Emerging therapies in pipeline for chronic hepatitis C

Navjot Kaur, Harish Negi, Avaneesh Pandey

Abstract


Hepatitis C infection represents a major global public health problem; as it leads to significant morbidity, mortality, and financial burden on healthcare system. According to world health organization, nearly 2- 3% (130-170 million) of the world’s population has been infected with hepatitis C. The current standard therapy is limited both in efficacy and tolerability which highlights the large unmet medical need in this area. Recent advances in the understanding of lifecycle of hepatitis C virus and host cell interactions have led to the identification of multiple novel antiviral targets. Intense research effort is currently being directed towards translating these targets into developing more efficacious and safe treatment options for patients living with HCV infection. Current review aims to discuss the emerging therapies in pipeline for chronic hepatitis C outlining their mode of action and current stage of development in clinical trials.


Keywords


Cyclophillin inhibitors, Direct acting antivirals, Hepatitis C, Novel targets, Sofosbuvir

Full Text:

PDF

References


Holmberg S. Infectious Diseases Related To Travel, 2011. Available at: http://wwwnc.cdc.gov/travel/ yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c. Accessed 15 April 2013.

World Health Organization Hepatitis C Fact Sheet 2012 Available at: http://www.who.int/ mediacentre/factsheets/fs164/en/. Accessed 14 April 2013.

Chung RT. A watershed moment in the treatment of hepatitis C. N Engl J Med 2012;366:273-5.

Lavanchy D. The global burden of hepatitis C. Liver Int 2009;29:74-81.

Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006;45: 529-38.

Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17: 107-15.

Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004;40: 993-99.

Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: 975-82.

Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: Efficacy, side effects and complications. Gut 2006;55: 1350-9.

Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology 2002;36(1): 237-44.

Bruno S, Crosignani A, Facciotto C, Rossi S, Roffi L, Redaelli A et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12- year prospective follow-up study. Hepatology 2010;51: 2069-76.

Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P et al. Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140: 346-55.

Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358: 958-65.

Ramachandran P, Fraser A, Agarwal K, Austin A, Brown A, Foster GR et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012;35: 647-62.

Shiffman ML, Esteban R. Triple therapy for HCV genotype 1 infection: telaprevir or boceprevir? Liver Int 2012;32: 54-60.

PoordadF, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364: 1195–06.

Hezode C, Dorival C, Zoulim F. Safety of telaprevir or boceprevir in combination with peginterferonalfa/ ribavirin, in cirrhotic non responders. First results of the French Early Access Program (ANRS CO20-CUPIC). J Hepatol 2012; 56:A8.

Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol 2012;11: 179-85.

Lee LY, Tong CY, Wong T, Wilkinson M. New therapies for chronic hepatitis C infection: a systematic review of evidence from clinical trials. Int J Clin Pract 2012;66: 342-55.

Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996; 87: 343-55.

Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Reesink HW, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007;46: 631-9.

Christian M. Lange, Stefan Zeuzem. Perspectives and challenges of interferon-free therapy for chronic hepatitis C. J Hepatology2013;58: 583-92.

Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010;138: 447-62

Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012;56: 4161-7.

deBruijne J, Bergmann JF, Reesink HW, Weegink CJ, Molenkamp R, Schinkel J et al. Antiviral activity of narlaprevir combined with ritonavir and pegylated interferon in chronic hepatitis C patients. Hepatology 2010;52: 1590-9.

Manns MP, Bourliere M, Benhamou Y, Pol S, Bonacini M, Trepo C, et al. Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitorBI201335 in patients with chronic HCV genotype-1 infection. J Hepatol 2011;54: 1114-22.

Forestier N, Larrey D, Guyader D. Treatment of chronic hepatitis C Patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. J Hepatol 2011;54: 1130-6.

TMC435-TiDP16-C208 – phase III trial of TMC435 in treatment-naive, genotype 1 hepatitis C-infected patients (QUEST-1), 2011. Available at:http:// clinicaltrials.gov/show/NCT01289782. Accessed 21 April 2013.

TMC435-TiDP16-C216 – phase III trial of TMC435 in treatment-naive, genotype 1 hepatitic C-infected patients (QUEST-2), 2011. Available at:http:// clinicaltrials.gov/ct2/show/NCT01290679. Accessed 21 April 2013.

TMC435HPC3007- Phase III trial of TMC435 in genotype 1 Hepatitis C- infected patients who relapsed after previous therapy (PROMISE), 2011. Available at: http://clinicaltrials.gov/ ct2/show/NCT01281839. Accessed 21 April 2013.

A pharmacokinetics/pharmacodynamics study of SCH 900518 in previously untreated subjects with chronic hepatitis C (NEXT-1). Available at:http://www.clinicaltrials.gov/ct2/show/NCT00797745?term=ritonavir+and+narlaprevir&rank=1. Accessed 30 April 2013.

A study of danoprevir/ritonavir and copegus with RO5024048 and/or pegasys with patients with chronic hepatiis C. Available at:http://www.clinicaltrials.gov/ct2/results?term=ritonavir+and+danoprevir+in+HCV&Search=Search. Accessed 25 May 2013.

Lohmann V. Hepatitis C virus RNA replication. Curr Top Microbiol Immunol 2013;369: 167-98.

Legrand-Abravanel F, Nicot F, Izopet J. New NS5B polymerase inhibitors for hepatitis C. Expert Opin Investig Drugs 2010;19: 963-75.

