TMC435 for the treatment of chronic hepatitis<scp>C</scp>

Tanwar, Sudeep; Trembling, Paul M.; Dusheiko, Geoffrey

doi:10.1517/13543784.2012.690392

Cited by 23 publications

(19 citation statements)

References 42 publications

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“…For faldaprevir, genotype 1b mutations encode changes in Asp-168, most frequently to valine (D168V), whereas the most common substitution observed in genotype 1a is Arg-155 to lysine (R155K), with substitutions of Asp-168, usually to valine, more common at higher doses (14). These same substitutions, along with several others, are also frequently observed for simeprevir (15) and are consistent with in vitro resistance studies performed in genotype 1a and 1b replicons (16,17). Both inhibitors are much less active versus these variants, so their emergence renders them much less effective at achievable doses.…”

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confidence: 99%

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

O'Meara

Lemke

Godbout

et al. 2013

Journal of Biological Chemistry

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Background: Antivirals must often be given in combinations to avoid rapid emergence of resistance. Results: We identified and structurally characterized protease inhibitors that maintain potency against genotype and resistant variants. Conclusion: Pan-variant potency was achieved by targeting invariant regions and incorporating flexibility where pocket variability occurs. Significance: Such inhibitors may yield simplified and/or more successful treatments for hepatitis C infections.

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confidence: 99%

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

O'Meara

Lemke

Godbout

et al. 2013

Journal of Biological Chemistry

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“…Although cirrhosis is likely going to lose its negative predictive power as a response moderator once potent anti‐HCV regimens are available, it might nonetheless remain a key determinant of reduced safety with some regimens. Indeed, some drugs have side effects that might be worrisome in patients with cirrhosis, such as increased bilirubin with simeprevir,66 while others (such as ASV) show significant pharmacokinetic modifications in patients with impaired liver function,67 and thus need to be managed with caution in this group of patients. The same safety questions need to be ascertained in post–liver transplantation patients as well as those on the transplant waiting list.…”

Section: Remaining Issuesmentioning

confidence: 99%

New horizons in hepatitis C antiviral therapy with direct-acting antivirals

2013

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Most direct-acting antivirals (DAAs) that are being developed as therapy against hepatitis C virus target the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers different target sites: the catalytic domain for nucleos(t)ide analogues as well as a number of allosteric sites for nonnucleos(t)ide inhibitors. Two NS3/ 4A protease inhibitors have been approved recently, and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development. These agents can achieve very high cure rates when combined with pegylated interferon-a and ribavirin and show promising clinical results when administered in all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small-molecule drug development are emerging, such as p7 or NS4B and viral entry. Future research will need to define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration. (HEPATOLOGY 2013;58:428-438) F or more than a decade, the standard treatment of chronic hepatitis C virus (HCV) infection has been based on the combination of pegylated interferon-a (PEG-IFN) and ribavirin (RBV) administered for 24 or 48 weeks. These regimens eradicate infection in 40% to 50% of treated patients with genotype 1 (HCV-1) infection and 80% of treated patients with genotype 2 (HCV-2) and 3 (HCV-3) infection. In addition, PEG-IFN/RBV regimens are poorly tolerated and contraindicated in a high percentage of patients. In order to address the shortcomings of PEG-IFN/RBV therapy, new direct-acting antivirals (DAAs) are being developed that target specific HCV functions. The recent approval of the first two NS3/4A oral protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TVR), for use in combination with the PEG-IFN/RBV backbone has represented a dramatic advance in the efficacy of pharmacotherapy against chronic hepatitis C. With this new triple therapy regimen, patient cure rates for chronic HCV-1 infection have increased to 70% to 80% while significantly reducing treatment duration. However, these recently approved DAA regimens are poorly tolerated, are associated with a high pill burden and an inconvenient dosing frequency, and are not indicated for genotypes other than HCV-1. Moreover, selection of DAA-resistant viral variants occurs in patients who respond poorly to the PEG-IFN/RBV component of combination therapy. In light of these limitations, newer DAAs are being developed to identify regimens that are more convenient and efficacious, are better tolerated, are pan-genotypic, and have a low propensity to develop viral resistance. These are primarily targeted at the NS3/4A protease, NS5A protein, or NS5B RNA-dependent RNA polymerase. In addition, other less-studied viral proteins (e.g., NS4B or p7) or the virus entry steps have been recently demonstrated t...

