1646. Combined Resistance Analyses From Phase 2b Studies of Presatovir Treatment in RSV-Infected Adults

Abstract

BackgroundPresatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor in development for the treatment of RSV infection. Results from a healthy volunteer challenge study show that presatovir significantly reduced RSV viral load and clinical signs and symptoms. Here we present combined resistance analyses from 4 phase 2b studies in naturally RSV-infected adults.MethodsRSV RNA was isolated from nasal swabs collected at baseline and postbaseline in studies GS-US-218-0108, GS-US-218–1502, GS-US-218–1227, and GS-US-218–1797. Full-length RSV fusion (F) gene was PCR amplified and population sequencing was performed.ResultsOf 233 presatovir-treated adults in the efficacy analyses, post-baseline resistance-associated substitutions were detected in 18 (7.7%) subjects. Frequencies of resistance development varied by study (Table 1). Resistance substitutions known to confer high-level (>200 fold) reduced susceptibility to presatovir detected in >1 subject were: T400I (n = 6), S398L (n = 3), L141F (n = 2), and F140I (n = 2) in F. Subjects with resistant virus had less viral load reduction than presatovir-treated subjects without resistant virus. Resistance development did not impact clinical outcomes. In study GS-US-218-0108, subjects with lymphopenia (<200 cells/μL) at baseline were significantly more likely to develop resistance substitutions.Table 1:Resistance Development Frequencies in Phase 2b StudiesStudySubject PopulationPresatovir DosePresatovir-Treated Subjects in Efficacy Analysis, nSubjects with Resistance- Associated Substitutions, n (%)GS-US-218-0108Hematopoietic cell transplant (HCT) recipients with upper respiratory tract infectionDays 1, 5, 9, 13, and 17: 200 mg8910 (11.2%)GS-US-218-1502HCT recipients with lower respiratory tract infectionDays 1, 5, 9, 13, and 17: 200 mg296 (20.7%)GS-US-218-1227Hospitalized adultsDay 1: 200 mg801 (1.3%)GS-US-218-1797Lung transplant recipientsDay 1: 200 mg Days 2–14: 100 mg351 (2.9%)ConclusionPresatovir treatment resulted in varying rates of resistance development across 4 phase 2b studies. Resistance development impacted virologic response without affecting clinical outcomes. Differences among study populations and dosing regimens may have influenced rates of resistance development.Disclosures D. Porter, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. Y. Guo, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. J. Perry, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. D. Gossage, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. T. Watkins, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. J. Chien, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. R. Jordan, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks.