Subject Review By: Dr. Rajani Anil Kanaiyalal Date: 14th October, 2011.

Newer drugs for hepatitis C

Table of contents
Introduction Current standard of care (SoC) Natural history and HCV life cycle Future drugs for chronic hepatitis C 1) Drugs targeting viral factors 2) Drugs targeting host factors 3) Modification of existing SoC drugs Vaccines Pharmacogenomics of hepatitis C Challenges in development of newer drugs for hepatitis C Conclusion References

Introduction
Chronic liver diseases caused by Hepatitis C virus (HCV) are the major public health problem, with estimated 170 million people infected worldwide. In US, at least 5 million people are infected with HCV which is 5 times as many people as infected with HIV. Hepatitis C is also the leading cause of death due to liver disease and the leading indication for liver transplantation in US. According to predictions, prevalence of HCV related liver diseases is expected to peak around 2020 and mortality will continue to increase. In india, HCV accounts for one-fourth of all cases of chronic liver diseases. It is estimated that there are 12.5 million HCV carriers in our country, and at least a quarter of them are likely to develop chronic liver disease in the next 10 to 15 years. Studies among indian blood donors have noted the prevalence of HCV infection to be below 2%. However, chronic hepatitis C is one of the very few chronic diseases that can be actually cured.

Current standard of care (SoC)

Current standard of care for chronic hepatitis C is the combination of peginterferon alfa and ribavirin. Patients achieving sustained virological response (SVR-defined as HCV RNA negative 24 weeks after cessation of treatment) are considered as cured. SVR is the single best predictor for long term response to treatment as it is associated with substantially reduced all-cause mortality and relapse occurs only in 1-2% of patients achieving SVR. Duration of treatment is 48 weeks for HCV genotype 1 and 4, 24 weeks for genotype 2 and 3. Patients with genotype 2/3 have SVR rates of 7080%, while in genotype 1/4, despite a longer duration of treatment SVR is achieved in 40-50% patients only. In addition to longer duration of therapy, PEG INF/RBV combination has other drawbacks also like intolerable side effects [flu like symptoms, neuropsychiatric effects with INF; haemolytic anemia, cough, shortness of breath, teratogenicity with RBV] which result in discontinuation by 10-15% of patients. Hence the newer drugs which either improve the tolerability, decrease the duration of therapy or increase the SVR rates are urgently needed.

Natural history
Following acute infection, ~20% spontaneously clear the infection. Although only 25% of new infections are symptomatic, 60-80% of patients develop chronic liver disease. Of these, 20% progress to cirrhosis and 1-4% develop hepatocellular carcinoma.

HCV life cycle

IRES (Internal ribosome entry site) within 5-NTR

3 Structural proteins C, E1, E2

6 Non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, NS5B

Figure 1. HCV life cycle.

HCV is a ssRNA enveloped virus of flaviviridae family having 9.6 kb RNA genome coding for polyprotein of about 3000 amino acids. Life cycle begins with attachment of HCV envelope glycoproteins E1 and E2 to a variety of host proteins like CD81, SR-B1 (scavenger receptor-B1), caudin-1, occludin etc. This is followed by clathrin-dependant endocytosis and release of viral RNA into cytoplasm. Translation of polyprotein is directed by internal ribosome entry site (IRES) within 5NTR. Polyprotein is then processed into structural proteins (core protein C, envelope proteins E1, E2) and non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) by viral and cellular proteases. Then occurs the assembly of viral proteins followed by release. Knowledge of viral structure and its life cycle provides newer targets for development of drugs. An important feature to be noted in the life-cycle is that unlike HIV, HCV genome does not integrate into host genome. Thus, eradication of HCV possible.

Future drugs for HCV

Newer drugs being developed for HCV can be divided into: 1) Drugs targeting viral factors 2) Drugs targeting host factors 3) Modification of existing SoC drugs

1. Drugs targeting viral factors

Figure 2: HCV genome, its proteins and their role HCV life cycle. RdRP RNA dependant RNA polymerase; Closed circles signal peptidase cleavage sites; Open circle signal peptide peptidase

cleavage site; Closed arrow sites of cleavage by NS3; Open arrow site of autoproteolytic cleavage.

