An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Lamarre, Daniel; Anderson, Paul C.; Bailey, Murray; Beaulieu, Pierre L.; Bolger, Gordon T.; Bonneau, Pierre; Bös, Michael; Cameron, Dale R.; Cartier, Mireille; Cordingley, Michael G.; Faucher, Anne‐Marie; Goudreau, Nathalie; Kawai, Stephen H.; Kukolj, George; Lagacé, Lisette; LaPlante, Steven R.; Narjes, H.; Poupart, Marc‐André; Rancourt, James D.; Sentjens, Roel E.; George, Roger St.; Simoneau, Bruno; Steinmann, Gerhard; Thibeault, Diane; Tsantrizos, Youla S.; Weldon, Steven M.; Yong, Chan‐Loi; Llinàs‐Brunet, Montse

doi:10.1038/nature02099

Cited by 870 publications

(550 citation statements)

References 23 publications

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“…Plasma HCV RNA levels were measured using the Roche COBAS TaqMan HCV/HPS assay (Roche, Pleasanton, CA), at a central laboratory, at the time of screening and during the treatment period at days 1 and 4 and weeks 1,2,4,8,10,12,16,20,24,28,36, and 48. The LLOQ was 25 IU/mL, and the LLOD was 17 IU/mL.…”

Section: Efficacy Assessmentsmentioning

confidence: 99%

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143-2154

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Section: Efficacy Assessmentsmentioning

confidence: 99%

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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“…6,7 Several NS3/4 protease protease inhibitors (PIs) have been developed to block this step of the viral life cycle and have been proved, in some cases, to significantly decrease the plasma viral load of infected individuals. [8][9][10][11] Since the first description of HCV, numerous studies have described the HCV variability found in infected individuals. 12,13 The observed HCV heterogeneity, like other RNA viruses, originates from the high rate of incorrect nucleotide substitutions during viral RNA replication (10 Ϫ4 -10 Ϫ5 mutations per nucleotide and per replication cycle) 14 and rapid viral turnover (producing on average 10 12 virions per day in infected individuals).…”

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confidence: 99%

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

Franco¹,

Parera²,

Aparicio³

et al. 2007

Hepatology

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The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. Conclusion: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival. (HEPATOLOGY 2007;45:899-910.)

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“…Several new HCV protease and polymerase inhibitors are under investigation in clinical studies and may become approved in the near future. [46][47][48][49] Kinetic analyses of monotherapy or combination therapy with new drugs that are designed to specifically inhibit viral enzymes with or without interferon can be used to compare efficacy of these new treatments with that of existing interferon-based treatments. A kinetic analysis of the serine protease inhibitor BILN 2061 demonstrated that the effectiveness in blocking viral production was dose-dependent and high compared with interferon-␣.…”

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confidence: 99%

New Kinetic Models for the Hepatitis C Virus *

et al. 2005

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K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

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An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Cited by 870 publications

References 23 publications

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Genetic and catalytic efficiency structure of an HCV protease quasispecies†

New Kinetic Models for the Hepatitis C Virus *

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