Telaprevir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Overview
Telaprevir (INN) is a protease inhibitor being studied as a treatment for hepatitis C.
Telaprevir is currently being marketed as Incivek. It has completed its phase III trials (ADVANCE; A New Direction in HCV Care: A Study of Treatment-naïve Hepatitis C Patients with Telaprevir) in previously untreated patients with genotype 1, the most common strain in North American and Europe It is an orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV serine protease. [1] [2] It was approved by the FDA on May 23rd, 2011 as a hepatitis C virus protease inhibitor, making it the second direct-acting antiviral HCV drug therapy to be approved behind boceprevir. [3] Telaprevir is most successful in patients who have not yet been previously treated for the condition.2
Currently, it is reported by the World Health Organization that 170-180 million people worldwide suffer from the hepatitis C virus (HCV ) and it is considered to be a serious global health crisis. [4] [5] [6] It is the most common blood born infection worldwide.5 Of this population, at least 130 million patients are estimated to be chronic HCV carriers who are at severe risk of developing liver cirrhosis and liver cancer.4, 6 The HCV RNA genome serves as a template for viral replication and as a viral messenger RNA for viral production. It is translated into a polyprotein that is cleaved by proteases, and then viral assembly occurs.4
The previously leading treatment therapy, a regimen of pegylated interferon and ribavirin, was only effective in about 38% - 46% of patients.2[7] [8] It was administered for 24 weeks in patients with genotypes 2 or 3, or for 48 weeks in patients with genotype 1, the most common strain in Europe and North America.2 Fortunately, the recently FDA approved telaprevir is a significant and improved development in the successful treatment of HCV. Telaprevir is a polymerase-inhibiting direct-acting antiviral (DAA) agent that is to be administered to the patients in combination with peginterferon and ribavirin.1 DAA drug agents work to attack the virus directly; they work by different mechanisms of action than previous treatments which indirectly fought the virus by trying to boost the immune system.4, [9] The introduction of this drug has broadened treatment options for patients suffering HCV considerably with the main goal of treatment being the achievement of a sustained virologic response (SVR), defined as an undetectable serum HCV RNA level 24 weeks after cessation of therapy.2 The achievement of SVR means that the virus has been eradicated and will further complications such as cirrhosis and hepatocellular carcinoma (HCC) are prevented.1,4
Serine protease inhibitors such as telaprevir used in the treatment of HCV for post-translational processing and the inhibition viral replication. It is most successful when given in combination with peginterferon and ribavirin at achieving sustained virologic responses in most patients who have genotype 1. However, when used as monotherapy, without the combination of the other standard drugs, the body quickly develops resistance.6
Category
Antiviral
US Brand Names
INCIVEK®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages
Mechanism of Action
Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM.
References
- ↑ Poordad F (February 2011). "Big Changes Are Coming in Hepatitis C ". Curr Gastroenterol Rep. 13 (1): 72-7. PMCID: PMC3026711. doi: 10.1007/s11894-010-0153-9.<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026711/?tool=pubmed>
- ↑ McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ. (April 2009). "Telaprevir with Peginterferon and Ribavirin for Chronic HCV Genotype 1 Infection". N Engl J Med. 360 (18): 1827-38. <http://www.nejm.org/doi/full/10.1056/nejmoa0806104#t=citedby>
- ↑ Klein R, Struble K. (May 2011). "Approval of Incivek (telaprevir), a direct acting antiviral drug (DAA) to treat hepatitis C (HCV)". U.S. Food and Drug Administration. <http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm256328.htm>
- ↑ Walker EP, (May 2011). "Boceprevir Wins FDA Approval to Treat Hepatitis C". MedPage Today.<http://www.medpagetoday.com/InfectiousDisease/Hepatitis/26469>
- ↑ Njoroge FG, Chen KX, Shih NY, Piwinski JJ (January 2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Acc. Chem. Res. 41 (1): 50–9.
- ↑ Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, Hughes E, Ralston R, Tong X, Herrmann E, Zeuzem S, Sarrazin C. (December 2009). "Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus–infected patients". Hepatology. 50 (6): 1709-18. DOI: 10.1002/hep.23192 <http://onlinelibrary.wiley.com/doi/10.1002/hep.23192/full>
- ↑ Asselah T, Marcellin P. (January 2011). "New direct-acting antivirals' combination for the treatment of chronic hepatitis C". Liver International. 31 (s1): 68-77. DOI: 10.1111/j.1478-3231.2010.02411.x <http://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2010.02411.x/abstract>
- ↑ Kwo PY, Vinayek R. (November 2011). "The Therapeutic Approaches for Hepatitis C Virus: Protease Inhibitors and Polymerase Inhibitors". Gut Liver. 5 (4): 406-17. doi: 10.5009/gnl.2011.5.4.406 PMCID: PMC3240782 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240782/?tool=pubmed>
- ↑ Adiwijaya BS, Kieffer TL, Henshaw J, Eisenhauer K, Kimko H, Alam JJ, Kauffman RS, Garg V. (January 2012). "A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection". PLoS Comput Biol. 8 (1): 1-11. PMCID: PMC3252270 doi: 10.1371/journal.pcbi.1002339 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252270/?tool=pubmed>