A) Protease inhibitors
NS3 is a multifunctional enzyme with N-terminal serine protease domain and C-terminal RNA helicase/NTPase activity. Along with the co-factor NS4A, it catalyzes proteolytic cleavage at NS3/NS4A, NS4A/4B, NS4B/5A and NS5A/5B. Thus NS3 plays an essential role in viral replication and maturation. Apart from this, NS3-4A protease may also participate in host immune invasion by degrading several key cellular signalling molecules involved in endogenous INF production and responsiveness. Therefore, targeting NS3/4A offers dual advantage of inhibiting viral replication and restoring innate response. Two drugs belonging to NS3/4A protease inhibitors class are recently approved by FDA in May 2011 telaprevir and boceprevir. Later telaprevir was also approved in Europe.

Figure 3: Comparisons of SVR rates between protease inhibitors and standard of care (PR PEG INF/RBV) in phase III trials. ADVANCE, ILLUMINATE and SPRINT-2 were conducted in treatment-nave patients, while REALIZE and REPOND-2 in previously treated patients. Both these protease inhibitors not only considerably improved SVR rates but also lowered the relapse rate. Also the treatment duration could be reduced to approximately half in patients showing favourable HCV RNA response. These protease inhibitors do cause additional side-effects; the most troublesome being anemia with boceprevir and rash with telaprevir. Also these drugs complement rather than replacing the SoC, hence increasing the cost of therapy. HCV PIs are approved only for genotype 1 infections and with

compensated liver status. HCV PIs offer low barrier to resistance and boceprevir and telaprevir have overlapping resistance profiles.

Other protease inhibitors:

Among other protease inhibitors, two compounds (TMC435, BI201335) are currently in phase III. Danoprevir (ITNM-191), GS-9256, ABT-450, BMS-650032 and Vaniprevir (MK-7009) have reached phase II; while PHX1766, ACH-1625, MK-5172, VX-985, GS-9451 and Narlaprevir (SCH900518) are being evaluated in phase I. Many of these newer compounds have shown improved potency. Some of these may also offer better pharmacokinetic properties like longer half-life, requiring OD/BD dosing compared to TDS dosing with approved PIs. Danoprevir achieves higher liver concentrations after oral dosing. Other potential advantages of these newer compounds are broader genotypic activity and better tolerability. While telaprevir, boceprevir and narlaprevir are reversible covalent inhibitors; others are non-covalent inhibitors. Additionally, ritonavir boosting is also being investigated with many PIs for possibility of reducing side-effects, overcoming resistance, allowing less frequent dosing by enhancing exposure to PIs. One such phase II study is planned to evaluate ABT-450 in combination with low dose ritonavir.

B) NS5B polymerase inhibitors

NS5B is RNA-dependant RNA polymerase required for synthesis of both positive and negative strands of HCV RNA. Two classes of NS5B polymerase inhibitors are under development: (i) nucloes(t)ide analogue inhibitors By mimicking natural substrates, they bind to active site and get incorporated into elongated RNA thereby causing chain termination. (ii) non-nucleoside analogue inhibitors which bind to different allosteric site resulting in a conformational change before elongation complex is formed. (I) Nucleos(t)ide inhibitors As active site of NS5B polymerase is highly conserved, nucleos(t)ide inhibitors potentially show similar efficacy against all HCV genotypes. Also they offer higher barrier to resistance. First nucleos(t)ide inhibitor to be tested was valopicitabine. However it showed weak efficacy against HCV and also showed dose limiting GI side-effects. Hence it was suspended from further development after phase II. Second compound R 1626 showed marked antiviral activity with no viral breakthrough. But further development after phase II was stopped due to side effects like bone marrow suppression, high relapse rates. Currently most advanced compound in this category is Mericitabine (RG 7128). Interim data from phase II has shown >80% RVR (rapid virological response) 6

rates with no serious adverse events and no resistance-related breakthrough. Currently larger phase IIb study is planned. It is also under evaluation in combination with danoprevir (INFORM-1 trial). IDX 184: It is a second generation nucleos(t)ide inhibitor with higher hepatic extraction ratio, theoretically increasing efficacy and safety. It is currently in phase II trials. Another compound in phase II is PSI-7977. PSI-938 in phase I trial showed potent antiviral activity and is generally safe and well tolerated both as monotherapy and in combination with PSI-7977. PSI-938 has received fast track designation from FDA, highlighting the need for HCV treatments with improved tolerability, safety and efficacy over the existing SoC. An interferon-free combination trial with PSI-938 and PSI-7977 is planned. (II) Non-nucleoside inhibitors The structure of NS5B polymerase resembles a characteristic right hand motif with finger, palm and thumb domain. As non-nucleoside inhibitors bind more distant from active site, resistant mutation occur more frequently as mutations at this site do not necessarily impair the enzyme activity. Also they have genotype selective activity.

