1189. Analysis of GS-5806 Resistance Emergence in Human Healthy Adult Subjects Experimentally Infected with Respiratory Syncytial Virus (RSV)
Session: Poster Abstract Session: Resistance Mechanisms
Friday, October 9, 2015
Room: Poster Hall
Posters
  • Bio Jordan IDWeek 88x44@275-PrintReady.pdf (142.1 kB)
  • Background: GS-5806 is a potent small molecule RSV fusion inhibitor that has been shown to reduce viral load and disease severity in adults experimentally infected with RSV Mem 37 (DeVincenzo et al. NEJM, 2014). In this Phase 2a study, GS-5806 was administered in 4 different dosing regimens following the detection of RSV in nasal wash samples: Regimen 1 (Day 1: 50 mg; Days 2-5: 25 mg), Regimen 2 (Day 1: 50 mg; Day 2-3: 25 mg), Regimen 3 (Day 1: 100 mg once), and Regimen 4 (Day 1: 10 mg; Day 2-5: 5 mg).

    Methods: The emergence of drug resistance was analyzed by population sequencing of RSV from nasal wash samples taken at the viral load peak, end of dosing, and at the last day of RSV detection. The sequence of the RSV F gene from treated subjects was compared to the inoculum sequence to identify mutations associated with GS-5806 treatment. Recombinant viruses containing the GS-5806 treatment emergent mutations were constructed and the susceptibility to GS-5806 was measured in cell-based antiviral assays. 

    Results: Mutations conferring reduced susceptibility to GS-5806 (EC50 values shift > 4-fold relative to RSV Mem 37) were identified in 15 out of 87 subjects treated with GS-5806. The resistance frequency was 8% (3/39) in Regimen 1, 35% (6/17) in Regimen 2, 29% (4/14) in Regimen 3, and 12% (2/17) in Regimen 4. The mean AUC viral load was significantly higher for the subjects harboring resistant virus compared to those who did not (784 vs. 156 log10 PFUe x h / mL; p < 0.0001). However, the mean AUC disease severity scores were not significantly different between the two groups (152 vs. 181 x h; p = 0.72). The most commonly identified F protein mutations were at positions 400 (T400I; 4/15) and 140 (F140I/L; 2/15).  The T400I and F140L variants showed reduced replication compared to wild-type RSV in an in vitro competitive fitness assay. All recombinant viruses expressing GS-5806 resistance mutations remained susceptible to ribavirin and palivizumab and were cross-resistant to the fusion inhibitor VP-14637. 

    Conclusion: The emergence of resistance to GS-5806 in subjects experimentally challenged with RSV may be reduced by higher drug exposure and/or dosing duration.  Dosing regimens that should further minimize GS-5806 resistance emergence are being investigated in ongoing Phase 2 studies.

    Robert Jordan, Ph.D.1, Kirsten Stray, B.S.1, Francisco Anderson, B.S.1, Michel Perron, Ph.D.1, Richard Mackman, Ph.D.1, Michael Miller, Ph.D.1, Hongmei Mo, Ph.D.1, Evguenia Svarovskaia, Ph.D.1, Ross Martin, B.S.1, Yan Xin, Ph.D.2, Srini Ramanathan, PhD2, Thomas O'riordan, M.D.1, Sandra Lewis, Ph.D.1, Xiaoming Li, Ph.D.1, Seth Toback, M.D.2, Jason Chien, M.D.2, John Sundy, M.D.1, John Devincenzo, MD3 and Tomas Cihlar, Ph.D.1, (1)Gilead Sciences, Foster City, CA, (2)Gilead Sciences, Inc., Foster City, CA, (3)Pediatrics, University of Tennessee Health Science Center, Memphis, TN

    Disclosures:

    R. Jordan, Gilead Sciences: Employee and Shareholder , Salary

    K. Stray, Gilead Sciences: Employee and Shareholder , Salary

    F. Anderson, Gilead Sciences: Employee , Salary

    M. Perron, Gilead Sciences: Employee and Shareholder , Salary

    R. Mackman, Gilead Sciences: Employee and Shareholder , Salary

    M. Miller, Gilead Sciences: Employee and Shareholder , Salary

    H. Mo, Gilead Sciences: Employee and Shareholder , Salary

    E. Svarovskaia, Gilead Sciences: Employee and Shareholder , Salary

    R. Martin, Gilead Sciences: Employee and Shareholder , Salary

    Y. Xin, Gilead Sciences: Employee and Shareholder , Salary

    S. Ramanathan, Gilead Sciences: Employee and Shareholder , Salary

    T. O'riordan, Gilead Sciences: Employee and Shareholder , Salary

    S. Lewis, Gilead Sciences: Employee and Shareholder , Salary

    X. Li, Gilead Sciences: Employee and Shareholder , Salary

    S. Toback, Gilead Sciences: Employee and Shareholder , Salary

    J. Chien, Gilead Sciences: Employee and Shareholder , Salary

    J. Sundy, Gilead Sciences: Employee and Shareholder , Salary

    J. Devincenzo, Gilead Sciences: Consultant , Consulting fee

    T. Cihlar, Gilead Sciences: Employee and Shareholder , Salary

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