Rapid Viral Response of Once-Daily Tmc435 plus Pegylated Interferon/Ribavirin in Hepatitis C Genotype-1 Patients: A Randomized Trial

Manns, Michael P.; Reesink, H. W.; Berg, Thomas; Dusheiko, Geoffrey; Flisiak, Robert; Marcellin, Patrick; Moreno, Christophe; Lenz, Oliver; Meyvisch, Paul; Peeters, Monika; Sekar, Vanitha; Simmen, Kenneth; Verloes, René

doi:10.3851/imp1894

Cited by 62 publications

(49 citation statements)

References 18 publications

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“…A 200 mg dose was selected as this was the highest dose which was previously administered to patients infected with HCV genotype 1 in the TMC435-C201 trial [35], had previously exhibited a good safety and tolerability profile, and had also maximised the potential for antiviral activity across all genotypes.…”

Section: Methodsmentioning

confidence: 99%

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Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

Moreno

Berg

Tanwandee

et al. 2012

Journal of Hepatology

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Section: Methodsmentioning

confidence: 99%

“…Phase I and II trials in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily (q.d.) dosing, and demonstrates potent antiviral activity and efficacy [33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

Moreno

Berg

Tanwandee

et al. 2012

Journal of Hepatology

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“…The main side effect of RBV is hemolytic anemia, which increases the heme load, resulting in usually mild, indirect hyperbilirubinemia that is isolated (i.e., with no other clinical symptoms indicative of liver injury) (Korenblat and Berk, 2005;McHutchison et al, 2009;Perico et al, 2009). Hyperbilirubinemia or anemia has been reported during trials of a number of other HCV protease inhibitors currently approved or in clinical development, such as telaprevir (Zeuzem et al, 2011), asunaprevir (Suzuki et al, 2013), daclatasvir (Suzuki et al, 2013), simeprevir (Manns et al, 2011b), and ABT-450 (paritaprevir; AbbVie, Chicago, IL; Poordad et al, 2013). Second-wave direct-acting antivirals, including simeprevir, sofosbuvir, and faldaprevir, demonstrate better efficacy over a shorter treatment duration and improved safety profiles, compared with earlier directacting antivirals (Asselah and Marcellin, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

Sane

Steinmann

Huang

et al. 2014

J Pharmacol Exp Ther

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Faldaprevir, an investigational agent for hepatitis C virus treatment, is well tolerated but associated with rapidly reversible, dosedependent, clinically benign, unconjugated hyperbilirubinemia. Multidisciplinary preclinical and clinical studies were used to characterize mechanisms underlying this hyperbilirubinemia. In vitro, faldaprevir inhibited key processes involved in bilirubin clearance: UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1) (IC 50 0.45 mM), which conjugates bilirubin, and hepatic uptake and efflux transporters, organic anion-transporting polypeptide (OATP) 1B1 (IC 50 0.57 mM), OATP1B3 (IC 50 0.18 mM), and multidrug resistanceassociated protein (MRP) 2 (IC 50 6.2 mM), which transport bilirubin and its conjugates. In rat and human hepatocytes, uptake and biliary excretion of [ 3 H]bilirubin and/or its glucuronides decreased on coincubation with faldaprevir. In monkeys, faldaprevir ($20 mg/kg per day) caused reversible unconjugated hyperbilirubinemia, without hemolysis or hepatotoxicity. In clinical studies, faldaprevir-mediated hyperbilirubinemia was predominantly unconjugated, and levels of unconjugated bilirubin correlated with the UGT1A1*28 genotype. The reversible and dose-dependent nature of the clinical hyperbilirubinemia was consistent with competitive inhibition of bilirubin clearance by faldaprevir, and was not associated with liver toxicity or other adverse events. Overall, the reversible, unconjugated hyperbilirubinemia associated with faldaprevir may predominantly result from inhibition of bilirubin conjugation by UGT1A1, with inhibition of hepatic uptake of bilirubin also potentially playing a role. Since OATP1B1/1B3 are known to be involved in hepatic uptake of circulating bilirubin glucuronides, inhibition of OATP1B1/1B3 and MRP2 may underlie isolated increases in conjugated bilirubin. As such, faldaprevirmediated hyperbilirubinemia is not associated with any liver injury or toxicity, and is considered to result from decreased bilirubin elimination due to a drug-bilirubin interaction.

