Respiratory syncytial virus (RSV) is a common seasonal virus that most severely affects infants, immunosuppressed patients, and the elderly with cardiopulmonary disease.  Upper respiratory tract infection can progress to the lower respiratory tract causing bronchiolitis, pneumonia and respiratory failure. RSV is the leading cause of infant hospitalizations and has a mortality rate approximately 10x that of influenza in US infants. Currently there are no accepted effective antiviral options.  GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a hit originated from a phenotypic RSV antiviral high-throughput screen. Lead optimization focused on improving human plasma protein-binding adjusted antiviral potency, permeability, pharmacokinetic properties that would support once daily oral administration, and aqueous solubility properties to enable solution formulations for infants. GS-5806 is potent against RSV A and B clinical isolates (N=75, mean EC50=0.43 nM). Oral bioavailability in preclinical species ranged from 46-100% and moreover, GS-5806 efficiently penetrated into the lung tissue of Sprague-Dawley rats.  Dose-dependent (0-30 mg/kg) antiviral efficacy was observed in a cotton rat model of RSV infection.  Oral GS-5806 appeared safe, and in healthy human volunteers experimentally infected with RSV, demonstrated a potent antiviral effect (at the time of mean peak viral load for placebo subjects, the mean viral load in GS-5806 treated subjects was 4.2log10 lower), and reduction in disease severity.  In conclusion, GS-5806 is a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults.

Discovery of respiratory syncytial virus (RSV) fusion inhibitor GS-5806 and clinical proof of concept in a human RSV challenge study

248th National Meeting (2014)

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