Hepatitis C future or investigational therapies: Difference between revisions

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{{Hepatitis C}}
{{Hepatitis C}}
{{CMG}}; '''Assistant Editor-In-Chief:''' Nina Axiotakis [mailto:naxiotak@oberlin.edu]
{{CMG}}; '''Assistant Editor-In-Chief:''' Nina Axiotakis [mailto:naxiotak@oberlin.edu]
==Overview==
Several investigational drugs are being tested for use in hepatitis C such as danoprevir, asunaprevir, vaniprevir, and ledipasvir among others.


==Future Or Investigational Therapies==
==Future Or Investigational Therapies==
The drug [[viramidine]], which is a prodrug of [[ribavirin]] which has better targeting for the liver, and therefore may be more effective against hepatitis C for a given tolerated dose, is in phase III experimental trials against hepatitis C. It will be used in conjunction with [[interferon]], in the same manner as ribavirin. However, this drug is not expected to be active against ribavirin-resistant strains, and the use of the drug against infections which have already failed ribavirin/interferon treatment, is unproven.<p> There are new drugs under development like the [[protease inhibitor (pharmacology)|protease inhibitors]] (including ''[[VX 950]]'') and polymerase inhibitors (such as ''NM 283''), but development of these is still in the early phase.<!--
Several investigational drugs are being tested for use in hepatitis C. These agents focus on proteins essential for viral replication. The table below summarizes the agents currently being investigated.
  --><ref name="hinrichsen">{{cite journal | author = Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens R, Calleja J, Forns X, Erhardt A, Crönlein J, Chaves R, Yong C, Nehmiz G, Steinmann G | title = Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. | journal = Gastroenterology | volume = 127 | issue = 5 | pages = 1347-55 | year = 2004 | id = PMID 15521004}}</ref><!--
  --><ref name="lamarre">{{cite journal | author = Lamarre D, Anderson P, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bös M, Cameron D, Cartier M, Cordingley M, Faucher A, Goudreau N, Kawai S, Kukolj G, Lagacé L, LaPlante S, Narjes H, Poupart M, Rancourt J, Sentjens R, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos Y, Weldon S, Yong C, Llinàs-Brunet M | title = An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. | journal = Nature | volume = 426 | issue = 6963 | pages = 186-9 | year = 2003 | id = PMID 14578911 doi:10.1038/nature02099}}</ref>
One protease inhibitor, ''BILN 2061'', had to be discontinued due to safety problems early in the clinical testing. Some more modern new drugs that provide some support in treating HCV are ''Albuferon'', ''Zadaxin'', and ''DAPY''. Antisense phosphorothioate oligos have been targeted to hepatitis C<!--
  --><ref name="zhang">{{cite journal | author = Zhang H, Hanecak R, Brown-Driver V, Azad R, Conklin B, Fox M, Anderson K | title = Antisense oligonucleotide inhibition of hepatitis C virus (HCV) gene expression in livers of mice infected with an HCV-vaccinia virus recombinant. | journal = Antimicrob Agents Chemother | volume = 43 | issue = 2 | pages = 347-53 | year = 1999 | id = PMID 9925530 | url=http://aac.asm.org/cgi/content/full/43/2/347?view=long&pmid=9925530}}</ref>.  Antisense [[Morpholino]] oligos have shown promise in preclinical studies<!--
  --><ref name="mccaffrey">{{cite journal | author = McCaffrey A, Meuse L, Karimi M, Contag C, Kay M | title = A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice. | journal = Hepatology | volume = 38 | issue = 2 | pages = 503-8 | year = 2003 | id = PMID 12883495}}</ref> and are in a clinical [http://clinicaltrials.gov/ct/show/NCT00229749?order=1| trial].


