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eCommons@AKU Department of Biological & Biomedical Sciences Medical College, Pakistan December 2009 Hepatitis C therapy-the future looks bright Sohail A. Qureshi Aga Khan University Humaira Qureshi Aga Khan University Anam Hameed Aga Khan University Follow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_bbs Part of the Cellular and Molecular Physiology Commons Recommended Citation Qureshi, S., Qureshi, H., Hameed, A. (2009). Hepatitis C therapy-the future looks bright. European Journal of Clinical Microbiology & Infectious Diseases, 28(12), 1409-1413. Available at: http://ecommons.aku.edu/pakistan_fhs_mc_bbs/84 Eur J Clin Microbiol Infect Dis (2009) 28:1409–1413 DOI 10.1007/s10096-009-0798-1 REVIEW Hepatitis C therapy—the future looks bright Sohail A. Qureshi & Humaira Qureshi & Anam Hameed Received: 4 February 2009 / Accepted: 24 July 2009 / Published online: 29 August 2009 # Springer-Verlag 2009 Abstract Hepatitis C virus (HCV) infections affect about 170 million individuals worldwide and can be lifethreatening if left untreated. Over the past three decades, ribavirin and interferon-α have remained the only available medicines for treating hepatitis C sufferers. Given that this combination therapy is partially effective at best and is associated with severe side-effects, there is an unmet need for new molecular entities which inhibit HCV replication. By employing a combination of structurebased drug design together with high-throughput screening approaches, several pharmaceutical companies have been successful in identifying potentially useful compounds for treating HCV infections. This article provides an overview of some of the small-molecule inhibitors that have shown promise so far in clinical trials and which could reach the clinic within the next three years. Introduction Hepatitis C is the most common chronic blood-borne infectious disease that is caused by the hepatitis C virus (HCV). The most common mode of HCV transmission is through blood transfusions, hemodialysis, and organ transS. A. Qureshi (*) : H. Qureshi Department of Biological & Biomedical Sciences, The Aga Khan University Hospital, Stadium Road, Karachi 74800, Pakistan e-mail: [email protected] A. Hameed Medical College, The Aga Khan University Hospital, Stadium Road, Karachi 74800, Pakistan plants, but the sharing of used needles, razor blades, and the use of tattooing guns have also contributed significantly to virus spread. Although HCV is present in semen, vaginal fluid, and saliva, the risk of viral transmission from an infected individual to a non-infected spouse or partner without the use of condoms over a lifetime is only about 1– 4%. Once in circulation, HCV selectively targets the CD81 and its co-receptor Claudin-1-expressing hepatocytes and its entry triggers an innate response in infected cells which promotes interferon (IFN)-α and β synthesis, both of which act in an autocrine manner to produce a nonpermissive milieu for virus replication [1]. The acute phase of infection is mostly asymptomatic and, hence, difficult to detect, but a small number of patients, however, experience decreased appetite, fatigue, abdominal pain, jaundice, itching, and flulike symptoms. It is estimated that about one-fifth of the infected individuals are able to ward off infection completely without relying on any medication, whereas the rest (∼80%) go on to develop chronic infections which threaten liver failure. A small percentage of chronically infected individuals develop hepatocellular carcinoma. The disease progression of hepatitis C is influenced by numerous factors, which include age, gender, alcohol consumption, HIV infection, and fatty liver. A member of the Flaviviridae family, HCV is approximately 50 nm in diameter and contains a cap-less 9-kb positive-strand RNA genome that encodes 11 proteins. Two untranslated regions located at the extreme 5′ and 3′ ends play important roles in the translation and replication of viral RNA. The 5′ UTR harbors an internal ribosome binding site (IRES), from which protein synthesis begins. Translation of the continuous open reading frame culminates in a ∼3,000 amino acid polyprotein, which is subsequently processed by cellular as well as two HCVencoded proteases to yield functional proteins. 