title: Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model.
abstract: BACKGROUND
  The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI).
  
  
  METHODS
  African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033 mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3: control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis.
  
  
  RESULTS
  TMC353121 showed a dose-dependent antiviral activity, varying from 1 log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 μg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated.
  
  
  CONCLUSIONS
  TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Ispas
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Janssen Research & Development, London, United Kingdom.
authors.forename: Johan
authors.initials: J
authors.lastname: Verbeeck
authors.affiliation: Huntingdon Life Sciences, 100 Mettlers Road, Somerset, NJ 08873, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sheehan
authors.affiliation: BIOQUAL, Inc., 9600 Medical Center Drive, Rockville, MD 20850, United States of America.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sanders-Beer
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Roymans
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rouan
authors.affiliation: Janssen Research & Development, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Jonghe
authors.affiliation: Jan-Cil France, Janssen Research & Development, Paris, French Republic.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bonfanti
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Vanstockem
authors.affiliation: Jan-Cil UK, J&J Pharmaceutical Research & Development, High Wycombe, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Rene
authors.initials: R
authors.lastname: Verloes
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000821:virology; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D053586:Virus Internalization / Q000187:drug effects*; D017201:Virus Shedding / Q000187:drug effects
chemical_list: C528854:2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol; D000998:Antiviral Agents; D001562:Benzimidazoles; D016207:Cytokines; D011725:Pyridines