The Internet Journal of Pharmacology ISPUB.COM Volume 6 Number 2

The Present And Emerging Investigational Drugs For Chronic : Current Status R Kumar

Citation R Kumar. The Present And Emerging Investigational Drugs For Chronic Hepatitis C: Current Status. The Internet Journal of Pharmacology. 2008 Volume 6 Number 2.

Abstract Chronic hepatitis C is caused by flavi virus (RNA virus) and is the leading cause for cirrhosis, hepatocellular carcinoma and liver transplantation. The standard therapy of chronic hepatitis C is peg α weekly plus oral- daily is not effective in all patients and is limited by adverse effect. Therefore new investigational drugs are being developed and in pipeline. This article focuses on new investigational drugs that are presently in an advance stage of development also focuses on newer , ribavirin analogue and anti apoptotic drug.

INTRODUCTION of ribavirin include dose dependent hemolytic anaemia,

Viruses are obligate intracellular parasites, their replication depression, instability, cough and insomnia 2 . depends on synthetic processes of the host cell. Hepatitis C Currently available therapy for patient with chronic hepatitis caused by RNA flavi virus, 80% of individual will become C provides a cure rate of 40-90% and associated with chronically infected. Chronic hepatitis C is the leading cause significant adverse effects that often necessitate for cirrhosis, hepatocellular carcinoma and liver discontinuation. Therefore new drugs with higher efficacy transplantation . 1 and better tolerability are needed. The goal of therapy patients with chronic hepatitis C is viral The availability of a full length HCV genome has enabled eradication and primary efficacy and point of treatment is the identification of new targets and facilitates screening of achievement of SVR (Sustained Viral Response). SVR new anti HCV drug 34 . Several targets have been identified defined as the absence of detectable viremia for 6 months in HCV genome for anti HCV drug, including IRES after completion of treatment. Sustained viral response is (Internal Ribosome Entry Site), E1/E2 (Envelop associated with improvement in liver pathology and glycoprotein), P7 NS2, NS3, NS5 and NS5B (5-6). Many reduction in risk of cirrhosis and hepatocellular carcinoma . 2 specifically targeted small molecule inhibitors are being The standard treatment in patients with chronic hepatitis C developed and are emerging, future drug for patient with is once weekly pegylated interferon alpha with oral chronic hepatitis C infection 56 . ribavirin (a synthetic nucleotide analogoue) daily. This article focuses on emerging future anti-HCV drugs that Combination therapy is more effective than monotherapy are currently in clinical trial and in advance stage of with interferon. Therefore monotherapy with pegylated development. interferon alpha is indicated in patients with chronic hepatitis

C infection who can not tolerate oral ribavirin 12 . Side INVESTIGATIONAL NEW DRUGS (IND) effects with the use of inteferon alfa include a flu like NS3/4A SERINE PROTEASE INHIBITOR syndrome i.e. headache, fever, chills and myaligias occurs in (VX-950) (Manufactured by vertex) is a more than 30% of patients within 6 hours after dosing and peptidomimetic inhibitor of NS3/4A protease. In a phase-Ib finds to resolve during therapy. During chronic therapy trial (nonresponders to previous antiviral therapy) telaprevir adverse effects include neurotoxicities (i.e. mood disorder, monotherapy reduced HCV RNA rapidly by 3.5 – 4.8 log in depression, seizures) pneumonitis, myelosuppression a dose dependent manner ( in this trial patients were treated alopecia, tinnitus and retinopathy. Side effects with the use for 14 days with Telaprevir at three different doses. 450mg

1 of 6 The Present And Emerging Investigational Drugs For Chronic Hepatitis C: Current Status every 8 hours, 750mg every 8 hours or 250mg every 12 azidocytidine, a nucleoside analogue (manufactured by hours or with placebo). Mild gastrointestinal symptoms were Roche). R1626 showed greatest viral blood reduction in a noted in patient with telaprevir therapy 7 . multi-dose study (phase-Ib trial) in patients with chronic

