Broad Spectrum Antiviral Remdesivir for the Treatment of Emerging Viral Infections with High Outbreak Potential
Danielle Porter1, Travis Warren2, Emmie de Wit3, Timothy Sheahan4, Michael Lo5, Jessica Weidner2, Laura Gomba2, Friederike Feldmann3, Jacqueline Cronin3, Amy Sims4, Adam Cockrell4, Joy Feng1, Darius Babusis1, Roy Bannister1, Richard Mackman1, Huyen Cao1, Scott Sellers1, Mark Denison6, Christina Spiropoulou5, Robert Jordan1, Michel Perron1, Tomas Cihlar1, Stuart Nichol5, Ralph Baric4, Heinrich Feldmann3, Sina Bavari2.
1Gilead Sciences Inc. Foster City, CA, USA; 2United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA; 3National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA; 4University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Centers for Disease Control and Prevention, Atlanta, GA, USA; 6Vanderbilt University Medical Center, Nashville, TN, USA
Remdesivir (RDV, GS-5734) is a nucleotide prodrug with potent in vitro activity against multiple emerging virus families with high outbreak potential including filoviruses, coronaviruses and paramyxoviruses (Warren et al, Nature 2016; Sheahan et al, Sci. Transl. Med. 2017; Lo et al, Sci. Rep. 2017). Herein, we describe the in vivo efficacy of RDV in various animal models of emerging viral infections.
Rhesus monkeys infected with lethal doses of Ebola virus (Kikwit or Makona) or Marburg virus (Angola) and treated with i.v. administration of 5-10 mg/kg RDV once-daily starting 3 to 5 days post-infection (p.i.) demonstrated 60-100% survival depending on the treatment regimen. In surviving animals, RDV treatment reduced systemic viremia and ameliorated severe clinical disease signs. In mice infected with MERS coronavirus, twice-daily s.c. administration of 25 mg/kg RDV beginning 1 day p.i. significantly reduced lung viral load and improved respiratory functions. In rhesus monkeys, once-daily i.v. administration of 5 mg/kg RDV initiated 1 day prior to MERS coronavirus infection reduced lung viral load, and improved clinical disease and lung pathology. In African green monkeys infected with a lethal dose of Nipah virus (Bangladesh), once-daily i.v. dosing of 10 mg/kg RDV starting 1 day p.i. resulted in 100% survival without any major disease symptoms.
Ph1 studies with RDV have been completed. RDV has been used for post-exposure prophylaxis and treatment of Ebola virus infection under several emergency protocols, and is now being tested in a Ph2 study in male Ebola survivors with persistent viral shedding in semen. Lyophilized drug formulation that does not require cold chain has been developed and made available for the recent Ebola outbreak in the DRC. Together, the current preclinical and clinical drug profiles support further development of RDV as a broad spectrum antiviral to manage emerging viral infections with high mortality and significant outbreak potential.