1410 HCV genome encodes for 11 proteins: core, F, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Core encodes the viral encapsulating capsid protein, as well as an F protein (or alternatively reading frame protein; AFRP) of unknown function that is produced by ribosomal translational frame-shifting. E1 and E2 are envelope glycoproteins capable of forming heterodimers with each other. p7 is a 63-amino acid transmembrane polypeptide that exhibits properties of an ion channel. NS2 and NS3 are cysteine and serine proteases, respectively. As a GTPbinding membrane protein localized to the ER, NS4B has been found to be crucial for HCV replication. NS5A is a phosphoprotein of unknown function. RNA-dependent RNA polymerase is the product of the NS5B gene. The core-E1-E2-p7-NS2 segment of the polyprotein is processed by host cell proteases. NS2 catalyzes the NS2-NS3 junction, whereas NS3-NS4A processes the rest of the polyprotein [2]. Viral replication involves the synthesis of the negative strand first, which is subsequently employed as a template to polymerize multiple copies of the positive-stranded HCV genome. It is the poor fidelity associated with NS5B which accelerates viral evolution and leads to the production of viral quasi-species. Six major genotypes and a number of subtypes of HCV have been identified so far. Current treatment regimens Standard therapy for patients with acute or chronic hepatitis C is comprised of a combination of a weekly injection of pegylated IFN-α and twice-a-day oral administration of ribavirin. Initially, unmodified IFN-α was used, but it had a short half-life in systemic circulation and, therefore, poor pharmacokinetic properties. The new generation of polyethylene glycol (PEG) modified IFN-α, such as Peg-Intron (Schering-Plough, Kenilworth, NJ) and Pegasys (HoffmanLa Roche, Nutley, NJ) are longer lasting and produce a significantly more efficacious antiviral response than the unmodified protein. Pegasys has been found to be effective for treating Peg-Intron non-responders [3]. The two-component combination therapy is significantly more effective as compared to IFN-α monotherapy. The mechanism by which ribavirin acts remains elusive, but it is thought to act either directly by becoming incorporated into newly synthesized HCV RNA, causing premature chain termination, or indirectly by inhibiting the inosine monophosphate dehydrogenase (IMPDH) activity. It remains unclear as to why different HCV genotypes respond differently to combination therapy. For example, approximately 40% of people with genotype 1 have a sustained response with peginterferon and ribavirin. In comparison, patients with genotypes 2 and 3 are significantly more Eur J Clin Microbiol Infect Dis (2009) 28:1409–1413 responsive to standard therapy. The recommended treatment time is also dependent on the HCV genotype. For patients with genotypes 2 and 3, a 24-week course of combination treatment is adequate, whereas for those carrying genotype 1, a 48-week course is recommended. The approximate cost of 48-week therapy is US $35,000. The standard therapy is contraindicated during pregnancy and is associated with adverse effects, including depression, fatigue, and flu-like symptoms caused by IFN-α and hemolytic anemia promoted by ribavirin. Taribavirin (Valeant Pharmaceuticals), a prodrug of ribavirin, as well as advanced versions of IFN-α such as the longer-acting Albuferon (Human Genome Sciences) and controlled-release Locteron (Biolex), are presently undergoing late-stage clinical trials. Given the severe side-effects associated with the current therapy, together with the fact that about one-half of hepatitis C sufferers do not respond to it, there is an unmet need for small-molecule drugs with minimal side-effects that inhibit HCV replication to be brought to market. Targets for therapeutic intervention From the 11 different HCV-encoded proteins, NS3 serine protease and NS5B RNA-dependent RNA polymerase (RdRP) have emerged as the best targets for drug development. NS3 has two important functions: it dampens the host cell innate response by degrading retinoic acid inducible gene-1 (RIG-1), as well as the TLR3 (Toll-like receptor) adaptor proteins Cardiff and TRIF (TLR3-interacting factor), and is required for the processing of polyprotein. The inhibition of NS3 catalytic activity should, therefore, launch a powerful two-pronged attack against the virus that is expected to rejuvenate the innate response in infected cells, as well as promote the accumulation of unprocessed and, hence, dysfunctional viral proteins incapable of replicating HCV. Similarly, debilitating the activity of NS5B will attenuate viral replication. The IRES region within the 5′ UTR also serves as a useful target for intervention, but the intracellular delivery of nucleic acids >500 Da in size that are complimentary to this region across the cell membrane continues to pose a serious technical hurdle. Cellular proteins and nucleic acids that facilitate viral replication, such as cyclophilin and microRNA-122 (miR-122), are also attractive targets for drug development against HCV. High-throughput screening and structure-based drug design approaches have been used to identify several small molecules that specifically target the serine protease and RdRP. A number of these compounds are in clinical trials, but we discuss only those entities that have shown promise (Table 1). Eur J Clin Microbiol Infect Dis (2009) 28:1409–1413 1411 RNA-dependent RNA polymerase inhibitors Over the past decade, a number of putative RdRP inhibitors have entered the clinical pipelines of various companies, but their development had to be aborted due to the lack of efficacy or toxicity or the establishment of adaptive mutations in the NS5B gene. At present, R1626 (Roche) is the most promising oral RdRP inhibitor that is in phase II clinical trials. R1626 has a good safety profile and has shown a profound antiviral effect when combined with standard therapy. The results from a trial conducted earlier in 2008 found that 84% of HCV genotype 1-infected patients responded positively to 4 weeks of R1626, Pegasys, and ribavirin triple therapy, followed by 44 weeks of standard therapy. Even at high doses, R1626 does not appear to promote any adaptive mutations in the HCV quasispecies [4, 5]. As an oral cytidine nucleoside analog, R7128 (Pharmasset/ Roche) has shown a superior profile over R1626 in terms of both reduced toxicity and efficacy. Data from phase I clinical trials have revealed that, when treatment-naïve chronically infected HCV genotype 1 subjects were coadministered R7128 (1,500 mg twice-daily) together with Pegasus and ribavirin over a 4-week period, HCV RNA was undetectable in almost 85% of the patients, demonstrating that R7128 is a potent inhibitor of HCV replication. Moreover, preliminary results from another phase 1 study have shown that 4 weeks of the above triple therapy is also effective in treating patients infected with HCV genotypes 2 and 3, demonstrating that R7128 possesses significant antiviral activity against a broad spectrum of HCV variants. The emergence of R7128induced resistance mutations in the HCV genome has not been observed [6]. MK0608 (Merck) is another nucleoside inhibitor that is presently in phase I trials [7]. Development of the non-nucleoside RdRP inhibitor PF 868,544 (Pfizer; phase II) is also underway. This compound inhibits the enzymatic activity by binding to an allosteric site away from the catalytic site and has an in vitro EC50 of 59 nM against HCV genotype 1. How well it performs in patients who are not responsive to standard therapy or those who have relapsed remains to be assessed [8]. Serine protease inhibitors The development of potent NS3-4A inhibitors has been a challenge. Initial efforts to identify useful lead compounds by screening sensitive biochemical assays against a large library of compounds did not culminate in much success. Moreover, resolving the three-dimensional structure of the enzyme also did not offer much hope to medicinal chemists because the substrate-binding region of protease was solvent-exposed, shallow, and did not contain any exploitable binding pockets. These issues notwithstanding, several promising NS3-4A inhibitors have been identified and their therapeutic utility is currently being evaluated. The most advanced inhibitor of the serine protease is Telaprevir (VX-950; Vertex Pharmaceuticals/Johnson & Johnson), a peptidomimetic compound harboring an αketoamide group optimized to form a reversible covalent bond with the catalytic serine 139. Telaprevir can be taken orally and has produced impressive results so far in clinical trials for treating genotype 1-infected patients who have failed prior therapy. Having successfully undergone phase I and II clinical trials, it is currently in phase III clinical evaluation. Interim results from phase II (PROVE 3) Table 1 Anti-hepatitis C virus (HCV) drugs in the pipeline Drug Company Phase Target R1626 R7128 MK0608 PF868544 Roche Pharmasset/Roche Merck Pfizer II I I II NS5B NS5B NS5B NS5B Telaprevir (VX-950) Vertex Pharma/ Johnson