Non-nucleoside site 1 (thumb pocket 1) inhibitors

BILB1941 was the first inhibitor of this site to show antiviral efficacy but was not developed further due to GI side-effects. MK-3281 development was also halted due to GI adverse effects. Currently BI 207127 is being evaluated in phase II. It showed reduction of 5.6 log in HCV RNA in genotype 1 infections with no viral breakthrough.

Non-nucleoside site 2 (thumb pocket 2) inhibitors

Filibuvir has shown medium anti-viral efficacy in phase I. Interim data from phase I showed similar SVR rates between filibuvir with PEG INF/RBV for 4 weeks followed by SoC for 44 weeks and SoC in genotype 1a and 1b infections. Hence the phase II trial with longer dosing duration is undertaken. Other inhibitors of this site include VX-222 (phase II) and VX-759 (phase I).

Non-nucleoside site 3 (palm 1) inhibitors

Setrobuvir (ANA598) 400 mg BD with PEG INF/RBV in phase II showed that 75% patients achieved undetectable HCV RNA at week 12 [complete early virological response cEVR]. Effect was more

pronounce in genotype 1b patients than genotype 1a. However higher incidence of skin rash was observed. Other two inhibitors ABT-072 and ABT-333 have also progressed to phase II.

Non-nucleoside site 4 (palm 2) inhibitors

Nesbuvir showed low anti viral activity and resulted in seletion of resistant variant. Also it was associated with significant hepatotoxicity, hence it was taken from further trials. Tegobuvir has entered phase II and IDX 375 is in phase I trials. o: Although these directly acting antivirals (DAAs) are promising, PEG INF and RBV still remain the part of treatment regimens. Hence the ultimate goal is to achieve SVR by INF-free regimen. This will not only remove the major cause of side effects and treatment discontinuation, but also it will make the regimen all-oral and more acceptable for a long term therapy. One such trial (INFORM-1) has provided some hope in this direction. In this trial, combination of danoprevir and mericitabine showed the efficacy and tolerability. Also no viral breakthrough was observed during 4 week treatment. As per protocol design, all patients received full course of PEG INF/RBV following 12 weeks of combination of DAAs; hence proof of concept that SVR can be achieved with DAAs alone is still missing. Nevertheless some trials are currently evaluating the efficacy of various DAAs combination with or without ribavirin. Overcoming resistance will be the primary challange in DAAs combination therapy. Combinations that have genetic barrier of four or more mutation may be required.

C) NS5A inhibitors
NS5A is multifunctional protein. It interacts with NS5B and also involved in viral assembly. These agents also are potentially active against all genotypes. Most advanced compound in this class is BMS-790052. It binds to domain 1 of NS5A which is crucial for regulating replication, assembly and release. Interim data from phase II showed that RVR (rapid virological response) rates were 83% and 92% in 10 mg OD and 60 mg OD groups; and complete EVR was achieved in 83%. Other compounds in phase I are BMS-824393, PPI-461, AZD7295.

D) NS4A inhibitors
NS4A is the co-factor for NS3 protease. One NS4A inhibitor identified is ACH 806 which showed anti HCV effect but reversible nephrotoxicity prohibits its additional clinical progress.

E) p7 inhibitors
p7 protein has channel activity and is believed to be involved in virion secretion. A p7 inhibitor BIT225 is currently in phase II. Other proteins like NS3 helicase/NTPase, NS2, autoproteolytic cleavage between NS2 and NS3 are not druggable targets.

2. Drugs targeting host factors

Many host proteins are also involved in the process of viral replication; which offer additional targets for development of anti HCV drugs. The advantage of targeting host proteins is higher barrier to resistance. However this approach will also be associated with greater potential for cellular toxicity.

Figure 4: Involvement of host factors in HCV life cycle

a) Entry inhibitors
ITX-5061: It is an orally bioavailable small molecule inhibitor which interact with SR-B1, the host hepatocyte cell membrane protein involved in the docking and entry of the virus. Presently it is in phase Ib stage. Other entry inhibitors which are in preclinical stage include antibody targeting CD81, erlotinib targeting EGFR. These entry inhibitors will be particularly more useful in patients receiving liver transplant as they can prevent the re-infection of liver graft.

b) Bavituximab
It is a chimeric monoclonal antibody targeting phosphatidylserine. This moiety is normally intracellular, but gets exposed in infected cells. Binding of bavituximab blocks the immunosuppressive signals generated by phosphatidylserine, thereby allowing the immune system to mount a robust response against infected cells. Bavituximab in phase I showed positive safety profile with no dose-limiting toxicities or serious adverse events. It also showed antiviral activity of up to 1.5 log viral load reduction. Currently it is being evaluated in phase II.

c) Miravirsen
It is a locked nucleic acid-modified oligonucleotide complementary to the 5-end of miR-122 and it causes functional inactivation of miRNA-122. miRNA-122 is abundant liver-specific miRNA which is crucial for efficient HCV RNA replication. It stimulates HCV RNA replication and translation through interaction with two adjacent sites downstream of stem loop I within the HCV 5 untranslated region. Miravirsen was shown to be active in HCV positive chimpanzees, markedly reducing HCV RNA replication and showing no significant side effects except for a profound decrease in serum cholesterol. Moreover, it had a potent antiviral effect against HCV genotypes 1-6 in vitro. A phase II trial is currently recruiting patients.

d) Cyclophilin inhibitors
Cyclophilins are a family of highly conserved cellular peptidyl-prolyl cis-trans isomerase (PPIase), involved in many cellular processes such as protein folding and trafficking. Cyclophilins (mainly A and B) are involved in HCV replication by (i) interacting directly with viral proteins (NS5A and NS5B) and acting as functional regulator of NS5B polymerase and/or (ii) mediating correct folding and 10

trafficking of viral proteins to the site of replication. Hence the cyclophilin inhibitors block interaction of cyclophilins with HCV proteins and so the formation of a functional replication complex. NIM811: Its a non-immunosuppressive cyclosporine analogue. In combination with INF and protease/polymerase inhibitors, it not only enhanced anti-HCV activity but also suppressed the emergence of resistance. In a phase Ib trial in genotype 1 patients who had relapse to INF therapy, 600 mg BD dose led to decrease of 2.78 log in HCV RNA. Alisporivir: It is more potent cyclosporine analogue. In a phase II, 600 mg OD with PEG INF caused reduction in viral load of 4.6 log in genotype 1 and 4, and 5.9 log in genotype 3. Third cyclosporine analogue, SCY-635 is currently in phase I.

e) -glucosidase 1 inhibitor
-glucosidase 1 is involved in glycoprotein processing and is important for viral maturation and release. -glucosidase 1 inhibitors cause misfolding of HCV envelope protein, thus blocking viral assembly and release. One -glucosidase 1 inhibitor in trials is celgosivir. 400 mg in combination with PEG INF/RBV resulted in >2 log reduction in HCV RNA in 45% patients vs 10% with PEG INF/RBV only.

f) Toll like receptor 7 agonist

TLR 7 recognizes ss RNA virus and activates type 1 IFNs as part of innate immune response. Isatoribine and its oral prodrug ANA975 showed clinical efficacy in HCV but were taken out from further development due to significant side-effects and insufficient therapeutic window. ANA773, a novel oral TLR7 agonist has shown significant anti-viral response without any serious adverse events.

g) Nitazoxanide
It is an anti-parasitic drug shown to inhibit HCV through inducing phosphorylation of eukaryotic initiation factor 2, a known mediator of host antiviral defence. Moreover this mechanism is triggered in HCV infected cells, with no effect in uninfected cells. Thus it has low rates of toxicity. Furthermore, it does not appear to induce resistance. In a phase II trial in genotype 4 patients showed SVR rates of 79% in combination with PEG INF/RBV compared to 50% with PEG INF/RBV alone. However SVR rates in genotype 1 were only 44%.

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h) Silibinin
It is one of the 6 major flavonolignans in silymarin. Possible mechanisms of anti HCV activity proposed are: inhibition of HCV-RNA dependant RNA polymerase, blockade of viral entry and transmission possibly by targeting host cells. Intravenous silibinin was investigated in nonresponders to prior INF based therapy and led to a significant decline in HCV RNA between 0.55 to 3.02 log after 7 days. Studies in larger patient cohort are underway.

I) Other host targets

Other targets which are tried include targeting host metabolism by inhibiting lipid biosynthesis, improving insulin resistance. While statins have shown promise in vitro, they do not appear to be active in vivo. Antisense oligonucleotide targeting ApoB and MTP (microsomal triglyceride protein) inhibitors have also been tried. Obesity and diabetes are identified as host factors associated with lower SVR rates. Recently, addition of metformin is shown to increase SVR rates by 10%. PPAR / agonist may also improve SVR rates.

3. Modification of existing SoC drugs New interferons

These newer interferons are designed to improve convenience and tolerability of IFN-based therapy. Response rates however, will not be dramatically improved. Albinterferon: It is a fusion polypeptide of albumin and interferon -2b with a longer t than pegylated interferons. In phase III studies, albinterferon (given every 2 weekly) demonstrated noninferiority to peginterferon -2a, with similar SVR rates. However, adverse events were similar. Locteron: It is a controlled release interferon -2b injected every 2 weekly. In a short term study, it showed less flu-like symptoms than peginterferon -2b. Larger trials to evaluate tolerability and efficacy are initiated. Peginterferon : It is pegylated type III interferon and binds to a unique receptor with more limited distribution than type I interferons. Phase I trials showed that peginterferon was pharmacologically active without flu-like symptoms or haematological side effects.

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Ribavirin prodrug
Taribavirin (Viramidine): It is a prodrug of ribavirin, designed to concentrate within hepatocytes and minimize distribution within RBCs. 2 phase III studies comparing ribavirin and taribavirin, although showed significant reduction in occurance of anemia, neither of the study achieved non-inferiority in terms of SVR rates. Taribavirin group had lower SVR rates and higher relapse rates.

Vaccines
One quater of acutely infected individuals do spontaneously eradicate the virus giving hope that successful immune response by appropriate vaccination may be protective. However HCV poses several obstacles to vaccine development. Firstly, hepacivirus genus exhibits considerable primary sequence divergence (>30% difference at the level of primary nucleotide and amino acid sequence), being greater than that of HIV. Also RNA dependant RNA polymerase enzyme of the virus is highly error-prone and lacks proof reading functions, which gives rise to large number of quasispecies. From these quisispecies, mutants resistant to neutralizing antibody and CD8+ cytotoxic T cell response can emerge. Despite these difficulties, there is still significant encouragement for development of at least partially effective vaccine, which may not provide the sterilizing immunity against the reinfection but may protect against development of chronic state. Few of these vaccine candidates have progressed to reach clinical trials. Table 1: Vaccine candidates that have reached clinical trials Vaccine Recombinant protein vaccines HCV E1/E2 glycoproteins/MF59C adjuvant GI5005: recombinant yeast transfected with HCV NS3-core fusion protein HCV core protein Peptide vaccines IC41: five peptides from core, NS3 and NS4 + poly-L-arginine adjuvant Peptide derived from core protein (C3544) CD8+ A24 peptides + Freunds adjuvant Autologous dendritic cell delivered HLA A2 epitopes NS3/Virosome II I I I I I II II Phase

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DNA vaccine CICGB-230: plasmid core/E1/E2 + recombinant core protein ChonVac-C: plasmid NS3/4a + electroporation Viral-vectored vaccine TG4040: MVA vector expressing NS3/4/5B proteins Adenovirus vector (Ad6 and AdCh3) expressing NS35B proteins I I I I

