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The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma.
Clin Exp Allergy. 2014 Sep; 44(9):1146-53.CE

Abstract

BACKGROUND

SH2-containing inositol-5'-phosphatase 1 (SHIP1) is an endogenous inhibitor of the phosphoinositide-3-kinase pathway that is involved in the activation and chemotaxis of inflammatory cells. AQX-1125 is a first-in-class, oral SHIP1 activator with a novel anti-inflammatory mode of action.

OBJECTIVE

To evaluate the effects of AQX-1125 on airway responses to allergen challenge in mild-to-moderate asthmatic patients.

METHODS

A randomized, double-blind, placebo-controlled, two-way crossover study was performed in 22 steroid-naïve mild-to-moderate asthmatics with a documented late-phase response to inhaled allergen (LAR). AQX-1125 (450 mg daily) or placebo was administered orally for 7 days. Allergen challenge was performed on day 6 (2 h postdose), followed by methacholine challenge (day 7), and induced sputum collection and fractional exhaled nitric oxide (FeNO).

RESULTS

AQX-1125 significantly attenuated the late-phase response compared with placebo (FEV1 4-10 h: mean difference 150 mL, 20%; P = 0.027) and significantly increased the minimum FEV1 during LAR (mean difference 180 mL; P = 0.014). AQX-1125 had no effect on the early-phase response. AQX-1125 showed a trend in reduction of sputum eosinophils, neutrophils and macrophages although this did not achieve significance as there were only 11 paired samples for analysis. There was no effect on methacholine responsiveness or FeNO. Pharmacokinetic data showed AQX-1125 was rapidly absorbed with geometric mean Cmax and AUC0-24 h values of 1417 ng/mL and 16 727 h ng/mL, respectively. AQX-1125 was well tolerated, but mild GI side-effects (dyspepsia, nausea and abdominal pain) were described in 4/22 subjects on active treatment. These side-effects were mild self-limiting, required no further treatment and did not lead to discontinuation of therapy.

CONCLUSION AND CLINICAL RELEVANCE

AQX-1125, a novel oral SHIP1 activator, significantly reduces the late response to allergen challenge, with a trend to reduce airway inflammation. AQX-1125 was safe and well tolerated and merits further investigation in inflammatory disorders.

Authors+Show Affiliations

Respiratory Clinical Trials Ltd., London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25040039

Citation

Leaker, B R., et al. "The Effects of the Novel SHIP1 Activator AQX-1125 On Allergen-induced Responses in Mild-to-moderate Asthma." Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, vol. 44, no. 9, 2014, pp. 1146-53.
Leaker BR, Barnes PJ, O'Connor BJ, et al. The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. Clin Exp Allergy. 2014;44(9):1146-53.
Leaker, B. R., Barnes, P. J., O'Connor, B. J., Ali, F. Y., Tam, P., Neville, J., Mackenzie, L. F., & MacRury, T. (2014). The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, 44(9), 1146-53. https://doi.org/10.1111/cea.12370
Leaker BR, et al. The Effects of the Novel SHIP1 Activator AQX-1125 On Allergen-induced Responses in Mild-to-moderate Asthma. Clin Exp Allergy. 2014;44(9):1146-53. PubMed PMID: 25040039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. AU - Leaker,B R, AU - Barnes,P J, AU - O'Connor,B J, AU - Ali,F Y, AU - Tam,P, AU - Neville,J, AU - Mackenzie,L F, AU - MacRury,T, PY - 2014/04/16/received PY - 2014/06/02/revised PY - 2014/07/01/accepted PY - 2014/7/22/entrez PY - 2014/7/22/pubmed PY - 2015/5/15/medline KW - SH2-containing inositol-5′-phosphatase 1 KW - airway hyperresponsiveness KW - asthma KW - induced sputum KW - inhaled allergen challenge KW - phosphoinositide-3-kinase SP - 1146 EP - 53 JF - Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology JO - Clin Exp Allergy VL - 44 IS - 9 N2 - BACKGROUND: SH2-containing inositol-5'-phosphatase 1 (SHIP1) is an endogenous inhibitor of the phosphoinositide-3-kinase pathway that is involved in the activation and chemotaxis of inflammatory cells. AQX-1125 is a first-in-class, oral SHIP1 activator with a novel anti-inflammatory mode of action. OBJECTIVE: To evaluate the effects of AQX-1125 on airway responses to allergen challenge in mild-to-moderate asthmatic patients. METHODS: A randomized, double-blind, placebo-controlled, two-way crossover study was performed in 22 steroid-naïve mild-to-moderate asthmatics with a documented late-phase response to inhaled allergen (LAR). AQX-1125 (450 mg daily) or placebo was administered orally for 7 days. Allergen challenge was performed on day 6 (2 h postdose), followed by methacholine challenge (day 7), and induced sputum collection and fractional exhaled nitric oxide (FeNO). RESULTS: AQX-1125 significantly attenuated the late-phase response compared with placebo (FEV1 4-10 h: mean difference 150 mL, 20%; P = 0.027) and significantly increased the minimum FEV1 during LAR (mean difference 180 mL; P = 0.014). AQX-1125 had no effect on the early-phase response. AQX-1125 showed a trend in reduction of sputum eosinophils, neutrophils and macrophages although this did not achieve significance as there were only 11 paired samples for analysis. There was no effect on methacholine responsiveness or FeNO. Pharmacokinetic data showed AQX-1125 was rapidly absorbed with geometric mean Cmax and AUC0-24 h values of 1417 ng/mL and 16 727 h ng/mL, respectively. AQX-1125 was well tolerated, but mild GI side-effects (dyspepsia, nausea and abdominal pain) were described in 4/22 subjects on active treatment. These side-effects were mild self-limiting, required no further treatment and did not lead to discontinuation of therapy. CONCLUSION AND CLINICAL RELEVANCE: AQX-1125, a novel oral SHIP1 activator, significantly reduces the late response to allergen challenge, with a trend to reduce airway inflammation. AQX-1125 was safe and well tolerated and merits further investigation in inflammatory disorders. SN - 1365-2222 UR - https://www.unboundmedicine.com/medline/citation/25040039/The_effects_of_the_novel_SHIP1_activator_AQX_1125_on_allergen_induced_responses_in_mild_to_moderate_asthma_ L2 - https://doi.org/10.1111/cea.12370 DB - PRIME DP - Unbound Medicine ER -