Hepatitis C: Telaprevir and HCV NS3-4A is covalent yet reversible, with a slow-on, slow-off process

A Targeted Approach to Hepatitis C Treatment

Peter Mueller PhD, CSO and EVP of Global R&D; Vertex Pharmaceuticals, Cambridge, Mass.
Drug Discovery & Development -

December 01, 2010

Hepatitis C is a serious liver disease caused by the hepatitis C virus (HCV) that affects approximately 170 million people worldwide.1 Up to 3.9 million Americans may be infected with HCV and 75 percent are unaware of their infection.2,3 Hepatitis C can be cured with drug therapy. However, for people infected with the most common form of HCV in the United States (genotype 1), less than half achieve a sustained viral response (SVR), or viral cure, with current therapies.4-6

Without effective treatment, chronic hepatitis C can cause liver failure, liver cancer, and death.1 The need for more effective therapy for people with genotype 1 hepatitis C has led to research into direct-acting antivirals (DAAs) that target viral replication proteins such as the HCV protease and HCV polymerase.

Vertex Pharmaceuticals used a structure-based drug design approach to identify telaprevir, a novel small molecule DAA.7 Telaprevir inhibits a protease essential for viral replication, HCV NS3-4A. The complex formed between telaprevir and HCV NS3-4A is covalent yet reversible, with a slow-on, slow-off process.7
This potent, selective inhibitor significantly reduced HCV RNA levels (an indicator of reduced viral replication) in both cell culture systems and early-phase clinical trials.7,8

To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir-based therapy as part of Phase 2 and Phase 3 clinical trials. Telaprevir was given in combination with pegylated-interferon and ribavirin for the first 12 weeks of treatment followed by pegylated-interferon and ribavirin alone for either 12 or 36 weeks of additional therapy. Telaprevir has been studied in three Phase 3 trials: ADVANCE, ILLUMINATE, and REALIZE. ADVANCE and ILLUMINATE included patients who had never received treatment for hepatitis C (treatment-naïve), whereas REALIZE included patients who had not achieved SVR, or viral cure, after a prior course of interferon-based treatment (treatment-experienced).9-11 REALIZE was the only Phase 3 study of an investigational DAA designed to evaluate all major subgroups of people whose prior treatment was unsuccessful, including those who had a null response (less than a 2-log10 drop in HCV RNA by week 12 of a prior course of treatment) as defined by the U.S. Food and Drug Administration (FDA).6,11,12

The telaprevir Phase 2 study results were published in the New England Journal of Medicine, and Phase 3 results from ADVANCE and ILLUMINATE were presented at the annual meeting of the American Association for the Study of Liver Diseases in October 2010.9,10,13-15

References
1. World Health Organization. Hepatitis C. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html .
Updated 2002. Accessed August 18, 2010.
2. Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed August 18, 2010.
3. Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed August 18, 2010. This report was commissioned by Vertex Pharmaceuticals.
4. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000;7:196-202.
5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Eng J Med. 2002;347(13):975-982.
6. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: An update. Hepatology. 2009;49(4): 1335-1374.
7. Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50(3):899-909.
8. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131(4):997–1002.
9. Jacobson IM, McHutchison JG, Dusheiko GM et al. Telaprevir in combination with Peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology. 2010;52(Suppl 4): 427A. Abstract 211.
10. Vertex Pharmaceuticals Press Release: Vertex Pharmaceuticals to Start Phase 3 'REALIZE' Trial with Telaprevir in Treatment-Failure HCV Patients, August 19, 2008. Available at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=328603. Accessed on August 25, 2010.
11. Sherman KE, Flamm SL, Afdhal NH, et al. Telaprevir in combination with peginterferon alfa3a and ribavirin for 34 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of the Phase 3 ILLUMINATE study. Hepatology. 2010;52(Suppl 4):401A. Abstract LB-2.
12 United States Food and Drug Administration. Chronic hepatitis C virus infection: developing direct-acting antiviral agents for treatment. http://www.federalregister.gov/articles/2010/09/14/2010-22806/draft-guidance-for-industry-on-chronic-hepatitis-c-virus-infection-developing-directacting-antiviral. Updated September 14, 2010. Accessed September 14, 2010.
13. McHutchison JG, Everson GT, Gordon SC, et al. and the PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. New Eng J Med. 2009;360(18):1827-1838.
14. Hezode C, Forestier N, Dusheiko G, et al. and the PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. New Eng J Med. 2009;360(18):1839-1850.
15. McHutchison JG, Manns MP, Muir AJ, et al. and the PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. New Eng J Med. 2010;362(14):1292-1303.