NNI, respectively). In their active triphosphate (TP) forms, NI metabolites act as nonobligate chain terminators while competing with the natural substrate nucleotides [i.e. for β-D-2'-deoxy-2'-fluoro-2'-C-methycytidine (PSI-6130), CTP or 2'-C-methyl-7-deaza-adenosine, ATP] for the HCV NS5B RdRp, thereby reducing the efficiency of further RNA elongation through steric resistance. To date, the primary NI are the 2'-C-methyl (containing a hydroxy or fluorine function also at the 2' position) and 4'-C-azido nucleosides.

Nucleosides Inhibitors (NI)

The cytidine NI PSI-6130 demonstrated potent and specific in vitro anti-HCV activity, with no apparent cytotoxicity[33–36] and functions synergistically with IFN-α2b and ribavirin to inhibit HCV RNA replication using the replicon system.[36] In addition, PSI-6130 displays greater potency against the S282T mutant vs 2'-C-methyl nucleoside analogues in both the HCV replicon and HCV-Cp7 systems.[35,37] In a 14-day Phase I monotherapy study, the tri-isobutyl ester prodrug of PSI-6130, named R-7128, demonstrated high oral bioavailability, significant potency and conferred a substantial drop in levels of HCV RNA, with a 2.7-log reduction in the viral load for individuals infected with genotype 1 who had failed prior IFN therapy.[38,39] In addition, co-administration of R-7128 with peg-IFN-α2b and ribavirin resulted in a 5.0-log viral load reduction for patients infected with genotype 2 and 3 who were previously classified as nonresponders.[40] R-7128 has advanced to an expanded Phase 2b study, for the investigation of co-administration of R-7128 with IFN-α2b and ribavirin in genotype 1 or 4 treatment-naïve infected individuals. Such studies provide a strong virological foundation for using 2'-C-methyl (or 2'-C-fluorine) nucleoside analogues together with the standard of care (peg-IFNα2b with or without ribavirin) treatment for HCV infection. In addition, a recent late breaker abstract presented at European Association for the Study of the Liver (EASL) 2009 reported that co-administration of R-7128 plus ITMN-191 over the course of a 14-day study reduced HCV viral loads to below the limit of quantification for 63% of subjects enrolled.[41] Of interest is that PS-6130 in its monophosphate form can be deaminated intracellularly to the uridine analogue. The U analogue like PSI-6130 can be phosphorylated to the 5'-triphosphate, which is a potent inhibitor of HCV polymerase.[42] Thus, delivery of the active form of the uridine plus cytidine 5'-triphosphate analogue intracellular provides potential for synergy and a high genetic barrier towards selection of resistant virus because of this combination. This led to the realization that the uridine analogue in a prodrug form could itself be a potent inhibitor of HCV. PSI-7851 represents such a promising nontoxic uridine nucleoside 5'-monophosphate prodrug under Phase 1 clinical evaluation. The mechanism of action is linked to deamination of PSI-6130 in hepatic cells, and in vitro studies demonstrated superior anti-HCV activity of PSI-7851, with 10- to 20-fold greater potency vs first generation Phase 2b inhibitor of NS5B RdRp, R-7128.[43]

PSI-938 was recently reported as a novel proprietary nucleotide purine analogue for the treatment of HCV.[44] PSI-938 confers a resistance profile that differs from the pyrimidine analogues R-7128 and PSI-7851 and is metabolized by a phosphorylation pathway that is distinct from both R-7128 and PSI-7851.[44] Together, R-7128, PSI-7851 and PSI-938 provide a multifaceted approach for combination therapy, wherein utilization of various combinations of C or U pyrimidine analogues with a purine analogue can be administered for maximized inhibition of viral replication. This strategy has proven to be very successful for the treatment of HIV infections (e.g. Truvada or Combivir).

