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

Details

• Alternative Title:
  Open Forum Infect Dis
• Personal Author:
  Jordan, Robert ; Hogg, Alison ; Warren, Travis ; De Wit, Emmie ; Sheahan, Timothy ; Lo, Michael ; Soloveva, Veronica ; Weidner, Jessica ; Gomba, Laura ; Feldmann, Friederike ; Cronin, Jacqueline ; Sims, Amy ; Cockrell, Adam ; Feng, Joy ; Trantcheva, Iva ; Babusis, Darius ; Porter-Poulin, Danielle ; Bannister, Roy ; Mackman, Richard ; Siegel, Dustin ; Ray, Adrian ; Denison, Mark ; Spiropoulou, Christina ; Nichol, Stuart ; Cihlar, Tomas ; Baric, Ralph ; Feldmann, Heinrich ; Bavari, Sina
• Description:
  Background
  
  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
  
  
• Subjects:
  Ebola Vaccine Ebolavirus Hemorrhagic Fever, Ebola
• Source:
  Open Forum Infect Dis. 2017; 4(Suppl 1):S737.
• Pubmed Central ID:
  PMC5630887
• Document Type:
  Journal Article
• Volume:
  4
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:63f5bc6f347f62a85a6f095dae19f49a94f22905a2ea61038882038ae7edf582
• Download URL:
  https://stacks.cdc.gov/view/cdc/53872/cdc_53872_DS1.pdf
• File Type:
  [PDF - 258.54 KB ]