Pharmacogenomics of hepatitis C
Recently five genetic association studies have conclusively identified SNPs close to IL28B (interleukin 28B) gene as the strongest pretreatment predictor of SVR. Patients with CC genotype at rs12979860 are ~5 times more likely to achieve SVR than nonCC genotype. Another SNP shown to influence SVR rates is rs8099917 (T allele more favourable than G). Both these SNPs appear to be in linkage disequilibrium, and likely to share a haplotype. Although no firm guidelines have been established, genotyping for IL28B can provide the basis for personalizing treatment of chronic hepatitis C. Patients with favourable genotype might achieve same SVR rates with shorter duration of current SoC. Directly acting antivirals may overcome the effect of poor response genotype to some extent. Also while designing future trials; patients can be stratified according to genotype to evaluate the treatment efficacy across genotypes. A study in European population also showed correlation between HLA-C genotype and treatment respone, with C2C2 genotype associated with more chances of treatment failure than C1C1 genotype. Authors also showed that combining IL28B and HLA-C genotypes can yield higher positive predictive value for identifying non-responders than the either genotype alone. 2 ITPA (inosine triphosphatase) polymorphisms which are functionally responsible for ITPA deficiency are strongly protective against RBV induced haemolytic anemia.

Challenges in development of new drugs for HCV

Drug discovery effort on HCV has been hampered by lack of an in vitro virus culture system and suitable animal models. Few attempts have been made to fulfil this gap. Development of subgenomic HCV replicon system has greatly facilitated study of viral replication; although it contains only non-structural proteins and lacks structural proteins. HCV pseudotype particle

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(HCVpp), generated from lentivirus replacing native glycoproteins with HCV E1 and E2, provides useful tool to study viral entry. A newely discovered genotype 2a HCV (JFH-1 strain) recapitulates complete viral life cycle. Still no robust reproducible method has been established to culture HCV from patients serum using primary human hepatocytes. Regarding animal models, chimpanzees are the only immunocompetent animals that can be chronically infected with HCV. But their use is restricted by ethical concerns, limited availability and prohibitively high cost. SCID (severe combined immunodeficiency) mice with human hepatocytes repopulated in mouse liver can be infected with HCV. However these mice are also of limited availability and substantial variability and they cannot be used to study pathological or immunological aspects of infection. Researchers at Rockford University have developed black mice engineered to express human genes. These are the first small animals with fully functional immune system that is prone to HCV infection. These can provide cheaper and ethically sound models. atleast for study of viral entry and its modulation by drugs/vaccines.

Conclusion
Approval of two new protease inhibitors has drastically improved the outcome of HCV therapy. Although these new drugs have their own limitations like additional cost, necessity to be given only in combination with PEG INF/RBV, thrice daily dosing etc. Also they address only to a limited subgroup of chronic hepatitis C patients. Many other compounds are under development to overcome these limitations. Considerable progress has been witnessed in areas related to models for hepatitis C. With advent of these newer drugs as well as newer techniques, it might be possible in future to develop all oral INF free regimens for majority of patients. Additionaly, more evidence in relationship of genotyping and treatment response can help in personalizing HCV therapies. Lastly, development of vaccine also seems to be a possible starategy. Drugs in various stages of clinical trials are summarized in the table 2.

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Table 2: Drugs under development Drugs and mechanism NS3/4A protease inhibitors Telaprevir, Boceprevir TMC435, BI201335 Danoprevir, Vaniprevir, GS-9256, ABT-450, BMS-650032 ABT-450 with low dose ritonavir Narlaprevir, PHX1766, ACH-1625, MK-5172, VX-985, GS-9451 NS5B polymerase inhibitors [Nucleos(t)ide inhibitors] Mericitabine, IDX 184, PSI-7977 PSI-938 NS5B polymerase inhibitors [Non-nucleoside inhibitors] Filibuvir, Setrobuvir, Tegobuvir, BI 207127, VX-222, ABT-072, ABT-333 VX-759, IDX 375 NS5A inhibitors BMS-790052 BMS-824393, PPI-461, AZD7295 p7 inhibitors BIT225 Cyclophilin inhibitors Alisporivir NIM811, SCY-635 -glucosidase 1 inhibitor Celgosivir TLR7 agonist ANA773 Monoclonal antibody against phosphatidylserine Bavituximab Entry inhibitors Small molecule inhibitor of SRB1 (ITX-5061) Erlotinib, antibody targeting CD81 Locked nucleic acid-modified oligonucleotide inactivator of miRNA-122 Miravirsen Phase II 16 Phase I Preclinical Phase II Phase I Phase II Phase II Phase I Phase II Phase II Phase I Phase II Phase I Phase II Phase I Approved Phase III Phase II Phase II Phase I Phase

Others Nitazoxanide Silibinin Locteron (controlled release interferon -2b) Peginterferon Phase II Phase II Phase II Phase II

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