【病毒外文文獻】2017 Broad-spectrum Investigational Agent GS-5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Vira

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Late Breaker Abstract OFID 2017 4 Suppl 1 S737 Conclusions Surges in MMR administration and heightened community aware ness during a measles outbreak can result in a large number of VARI consuming considerable public health resources When evaluating the need to suspect measles among patients with febrile rash clinicians should consider time since MMR admin istration clinical presentation and history of measles exposure Collecting appro priate specimens for timely virus genotyping could inform appropriate public health action Disclosures All authors No reported disclosures LB 9 Broad spectrum Investigational Agent GS 5734 for the Treatment of Ebola MERS Coronavirus and Other Pathogenic Viral Infections with High Outbreak Potential Robert Jordan PhD 1 Alison Hogg PhD 1 Travis Warren PhD 2 Emmie De Wit PhD 3 Timothy Sheahan PhD 4 Michael Lo PhD 5 Veronica Soloveva PhD 2 Jessica Weidner PhD 2 Laura Gomba MBA 2 Friederike Feldmann BS 3 Jacqueline Cronin BS 3 Amy Sims PhD 4 Adam Cockrell PhD 4 Joy Feng PhD 1 Iva Trantcheva FPD 1 Darius Babusis MS 1 Danielle Porter Poulin PhD 1 Roy Bannister PhD 1 Richard Mackman PhD 1 Dustin Siegel PhD 1 Adrian Ray PhD 1 Mark Denison MD 6 Christina Spiropoulou PhD 5 Stuart Nichol PhD 5 Tomas Cihlar PhD 1 Ralph Baric PhD 4 Heinrich Feldmann MD PhD 3 Sina Bavari PhD 2 1 Gilead Sciences Inc Foster City California 2 United States Army Medical Research Institute of Infectious Diseases Frederick Maryland 3 Laboratory of Virology Division of Intramural Research National Institute for Allergy and Infectious Diseases National Institutes of Health Rocky Mountain Laboratories Hamilton Montana 4 Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill North Carolina 5 Centers for Disease Control and Prevention Atlanta Georgia 6 Pediatrics Vanderbilt University Medical Center Nashville Tennessee Session 228 Late Breaker Oral Abstracts Saturday October 7 2017 10 30 AM Background Recent viral outbreaks with significant mortality such as Ebola virus EBOV SARS coronavirus CoV and MERS CoV reinforced the need for effective antiviral therapeutics to control future epidemics GS 5734 is a novel nucleo tide analog prodrug in the development for treatment of EBOV Method Antiviral activity of GS 5734 has been established in vitro against a wide range of pathogenic RNA virus families including filoviruses coronaviruses and par amyxoviruses EC 50 37 to 200 nM Warren et al Nature 2016 Sheahan et al Sci Transl Med 2017 Lo et al Sci Rep 2017 Herein we describe the in vivo translation of the broad spectrum activity of GS 5734 in relevant animal disease models for Ebola Marburg MERS CoV and Nipah Result Therapeutic efficacy against multiple filoviruses with 80 100 survival was observed in rhesus monkeys infected with lethal doses of EBOV Kikwit 1995 or Makona 2014 or Marburg virus and treated with once daily intravenous IV admin istration of 5 to 10 mg kg GS 5734 beginning 3 to 5 days post infection p i In all rhe sus monkey filovirus infection models GS 5734 significantly reduced systemic viremia and ameliorated severe clinical disease signs and anatomic pathology In mice infected with MERS CoV twice daily subcutaneous administration of 25 mg kg GS 5734 beginning 1 day p i significantly reduced lung viral load and improved respiratory function In rhesus monkeys once daily IV administration of 5 mg kg GS 5734 initi ated 1 day prior to MERS CoV infection reduced lung viral load improved clinical dis ease signs and ameliorated severe lung pathology Finally in African green monkeys infected with a lethal dose of Nipah virus therapeutic once daily IV administration of 10 mg kg GS 5734 starting 1 day p i resulted in 100 survival to at least day 35 without any major respiratory or CNS symptoms Conclusion GS 5734 is currently being tested in a phase 2 study in male Ebola