Elsevier

Journal of Hepatology

Volume 58, Issue 3, March 2013, Pages 445-451
Journal of Hepatology

Research Article
Virologic response and characterisation of HCV genotype 2–6 in patients receiving TMC435 monotherapy (study TMC435-C202)

https://doi.org/10.1016/j.jhep.2012.10.028Get rights and content

Background & Aims

TMC435 is a potent, once-daily, investigational hepatitis C virus (HCV) NS3/4A protease inhibitor in phase III clinical development. In the phase II trial TMC435-C202 (NCT00812331), TMC435 displayed potent activity in genotype 4, 5 and 6 patients and in 3/6 genotype 2 patients, whereas no activity was observed with genotype 3.

Methods

Thirty-seven patients received TMC435 monotherapy (200 mg once daily) for 7 days. HCV RNA, NS3 protease sequences and the corresponding phenotypes were evaluated.

Results

Genotype and isolate-specific baseline polymorphisms at NS3 positions known to affect HCV protease inhibitor activity were present in all genotypes. Consistent with the antiviral activity observed in genotypes 4 and 6, TMC435 was active in vitro against all genotype 4 isolates, and against most genotype 6 polymorphisms when tested as single or double mutants. In contrast, in genotype 3 where no HCV RNA decline was observed, isolates displayed >700-fold increases in EC50 attributed to the D168Q polymorphism. In genotypes 2 and 5, HCV RNA changes from baseline to Day 3 ranged between −0.3 to −3.6 and −1.5 to −4.0 log10 IU/ml, respectively, and isolates or site-directed mutants displayed intermediate in vitro susceptibility to TMC435 with fold changes in EC50 between 15 and 78. Viral breakthrough in genotypes 4–6 was associated with emerging mutations including Q80R, R155K and/or D168E/V.

Conclusions

Sequence and phenotypic analyses of baseline isolates identified polymorphisms which could explain the differences in antiviral activity between genotypes. Pathways of TMC435 resistance in genotypes 2–6 were similar to those identified in genotype 1.

Introduction

An estimated 3% (170 million people) of the global population is infected with hepatitis C virus (HCV), a leading cause of chronic liver disease [1]. At least six major genotypes of HCV have been identified with distinct geographical distributions [2], [3].

Until recently, the standard of care for the treatment of chronic HCV infection consisted of 24–48 weeks of pegylated interferon (PegIFN) and ribavirin (RBV) [4]. Sustained virologic response (SVR, undetectable plasma HCV RNA 24 weeks after end of treatment) with this regimen ranged between 40% and 80% depending upon multiple factors such as HCV genotype, patient IL28B genotype and race.

Novel direct-acting antiviral agents (DAAs) are being developed in combination with PegIFN/RBV or in IFN-free DAA combinations to improve efficacy and shorten treatment duration. Two HCV NS3/4A protease inhibitors (PIs), boceprevir [5], [6] and telaprevir [7], [8] have demonstrated significantly improved SVR rates when given in combination with PegIFN/RBV in genotype 1 patients. Their approval for the treatment of HCV genotype 1 infection has led to expectations of a paradigm shift in the way this disease is managed [9]. However, these new agents require thrice-daily dosing, are associated with more frequent and severe anaemia and rash, and have only been investigated in vivo in a limited number of patients infected with HCV genotypes 2-4 [10], [11], [12].

Improved in vitro replication and infection models have allowed assessment of antiviral activity in non-genotype 1 HCV [11], [13], [14]. Nucleotide inhibitors generally have in vitro activity across genotypes and show promising results in non-genotype 1 patients [15]. Pan-genotypic activity is more difficult to achieve with NS3/4A, NS5A and non-nucleoside NS5B inhibitors due to the sequence variation observed between genotypes and subtypes, occurring in sequences encoding the binding pocket of the respective inhibitors [16]. The first PI to advance to clinical evaluation, BILN2061, demonstrated good antiviral activity against genotype 1 [17] but had little or no activity against genotypes 2 and 3 [18]. Variation at the inhibitor binding pocket residues was prevalent in these genotypes and may explain the reduced activity [19], [20]. Recent clinical studies with telaprevir monotherapy suggested activity in genotype 2, limited activity in genotype 4 and no activity against genotype 3 [10], [12]. In a short monotherapy study with boceprevir, some antiviral activity was demonstrated in patients infected with genotypes 2 and 3 [21].

