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

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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BECLOMETHASONE GIVEN AFTER THE EARLY ASTHMATIC RESPONSE INHIBITS THE LATE RESPONSE AND THE INCREASED METHACHOLINE RESPONSIVENESS AND CROMOLYN DOES NOT

PEDIATRICS ◽

10.1542/peds.94.2.267 ◽

1994 ◽

Vol 94 (2) ◽

pp. 267-267

Author(s):

David F. Graft

Keyword(s):

Single Dose ◽

Late Phase ◽

Allergen Challenge ◽

Allergen Exposure ◽

Phase Response ◽

Atopic Asthma ◽

Late Response ◽

Double Blind ◽

Asthmatic Response ◽

Late Asthmatic Response

Purpose of the Study. To investigate whether beclomethasone or cromolyn provides any protection from the late asthmatic response if given after the allergen exposure. Methods. Ten patients with mild, stable, atopic asthma with late asthmatic responses entered a double blind, double dummy trial comparing a single dose of inhaled beclomethasone (500 µg), cromolyn (20 mg), and placebo administered 2 hours after allergen challenge on the severity of the late asthmatic response and the change in the log of PC20 methacholine. Findings. The late asthmatic response after beclomethasone of 7.3% ± 6.1% decrease in FEV1 was significantly less than that experienced after cromolyn (20.4% ± 15.2%) or placebo (26.4% ± 8.2%); cromolyn was not different than placebo. There was a trend for the change in log PC20 methacholine to be less following beclomethasone administration than that seen with placebo or cromolyn. Reviewer's Comments. It is well known that a single dose of cromolyn given before allergen exposure inhibits both the early and late phase response, whereas beclomethasone given prior to exposure will only prevent the late phase response. However, many individuals don't plan ahead well enough and need to know what medication should be taken if they have forgotten to take any pretreatment. This study indicates that, if bedomethasone, albeit in a dose equal to 12 puffs of the U.S. concentration, is taken even as late as 2 hours after the exposure, it can significantly inhibit the development of the late phase response. Cromolyn given at that time provides only minimal benefit.

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Expression of Surface Markers on the Blood Cells during the Delayed Asthmatic Response to Allergen Challenge

Allergy & Rhinology ◽

10.2500/ar.2014.5.0087 ◽

2014 ◽

Vol 5 (2) ◽

pp. ar.2014.5.0087 ◽

Cited By ~ 11

Author(s):

Zdenek Pelikan

Keyword(s):

Nk Cells ◽

Blood Cells ◽

Allergen Challenge ◽

Surface Markers ◽

Asthmatic Response ◽

Bronchial Challenge ◽

Late Asthmatic Response ◽

The Mean ◽

Hypersensitivity Mechanism ◽

Bronchial Allergen Challenge

Patients with bronchial asthma develop various types of asthmatic response to bronchial challenge with allergen, such as immediate/early asthmatic response (IAR), late asthmatic response (LAR) or delayed asthmatic response (DYAR), because of different immunologic mechanisms. The DYAR, occurring between 24 and 56 hours after the bronchial allergen challenge (p < 0.01), differs from IAR and LAR in clinical as well as immunologic features. This study investigates the expression of CD molecules (markers) on the surface of particular cell populations in the peripheral blood and their changes during the DYAR. In 17 patients developing the DYAR (p < 0.01), the bronchial challenge with allergen was repeated 2–6 weeks later. The repeated DYAR (p < 0.001) was combined with recording of CD molecule expression on various types of blood cells by means of flow cytometry up to 72 hours after the challenge. The results were expressed in percent of the mean relative fluorescence intensity. The DYAR was accompanied by (a) increased expression of CD11b, CD11b/18, CD16, CD32, CD35, CD62E, CD62L, CD64, and CD66b on neutrophils; CD203C on basophils; CD25and CD62L on eosinophils; CD14, CD16, CD64, and CD86 on monocytes; CD3, CD4, CD8, CD11a, CD18, and CD69 on lymphocytes; CD16, CD56, CD57, and CD94 on natural killer (NK) cells; and CD31, CD41, CD61, CD62P, and CD63 on thrombocytes and (b) decreased expression of CD18 and CD62L on eosinophils, CD15 on neutrophils, and CD40 on lymphocytes. These results suggest involvement of cell-mediated hypersensitivity mechanism, on participation of Th1- lymphocytes, neutrophils, monocytes, NK cells, and thrombocytes in the DYAR.

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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

Respiratory Research ◽

10.1186/s12931-019-1252-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 2

Author(s):

Brian R. Leaker ◽

Dave Singh ◽

Sam Lindgren ◽

Gun Almqvist ◽

Leif Eriksson ◽

...

Keyword(s):

Immune System ◽

Allergic Asthma ◽

Allergen Challenge ◽

Forced Expiratory Volume ◽

Post Treatment ◽

Double Blind ◽

Parallel Group Study ◽

Parallel Group ◽

Significant Difference ◽

Th2 Responses

Abstract Background Although 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. Methods In 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. Results AZD8848 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 relevance In 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 registration clinicaltrials.gov identifier NCT00999466.

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Symposium on allergy and respiratory diseases. (2)-a. Asthmatic responses in allergic asthma, especially late asthmatic response.

