Oral GS-5806 activity in a respiratory syncytial virus challenge study

John Devincenzo, Richard J. Whitley, Richard L. Mackman, Cecilia Scaglioni-Weinlich, Lisa Harrison, Eric Farrell, Stephen McBride, Robert Lambkin-Williams, Robert Jordan, Yan Xin, Srini Ramanathan, Thomas O'Riordan, Sandra A. Lewis, Xiaoming Li, Seth L. Toback, Shao Lee Lin, Jason W. Chien

Research output: Contribution to journalArticle

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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] x 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 x 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.

Original languageEnglish (US)
Pages (from-to)711-722
Number of pages12
JournalNew England Journal of Medicine
Volume371
Issue number8
DOIs
StatePublished - Jan 1 2014

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Respiratory Syncytial Viruses
Viral Load
Mucus
Area Under Curve
Placebos
Weights and Measures
Respiratory Syncytial Virus Infections
Virus Internalization
Alanine Transaminase
Antiviral Agents
Hospitalization
Neutrophils
Cohort Studies
Therapeutics
GS-5806
Morbidity
Mortality

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Devincenzo, J., Whitley, R. J., Mackman, R. L., Scaglioni-Weinlich, C., Harrison, L., Farrell, E., ... Chien, J. W. (2014). Oral GS-5806 activity in a respiratory syncytial virus challenge study. New England Journal of Medicine, 371(8), 711-722. https://doi.org/10.1056/NEJMoa1401184

Oral GS-5806 activity in a respiratory syncytial virus challenge study. / Devincenzo, John; Whitley, Richard J.; Mackman, Richard L.; Scaglioni-Weinlich, Cecilia; Harrison, Lisa; Farrell, Eric; McBride, Stephen; Lambkin-Williams, Robert; Jordan, Robert; Xin, Yan; Ramanathan, Srini; O'Riordan, Thomas; Lewis, Sandra A.; Li, Xiaoming; Toback, Seth L.; Lin, Shao Lee; Chien, Jason W.

In: New England Journal of Medicine, Vol. 371, No. 8, 01.01.2014, p. 711-722.

Research output: Contribution to journalArticle

Devincenzo, J, Whitley, RJ, Mackman, RL, Scaglioni-Weinlich, C, Harrison, L, Farrell, E, McBride, S, Lambkin-Williams, R, Jordan, R, Xin, Y, Ramanathan, S, O'Riordan, T, Lewis, SA, Li, X, Toback, SL, Lin, SL & Chien, JW 2014, 'Oral GS-5806 activity in a respiratory syncytial virus challenge study', New England Journal of Medicine, vol. 371, no. 8, pp. 711-722. https://doi.org/10.1056/NEJMoa1401184
Devincenzo J, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. New England Journal of Medicine. 2014 Jan 1;371(8):711-722. https://doi.org/10.1056/NEJMoa1401184
Devincenzo, John ; Whitley, Richard J. ; Mackman, Richard L. ; Scaglioni-Weinlich, Cecilia ; Harrison, Lisa ; Farrell, Eric ; McBride, Stephen ; Lambkin-Williams, Robert ; Jordan, Robert ; Xin, Yan ; Ramanathan, Srini ; O'Riordan, Thomas ; Lewis, Sandra A. ; Li, Xiaoming ; Toback, Seth L. ; Lin, Shao Lee ; Chien, Jason W. / Oral GS-5806 activity in a respiratory syncytial virus challenge study. In: New England Journal of Medicine. 2014 ; Vol. 371, No. 8. pp. 711-722.
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AU - Devincenzo, John

AU - Whitley, Richard J.

AU - Mackman, Richard L.

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AU - Harrison, Lisa

AU - Farrell, Eric

AU - McBride, Stephen

AU - Lambkin-Williams, Robert

AU - Jordan, Robert

AU - Xin, Yan

AU - Ramanathan, Srini

AU - O'Riordan, Thomas

AU - Lewis, Sandra A.

AU - Li, Xiaoming

AU - Toback, Seth L.

AU - Lin, Shao Lee

AU - Chien, Jason W.

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N2 - 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] x 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 x 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.

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