Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848

Abstract

BackgroundMany 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.MethodsIn 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.ResultsAZD8848 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.ConclusionsThe 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 numberNCT01560234, NCT01818869.

First‐in‐Human Study With the Inhaled TLR9 Oligonucleotide Agonist AZD1419 Results in Interferon Responses in the Lung, and Is Safe and Well‐Tolerated

“…The flu‐like AEs for AZD1419 occurred with an onset time mostly in the range from 7 to 12 h after dosing. This is slower than observed with AZD8848, where the onset of flu‐like symptoms was reported 2.5–4.5 h after dosing . This may reflect the slower bioavailability and consequent onset of action of the larger, highly charged ODN compared to the TLR7 antedrug agonist that contributes to the superior tolerability profile seen with AZD1419.…”

“…This may reflect the slower bioavailability and consequent onset of action of the larger, highly charged ODN compared to the TLR7 antedrug agonist that contributes to the superior tolerability profile seen with AZD1419. An alternative possibility is that TLR9 agonism does not result in an amplification of receptor which has been reported for other TLR7 agonists that have entered clinical development …”

Allergen Immunotherapy in Children User’s Guide

“…When administered before allergen challenge, this was again demonstrated with a promotion of interferons to reduce allergic responsiveness . Interestingly, an antedrug approach was utilized to limit systemic exposure of this IFN response, although this was shown to be insufficient following multiple doses . The capacity of TLR7 to robustly suppress allergic responses is desirable; however, limiting systemic effects remains priority before it may become a viable adjuvant.…”

Pulmonary Metabolism of Substrates for Key Drug-Metabolizing Enzymes by Human Alveolar Type II Cells, Human and Rat Lung Microsomes, and the Isolated Perfused Rat Lung Model

“…Nevertheless, prior to clinical drug development it is important to have available in vitro systems that can be used with confidence to determine if a novel inhaled candidate drug has the possibility of being metabolized in the lungs of humans and/or pre-clinical species used in drug safety testing. Sub-cellular fractions of lung tissue are typically used for such in vitro experiments [21] and our experience is that observing metabolism of novel inhaled candidate drugs in these studies is extremely rare, unless the molecule is designed as a pro-drug [22]. One purpose of this work was to determine if these in vitro systems are fit for purpose or whether it is more appropriate to use specific cells where drug-metabolizing enzymes are concentrated.…”