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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.

 

B.R. Leaker, MD1, P.J. Barnes, FRS2, B.J. O’Connor, MD1, F.Y. Ali, PhD1, P. Tam, PhD3, J. Neville, PhD3, L.F. Mackenzie, PhD3 and T. MacRury, PhD3

1Respiratory Clinical Trials Ltd., London, United Kingdom; 2National Heart & Lung Institute, Imperial College London, United Kingdom; 3Aquinox Pharmaceuticals Inc., Vancouver, BC, Canada

 

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.

KEYWORDS: SH2-containing inositol-5′-phosphatase 1; airway hyperresponsiveness; asthma; induced sputum; inhaled allergen challenge; phosphoinositide-3-kinase

PMID: 25040039

 

Summary

Inhaled corticosteroids (ICS)/long acting β agonists (LABA) combination therapy remains the mainstay treatment for asthma. However compliance with inhaled therapies is often poor, possibly related to fears over long term steroid usage [1]. Certain patient groups such as young children and the elderly are unable to use inhalers effectively. Therefore there remains an unmet medical need for novel anti-inflammatory agents that can be administered orally.

AQX-1125 is an orally active small molecule with a novel mechanism of action. It is a next generation SHIP1 activator. Targeting SHIP is an alternative way of modulating the PI3K pathway, which plays a key role in regulating cell migration and activation (Figure 1). SHIP1 expression is restricted to hematopoietic derived cells, which limits off-target toxicity. Activation of SHIP1 redirects cellular PI3K signalling rather than preventing it.

 

Figure 1. Regulation of phosphoinositide metabolism by SHIP1 and closely related pathways in cells of haematopoietic origin.

 

AQX-1125 has many of the biological effects of the earlier generation SHIP1 activators, but has an improved drug scaffold and superior drug-like properties. AQX-1125 displays anti-inflammatory properties in cellular and murine models. In vitro studies demonstrate anti-inflammatory effects in both neutrophil- and eosinophil-mediated animal models of disease.

AQX-1125 was evaluated in mild to moderate asthmatics using an inhaled allergen challenge 2-way cross-over study. In each treatment period either 450mg AQX-1125 or placebo was administered once daily for 7 days. A total of 22 subjects were randomised. At baseline, the study population had mean PC20 value ≤ 16mg/mL and FEV1 ≥ 70% of predicted. Allergen challenge was performed on day 6, followed by methacholine challenge on day 7. Sputum induction and fractional exhaled nitric oxide (FeNO) measurements were performed. Pharmacokinetic blood sampling was also performed throughout the study.

AQX-1125 significantly inhibited the late response (LAR) following allergen challenge (Figure 2). The magnitude of improvement on FEV1 during the LAR compared to placebo was 150mL (20%; p=0.027). The minimum FEV1 during the LAR was significantly increased by 180mL (p=0.014). AQX-1125 had no effect on the early response (EAR) or on FeNO.

 Figure 2. Mean and SEM FEV1 values over time after inhaled allergen challenge. The late response between 4-10 hours after inhaled allergen (LAR4-10) is reduced by 20% vs. placebo (p=0.027).

 

The effect on lung function was correlated with nominal reductions in induced sputum cell counts for eosinophils, neutrophils and macrophages.

The only AQX-1125 related adverse events were gastrointestinal related and were mild and self-limiting. Pharmacokinetics of AQX-1125 supports a once-daily dosing regimen.

The allergen-induced response is a robust model that is commonly used to assess the therapeutic potential of novel treatments for asthma [2-4]. All of the currently available and effective treatments for asthma modify the LAR following allergen-induced responses and there are no false positives [5]. These medications include short-acting and long-acting inhaled β2-agonists, inhaled corticosteroids, cromones, methylxanthines, anti-leukotriene and anti-IgE monoclonal antibody.

Future studies with AQX-1125 are being conducted in COPD (neutrophil mediated inflammation). There is, however greater potential, in the author’s opinion, to show benefit in asthma. The compound shows superior anti-inflammatory effects in pre-clinical models of eosinophilic inflammation & in addition the positive allergen challenge study reported herein suggests that AQX125 may show therapeutic benefit in asthma. Further studies in wild type asthma are therefore indicated.

References

  1. Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique. Chest. 2000; 117(2):542-50.
  2. Harbinson PL, MacLeod D, Hawksworth R, O’Toole S, Sullivan PJ, Heath P, Kilfeather S, Page CP, Costello J, Holgate ST, Lee TH. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J. 1997; 10(5):1008-14.
  3. van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbröker D, Bardin PG. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol. 2005; 116(2):292-8.
  4. Palmqvist M, Bruce C, Sjöstrand M, Arvidsson P, Lötvall J. Differential effects of fluticasone and montelukast on allergen-induced asthma. Allergy. 2005; 60(1):65-70.
  5. O’Byrne PM. Allergen-induced airway inflammation and its therapeutic intervention. Allergy Asthma Immunol Res. 2009; 1(1):3-9.

 

Correspondence

Dr B Leaker

Respiratory Clinical Trials Ltd., 20 Queen Anne Street, London W1G 8HU, UK.

+44 (0)20 7034 3301

Brian.Leaker@qasmc.com