hepatitis C genotype I 16 . In a phase-IIa study R1626 with The combination treatment with telaprevir plus peginterferon plus ribavirin (triple combination treatment) peginterferon-α–2a reduced the HCV RNA by 5.5 log after resulted 5.2 log decline in HCV RNA showing robust 14 days in previously untreated patients with chronic synergistic antiviral effect 17 and the antiviral effect was hepatitis C genotype-I 89 . Combination therapy causes more sustained 18 . Haemotological adverse effects were observed. reduction in HCV RNA indicating additive effect of telaprevir with peginterferon-α-2a. HCV mutant resistant to R7128 is a prodrug, a nucleoside analogue NS5B telaprevir remained sensitive to peginterferon-α-2a. The triple polymerase inhibitor (manufactured by Roche). R7128 in a combination treatment with telaprevir, peginterferon-α-2a phase-I trial, following multiple, ascending, oral doses and ribavirin in the PROVE trials (Phase II trials) yielded showed antiviral effects in patients with HCV genotype-I good results. At the EASL (Europian Association for the infection, who have failed with prior interferon therapy,

Study of the Liver) 2008 meeting in Milan, Italy, final headache was the most common adverse events 19 . R7128 in results of the PROVE trials recently became available, both triple combination with peginterferon and ribavirin the early

PROVE 1 and PROVE 2 trials had shown that the telaprevir result showed synergistic effect similar to R1626 20 . based (triple combination) regimen resulted in a 20% higher SVR than previously achieved with standard treatment with Non-nucleoside analogue NS5B polymerase inhibitor- peginterferon plus ribavirin in patients with chronic hepatitis BILB1941 (manufactured by Boehringer ingelheim) BILB1941 in a phase-I trial showed antiviral activity after 5 C 1011 . Adverse effect with telaprevir therapy were rash and anaemia. days treatment, in patient with chronic hepatitis C genotype- I but gastrointestinal adverse effect are limiting factor 21 . (SCH 503034): Similar to telaprevir is peptidonimetic NS3/4 protease inhibitor (manufactured by GS9190 (manufactured by Gilead) in a phase-I trial and shering–Plough) Boceprevir based regimen revealed an interim result showed antiviral effect ie decline HCV-RNA additive effect over peginterferon-α-2b in a phase 1b study, and doses which was well tolerated 22 . in patient with chronic hepatitis C genotype-I Cyclophelin Inhibitor: Cyclophelin are intracellular protein (nonresponders to previous peginterferon-α-2b plus ribavirin and are involved in protein folding, serve as cofactor of the therapy) 12 . In an ongoing phase-II trial (SPRINT–I study) NS5B RNA dependent RNA polymerase 23 . interim result were presented as abstract at the EASL 2008 meeting 13 suggest that triple combination treatment with DEBIO-025 (manufactured by Debiopharm) the cyclophelin boceprevir, peginterferon-α-2b and ribavirin in treatment inhibitor has dual anti HCV and anti HCV activity. In a naïve HCV genotype-I patient resulted in an early virologic phase-I trial DEBIO-025 was administered in HIV/HCV response than therapy with peginterferon plus ribavirin. The coinfected patients showed antiviral effect (ie. Decline in boceprevir based treatment was associated with HIV-I viral load and decline in HCV RNA) 24 . gastrointestinal discomfort, anaemia and dyspepsia as adverse effect. CURRENTLY AVAILABLE THERAPY FOR HEPATITIS C INFECTION-INTERFERONS TMC435350 – (manufactured by tibotec) a protease Interferons are host cytokine proteins that exhibits antiviral, inhibitor is presently in an ongoing phase-I trial showed a immunomodulatry and anti-proliferate activity. Interferons reduction in HCV RNA and well tolerated 14 . are grouped into three families IFN- α, IFN-β and IFN-γ. The IFN- α, IFN- β families comprise type-I IFN, ie. acid stable NS5A inhibitor A-831, (manufactured by arrow therapeutic) proteins induced by viral infection and act on same receptor NS5A, a non-structured protein essential for hepatitis C on target cell. IFN- γ-a type-II IFN is acid labile product of virus replication. A831 inhibit NS5A protein in HCV and activated T lymphocyte and act on separate receptor on exert antiviral activity currently being studied in phase-I trial target cells. IFN-α approved for use in hepatitis C infection . 15 and act by inducing intracellular signal, following binding NS5B polymerase inhibitor: R1626 is a prodrug of the ‘4’- with specific cell membrane receptor resulting in inhibition

