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The effects of the novel SHIP 1 activator AQX ‐1125 on allergen‐induced responses in mild‐to‐moderate asthma
Author(s) -
Leaker B. R.,
Barnes P. J.,
O'Connor B. J.,
Ali F. Y.,
Tam P.,
Neville J.,
Mackenzie L. F.,
MacRury T.
Publication year - 2014
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12370
Subject(s) - methacholine , medicine , exhaled nitric oxide , placebo , asthma , allergen , crossover study , sputum , pharmacology , immunology , allergy , spirometry , lung , respiratory disease , pathology , tuberculosis , alternative medicine
Summary Background SH 2‐containing inositol‐5′‐phosphatase 1 ( SHIP 1) 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 SHIP 1 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 (FEV 1 4–10 h: mean difference 150 mL, 20%; P = 0.027) and significantly increased the minimum FEV 1 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 C max and AUC 0–24 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 SHIP 1 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.