title: Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848.
abstract: BACKGROUND
  Many patients with asthma have a T-helper type 2 (Th2) driven inflammation of the lung, whereas toll-like receptor 7 (TLR7) agonists, by inducing type I interferons, inhibit Th2 responses. In man, oral or parenteral TLR7 agonists can induce influenza-like symptoms through systemic induction of type I interferons. Design of a TLR7 agonist that is only active in the lung could reduce the risk of side effects and offer a new means for treating asthma. We developed a TLR7 agonist antedrug, AZD8848, to determine its local and systemic effects in preclinical models and man.
  
  
  METHODS
  In vitro cellular potencies for the TLR7 antedrug agonist, AZD8848, were determined along with pharmacokinetics and efficacy in a rat allergy model. Sputum and blood biomarkers were measured in single ascending and multiple ascending dose clinical studies following inhalation delivery of AZD8848 and tolerability assessed.
  
  
  RESULTS
  AZD8848 was potent in cellular assays and pharmacokinetics confirmed lack of systemic exposure to AZD8848. Weekly lung dosing in an animal model showed efficacy 26 days beyond the final dose. In healthy volunteers, AZD8848 was initially well tolerated with target engagement being demonstrated by induction of CXCL10 in sputum. A second inhaled dose, given 1 week later, amplified the systemic interferon signal in more than half the participants and resulted in significant influenza-like symptoms.
  
  
  CONCLUSIONS
  The antedrug design restricted the direct actions of AZD8848 to the lung. However, the type I interferon induced locally by TLR7 spilled over systemically, limiting the utility of this inhaled antedrug approach.
  
  
  BACKGROUND
  NCT01560234, NCT01818869.
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca , Mölndal , Sweden.
authors.forename: Stephen
authors.initials: S
authors.lastname: Delaney
authors.affiliation: Bisocience, AstraZeneca R&D Charnwood , Loughborough , UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Biffen
authors.affiliation: Personalised Healthcare and Biomarkers, Innovative Medicines and Early Development, Alderley Park , Macclesfield , UK.
authors.forename: Justine
authors.initials: J
authors.lastname: Maltby
authors.affiliation: Bisocience, AstraZeneca R&D Charnwood , Loughborough , UK.
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.affiliation: Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca , Mölndal , Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Asimus
authors.affiliation: Early Clinical Development, Innovative Medicines and Early Development, AstraZeneca , Waltham, Massachusetts , USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca , Mölndal , Sweden.
authors.forename: Maarten
authors.initials: M
authors.lastname: Kraan
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca , Mölndal , Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Keeling
keywords: Allergic lung disease; Asthma; Asthma Mechanisms