The 4'-C-azido nucleoside inhibitor R-1626, another tri-isobutyl ester prodrug of R-1479, provided a robust antiviral activity while inducing ≥2.6 log10 reduction in plasma HCV RNA levels of genotype 1-infected individuals in a 14-day monotherapy, with no appearance of resistance to R-1479.[45] Nevertheless, severe adverse haematological effects were reported with the highest dose of 4500 mg R1626, leading its termination of further development.[45]

Valopicitabine (NM283), the 3'-valine ester of β-D-2'-C-methylcytidine (2'-C-MeC; NM107), was the first prodrug nucleoside under clinical investigation by Idenix Pharmaceuticals (Cambridge, MA, USA). NM107-TP inhibited the activity of HCV NS5B RdRp by competing with the natural substrate CTP and terminates the RNA elongation step and demonstrated potent in vitro antiviral activity against both genotype 1 (HCV replicons),[36,46] and genotype 2 (JFH-1-based system, Cp7 wild type). In addition, in vitro synergistic activity has been demonstrated when combined with IFN-α2b or triple combination with IFN-α2b and ribavirin, with no evidence of cytotoxicity.[36] Although valopicitabine was evaluated in clinical trials, and co-administration with peg-IFN-α has led to successful viral RNA suppression in numerous HCV-infected persons,[47] this drug was discontinued in its present form, largely as a function of gastrointestinal toxicity and pancreatitis.[48] Learning from that failure, IDX184 was developed as a novel liver-targeted nucleotide HCV NI, which demonstrated potent antiviral activity against genotype-1-infected chimpanzees (>3.0 log10 HCV viral reduction for 4 days), with no emergence of the S282T mutation. IDX184 was generally well tolerated in healthy subjects at single dose up to 100 mg in a Phase 1 clinical trial.[49] Although extensive additional studies must be conducted to determine the long-term impact of IDX184 on viral loads, viral clearance and toxicity, these data are promising.

Nonnucleosides Inhibitors (NNI)

The primary mechanism of action for non-nucleoside inhibitors (NNI) is specific targeting of different and less conserved allosteric sites of the HCV NS5B polymerase. NNI present with differences when comparing the mechanism of action of NI, which exert their inhibitory effect by binding the active site of HCV. Multiple NS5B HCV inhibitors are under clinical investigation, and extensive data exist for numerous compounds. To date, many other NS5B polymerase inhibitors are under early stages of clinical investigation and present with promising results thus far including GS-9190, ABT-333 and PF-00868554. GS-9190 is currently the most advanced NS5B polymerase NNI (Phase 2) and reported encouraging antiviral data when administered in a combination therapy with peg-IFN-α and ribavirin. ABT-333 has demonstrated a promising in vitro antiviral profile, with enzyme inhibition IC50 levels of 2.2 nM against HCV genotypes 1 and 2 and EC50 values of 0.5–0.8 nM in the context of the replicon system against HCV genotypes 1a and 1b (EASL 2009).

PF-00868554 is a novel NNI of HCV NS5B with potent and selective inhibition of HCV polymerase, which demonstrates an encouraging pharmacokinetic profile in rats and monkeys.[50] In vitro, PF-00868554 displayed potent antiviral activity against genotypes 1a and 1b (EC50 of 0.06 μM) without apparent toxicity. M423T is the primary mutation associated with PF-00868554 resistance, but no cross-resistance to other polymerase inhibitors was identified in replicons containing this mutation.[51] Similar levels of potency have been observed with NNI Phase 1 antiviral ANA598 (Anadys Pharmaceuticals, San Diego, CA, USA). Four days of monotherapy resulted in a 2-log10 decrease in plasma HCV RNA levels. In quadruple combination with IFN-α, telapravir [protease inhibitors (PI)], and PSI-6130 (NI), ANA598 demonstrated a favourable pharmacokinetic and tolerability profile in vivo.[52] IDX375 (Idenix Pharmaceuticals) is a novel preclinical HCV NNI candidate targeting the palm pocket of NS5B polymerase. IDX375 demonstrated strong inhibition of HCV replication (EC50 = 2.3 nM) in the subgenomic replicon system, with no in vitro cytotoxicity in rat, mouse, monkey and human hepatocytes, and no apparent in vivo adverse events in monkeys.[53,54]

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