title: Oral GS-5806 activity in a respiratory syncytial virus challenge study.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.
  
  
  METHODS
  We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.
  
  
  RESULTS
  Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.
  
  
  CONCLUSIONS
  Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).
authors.affiliation: From the University of Tennessee School of Medicine (J.P.D., C.S.-W., L.H., E.F., S.M.) and Le Bonheur Children's Hospital, Children's Foundation Research Institute (J.P.D.) - both in Memphis; University of Alabama School of Medicine, Birmingham (R.J.W.); Gilead Sciences, Foster City, CA (R.L.M., R.J., Y.X., S.R., T.O., S.A.L., X.L., S.L.T., S.-L.L., J.W.C.); and Retroscreen Virology, London (R.L.-W.). Address reprint requests to Dr. DeVincenzo at the Children's Foundation Research Institute, Le Bonheur Children's Hospital, Rm. 400R, 50 North Dunlap St., Memphis, TN 38103, or at jdevincenzo@uthsc.edu .
authors.forename: John P
authors.initials: JP
authors.lastname: DeVincenzo
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitley
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.forename: Cecilia
authors.initials: C
authors.lastname: Scaglioni-Weinlich
authors.forename: Lisa
authors.initials: L
authors.lastname: Harrison
authors.forename: Eric
authors.initials: E
authors.lastname: Farrell
authors.forename: Stephen
authors.initials: S
authors.lastname: McBride
authors.forename: Robert
authors.initials: R
authors.lastname: Lambkin-Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Riordan
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Lewis
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Seth L
authors.initials: SL
authors.lastname: Toback
authors.forename: Shao-Lee
authors.initials: SL
authors.lastname: Lin
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D007191:Indazoles; D011720:Pyrazoles; D013449:Sulfonamides; C000591241:presatovir