survivors with persistent viral RNA in semen Lyophilized drug formulation has been developed that can be administered to humans via a 30 minutes IV infusion and does not require cold chain storage Together these results support further development of GS 5734 as a broad spectrum antiviral to treat viral infections with high mortality and significant outbreak potential Disclosures R Jordan Gilead Employee Salary J Feng Gilead Employee Salary I Trantcheva Gilead Employee Salary D Babusis Gilead Employee Salary D Porter Poulin Gilead Employee Salary R Bannister Gilead Employee Salary R Mackman Gilead Employee Salary D Siegel Gilead Employee Salary A Ray Gilead Employee Salary T Cihlar Gilead Employee Salary 1689b Week 48 Results of EMERALD A Phase 3 Randomized Non inferiority Study Evaluating the Efficacy and Safety of Switching from Boosted protease Inhibitors bPI Plus Emtricitabine FTC Tenofovir Disoproxil Fumarate TDF Regimens to the Once Daily QD Single tablet Regimen STR of Darunavir Cobicistat Emtricitabine Tenofovir Alafenamide D C F TAF in Virologically Suppressed HIV 1 infected Adults Chloe Orkin MD 1 Jean Michel Molina MD PhD 2 Joel Gallant MD MPH FIDSA 3 Eugenia Negredo MD PhD 4 Joseph Gathe MD 5 Joseph Eron MD 6 Erika Van Landuyt MD 7 Erkki Lathouwers PhD 7 Veerle Hufkens MSc 7 Romana Petrovic MSc 7 Magda Opsomer MD 7 EMERALD Study Group 1 Barts Health NHS Trust London UK 2 Department of Infectious Diseases Saint Louis Hospital Paris France 3 Southwest CARE Center Santa Fe New Mexico 4 Germans Trias i Pujol University Hospital Badalona Spain 5 Plaza Medical Center Houston Texas 6 University of North Carolina at Chapel Hill Chapel Hill North Carolina 7 Janssen Pharmaceutica NV Beerse Belgium Session 188 HIV Modern ART Friday October 6 2017 2 00 PM Background EMERALD is evaluating the efficacy and safety of switching from bPI FTC TDF regimens control to D C F TAF 800 150 200 10 mg in virologically suppressed HIV 1 infected adults We present Week 48 primary results Method EMERALD NCT02269917 is a randomized active controlled open label international multicenter parallel group non inferiority trial Virologically suppressed viral load VL 2 previous ARVs prior to screening regimen 15 with previous non DRV virologic failure VF Virologic rebound through Week 48 was non inferior for D C F TAF 2 5 n 19 vs control 2 1 n 8 0 4 95 CI 1 5 2 2 P 0 001 Most rebounders 12 19 63 vs 4 8 50 resuppressed by Week 48 without change in therapy Week 48 virologic suppression rates VL 50 c mL FDA Snapshot were 94 9 vs 93 7 1 2 95 CI 1 7 4 1 and VF rates VL 50 c mL Snapshot were 0 8 vs 0 5 0 3 95 CI 0 7 1 2 with no discontinuations for VF No resistance associated muta tions related to any study drug were observed Adverse events AEs were similar between arms AE related discontinuations 1 4 vs 1 3 grade 3 4 AEs 6 8 vs 8 2 serious AEs 4 6 vs 4 8 and no deaths Renal and bone parameters favored D C F TAF vs control TC and LDL C slightly favored control vs D C F TAF with no clinically significant difference in TC HDL C ratio between arms Table 1 Conclusion Percentage of virologic rebound after switching to D C F TAF was non inferior to control cumulative through Week 48 with high suppression rates 94 9 no resistance development better bone and renal safety parameters and similar TC HDL C ratio D C F TAF maintains the high genetic barrier to resist ance of darunavir with the safety advantages of TAF even in patients with a history of non DRV VF Table 1 Changes from baseline at Week 48 in renal lipid and bone parameters Disclosures C Orkin Janssen Pharmaceuticals Grant Investigator Scientific Advisor and Speaker s Bureau Consulting fee Research grant Speaker honorarium and Travel bursary to attend conference MSD Grant Investigator Scientific Advisor and Speaker s Bureau Consulting fee Research grant Speaker honorarium and T ravel bursary to attend conference Viiv Healthcare Grant Investigator Scientific Advisor Downloaded from by guest on 21 April 2018