title: The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma.
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.
  
  
  CONCLUSIONS
  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.affiliation: Respiratory Clinical Trials Ltd., London, UK.
authors.forename: B R
authors.initials: BR
authors.lastname: Leaker
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: B J
authors.initials: BJ
authors.lastname: O'Connor
authors.forename: F Y
authors.initials: FY
authors.lastname: Ali
authors.forename: P
authors.initials: P
authors.lastname: Tam
authors.forename: J
authors.initials: J
authors.lastname: Neville
authors.forename: L F
authors.initials: LF
authors.lastname: Mackenzie
authors.forename: T
authors.initials: T
authors.lastname: MacRury
mesh_terms: D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000704:Analysis of Variance; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000494:pharmacology* / Q000627:therapeutic use*; D045853:Exhalation; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use*; D000072181:Inositol Polyphosphate 5-Phosphatases; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D012307:Risk Factors; D012720:Severity of Illness Index; D015398:Signal Transduction; D013183:Sputum; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C582990:4-(4-(aminomethyl)-7a-methyl-1-methylideneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol; D000485:Allergens; D018927:Anti-Asthmatic Agents; D003511:Cyclohexanols; D007189:Indans; D010716:Phosphatidylinositols; D009569:Nitric Oxide; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: SH2-containing inositol-5′-phosphatase 1; airway hyperresponsiveness; asthma; induced sputum; inhaled allergen challenge; phosphoinositide-3-kinase