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Broad-spectrum Investigational Agent GS-5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Viral Infections with High Outbreak Potential

Identifieur interne : 000E76 ( Main/Exploration ); précédent : 000E75; suivant : 000E77

Broad-spectrum Investigational Agent GS-5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Viral Infections with High Outbreak Potential

Auteurs : Robert Jordan ; Alison Hogg ; Travis Warren ; Emmie De Wit ; Timothy Sheahan ; Michael Lo ; Veronica Soloveva ; Jessica Weidner ; Laura Gomba ; Friederike Feldmann ; Jacqueline Cronin ; Amy Sims ; Adam Cockrell ; Joy Feng ; Iva Trantcheva ; Darius Babusis ; Danielle Porter-Poulin ; Roy Bannister ; Richard Mackman ; Dustin Siegel ; Adrian Ray ; Mark Denison [États-Unis] ; Christina Spiropoulou ; Stuart Nichol ; Tomas Cihlar ; Ralph Baric ; Heinrich Feldmann ; Sina Bavari

Source :

RBID : PMC:5630887

Abstract

AbstractBackground

Recent viral outbreaks with significant mortality such as Ebola virus (EBOV), SARS-coronavirus (CoV), and MERS-CoV reinforced the need for effective antiviral therapeutics to control future epidemics. GS-5734 is a novel nucleotide analog prodrug in the development for treatment of EBOV.

Method

Antiviral activity of GS-5734 has been established in vitro against a wide range of pathogenic RNA virus families, including filoviruses, coronaviruses, and paramyxoviruses (EC50 = 37 to 200 nM) (Warren et al., Nature 2016; Sheahan et al., Sci Transl Med 2017; Lo et al., Sci Rep 2017). Herein, we describe the in vivo translation of the broad-spectrum activity of GS-5734 in relevant animal disease models for Ebola, Marburg, MERS-CoV, and Nipah.

Result

Therapeutic efficacy against multiple filoviruses with 80–100% survival was observed in rhesus monkeys infected with lethal doses of EBOV (Kikwit/1995 or Makona/2014) or Marburg virus and treated with once daily intravenous (IV) administration of 5 to 10 mg/kg GS-5734 beginning 3 to 5 days post-infection (p.i.). In all rhesus monkey filovirus infection models, GS-5734 significantly reduced systemic viremia and ameliorated severe clinical disease signs and anatomic pathology. In mice infected with MERS-CoV, twice daily subcutaneous administration of 25 mg/kg GS-5734 beginning 1 day p.i. significantly reduced lung viral load and improved respiratory function. In rhesus monkeys, once-daily IV administration of 5 mg/kg GS-5734 initiated 1 day prior to MERS-CoV infection reduced lung viral load, improved clinical disease signs, and ameliorated severe lung pathology. Finally, in African green monkeys infected with a lethal dose of Nipah virus therapeutic once-daily IV administration of 10 mg/kg GS-5734, starting 1 day p.i. resulted in 100% survival to at least day 35 without any major respiratory or CNS symptoms.

Conclusion

GS-5734 is currently being tested in a phase 2 study in male Ebola survivors with persistent viral RNA in semen. Lyophilized drug formulation has been developed that can be administered to humans via a 30-minutes IV infusion and does not require cold chain storage. Together, these results support further development of GS-5734 as a broad-spectrum antiviral to treat viral infections with high mortality and significant outbreak potential.

Disclosures

R. Jordan, Gilead: Employee, Salary. J. Feng, Gilead: Employee, Salary

I. Trantcheva, Gilead: Employee, Salary. D. Babusis, Gilead: Employee, Salary. D. Porter-Poulin, Gilead: Employee, Salary. R. Bannister, Gilead: Employee, Salary

R. Mackman, Gilead: Employee, Salary. D. Siegel, Gilead: Employee, Salary

A. Ray, Gilead: Employee, Salary, T. Cihlar, Gilead: Employee, Salary.


Url:
DOI: 10.1093/ofid/ofx180.008
PubMed: NONE
PubMed Central: 5630887


Affiliations:

Links toward previous steps (curation, corpus...)