TMC435 is a potent, investigational HCV NS3/4A PI in phase III clinical development for the treatment of HCV genotypes 1 and 4 infection with a once-daily (QD) 150 mg dose in combination with PegIFN/RBV. Phase I and II trials in patients infected with HCV genotype 1 have demonstrated that TMC435 is a highly potent and efficacious antiviral which is generally well tolerated [22], [23], [24].

A phase IIa, open-label, proof-of-concept study (TMC435-C202; clinicaltrials.gov ID: NCT00812331), assessed antiviral activity, safety, tolerability and pharmacokinetics of TMC435 (200 mg QD for 7 days) in treatment-naïve patients infected with HCV genotypes 2–6 [25]. Here we describe the virologic analysis of this study, including the role of baseline genotype and subtype specific polymorphisms and their effect on virologic response to TMC435, and characterisation of viral variants in patients with viral breakthrough.

Section snippets

Study design and patient population

Thirty-seven treatment-naïve patients, enrolled across Germany, Belgium, and Thailand (genotypes 2 [n = 6], 3 [n = 8], 4 [n = 8], 5 [n = 7], and 6 [n = 8]), received oral TMC435 200 mg QD monotherapy for 7 days. After the TMC435 treatment period, all patients received PegIFN/RBV. The follow-up period was up to Day 42 (35 days after the last TMC435 administration) including two assessments: follow-up 1 (Day 21) and follow-up 2 (Days 37–42). Multiple subtypes were included in cohorts for genotype 2 (2, 2b,

Antiviral activity

Antiviral activity and safety results from this study have been reported previously. TMC435 demonstrated activity against multiple HCV genotypes, except for genotype 3 (Fig. 1) [25]. The greatest reduction in HCV RNA was observed for genotypes 4 and 6, followed by genotype 5. A rapid and substantial decline in HCV RNA was evident for 3/6 genotype 2 patients.

NS3 protease polymorphisms present at baseline

Genotype- and isolate-specific baseline polymorphisms include changes associated with reduced in vitro susceptibility to PIs (Fig. 2) [27].

Discussion

The amino acid sequence diversity of the HCV NS3/4A protease, characteristic for the different HCV genotypes, can affect susceptibility to NS3/4A PIs. There are limited data from clinical studies in which patients infected with non-genotype 1 HCV were treated with HCV NS3/4A PIs. However, there is still a clear medical need for improved treatment options in non-genotype 1 HCV infections, especially for genotypes 4–6 [3], [28].

TMC435 monotherapy showed potent antiviral activity in patients

Conflict of interest

Oliver Lenz, Leen Vijgen, Jan Martin Berke, Bart Fevery, Monika Peeters, and Goedele De Smedt are employees of Janssen Infectious Diseases; Maxwell Cummings and Gaston Picchio are employees of Janssen Research and Development. Oliver Lenz also owns stocks in Janssen. Christophe Moreno has been paid as a speaker or adviser for MSD, Janssen Pharmaceuticals, Inc., Gilead Sciences and Bristol-Myers Squibb. He is an investigator for Novartis, Roche, MSD, Gilead Sciences, Bristol-Myers Squibb,

Acknowledgements

The authors wish to acknowledge the patients and their families, and the investigators. This study was funded by Janssen Research & Development. Editorial support was provided by Philip Matthews and Fiona Boswell of Complete Medical Communications and was funded by Janssen Research & Development. Special thanks to our colleagues from Janssen Research & Development and Virco who contributed to this work.

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