Newer Drugs for Hepatitis C

8/22/2019 Newer Drugs for Hepatitis C

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Subject Review

By: Dr. Rajani Anil Kanaiyalal

Date: 14th October, 2011.

Newer drugs for hepatitis CTable of contents

Introduction

Current standard of care (SoC)

Natural history and HCV life cycle

Future drugs for chronic hepatitis C

1) Drugs targeting viral factors2) Drugs targeting host factors3)

Modification of existing SoC drugs

Vaccines

Pharmacogenomics of hepatitis C

Challenges in development of newer drugs for hepatitis C

Conclusion

References


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IntroductionChronic 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 70-

80%, 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 historyFollowing 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.


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HCV life cycle

Figure 1. 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


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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 5-

NTR. 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 HCVNewer drugs being developed for HCV can be divided into:

1) Drugs targeting viral factors2) Drugs targeting host factors3) Modification of existing SoC drugs

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

1. Drugs targeting viral factors


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

cleavage.

A) Protease inhibitorsNS3 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


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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 inhibitorsNS5B 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)


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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) inhibitorsBILB1941 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) inhibitorsFilibuvir 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) inhibitorsSetrobuvir (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


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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) inhibitorsNesbuvir 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 inhibitorsNS5A 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 inhibitorsNS4A 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.


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E) p7 inhibitorsp7 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.

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

2. Drugs targeting host factors


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a) Entry inhibitorsITX-5061: It is an orally bioavailable small molecule inhibitor which interact with SR-B1, the hosthepatocyte 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) BavituximabIt 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) MiravirsenIt 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 inhibitorsCyclophilins 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


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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 agonistTLR 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) NitazoxanideIt 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) SilibininIt 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 non-

responders 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 targetsOther 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.

New interferonsThese 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 non-

inferiority 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.

3. Modification of existing SoC


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Ribavirin prodrugTaribavirin (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.

VaccinesOne 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 Phase

Recombinant protein vaccines

HCV E1/E2 glycoproteins/MF59C adjuvant I

GI5005: recombinant yeast transfected with HCV NS3-core fusion protein II

HCV core protein II

Peptide vaccines

IC41: five peptides from core, NS3 and NS4 + poly-L-arginine adjuvant II

Peptide derived from core protein (C3544) I

CD8+ A24 peptides + Freunds adjuvant I

Autologous dendritic cell delivered HLA A2 epitopes I

NS3/Virosome I


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DNA vaccine

CICGB-230: plasmid core/E1/E2 + recombinant core protein I

ChonVac-C: plasmid NS3/4a + electroporation I

Viral-vectored vaccine

TG4040: MVA vector expressing NS3/4/5B proteins I

Adenovirus vector (Ad6 and AdCh3) expressing NS35B proteins I

Pharmacogenomics of hepatitis CRecently 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-Cgenotypes 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 HCVDrug 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.

ConclusionApproval 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 Phase

NS3/4A protease inhibitors

Telaprevir, Boceprevir Approved

TMC435, BI201335 Phase III

Danoprevir, Vaniprevir, GS-9256, ABT-450, BMS-650032 Phase II

ABT-450 with low dose ritonavir Phase II

Narlaprevir, PHX1766, ACH-1625, MK-5172, VX-985, GS-9451 Phase I

NS5B polymerase inhibitors [Nucleos(t)ide inhibitors]

Mericitabine, IDX 184, PSI-7977 Phase II

PSI-938 Phase I

NS5B polymerase inhibitors [Non-nucleoside inhibitors]

Filibuvir, Setrobuvir, Tegobuvir, BI 207127, VX-222, ABT-072, ABT-333 Phase II

VX-759, IDX 375 Phase I

NS5A inhibitors

BMS-790052 Phase II

BMS-824393, PPI-461, AZD7295 Phase I

p7 inhibitors

BIT225 Phase II

Cyclophilin inhibitors

Alisporivir Phase II

NIM811, SCY-635 Phase I

-glucosidase 1 inhibitor

Celgosivir Phase II

TLR7 agonist

ANA773 Phase I

Monoclonal antibody against phosphatidylserine

Bavituximab Phase II

Entry inhibitors

Small molecule inhibitor of SRB1 (ITX-5061) Phase I

Erlotinib, antibody targeting CD81 Preclinical

Locked nucleic acid-modified oligonucleotide inactivator of miRNA-122

Miravirsen Phase II


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Others

Nitazoxanide Phase II

Silibinin Phase II

Locteron (controlled release interferon -2b) Phase II

Peginterferon Phase II

References:1. Rosen HR Clinical practice. Chronic hepatitis C infection. N Engl J Med. 2011;364(25):2429-

38.

2. Halliday J, Klenerman P, Barnes E Vaccination for hepatitis C virus: closing in on an evasivetarget. Expert Rev Vaccines 2011;10(5):659-72.

3. Pearlman BL The IL-28 genotype: how it will affect the care of patients with hepatitis C virusinfection. Curr Gastroenterol Rep 2011;13(1):78-86.

4. Jang JY, Chung RT New treatments for chronic hepatitis C. Korean J Hepatol. 2010;16(3):263-77.

5. Lin K Development of novel antiviral therapies for hepatitis C virus. Virol Sin. 2010;25(4):246-66.

6. Vermehren J, Sarrazin C New HCV therapies on the horizon. Clin Microbiol Infect.2011;17(2):122-34.

7. Deming P, Arora S Taribavirin in the treatment of hepatitis C. Expert Opin Investig Drugs.2011;20(10):1435-43.

8. Asselah T, Marcellin P New direct-acting antivirals' combination for the treatment of chronichepatitis C. Liver Int. 2011;31(Suppl 1):68-77.

9. Schltter J Therapeutics: new drugs hit the target. Nature. 2011;474(7350):S5-7.10.Maxmen A Pharmacogenomics: playing the odds. Nature. 2011;474(7350):S9-10.11.Eisenstein M Vaccines: a moving target. Nature. 2011;474(7350):S16-7.12.Sheridan C New Merck and Vertex drugs raise standard of care in hepatitis C. Nat Biotechnol.

2011;29(7):553-4.

Newer Drugs for Hepatitis C

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