Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study

Abstract

BackgroundAlthough allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug.MethodsIn this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment.ResultsAZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated.Conclusions and clinical relevanceIn patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses.Trial registrationclinicaltrials.gov identifier NCT00999466.

Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study

“…The absence of an anti-T2 effect and impact on the late asthmatic response in this study contrast with those of previous studies with GSK2245035 in allergic rhinitis by Ellis et al [ 13 ], and those by Leaker et al, assessing AZD8848 (another TLR7 agonist) in allergic asthma [ 20 , 24 ]. In the study by Ellis et al, a reduction of total nasal symptoms in response to nasal allergen challenge, and nasal allergic biomarker analyses, revealed trends supporting a response to GSK2245035, with reductions in T2-related cytokines [ 13 ].…”

“…In the study by Ellis et al, a reduction of total nasal symptoms in response to nasal allergen challenge, and nasal allergic biomarker analyses, revealed trends supporting a response to GSK2245035, with reductions in T2-related cytokines [ 13 ]. Leaker et al, found that, compared with placebo, intranasal AZD8848 attenuated the late asthmatic response by approximately 27% at 1 week after dosing, but the results were not sustained at 4 weeks after dosing; however, AZD8848 had no significant effect on eosinophil counts or T2 cytokines [ 20 , 24 ]. TNSS score was evaluated daily, and although some nasal inflammatory mediators were impacted by GSK2245035, no clinically relevant treatment effect on TNSS was observed; however, this finding should be interpreted with caution given that a minimal TNSS score at study enrollment was not mandated (unlike the study by Ellis et al [ 13 ]).…”

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

“…Systemic interferon production and induction of flu-like symptoms were observed, potentially limiting the utility of the compound ( 147 ). A further trial has shown that while drug-related adverse events were frequent, they were mild and well-tolerated ( 148 ). The TLR7 agonist AZD8848 was shown to suppress the allergen-induced late-phase asthmatic response in an RDBPCT where participants were administered AZD8848 intranasally once-weekly for eight weeks.…”

The Protective Effects of <b><i>Helicobacter pylori</i></b> Infection on Allergic Asthma

“…The exposure to environment and microbes can help to form the growing immunity system and protect subsequent immune-mediated diseases [32]. "Unhygienic exposure" to microorganisms in an early age can prevent the development of allergic diseases in later years [33]. H. pylori infection usually occurs in children, and the way to be infected is related to unhygienic family environment or habits, and this association appears in mouse asthma models [34].…”