The effects of the novel SHIP1 activator AQX‐1125 on allergen‐induced responses in mild‐to‐moderate asthma

Abstract

SummaryBackground SH2-containing inositol-5 0 -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-na€ ıve 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 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.Keywords airway hyperresponsiveness, asthma, induced sputum, inhaled allergen challenge, phosphoinositide-3-kinase, SH2-containing inositol-5 0 -phosphatase 1

Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain–containing inositol 5-phosphatase (SHIP-1)

“…Recent clinical studies with SHIP-1 agonists found a moderate therapeutic effect in patients with allergic asthma. 24 Although our results would suggest that activation of SHIP-1 in T cells and DCs would enhance disease severity, it is possible that SHIP-1 agonists have a net positive therapeutic effect through actions on specific leukocyte subsets, such as mast cells and basophils, where it has been shown to be an important regulator of their activation. [25][26][27][28] Placing these observations in the context of the current work, it is likely that specific targeting of SHIP-1 activity, either positively or negatively, in a lineage-specific manner could lead to improved control of AAI.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…SHIP is more amenable to activation and a small molecule activator of SHIP-1, AQX-1125, and is effective in reducing p-Akt and reducing mediator release, mast cell activation, and leukocyte chemotaxis in vitro (Stenton et al, 2013b) and inflammation in allergeninduced and cigarette smoke-induced pulmonary inflammation in mice in vivo (Stenton et al, 2013a). A recent clinical trial of oral AQX-1125 in patients with mild asthma showed a significant reduction in later response after allergen challenge and a (nonsignificant) reduction in inflammatory biomarkers (Leaker et al, 2014). The drug is well tolerated, suggesting that it might be a potential treatment of asthma and COPD.…”

Mechanisms of development of multimorbidity in the elderly

“…Since metformin is relatively well tolerated with chronic use it might be a suitable therapy for treating multimorbidity. PI3K signalling may also be inhibited by activators of the endogenous inhibitor SHIP-1 [138] and such drugs have already entered clinical trials for treatment of allergic disease [139]. Low concentrations of theophylline have been shown to inhibit oxidant-activated PI3Kδ, which may be involved in reduced SIRT1 levels after oxidative stress [29].…”