Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Travis K. Warren; Robert Jordan; Michael K. Lo; Adrian S. Ray; Richard L. Mackman; Veronica Soloveva; Dustin Siegel; Michel Perron; Roy Bannister; Hon C. Hui; Nate Larson; Robert Strickley; Jay Wells; Kelly S. Stuthman; Sean A. Van Tongeren; Nicole L. Garza; Ginger Donnelly; Amy C. Shurtleff; Cary J. Retterer; Dima Gharaibeh; Rouzbeh Zamani; Tara Kenny; Brett P. Eaton; Elizabeth Grimes; Lisa S. Welch; Laura Gomba; Catherine L. Wilhelmsen; Donald K. Nichols; Jonathan E. Nuss; Elyse R. Nagle; Jeffrey R. Kugelman; Gustavo Palacios; Edward Doerffler; Sean Neville; Ernest Carra; Michael O. Clarke; Lijun Zhang; Willard Lew; Bruce Ross; Queenie Wang; Kwon Chun; Lydia Wolfe; Darius Babusis; Yeojin Park; Kirsten M. Stray; Iva Trancheva; Joy Y. Feng; Ona Barauskas; Yili Xu; Pamela Wong; Molly R. Braun; Mike Flint; Laura K. McMullan; Shan Shan Chen; Rachel Fearns; Swami Swaminathan; Douglas L. Mayers; Christina F. Spiropoulou; William A. Lee; Stuart T. Nichol; Tomas Cihlar; Sina Bavari

doi:10.1038/nature17180

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Travis K. Warren, Robert Jordan, Michael K. Lo, Adrian S. Ray, Richard L. Mackman, Veronica Soloveva, Dustin Siegel, Michel Perron, Roy Bannister, Hon C. Hui, Nate Larson, Robert Strickley, Jay Wells, Kelly S. Stuthman, Sean A. Van Tongeren, Nicole L. Garza, Ginger Donnelly, Amy C. Shurtleff, Cary J. Retterer, Dima GharaibehRouzbeh Zamani, Tara Kenny, Brett P. Eaton, Elizabeth Grimes, Lisa S. Welch, Laura Gomba, Catherine L. Wilhelmsen, Donald K. Nichols, Jonathan E. Nuss, Elyse R. Nagle, Jeffrey R. Kugelman, Gustavo Palacios, Edward Doerffler, Sean Neville, Ernest Carra, Michael O. Clarke, Lijun Zhang, Willard Lew, Bruce Ross, Queenie Wang, Kwon Chun, Lydia Wolfe, Darius Babusis, Yeojin Park, Kirsten M. Stray, Iva Trancheva, Joy Y. Feng, Ona Barauskas, Yili Xu, Pamela Wong, Molly R. Braun, Mike Flint, Laura K. McMullan, Shan Shan Chen, Rachel Fearns, Swami Swaminathan, Douglas L. Mayers, Christina F. Spiropoulou, William A. Lee, Stuart T. Nichol, Tomas Cihlar, Sina Bavari

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Abstract

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg -1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

Original language	English
Pages (from-to)	381-385
Number of pages	5
Journal	Nature
Volume	531
Issue number	7594
DOIs	https://doi.org/10.1038/nature17180
State	Published - 17 Mar 2016
Externally published	Yes

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Warren, T. K., Jordan, R., Lo, M. K., Ray, A. S., Mackman, R. L., Soloveva, V., Siegel, D., Perron, M., Bannister, R., Hui, H. C., Larson, N., Strickley, R., Wells, J., Stuthman, K. S., Van Tongeren, S. A., Garza, N. L., Donnelly, G., Shurtleff, A. C., Retterer, C. J., ... Bavari, S. (2016). Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature, 531(7594), 381-385. https://doi.org/10.1038/nature17180

@article{413cb3987fae4e52a47aafc056a4be87,

title = "Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys",

abstract = "The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg -1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.",

author = "Warren, {Travis K.} and Robert Jordan and Lo, {Michael K.} and Ray, {Adrian S.} and Mackman, {Richard L.} and Veronica Soloveva and Dustin Siegel and Michel Perron and Roy Bannister and Hui, {Hon C.} and Nate Larson and Robert Strickley and Jay Wells and Stuthman, {Kelly S.} and {Van Tongeren}, {Sean A.} and Garza, {Nicole L.} and Ginger Donnelly and Shurtleff, {Amy C.} and Retterer, {Cary J.} and Dima Gharaibeh and Rouzbeh Zamani and Tara Kenny and Eaton, {Brett P.} and Elizabeth Grimes and Welch, {Lisa S.} and Laura Gomba and Wilhelmsen, {Catherine L.} and Nichols, {Donald K.} and Nuss, {Jonathan E.} and Nagle, {Elyse R.} and Kugelman, {Jeffrey R.} and Gustavo Palacios and Edward Doerffler and Sean Neville and Ernest Carra and Clarke, {Michael O.} and Lijun Zhang and Willard Lew and Bruce Ross and Queenie Wang and Kwon Chun and Lydia Wolfe and Darius Babusis and Yeojin Park and Stray, {Kirsten M.} and Iva Trancheva and Feng, {Joy Y.} and Ona Barauskas and Yili Xu and Pamela Wong and Braun, {Molly R.} and Mike Flint and McMullan, {Laura K.} and Chen, {Shan Shan} and Rachel Fearns and Swami Swaminathan and Mayers, {Douglas L.} and Spiropoulou, {Christina F.} and Lee, {William A.} and Nichol, {Stuart T.} and Tomas Cihlar and Sina Bavari",