All of these are not approved remedies and have not yet demonstrated their efficacy in clinical trials.
{| {{table}} style="align:center; text-align:center; width:700px;"
| align="center" style="background:#f0f0f0;"|'''Name'''
| align="center" style="background:#f0f0f0;"|'''Alternative'''
| align="center" style="background:#f0f0f0;"|'''Mechanism of Action'''
|-
| Danoprevir<ref name="pmid23672640">{{cite journal| author=Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S et al.| title=Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease. | journal=J Med Chem | year= 2014 | volume= 57 | issue= 5 | pages= 1753-69 | pmid=23672640 | doi=10.1021/jm400164c | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23672640  }} </ref>||RG7227/ITMN-191||Inhibitor of the HCV NS3/4A serine protease
|-
| Asunaprevir<ref name="pmid24704773">{{cite journal| author=Eley T, He B, Chang I, Colston E, Child M, Bedford W et al.| title=The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor. | journal=Antivir Ther | year= 2014 | volume=  | issue=  | pages=  | pmid=24704773 | doi=10.3851/IMP2773 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24704773  }} </ref>||BMS-650032||Inhibitor of the HCV NS3/4A serine protease
|-
| Vaniprevir<ref name="pmid23439259">{{cite journal| author=Lawitz E, Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Bhanja S et al.| title=A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. | journal=J Hepatol | year= 2013 | volume= 59 | issue= 1 | pages= 11-7 | pmid=23439259 | doi=10.1016/j.jhep.2013.02.008 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23439259  }} </ref> ||MK-7009||Inhibitor of the HCV NS3/4A serine protease
|-
| Daclatasvir<ref name="pmid23931586">{{cite journal| author=Herbst DA, Reddy KR| title=NS5A inhibitor, daclatasvir, for the treatment of chronic hepatitis C virus infection. | journal=Expert Opin Investig Drugs | year= 2013 | volume= 22 | issue= 10 | pages= 1337-46 | pmid=23931586 | doi=10.1517/13543784.2013.826189 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23931586  }} </ref>||BMS-790052||Inhibitor of the HCV non-structural protein NS5A
|-
| Mericitabine<ref name="pmid23359491">{{cite journal| author=Pockros PJ, Jensen D, Tsai N, Taylor R, Ramji A, Cooper C et al.| title=JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients. | journal=Hepatology | year= 2013 | volume= 58 | issue= 2 | pages= 514-23 | pmid=23359491 | doi=10.1002/hep.26275 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23359491  }} </ref> ||RG7128||Inhibitor of the HCV NS5B polymerase
|-
| Ledipasvir<ref name="pmid24720702">{{cite journal| author=Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E et al.| title=Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 20 | pages= 1879-88 | pmid=24720702 | doi=10.1056/NEJMoa1402355 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24720702  }} </ref>||GS-5885||Inhibitor of the HCV non-structural protein NS5A
|-
| Faldaprevir<ref name="pmid23944720">{{cite journal| author=Nishiguchi S, Sakai Y, Kuboki M, Tsunematsu S, Urano Y, Sakamoto W et al.| title=Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection. | journal=Liver Int | year= 2014 | volume= 34 | issue= 1 | pages= 78-88 | pmid=23944720 | doi=10.1111/liv.12254 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23944720  }} </ref>||BI-2010335||Protease inhibitor
|-
|}


[[Immunoglobulin]]s against the hepatitis C virus exist and newer types are under development. Thus far, their roles have been unclear as they have not been shown to help in clearing chronic infection or in the prevention of infection with acute exposures (e.g. needlesticks). They do have a limited role in transplant patients.
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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Latest revision as of 22:05, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Nina Axiotakis [2]

Overview

Several investigational drugs are being tested for use in hepatitis C such as danoprevir, asunaprevir, vaniprevir, and ledipasvir among others.

Future Or Investigational Therapies

Several investigational drugs are being tested for use in hepatitis C. These agents focus on proteins essential for viral replication. The table below summarizes the agents currently being investigated.

Name Alternative Mechanism of Action
Danoprevir[1] RG7227/ITMN-191 Inhibitor of the HCV NS3/4A serine protease
Asunaprevir[2] BMS-650032 Inhibitor of the HCV NS3/4A serine protease
Vaniprevir[3] MK-7009 Inhibitor of the HCV NS3/4A serine protease
Daclatasvir[4] BMS-790052 Inhibitor of the HCV non-structural protein NS5A
Mericitabine[5] RG7128 Inhibitor of the HCV NS5B polymerase
Ledipasvir[6] GS-5885 Inhibitor of the HCV non-structural protein NS5A
Faldaprevir[7] BI-2010335 Protease inhibitor

References

  1. ↑ Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S; et al. (2014). "Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease". J Med Chem. 57 (5): 1753–69. doi:10.1021/jm400164c. PMID 23672640.
  2. ↑ Eley T, He B, Chang I, Colston E, Child M, Bedford W; et al. (2014). "The effect of hepatic impairment on the pharmacokinetics of asunaprevir, an HCV NS3 protease inhibitor". Antivir Ther. doi:10.3851/IMP2773. PMID 24704773.
  3. ↑ Lawitz E, Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Bhanja S; et al. (2013). "A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment". J Hepatol. 59 (1): 11–7. doi:10.1016/j.jhep.2013.02.008. PMID 23439259.
  4. ↑ Herbst DA, Reddy KR (2013). "NS5A inhibitor, daclatasvir, for the treatment of chronic hepatitis C virus infection". Expert Opin Investig Drugs. 22 (10): 1337–46. doi:10.1517/13543784.2013.826189. PMID 23931586.
  5. ↑ Pockros PJ, Jensen D, Tsai N, Taylor R, Ramji A, Cooper C; et al. (2013). "JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients". Hepatology. 58 (2): 514–23. doi:10.1002/hep.26275. PMID 23359491.
  6. ↑ Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E; et al. (2014). "Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis". N Engl J Med. 370 (20): 1879–88. doi:10.1056/NEJMoa1402355. PMID 24720702.
  7. ↑ Nishiguchi S, Sakai Y, Kuboki M, Tsunematsu S, Urano Y, Sakamoto W; et al. (2014). "Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection". Liver Int. 34 (1): 78–88. doi:10.1111/liv.12254. PMID 23944720.

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