Schering-Plough III Schering-Plough II TMC435350 Tibotec Medivir II ITMN-191 InterMune/Roche I NS-3 (serine protease) NS-3 (serine protease) NS-3 (serine protease) NS-3 (serine protease) NS-3 (serine protease) Boceprevir (SCH503034) SCH900518 *Experimental dose II (RdRP) (RdRP) (RdRP) (RdRP) Genotype Dosage* Route 1 1, 2, 3 1,2 1 Oral Oral Oral Oral 1, 2 (also 3) 1,500–3,000 mg BID 1,500 mg BID 1 mg/kg 100–450 mg BID or 300 mg TID 750 mg/8 h 1 800 mg TID Oral 1 200–600 mg QD Oral 1, 2, 4, 5, 6 (also 3) 1 25–400 mg daily Oral 900 mg BID Oral Oral 1412 clinical trials have indicated that, when genotype 1-infected standard therapy non-responders and relapsers were administered Telaprevir plus pegylated interferon and ribavirin for 12 weeks followed by another 12 weeks of Pegasys and ribavirin only, 41% (27 of 66) and 73% (29 of 40) of patients showed an absence of HCV RNA 12 weeks post-treatment (SVR12), respectively. Telaprevir has also demonstrated potent reduction of HCV RNA following 14 or 28 days of therapy, prompting Vertex to assess the ability of Telaprevir to shorten treatment duration to 12 weeks [9]. The binding of Telaprevir to genotype 1a NS3-4A is a slow-on, slow-off process (half life ∼1 h), with a steadystate inhibition constant (Ki) of 7 nM. In comparison, Telaprevir binding to genotypes 2a and 3a serine proteases yields inhibition constants of 30–50 nM and 300 nM, respectively, indicating that the drug’s potency against each of these enzymes is reduced by 4–7-fold and 40-fold, respectively [10]. Boceprevir (SCH-503034; Schering-Plough) is another oral ketoamide inhibitor of serine protease found to prevent HCV polyprotein maturation and HCV replication. Its binding leads to adduct formation between the carbonyl carbon of its ketoamide group and serine-139 located in the active site of the enzyme. Boceprevir is a potent inhibitor of the NS3 protease, with an estimated Ki of 14 nM. The results from a phase II study have shown that a 48-week treatment regimen comprised of pegylated interferon and ribavirin for 4 weeks prior to including Boceprevir achieved an astounding 74% sustained virological response after 24 weeks (SVR24) in genotype 1-infected treatmentnaïve patients as compared to the control group, in which 48 weeks of pegylated interferon and ribavirin treatment yielded a 38% SVR24. Currently, the effectiveness of Boceprevir in treating non-responders is under evaluation. Additionally, a next-generation compound SCH-900518 has also entered clinical trials. Encouraging results from phase II studies have shown that SCH 900518 is an order of magnitude more potent than Boceprevir, could exhibit activity against HCV strains resistant to other protease inhibitors, and can potentially be dosed once per day [11, 12]. The macrocyclic serine protease inhibitor TMC 435350 (Tibotec/Medivir; phase II) has also shown promise in that it is well tolerated and produces a dose-dependent rapid antiviral response in genotype 1-infected subjects. It binds non-covalently to its target with a fast on-rate, but has a slow off-rate, and has been found to inhibit NS3 serine protease from genotypes 1, 2, 4, 5, and 6 with an IC50 of less than 10 nM; against the genotype 3 enzyme, however, its IC50 is approximately 100 nM [13, 14]. Albeit in an early stage of development, ITMN-191 (InterMune/Roche; phase I) is another NS3 inhibitor that is Eur J Clin Microbiol Infect Dis (2009) 28:1409–1413 tolerated well as monotherapy and significantly reduces viral load in chronically infected HCV patients who have not responded well to the standard combination therapy. At present, the effectiveness of ITMN-191 together with standard therapy is underway. Interestingly, data obtained from the HCV replicon system suggest that ITMN-191, when combined with the RdRP inhibitors R1626 or R7128, not only potently inhibits viral replication, but also reduces or suppresses the emergence of HCV variants that are drugresistant [15, 16]. Conclusion With an estimated 3% of the world population infected with hepatitis C virus (HCV), there is a dire need to develop not only potent molecules that will inhibit HCV replication, but also efficacious vaccines that will protect individuals from becoming infected. Towards that end, tremendous progress has been made in these areas over the past decade, which is likely to culminate in the approval of at least one compound within the next three years. Given that the various drugs currently in the pipeline preferentially target the North American HCV genotype 1, the obvious challenge for pharmaceutical and biotechnology companies is to develop a pan-HCV inhibitor that will be useful for treating infections caused by all HCV variants. The rapid rate at which HCV evolves will undoubtedly make the discovery of such a molecule challenging, as well as time-consuming. Until such a magic bullet is discovered, it is likely that a combination therapy consisting of a cocktail of one or more anti-HCV drugs together with standard therapy will be used for treating hepatitis C infections. References 1. Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wölk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446(7137):801–805 2. Qureshi SA (2007) Hepatitis C virus—biology, host evasion strategies, and promising new therapies on the horizon. Med Res Rev 27(3):353–373 3. Silva M, Poo J, Wagner F, Jackson M, Cutler D, Grace M, Bordens R, Cullen C, Harvey J, Laughlin M (2006) A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE). J Hepatol 45 (2):204–213 4. Le Pogam S, Seshaadri A, Kosaka A, Chiu S, Kang H, Hu S, Rajyaguru S, Symons J, Cammack N, Nájera I (2008) Existence of hepatitis C virus NS5B variants naturally resistant to nonnucleoside, but not to nucleoside, polymerase inhibitors among untreated patients. J Antimicrob Chemother 61(6):1205–1216 Eur J Clin Microbiol Infect Dis (2009) 28:1409–1413 5. Pockros PJ, Nelson D, Godofsky E, Rodriguez-Torres M, Everson GT, Fried MW, Ghalib R, Harrison S, Nyberg L, Shiffman ML, Nájera I, Chan A, Hill G (2008) R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin. Hepatology 48(2):385–397 6. Pharmasset Inc. (2009) R7128, a prodrug of PSI-6130. Home page at: http://www.pharmasset.com/pipeline/R7128.asp 7. Carroll SS, Ludmerer S, Handt L, Koeplinger K, Zhang NR, Graham D, Davies ME, Maccoss M, Hazuda D, Olsen DB (2009) Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees. Antimicrob Agents Chemother 53(3):926–934 8. Troke P, Lewis M, Simpson P, van der Ryst E, Hammond J, Craig C, Perros M, Westby M (2009) Genotypic characterisation of HCV NS5B following 8-day monotherapy with the polymerase inhibitor PF-00868554 in HCV-infected subjects. In: Poster presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen, Denmark, April 2009 9. Vertex Phamaceuticals (2008) Telaprevir presentations at the 59th AASLD meeting to feature SVR data in treatment-naïve and treatment-failure genotype 1 HCV patients, and clinical data exploring twice-daily dosing regimens. Available online at: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=336431 10. Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, Courtney LF, Decker CJ, Dinehart K, Gates CA, Harbeson SL, Heiser A, Kalkeri G, Kolaczkowski E, Lin K, Luong YP, Rao BG, Taylor WP, Thomson JA, Tung RD, Wei Y, Kwong AD, Lin C (2006) Preclinical profile of VX-950, a potent, selective, and 1413 11. 12. 13. 14. 15. 16. orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 50(3):899–909 Kwo P, Lawitz E, McCone J, Schiff E, Vierling J, Pound D, Davis M, Galati J, Gordon S, Ravendhran N, Rossaro L, Anderson F, Jacobson I, Rubin R, Koury K, Chaudhri E, Albrecht J (2008) Boceprevir plus peginterferon alfa-2b/ribavirin for treatment of genotype 1 chronic hepatitis C in previously untreated patients: interim results from the HCV SPRINT-1 study. In: Proceedings of the 59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, California, October/ November 2008 Schering-Plough (2009) Final results of boceprevir phase II HCV SPRINT-1 study showed significantly higher SVR rates compared to standard of care in treatment-naive genotype 1 hepatitis C patients. Available online at: http://www.schering-plough.com/ news/news_article.aspx?reqid=1279938 Medivir (2008) Focus on hepatitis C. Home page at: http://www. medivir.se/v3/en/ NATAP (2008) Inhibitory activity of TMC435350 on HCV NS3/ 4A proteases from genotypes 1 to 6. Available online at: http:// www.natap.org/2008/AASLD/AASLD_23.htm InterMune (2009) InterMune reports results from triple combination study of ITMN-191. Available online at: http://phx.corporate-ir.net/ phoenix.zhtml?c=100067&p=irol-newsArticle&ID=1243000&high light= NATAP (2008) Combination of the NS3/4A protease inhibitor ITMN-191 (R7227) with the active moiety of the NS5B inhibitors R1626 or R7128 enhances replicon clearance and reduces the emergence of drug resistant variants. Available online at: http:// www.natap.org/2008/AASLD/AASLD_26.htm