The Effects Of The Novel Toll-Like Receptor 7 (TLR7) Agonist AZD8848 On Allergen-Induced Responses In Patients With Mild Asthma

Leaker, Brian; Singh, Dave; Lindgren, S.; Källén, Anders; Almqvist, Gun; Young, Barbara; O’Connor, Brian

doi:10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4184

Cited by 5 publications

(7 citation statements)

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“…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 ].…”

Section: Discussioncontrasting

confidence: 99%

“…The study sample size was determined using a simulation-based approach that enumerated the probability of meeting the study success criteria (posterior probability [PP]) of any percentage attenuation >0.7) for ≥1 of the efficacy endpoints under a variety of assumed treatment effects (percentage attenuations) and number of participants per treatment arm. The sample size calculation assumed that the placebo response and the variability of the endpoints in this study were similar to previous studies conducted by GSK (assumptions consistent with the observed data), that the true treatment effect of GSK2245035 was no worse than that in a study of the TLR7 agonist AZD8848 (based on congress presentation data [ 20 ]), and that 20 patients had evaluable data at the first the follow-up assessment. Under those assumptions the probability of achieving the study success criteria was approximately 80%.…”

Section: Methodsmentioning

confidence: 65%

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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

Siddall¹,

Quint²,

Pandya³

et al. 2020

PLoS ONE

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Background Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses. Objective This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma. Methods This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4–10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success. Results Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was –4.6% (posterior probability: 0.385) and –10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common. Conclusions and clinical relevance Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.

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Section: Discussioncontrasting

confidence: 99%

Section: Methodsmentioning

confidence: 65%

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

Siddall¹,

Quint²,

Pandya³

et al. 2020

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…The 3‐week duration of treatment effect has not previously been shown with similar treatments under investigation for AR and asthma, the TLR7 agonist AZD8848 and the TLR8 agonist VTX‐1463 . The magnitude of treatment difference for TNSS (>1.0) provides strong evidence for the therapeutic potential of GSK2245035 despite the small sample size used in this study.…”

Section: Discussionmentioning

confidence: 58%

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial

Ellis

Tsitoura

Quint

et al. 2017

Clin Experimental Allergy

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“…This indicates topical delivery is a viable approach to limit systemic exposure while reducing allergic responses. However, in a challenge study in patients with mild to moderate allergic asthma, intranasal AZD8848 suppressed allergic responses 1 week after dosing but not at the subsequent allergen challenge at week 4 . This suggests the more durable allergic suppression seen in rodent studies may not be achievable in humans via dosing to the nasal cavity.…”

Section: Discussionmentioning

confidence: 96%

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

Jackson

Candia

Delaney

et al. 2017

Clin Pharma and Therapeutics

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Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase I clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung. In healthy volunteers, AZD1419 was found to be safe and well-tolerated. Target engagement in the lung was demonstrated at all dose levels tested. No evidence of tolerization or amplification of responses was evident on repeated dosing and 15.4 mg was defined as the maximum tolerated dose. AZD1419 clinical data supports its continued development as a potentially disease-modifying therapeutic in asthma.

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The Effects Of The Novel Toll-Like Receptor 7 (TLR7) Agonist AZD8848 On Allergen-Induced Responses In Patients With Mild Asthma

Cited by 5 publications

References 0 publications

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

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

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial

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

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