Lange CM, Sarrazin C, Zeuzem S. Review article: specifically targeted antiviral therapy for hepatitis C – a new era in therapy. Aliment Pharmacol Ther 2010;32: 14-28.

Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med 2013;368: 1878-87.

Jacobson IM, Gordon SC, Kowdley KV, Yoshida E M, Rodriguez-Torres M, Sulkowski MS et al. Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options. N Engl J Med 2013; 368:1867-77.

Pockros PJ, Jensen D, Tsai N, Taylor R, Ramji A, Cooper C, et al. JUMP-C: A randomized trial of mericitabine plus peginterferon alfa-2a/ribavirin for 24 weeks in treatment-naive HCV genotype 1/4 patients. Hepatology 2013 Jan 24. [Epub ahead of print] doi: 10.1002/hep.26275.

Aghemo A, De Francesco R. New horizons in Hepatitis C antiviral therapy with direct-acting antivirals. Hepatology. 2013 Mar 6. [Epub ahead of print] doi: 10.1002/hep.26371.

Wagner F, Thompson R, Kantaridis C, Simpson P, Troke PJ, Jagannatha S, et al. Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients. Hepatology 2011;54: 50-9.

Pockros PJ. Drugs in development for chronic hepatitis C: a promising future. Expert Opin Biol Ther 2011;11: 1611-22.

Larrey D, Lohse AW, de Ledinghen V, Trepo C, Gerlach T, Zarski JP et al. Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin. J Hepatol 2012; 57:39-46.

Macdonald A, Harris M. Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 2004;85: 2485-502.

Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5:453-63.

Suk-Fong Lok A. HCV NS5A inhibitors in development. Clin Liver Dis 2013;17: 111-21.

Pawlotsky JM. NS5A Inhibitors in the Treatment of Hepatitis C. J Hepatol 2013 Apr 5. [Epub ahead of print] doi: 10.1016/j.jhep.2013.03.030.

Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose finding, phase 2a trial. Lancet Infect Dis 2012;12: 671-77.

Vermehren J, Sarrazin C. New hepatitis C therapies in clinical development. Eur J Med Res 2011;16: 303-14

Gallay PA, Lin Kai. Profile of alisporivir and its potential in the treatment of hepatitis C. Drug Des Devel Ther 2013;7: 105-15.

Flisiak R, Pawlotsky J, Crabbé R, Calistru PI, Kryczka W, Haussinger D et al. Once daily alisporivir (Deb025) plus PEGIFNalfa2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naïve patients. J Hepatol 2011; 54:S2.

Pawlotsky JM, Sarin SK, Foster G, Peng CY, Rasenack J, Flisiak R et al. Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-G2 or G3 patients: SVR12 results from VITAL-1 phase 2b study. J Hepatol 2012; 56:S553.

Keller DM. Pancreatitis events halt development of alisporivir for HCV, 2012. Available at:http://www. medscape.com/viewarticle/762399. Accessed 2 May 2013.

Hopkins S, Di Massimo B, Rusnak P, Heuman D, Lalezari J, Sluder A et al. The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection. J Hepatol 2012;57: 47-54.

Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by liver-specific MicroRNA. Science 2005;309(5740): 1577-81.

Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010;327(5962): 198-01.

Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013;368: 1685-94.

Hunyady B, Kovács B, Battyáni Z. Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection. Orv Hetil 2011;152: 1997-09.

Kramer JR, Kanwal F, Richardson P, Mei M, El-Serag HB. Gaps in the achievement of effectiveness of HCV treatment in national VA practice. J Hepatol 2012;56: 320-5.

Shields WW, Pockros PJ. Ribavirin Analogs. Clin Liver Dis 2009;13: 419-27.

Pockros PJ. New Direct-acting Antivirals in the Development for Hepatitis C Virus Infection. Ther Adv Gastroenterol 2010;3: 191-02.

Poordad F, Lawitz E, Shiffman ML, Hassanein T, Muir AJ, Bacon BR, et al. Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C. Hepatology 2010;52: 1208-15.

Jansen PL, De Bruijne J. Controlled-release interferon alpha 2b, a new member of the interferon family for the treatment of chronic hepatitis C. Expert Opin Investig Drugs 2012;21: 111-8.

Dzyublyk I, Yegorova T, Moroz L, Popovych O, Zaytsev I, Miroshnichenko V, et al. Controlled release recombinant human interferon-α2b for treating patients with chronic hepatitis C genotype 1: a phase 2a clinical trial. J Viral Hepat 2011;18: 271-9.

Friborg J, Levine S, Chen C, Sheaffer AK, Chaniewski S, Voss S, et al. Combinations of lambda interferon with direct-acting antiviral agents are highly efficient in suppressing hepatitis C virus replication. Antimicrob Agents Chemother 2013;57: 1312-22.

Zeuzem S, Sulkowski MS, Lawitz EJ, Rustgi VK, Rodriguez-Torres M, Bacon BR, et al. Albinterferon alfa-2b was not inferior to pegylated interferon-alpha in a randomized trial of patients with chronic hepatitis C virus genotype 1. Gastroenterology 2010;139:1257-66.

Nelson DR, Benhamou Y, Chuang WL, Lawitz EJ, Rodriguez-Torres M, Flisiak R et al. Albinterferon alfa-2b was not inferior to pegylated interferon-alpha in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3. Gastroenterology 2010;139:1267-76.