Nihon Naika Gakkai Zasshi ◽

10.2169/naika.78.1277 ◽

1989 ◽

Vol 78 (9) ◽

pp. 1277-1279 ◽

Cited By ~ 1

Author(s):

Setsuo KOBAYASHI

Keyword(s):

Allergic Asthma ◽

Respiratory Diseases ◽

Asthmatic Response ◽

Late Asthmatic Response

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Precision Medicine in House Dust Mite-Driven Allergic Asthma

Journal of Clinical Medicine ◽

10.3390/jcm9123827 ◽

2020 ◽

Vol 9 (12) ◽

pp. 3827

Author(s):

Ibon Eguiluz-Gracia ◽

Francisca Palomares ◽

Maria Salas ◽

Almudena Testera-Montes ◽

Adriana Ariza ◽

...

Keyword(s):

Allergic Asthma ◽

House Dust ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Allergen Challenge ◽

Pharmaceutical Products ◽

House Dust Mites ◽

Dust Mites ◽

Bronchial Allergen Challenge

House dust mites (HDMs) are the allergenic sources most frequently involved in airway allergy. Nevertheless, not every sensitized patient develops respiratory symptoms upon exposure to HDM, and there is a clinical need to differentiate allergic asthmatics (AAs) from atopic non-allergic asthmatics with HDM sensitization. This differentiation sometimes requires in vivo provocations like the bronchial allergen challenge (BAC). Interestingly, recent data demonstrate that non-atopic patients with asthma can also develop positive BAC results. This novel phenotype has been termed local allergic asthma (LAA). The interest in identifying the allergic triggers of asthma resides in the possibility of administering allergen immunotherapy (AIT). AIT is a disease-modifying intervention, the clinical benefit of which persists after therapy discontinuation. Recently, new modalities of sublingual tablets of HDM immunotherapy registered as pharmaceutical products (HDM-SLIT tablets) have become commercially available. HDM-SLIT tablets have demonstrated a robust effect over critical asthma parameters (dose of inhaled corticosteroids, exacerbations, and safety), thus being recommended by international guidelines for patients with HDM-driven AA. In this review, we will summarize the current knowledge on the phenotype and endotype of HDM-driven AA, and LAA, address the difficulties for BAC implementation in the clinic, and discuss the effects of AIT in AA and LAA.

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Bimosiamose* reduces the late asthmatic response in patients with allergic asthma,

Inpharma Weekly ◽

10.2165/00128413-200314000-00016 ◽

2003 ◽

Vol &NA; (1400) ◽

pp. 6

Author(s):

&NA;

Keyword(s):

Allergic Asthma ◽

Asthmatic Response ◽

Late Asthmatic Response

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Histamine release from bronchoalveolar lavage cells from asthmatic subjects after allergen challenge and relationship to the late asthmatic response

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.1998.00228.x ◽

1998 ◽

Vol 28 (2) ◽

pp. 196-204 ◽

Cited By ~ 10

Author(s):

L. G. Heaney ◽

L. J. M. Cross ◽

M. Ennis

Keyword(s):

Bronchoalveolar Lavage ◽

Histamine Release ◽

Allergen Challenge ◽

Asthmatic Response ◽

Late Asthmatic Response

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Protective Effects of Fluticasone on Allergen-Induced Airway Responses and Sputum Inflammatory Markers

Canadian Respiratory Journal ◽

10.1155/2000/254213 ◽

2000 ◽

Vol 7 (4) ◽

pp. 313-319 ◽

Cited By ~ 29

Author(s):

Krishnan Parameswaran ◽

Mark D Inman ◽

Rick M Watson ◽

Marilyn M Morris ◽

Ann Efthimiadis ◽

...

Keyword(s):

Single Dose ◽

Protective Effect ◽

Allergen Challenge ◽

Airway Responsiveness ◽

Protective Effects ◽

Asthmatic Response ◽

Sputum Eosinophilia ◽

Late Asthmatic Response ◽

Cell Counts ◽

Allergen Inhalation

BACKGROUND:A direct comparison of the protective effects of single and regular doses of inhaled glucocorticoid on allergen-induced asthmatic responses and inflammation has not been made.OBJECTIVE:To compare the effects of pretreatment with fluticasone 250 µg 30 min before allergen inhalation and two weeks of 250 µg twice daily (last dose 24 h before challenge) with single and regular (twice daily) placebo doses on early and late asthmatic responses, induced sputum cell counts and measures of eosinophil activation at 7 h and 24 h, and methacholine airway responsiveness at 24 h.PATIENTS AND METHODS:Ten mild asthmatic patients were studied in a randomized, double-blind, placebo controlled crossover study.RESULTS:Regular fluticasone increased the baseline mean provocative concentration of methacholine to cause a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1) from 2.6 to 6.4 mg/mL (P<0.05) and lowered the eosinophil count from 3.1% to 0.4% (P<0.05) compared with regular placebo. Neither single nor regular fluticasone had any effect on the early asthmatic response. Single fluticasone attenuated the late asthmatic response, the mean ± SEM maximum percentage fall in FEV1(10.8±3.6 compared with single placebo 18.8±3.5, P=0.03), the allergen-induced increase of airway responsiveness (P<0.05), and the eosinophilia (P<0.005) and activated eosinophils at 7 h (P<0.01) but not at 24 h. Regular fluticasone also attenuated the late asthmatic response (11.1±2.5) compared with regular placebo (19.6±4.5), but this was not statistically significant and did not protect against the induced increase in airway responsiveness or the sputum eosinophilia.CONCLUSION:Two weeks of regular inhaled fluticasone discontinued 24 h before allergen challenge does not offer any additional protection against the early or late asthmatic responses, increased airway responsiveness or sputum eosinophilia compared with a single dose of 250 µg immediately before allergen challenge, despite increasing baseline PC20and decreasing sputum eosinophilia prechallenge. The significance of the protective effect of a single dose of inhaled steroid before an allergen inhalation and the duration of the protective effect need further investigation.

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