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“…Isolates collected pretreatment, at the time of failure, at the end of the study, and/or at other time points during the study of HCV genotype 1-infected patients naive to HCV NS3/4A protease inhibitors who received simeprevir alone (clinical studies TMC435-C101 [13] and -C201 [14]) or who were treated with simeprevir in combination with PegIFN/RBV (clinical studies TMC-C201, -C205 [15], -C206 [16], -C208 [3], -C216 [2], and HPC3007 [4]) were selected for phenotypic analysis. In addition, 4 pretreatment isolates from 4 patients enrolled in the placebo arm of clinical study TMC435-C201 were analyzed.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Activity of Simeprevir against Hepatitis C Virus Genotype 1 Clinical Isolates and Its Correlation with NS3 Sequence and Site-Directed Mutants

Verbinnen

Fevery

Vijgen

et al. 2015

Antimicrob Agents Chemother

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b Simeprevir (TMC435) is a once-daily, single-pill, oral hepatitis C virus (HCV) NS3 protease inhibitor approved for the treatment of chronic HCV infection. Phenotypic characterization of baseline isolates and isolates from HCV genotype 1-infected patients failing with a simeprevir-based regimen was performed using chimeric replicons carrying patient-derived NS3 protease sequences. Cutoff values differentiating between full susceptibility to simeprevir (<2.0-fold reduction in simeprevir activity) and low-level versus high-level resistance (>50-fold reduction in simeprevir activity) were determined. The median simeprevir fold change in the 50% effective concentration (FC) of pretreatment genotype 1a isolates, with and without Q80K, and genotype 1b isolates was 11, 0.9, and 0.4, respectively. Naturally occurring NS3 polymorphisms that reduced simeprevir activity, other than Q80K, were uncommon in the simeprevir studies and generally conferred low-level resistance in vitro. Although the proportion of patients with failure differed by HCV geno/subtype and/or presence of baseline Q80K, the level of simeprevir resistance observed at failure was similarly high irrespective of type of failure, HCV genotype 1 subtype, and presence or absence of baseline Q80K. At the end of the study, simeprevir activity against isolates that lost the emerging amino acid substitution returned to pretreatment values. Activity of simeprevir against clinical isolates and site-directed mutant replicons harboring the corresponding single or double amino acid substitutions correlated well, showing that simeprevir resistance can be attributed to these substitutions. In conclusion, pretreatment NS3 isolates were generally fully susceptible (FC, <2.0) or conferred low-level resistance to simeprevir in vitro (FC, >2.0 and <50). Treatment failure with a simeprevir-based regimen was associated with emergence of high-level-resistance variants (FC, >50). C urrently, multiple direct-acting antiviral agents (DAAs) with different mechanisms of action are approved, and this has revolutionized the treatment of chronic hepatitis C virus (HCV) infection (1). Simeprevir (TMC435) is a one-pill, once-daily, oral HCV NS3/4A protease inhibitor approved for the treatment of chronic hepatitis C infection. In clinical studies, simeprevir 150 mg in combination with peginterferon and ribavirin (PegIFN/ RBV) significantly improved sustained virologic response (SVR) rates in treatment-naive and treatment-experienced patients with chronic HCV genotype 1 infection versus PegIFN/RBV alone and enabled a shorter, 24-week overall treatment duration in treatment-naive patients and prior relapsers (2-4). Simeprevir in combination with sofosbuvir given for 12 or 24 weeks with or without RBV resulted in high SVR rates in traditionally difficult-to-cure HCV genotype 1-infected patients (5).The HCV NS5B polymerase has low fidelity, which, combined with the high replication rate of the virus, results in high genetic variability (6). Naturally occurring variants with DAA-resistant ami...

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Rapid Viral Response of Once-Daily Tmc435 plus Pegylated Interferon/Ribavirin in Hepatitis C Genotype-1 Patients: A Randomized Trial

Abstract: Once-daily TMC435 with P/R showed potent, dose-dependent antiviral activity over 28 days, and had a favourable tolerability profile.

Cited by 62 publications

References 18 publications

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

In Vitro Activity of Simeprevir against Hepatitis C Virus Genotype 1 Clinical Isolates and Its Correlation with NS3 Sequence and Site-Directed Mutants

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