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<title xml:lang="en" level="a" type="main">Broad-spectrum Investigational Agent GS-5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Viral Infections with High Outbreak Potential</title>
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<name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
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<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
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<name sortKey="Hogg, Alison" sort="Hogg, Alison" uniqKey="Hogg A" first="Alison" last="Hogg">Alison Hogg</name>
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<name sortKey="De Wit, Emmie" sort="De Wit, Emmie" uniqKey="De Wit E" first="Emmie" last="De Wit">Emmie De Wit</name>
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<name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name>
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<name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name>
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<name sortKey="Cronin, Jacqueline" sort="Cronin, Jacqueline" uniqKey="Cronin J" first="Jacqueline" last="Cronin">Jacqueline Cronin</name>
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<name sortKey="Cockrell, Adam" sort="Cockrell, Adam" uniqKey="Cockrell A" first="Adam" last="Cockrell">Adam Cockrell</name>
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<name sortKey="Feng, Joy" sort="Feng, Joy" uniqKey="Feng J" first="Joy" last="Feng">Joy Feng</name>
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</affiliation>
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<name sortKey="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
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<nlm:aff id="AF0001">
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,
<addr-line>Foster City, California</addr-line>
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</affiliation>
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<name sortKey="Babusis, Darius" sort="Babusis, Darius" uniqKey="Babusis D" first="Darius" last="Babusis">Darius Babusis</name>
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<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
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<author>
<name sortKey="Porter Poulin, Danielle" sort="Porter Poulin, Danielle" uniqKey="Porter Poulin D" first="Danielle" last="Porter-Poulin">Danielle Porter-Poulin</name>
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<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bannister, Roy" sort="Bannister, Roy" uniqKey="Bannister R" first="Roy" last="Bannister">Roy Bannister</name>
<affiliation>
<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mackman, Richard" sort="Mackman, Richard" uniqKey="Mackman R" first="Richard" last="Mackman">Richard Mackman</name>
<affiliation>
<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
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<name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
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<nlm:aff id="AF0001">
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,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ray, Adrian" sort="Ray, Adrian" uniqKey="Ray A" first="Adrian" last="Ray">Adrian Ray</name>
<affiliation>
<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Denison, Mark" sort="Denison, Mark" uniqKey="Denison M" first="Mark" last="Denison">Mark Denison</name>
<affiliation wicri:level="2">
<nlm:aff id="AF0006">
<institution>Pediatrics, Vanderbilt University Medical Center</institution>
,
<addr-line>Nashville, Tennessee</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName>
<region type="state">Tennessee</region>
</placeName>
<wicri:cityArea>Nashville</wicri:cityArea>
</affiliation>
</author>
<author>
<name sortKey="Spiropoulou, Christina" sort="Spiropoulou, Christina" uniqKey="Spiropoulou C" first="Christina" last="Spiropoulou">Christina Spiropoulou</name>
<affiliation>
<nlm:aff id="AF0005">
<institution>Centers for Disease Control and Prevention</institution>
,