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“…Simeprevir (TMC435) is a recently approved inhibitor of the NS3/4A HCV protease . Simeprevir is a macrocyclic, non‐covalent protease inhibitor, unlike boceprevir and telaprevir, which are covalent, ketoamide inhibitors .…”

Section: Future Prospectsmentioning

confidence: 99%

“…These large phase 3 trials are consistent with phase 2 trials of simeprevir‐containing triple therapy and suggest that newer protease inhibitors may be associated with substantial increases in the percentage of patients eligible to stop therapy after 24 weeks compared with the first‐generation agents boceprevir and telaprevir. Simeprevir is also active against a broader set of HCV genotypes, including 2, 4, 5, and 6, although phase 3 trials were not designed to investigate non‐genotype 1 patients . Simeprevir has a number of desirable properties compared with the first‐wave protease inhibitors, including more tolerable adverse events, fewer drug–drug interactions, and once‐daily dosing, which may favorably impact compliance relative to boceprevir (12 pills/day) and telaprevir (6 pills/day) …”

Section: Future Prospectsmentioning

confidence: 99%

“…Simeprevir (TMC435) is a recently approved inhibitor of the NS3/4A HCV protease. 38 Simeprevir is a macrocyclic, non-covalent protease inhibitor, unlike boceprevir and telaprevir, which are covalent, ketoamide inhibitors. 5 US Food and Drug Administration (FDA) approval was based on data from three randomized, placebo-controlled, phase 3 clinical trials of simeprevir-containing triple therapy (with PegIFN/RBV), all of which used RGT.…”

Section: Interferon-containing Regimensmentioning

confidence: 99%

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Response‐guided therapy in patients with genotype 1 hepatitis C virus: Current status and future prospects

Lawitz

Membreno

2014

J of Gastro and Hepatol

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On-treatment responses to antiviral therapy are used to determine duration of therapy in patients being treated for genotype 1 hepatitis C virus infection. Such use of responseguided therapy has successfully reduced exposure of patients to the side-effects of pegylated interferon and ribavirin without jeopardizing overall treatment success. Response-guided therapy is an integral part of treatment using the current standard treatments involving the direct-acting antiviral (DAA) agents-boceprevir or telaprevircombined with pegylated interferon/ribavirin. Improvements in our understanding of the kinetics of viral load during antiviral therapy have shown us that more potent suppression of viral replication increases the rate of viral eradication, providing impetus for the development of more potent DAAs. Emerging results from clinical trials of these agentsincluding trials of interferon-free DAA combinations-suggest that very high rates of viral eradication are achievable, even in patients who failed to respond to previous courses of interferon-based therapy. Furthermore, because of these high rates of treatment success, on-treatment assessment of viral response may become unnecessary. The field of hepatitis C virus therapy is evolving rapidly and current trends indicate that the era of simple treatment regimens with high rates of success and good tolerability are near.Disclosures: The authors received no direct compensation related to the development of the manuscript. Eric Lawitz, MD, has disclosed that he has received research or grant support from

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TMC435 for the treatment of chronic hepatitisC

Abstract: TMC435 is a 'second-wave' protease inhibitor that has the potential to play a pivotal role in the next phase of CHC treatment. The forthcoming results of Phase III trials involving TMC435 are awaited with interest.

Cited by 23 publications

References 42 publications

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance

New horizons in hepatitis C antiviral therapy with direct-acting antivirals

Response‐guided therapy in patients with genotype 1 hepatitis C virus: Current status and future prospects

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