2 of 6 The Present And Emerging Investigational Drugs For Chronic Hepatitis C: Current Status of viral penetration, translation, transcription, protein adverse effect associated with ribarivin is minimum, as processing, maturation and release as well as increased does not significantly accommulated in RBCs 34 . expression of major histo-compatibility complex antigen Taribavirin with peginterferon-α-2a in a phase-II trial study enhanced phagocytic activity of macrophages and showed similar antiviral effect and significantly less augmentation of the proliferation and survival of cytotoxic T haemolytic anaemia than ribavirin 35 . cell 25 . Other Investigational New Drugs (IND) - Toll like receptor Interferon α-2a and interferon-α-2b are currently available for agonist Resiquimod. Toll like receptor (TLRs) identify the treatment of hepatitis C virus infection administered presence of invading microorganism and initiate production subcutaneously or intramuscularly, elimination help life is of proinflamation cytokines and chemokines. Resiquimod 2-5 hours and need to be administered daily or 3 times through TLRs initiate induction of cytokines, interferon-α, weekly. interleukin 12 and TNF-α, oral resiquimod in a phase-IIa

study showed a antiviral effect 36 . Pegylated interferon-α is a fusion molecule of polyethylene glycolmolecule and interferon- α. Pegylated interferon α-2a Tumor Necrosis Factor Antagonist – Etanercept as an and pegylated interferon α-2b need to be administered once adjuvant to interferon and ribavirin, in a phase - II study weekly because of slower clearance of these drug result in showed on treatment virological response and attenuation of longer terminal half life allowing for less frequent dosing 2 . adverse effect in patient with chronic hepatitis C infection 37 . NEWER INTERFERONS IN DEVELOPMENT Albinterferon-α-2b: Albumin–interferon-α-2b (Albinterferon- IMPDH Inhibitor – Merimepodib – IMPDH is inosine 5 – α-2b) is a fusion molecule of interferon-α-2b and human monophasphate dehydrogenase, catalysis the biosynthesis of serum albumin, this result an extended half life of 150 hours, nucleotide. Merimepodib is non competitive allowing less frequent administration, albinterferon-α-2b inhibitor of IMPDH, in a phase-II study merimepodib with peginterferon α-2b and ribavirin showed on treatment administered ever 2-4 week 26 . Albinterferon -α-2b exhibit dose dependent antiviral activity both in non-responder and virological response in nonresponders to previous therapy 38 . treatment – naïve patients with chronic hepatitis C genotype INVESTIGATIONAL DRUG THAT REDUCES I . Albinterferon-α-2b with ribavirin in a phase-II trial 2728 HEPATIC FIBROSIS: showed antiviral efficacy (SVR) in nonresponders and in Antiapptotic caspase inhibitor–IDN6556: Pockron PJ et al treatment naïve patients with chronic hepatitis C genotype-I reported that IDN6556 may lower aminotransferase levels in . 2930 patient with chronic hepatitis C infection and may reduce

Omega Interferon: New drug delivery system – design to hepatitis C fibrosis 39 . provide continuous drugs delivery by an implantable device. Investigational drugs that have showed good antiviral effect Omega interferon in a phase-II trial showed antiviral in clinical trials in patient with chronic hepatitis C infection efficacy administered with or without ribavirin in patient but further development has been stopped due to toxicity – with chronic hepatitis C genotype-I . 31 includes. Recombinant interferon-α-2b – The controlled release lemna Ribozymes RPI13919 – was in a phase-II trial, halted due to derived interferon-α-2b (Loceteron TM ). The interferon α-2b severe toxicity in primates . Antisenseoligonucleotide attached to biodegradable microsphere providing slow 40 ISIS14803 – was in a phase-I trials, halted due to ALT level release of interferon-α-2b, allowing administration every 2 >10 times the upper limit of normal in patients 41 . week interval 32 . Loceteron with ribavirin in a phase-IIa trial showed antiviral efficacy with better safety and tolerability NS3/4A protease inhibitor (BILN2061) – was in a profile . 33 phase-I trials, halted because of cardiac toxicity in animals 42 . GS-9132 – was in a phase-I trial, halted because of nephro RIBAVIRIN ANALOGUE toxicity in patients 43 . Taribavirin – (Viramidine) is a prodrug of ribavirin, converted to ribavirin in liver. The advantage with (NM283) (a nucleoside analogue) NS5B- taribavirin is that the haemolytic anaemia which is the main RNA polymerase inhibitor - was in a phase-I trial, halted due

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Author Information Rajiv Kumar, MD Associate Professor, Deptt. of Pharmacology, Govt. Medical College & Hospital

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