LB-2. Nucleotide Prodrug GS-5734 is a Broad-Spectrum Filovirus Inhibitor that Provides Complete Therapeutic Protection Against the Development of Ebola Virus Disease (EVD) in Infected Non-human Primates
Session: Oral Abstract Session: Late Breaker Oral Abstract Session
Saturday, October 10, 2015: 10:40 AM
Room: 7--AB
Background: The high case-fatality rate during the recent Ebola virus (EBOV) outbreak in West Africa is due in part to the lack of effective antiviral therapies. Antiviral screening against EBOV identified GS-5734, a prodrug of adenine nucleotide analog, as an inhibitor of pathogenic filoviruses.

Method: In vitro activity was tested in filovirus-infected human endothelial cells, liver cells, and macrophages using quantitative GFP expression, PCR, and/or immunostaining. Intracellular metabolism was determined by LC/MS/MS and polymerase (pol) inhibition was tested in biochemical assays. Efficacy was assessed in blinded, placebo-controlled studies in EBOV-infected rhesus monkeys. Animals infected on Day 0 (N= 6 per treatment group) were treated once-daily for 12 days by intramuscular (IM) or intravenous (IV) injection. Survival (Day 28 post infection), plasma viral RNA, and signs of Ebola virus disease (EVD) were monitored.

Result: GS-5734 inhibits Ebola virus (Kikwit and Makona variants), Sudan, and Marburg virus (EC50 = 0.01 to 0.20 µM), and exhibits low cytotoxicity (CC50 = 2 to > 20 µM) in multiple human cell types. The compound undergoes fast intracellular conversion to the nucleoside triphosphate metabolite that persists in cells (T1/2 > 10 h) and inhibits a surrogate viral RNA pol from respiratory syncytial virus (IC50 = 1 µM), but not host mitochondrial RNA or DNA pols (IC50 > 200 µM). IM treatment of EBOV-infected monkeys with 3 mg/kg GS-5734 initiated after the detection of systemic viremia (Day 2 to 4) resulted in 50% survival compared to no survival in placebo-treated control animals (P < 0.003). Administration of 10 mg/kg GS-5734 IV initiated on Day 3 was associated with 100% survival, mean plasma viral RNA reduction of up to 5 log10 copies/mL relative to placebo (P < 0.001), and a profound suppression of EVD signs including thrombocytopenia, coagulopathy and serum chemistry alterations.

Conclusion: GS-5734 represents the first small-molecule antiviral agent that demonstrates robust therapeutic efficacy in a monkey model of EVD. Coupled with the potential for broad-spectrum anti-filovirus activity, further development of GS-5734 for the treatment of EBOV and other hemorrhagic filovirus infections is warranted.

Travis Warren, Ph.D.1, Robert Jordan, Ph.D.2, Michale Lo, Ph.D.3, Veronica Soloveva, Ph.D.4, Adrian Ray, Ph.D.2, Roy Bannister, Ph.D.2, Richard Mackman, Ph.D.2, Michel Perron, Ph.D.2, Kirsten Stray, B.S.2, Joy Feng, Ph.D.2, Yili Xu, Ph.D.2, Jay Wells, Ph.D.4, Kelly Stuthman, Ph.D.4, Lisa Welch, Ph.D.4, Edward Doerffler, Ph.D.2, Lijun Zhang, Ph.D.2, Kwon Chun, Ph.D.2, Hon Hui, Ph.D.2, Sean Neville, Ph.D.2, Willard Lew, Ph.D.2, Yeojin Park, Ph.D.2, Darius Babusis, Ph.D.2, Robert Strickley, Ph.D.2, Pamela Wong, Ph.D.2, Swami Swaminathan, Ph.D.2, William Lee, Ph.D.2, Douglas Mayers, Ph.D.4, Tomas Cihlar, Ph.D.2 and Sina Bavari, Ph.D.4, (1)Molecular and Translational Sciences, USAMRIID, Fort Detrick, MD, (2)Gilead Sciences, Foster City, CA, (3)Virology, Centers for Disease Control and Prevention, Atlanta, GA, (4)USAMRIID, Fort Detrick, MD

Disclosures:

T. Warren, None

R. Jordan, Gilead Sciences: Employee and Shareholder , Salary

M. Lo, None

V. Soloveva, None

A. Ray, Gilead Sciences: Employee and Shareholder , Salary

R. Bannister, Gilead Sciences: Employee and Shareholder , Salary

R. Mackman, Gilead Sciences: Employee and Shareholder , Salary

M. Perron, Gilead Sciences: Employee and Shareholder , Salary

K. Stray, Gilead Sciences: Employee and Shareholder , Salary

J. Feng, Gilead: Employee and Shareholder , Salary

Y. Xu, Gilead: Employee and Shareholder , Salary

J. Wells, None

K. Stuthman, None

L. Welch, None

E. Doerffler, Gilead: Employee and Shareholder , Salary

L. Zhang, Gilead: Employee and Shareholder , Salary

K. Chun, Gilead: Employee and Shareholder , Salary

H. Hui, Gilead: Employee and Shareholder , Salary

S. Neville, Gilead: Employee and Shareholder , Salary

W. Lew, Gilead: Employee and Shareholder , Salary

Y. Park, Gilead: Employee and Shareholder , Salary

D. Babusis, Gilead: Employee and Shareholder , Salary

R. Strickley, Gilead: Employee and Shareholder , Salary

P. Wong, Gilead: Employee and Shareholder , Salary

S. Swaminathan, Gilead: Employee and Shareholder , Salary

W. Lee, Gilead: Employee and Shareholder , Salary

D. Mayers, None

T. Cihlar, Gilead Sciences: Employee and Shareholder , Salary

S. Bavari, None

Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.