<addr-line>Atlanta, Georgia</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Nichol, Stuart" sort="Nichol, Stuart" uniqKey="Nichol S" first="Stuart" last="Nichol">Stuart Nichol</name>
<affiliation>
<nlm:aff id="AF0005">
<institution>Centers for Disease Control and Prevention</institution>
,
<addr-line>Atlanta, Georgia</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<affiliation>
<nlm:aff id="AF0001">
<institution>Gilead Sciences, Inc.</institution>
,
<addr-line>Foster City, California</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name>
<affiliation>
<nlm:aff id="AF0004">
<institution>Department of Epidemiology, University of North Carolina at Chapel Hill</institution>
,
<addr-line>Chapel Hill, North Carolina</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Feldmann, Heinrich" sort="Feldmann, Heinrich" uniqKey="Feldmann H" first="Heinrich" last="Feldmann">Heinrich Feldmann</name>
<affiliation>
<nlm:aff id="AF0003">
<institution>Laboratory of Virology, Division of Intramural Research, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories</institution>
,
<addr-line>Hamilton, Montana</addr-line>
;</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Bavari, Sina" sort="Bavari, Sina" uniqKey="Bavari S" first="Sina" last="Bavari">Sina Bavari</name>
<affiliation>
<nlm:aff id="AF0002">
<institution>United States Army Medical Research Institute of Infectious Diseases</institution>
,
<addr-line>Frederick, Maryland</addr-line>
;</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Open Forum Infectious Diseases</title>
<idno type="eISSN">2328-8957</idno>
<imprint>
<date when="2017">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<title>Abstract</title>
<sec id="s1">
<title>Background</title>
<p>Recent viral outbreaks with significant mortality such as Ebola virus (EBOV), SARS-coronavirus (CoV), and MERS-CoV reinforced the need for effective antiviral therapeutics to control future epidemics. GS-5734 is a novel nucleotide analog prodrug in the development for treatment of EBOV.</p>
</sec>
<sec id="s2">
<title>Method</title>
<p>Antiviral activity of GS-5734 has been established in vitro against a wide range of pathogenic RNA virus families, including filoviruses, coronaviruses, and paramyxoviruses (EC
<sub>50</sub>
 = 37 to 200 nM) (
<italic>Warren et al., Nature 2016; Sheahan et al., Sci Transl Med 2017; Lo et al., Sci Rep 2017</italic>
). Herein, we describe the in vivo translation of the broad-spectrum activity of GS-5734 in relevant animal disease models for Ebola, Marburg, MERS-CoV, and Nipah.</p>
</sec>
<sec id="s3">
<title>Result</title>
<p>Therapeutic efficacy against multiple filoviruses with 80–100% survival was observed in rhesus monkeys infected with lethal doses of EBOV (Kikwit/1995 or Makona/2014) or Marburg virus and treated with once daily intravenous (IV) administration of 5 to 10 mg/kg GS-5734 beginning 3 to 5 days post-infection (p.i.). In all rhesus monkey filovirus infection models, GS-5734 significantly reduced systemic viremia and ameliorated severe clinical disease signs and anatomic pathology. In mice infected with MERS-CoV, twice daily subcutaneous administration of 25 mg/kg GS-5734 beginning 1 day p.i. significantly reduced lung viral load and improved respiratory function. In rhesus monkeys, once-daily IV administration of 5 mg/kg GS-5734 initiated 1 day prior to MERS-CoV infection reduced lung viral load, improved clinical disease signs, and ameliorated severe lung pathology. Finally, in African green monkeys infected with a lethal dose of Nipah virus therapeutic once-daily IV administration of 10 mg/kg GS-5734, starting 1 day p.i. resulted in 100% survival to at least day 35 without any major respiratory or CNS symptoms.</p>
</sec>
<sec id="s4">
<title>Conclusion</title>
<p>GS-5734 is currently being tested in a phase 2 study in male Ebola survivors with persistent viral RNA in semen. Lyophilized drug formulation has been developed that can be administered to humans via a 30-minutes IV infusion and does not require cold chain storage. Together, these results support further development of GS-5734 as a broad-spectrum antiviral to treat viral infections with high mortality and significant outbreak potential.</p>