note = "Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

month = mar,

day = "17",

doi = "10.1038/nature17180",

language = "English",

volume = "531",

pages = "381--385",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7594",

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Warren, TK, Jordan, R, Lo, MK, Ray, AS, Mackman, RL, Soloveva, V, Siegel, D, Perron, M, Bannister, R, Hui, HC, Larson, N, Strickley, R, Wells, J, Stuthman, KS, Van Tongeren, SA, Garza, NL, Donnelly, G, Shurtleff, AC, Retterer, CJ, Gharaibeh, D, Zamani, R, Kenny, T, Eaton, BP, Grimes, E, Welch, LS, Gomba, L, Wilhelmsen, CL, Nichols, DK, Nuss, JE, Nagle, ER, Kugelman, JR, Palacios, G, Doerffler, E, Neville, S, Carra, E, Clarke, MO, Zhang, L, Lew, W, Ross, B, Wang, Q, Chun, K, Wolfe, L, Babusis, D, Park, Y, Stray, KM, Trancheva, I, Feng, JY, Barauskas, O, Xu, Y, Wong, P, Braun, MR, Flint, M, McMullan, LK, Chen, SS, Fearns, R, Swaminathan, S, Mayers, DL, Spiropoulou, CF, Lee, WA, Nichol, ST, Cihlar, T & Bavari, S 2016, 'Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys', Nature, vol. 531, no. 7594, pp. 381-385. https://doi.org/10.1038/nature17180

TY - JOUR

T1 - Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

AU - Warren, Travis K.

AU - Jordan, Robert

AU - Lo, Michael K.

AU - Ray, Adrian S.

AU - Mackman, Richard L.

AU - Soloveva, Veronica

AU - Siegel, Dustin

AU - Perron, Michel

AU - Bannister, Roy

AU - Hui, Hon C.

AU - Larson, Nate

AU - Strickley, Robert

AU - Wells, Jay

AU - Stuthman, Kelly S.

AU - Van Tongeren, Sean A.

AU - Garza, Nicole L.

AU - Donnelly, Ginger

AU - Shurtleff, Amy C.

AU - Retterer, Cary J.

AU - Gharaibeh, Dima

AU - Zamani, Rouzbeh

AU - Kenny, Tara

AU - Eaton, Brett P.

AU - Grimes, Elizabeth

AU - Welch, Lisa S.

AU - Gomba, Laura

AU - Wilhelmsen, Catherine L.

AU - Nichols, Donald K.

AU - Nuss, Jonathan E.

AU - Nagle, Elyse R.

AU - Kugelman, Jeffrey R.

AU - Palacios, Gustavo

AU - Doerffler, Edward

AU - Neville, Sean

AU - Carra, Ernest

AU - Clarke, Michael O.

AU - Zhang, Lijun

AU - Lew, Willard

AU - Ross, Bruce

AU - Wang, Queenie

AU - Chun, Kwon

AU - Wolfe, Lydia

AU - Babusis, Darius

AU - Park, Yeojin

AU - Stray, Kirsten M.

AU - Trancheva, Iva

AU - Feng, Joy Y.

AU - Barauskas, Ona

AU - Xu, Yili

AU - Wong, Pamela

AU - Braun, Molly R.

AU - Flint, Mike

AU - McMullan, Laura K.

AU - Chen, Shan Shan

AU - Fearns, Rachel

AU - Swaminathan, Swami

AU - Mayers, Douglas L.

AU - Spiropoulou, Christina F.

AU - Lee, William A.

AU - Nichol, Stuart T.

AU - Cihlar, Tomas

AU - Bavari, Sina

PY - 2016/3/17

Y1 - 2016/3/17

N2 - The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg -1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

AB - The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg -1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

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U2 - 10.1038/nature17180

DO - 10.1038/nature17180

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AN - SCOPUS:84982234143

SN - 0028-0836

VL - 531

SP - 381

EP - 385

JO - Nature

JF - Nature

IS - 7594

ER -

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

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