as published in The New England Journal of Medicine (NEJM) 21 August 2014
Oral GS-5806 Activity in a Respiratory Syncytial Virus Challenge Study
N Engl J Med 2014; 371:711-722August 21, 2014DOI: 10.1056/NEJMoa1401184
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.
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.
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.
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.)
Supported by Gilead Sciences.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Nicole Renton, Felicity Swift, and Matt McKevitt for managing study conduct; Chen Chi, Wei Lei, Ying Guo, and Uta Meyer (Gilead Sciences) for assistance with statistical programming; Kate Loughney for writing assistance (under the sponsorship of Gilead Sciences), and the late Dr. Caroline Breese-Hall for her mentorship, her poetic view of life, her dedication to the understanding of RSV, and her resolve and encouragement with regard to the process of translating knowledge into meaningful clinical practice.
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 firstname.lastname@example.org