</sec>
<sec id="s5">
<title>Disclosures</title>
<p>
<bold>R. Jordan</bold>
, Gilead: Employee, Salary.
<bold>J. Feng</bold>
, Gilead: Employee, Salary</p>
<p>
<bold>I. Trantcheva</bold>
, Gilead: Employee, Salary.
<bold>D. Babusis</bold>
, Gilead: Employee, Salary.
<bold>D. Porter-Poulin</bold>
, Gilead: Employee, Salary.
<bold>R. Bannister</bold>
, Gilead: Employee, Salary</p>
<p>
<bold>R. Mackman</bold>
, Gilead: Employee, Salary.
<bold>D. Siegel</bold>
, Gilead: Employee, Salary</p>
<p>
<bold>A. Ray</bold>
, Gilead: Employee, Salary,
<bold>T. Cihlar</bold>
, Gilead: Employee, Salary.</p>
</sec>
</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>États-Unis</li>
</country>
<region>
<li>Tennessee</li>
</region>
</list>
<tree>
<noCountry>
<name sortKey="Babusis, Darius" sort="Babusis, Darius" uniqKey="Babusis D" first="Darius" last="Babusis">Darius Babusis</name>
<name sortKey="Bannister, Roy" sort="Bannister, Roy" uniqKey="Bannister R" first="Roy" last="Bannister">Roy Bannister</name>
<name sortKey="Baric, Ralph" sort="Baric, Ralph" uniqKey="Baric R" first="Ralph" last="Baric">Ralph Baric</name>
<name sortKey="Bavari, Sina" sort="Bavari, Sina" uniqKey="Bavari S" first="Sina" last="Bavari">Sina Bavari</name>
<name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name>
<name sortKey="Cockrell, Adam" sort="Cockrell, Adam" uniqKey="Cockrell A" first="Adam" last="Cockrell">Adam Cockrell</name>
<name sortKey="Cronin, Jacqueline" sort="Cronin, Jacqueline" uniqKey="Cronin J" first="Jacqueline" last="Cronin">Jacqueline Cronin</name>
<name sortKey="De Wit, Emmie" sort="De Wit, Emmie" uniqKey="De Wit E" first="Emmie" last="De Wit">Emmie De Wit</name>
<name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name>
<name sortKey="Feldmann, Heinrich" sort="Feldmann, Heinrich" uniqKey="Feldmann H" first="Heinrich" last="Feldmann">Heinrich Feldmann</name>
<name sortKey="Feng, Joy" sort="Feng, Joy" uniqKey="Feng J" first="Joy" last="Feng">Joy Feng</name>
<name sortKey="Gomba, Laura" sort="Gomba, Laura" uniqKey="Gomba L" first="Laura" last="Gomba">Laura Gomba</name>
<name sortKey="Hogg, Alison" sort="Hogg, Alison" uniqKey="Hogg A" first="Alison" last="Hogg">Alison Hogg</name>
<name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name>
<name sortKey="Lo, Michael" sort="Lo, Michael" uniqKey="Lo M" first="Michael" last="Lo">Michael Lo</name>
<name sortKey="Mackman, Richard" sort="Mackman, Richard" uniqKey="Mackman R" first="Richard" last="Mackman">Richard Mackman</name>
<name sortKey="Nichol, Stuart" sort="Nichol, Stuart" uniqKey="Nichol S" first="Stuart" last="Nichol">Stuart Nichol</name>
<name sortKey="Porter Poulin, Danielle" sort="Porter Poulin, Danielle" uniqKey="Porter Poulin D" first="Danielle" last="Porter-Poulin">Danielle Porter-Poulin</name>
<name sortKey="Ray, Adrian" sort="Ray, Adrian" uniqKey="Ray A" first="Adrian" last="Ray">Adrian Ray</name>
<name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name>
<name sortKey="Siegel, Dustin" sort="Siegel, Dustin" uniqKey="Siegel D" first="Dustin" last="Siegel">Dustin Siegel</name>
<name sortKey="Sims, Amy" sort="Sims, Amy" uniqKey="Sims A" first="Amy" last="Sims">Amy Sims</name>
<name sortKey="Soloveva, Veronica" sort="Soloveva, Veronica" uniqKey="Soloveva V" first="Veronica" last="Soloveva">Veronica Soloveva</name>
<name sortKey="Spiropoulou, Christina" sort="Spiropoulou, Christina" uniqKey="Spiropoulou C" first="Christina" last="Spiropoulou">Christina Spiropoulou</name>
<name sortKey="Trantcheva, Iva" sort="Trantcheva, Iva" uniqKey="Trantcheva I" first="Iva" last="Trantcheva">Iva Trantcheva</name>
<name sortKey="Warren, Travis" sort="Warren, Travis" uniqKey="Warren T" first="Travis" last="Warren">Travis Warren</name>
<name sortKey="Weidner, Jessica" sort="Weidner, Jessica" uniqKey="Weidner J" first="Jessica" last="Weidner">Jessica Weidner</name>
</noCountry>
<country name="États-Unis">
<region name="Tennessee">
<name sortKey="Denison, Mark" sort="Denison, Mark" uniqKey="Denison M" first="Mark" last="Denison">Mark Denison</name>
</region>
</country>
</tree>
</affiliations>
</record>

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