Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848. Issue 1 (23rd February 2016)

• Record Type: Journal Article
• Authors: Delaney, Stephen; Biffen, Mark; Maltby, Justine; Bell, John; Asimus, Sara; Aggarwal, Ajay; Kraan, Maarten; Keeling, David
• Is Part Of: BMJ open respiratory research. Volume 3:Issue 1(2016)
• Publication Date: 2016-02-23
• Subjects: Asthma -- Allergic lung disease -- Asthma Mechanisms; Respiratory organs -- Diseases -- Periodicals; Respiratory organs -- Diseases -- Treatment -- Periodicals; Respiratory therapy -- Periodicals; 616.2005
• DOI: 10.1136/bmjresp-2015-000113
• Languages: English
• ISSNs: 2052-4439

Abstract

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. Trial registration number: NCT01560234, NCT01818869 .