Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis

Moss, Richard B.; Mistry, S.; Konstan, Michael W.; Pilewski, Joseph M.; Kerem, Eitan; Tal‐Singer, Ruth; Lazaar, Aili L.

doi:10.1016/j.jcf.2012.08.016

Cited by 106 publications

(81 citation statements)

References 19 publications

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“…Moreover, these neutrophilic chemokines have been shown to be significantly elevated in the blood of CXCR2 knockout mice compared with wild-type littermates [49]. There is also recent clinical evidence that blood concentrations of IL-8 were significantly increased in a dose-dependent manner in patients with cystic fibrosis receiving a CXCR2 antagonist (SB-656933) [23], and in patients with bronchiectasis who received AZD5069 [24], further indicating a potential compensatory upregulation of CXCR2-specific ligands. Although the specific mechanisms regulating this systemic mediator release have not been investigated, a possible explanation of this observed adaptive increase could be a limited physiological compensatory response following blockade of CXCR2 receptors.…”

Section: Discussionmentioning

confidence: 97%

“…Recent clinical studies demonstrated that a CXCR2 antagonist (AZD8309) given orally blocked the increase both in neutrophils (by 79%) and selected neutrophil chemoattractants, including IL-8 (by 52%), in induced sputum following inhaled LPS challenge [21], and significantly reduced LPS-induced neutrophil recruitment in the upper airways of healthy subjects [22]. Interestingly, however, treatment with the CXCR2 antagonists SB-656933 and AZD5069 caused a small but significant elevation in blood concentrations of IL-8 in studies of patients with cystic fibrosis and bronchiectasis, respectively [23,24]. Clinical data from a recent Phase 2b clinical trial showed that CXCR2 antagonism using MK-7123 can improve measures of lung function and reduce COPD exacerbations in current smokers but was associated with a decrease in absolute peripheral neutrophil count [25].…”

Section: Introductionmentioning

confidence: 99%

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The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions

Jurčević

Humfrey

Uddin

et al. 2015

Brit J Clinical Pharma

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Aims The aim of the present study was to investigate whether selective antagonism of the cysteine‐X‐cysteine chemokine receptor‐2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens. Methods In a double‐blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte‐colony stimulating factor (G‐CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli. Results AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of −1.67 (0.67) ×109 l–1 vs. 0.19 (0.78) ×109 l–1 for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10‐min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G‐CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo‐ and AZD5069‐treated subjects. Superoxide anion production in E. coli‐stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated. Conclusions CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions

Jurčević

Humfrey

Uddin

et al. 2015

Brit J Clinical Pharma

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“…Moreover, the associated increase in blood inflammatory markers upon CXCR2 inhibition warrants additional studies to fully understand the mode of action and therapeutic potential of this new treatment strategy in CF (Moss et al, 2013).…”

Section: Neutrophil-based Targeting Strategies and Their Implicationmentioning

confidence: 99%

Neutrophils in cystic fibrosis

Laval

Ralhan

Hartl

2016

Biological Chemistry

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Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

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“…These are in different stages of drug development and have been shown to have an effect on neutrophil recruitment to the lung in clinical studies (Holz et al, 2010;Lazaar et al, 2011;Virtala et al, 2012;Pavord et al, 2013). In addition, the effect of inhibiting neutrophil recruitment has been shown for clinical biomarkers and endpoints indicative of disease efficacy as investigated in cystic fibrosis, severe asthma, and COPD (Nair et al, 2012;Moss et al, 2013;Rennard et al, 2015). Despite a strong association of chemokine involvement in disease, to date, there are only two marketed products targeting chemokine receptors: plerixafor, a small-molecule antagonist of CXCR4, and maraviroc, an antagonist of CCR5 (Bachelerie et al, 2014).…”

Section: Abbreviations: Az10397767 (R)mentioning

confidence: 99%

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

Nicholls

Wiley

Dainty

et al. 2015

J Pharmacol Exp Ther

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In normal physiologic responses to injury and infection, inflammatory cells enter tissue and sites of inflammation through a chemotactic process regulated by several families of proteins, including inflammatory chemokines, a family of small inducible cytokines. In neutrophils, chemokines chemokine (CXC motif) ligand 1 (CXCL1) and CXCL8 are potent chemoattractants and activate G protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXCR2. Several small-molecule antagonists of CXCR2 have been developed to inhibit the inflammatory responses mediated by this receptor. Here, we present the data describing the pharmacology of 3S)-3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide], a novel antagonist of CXCR2. AZD5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC 50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA 2 of approximately 9.6, and adhesion molecule expression, with a pA 2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. With short incubation times, AZD5069 appeared to have an antagonist profile with insurmountable antagonism of calcium response curves. This behavior was also observed in vivo in an acute lipopolysaccharide-induced lung inflammation model. Altogether, the data presented here show that AZD5069 represents a novel, potent, and selective CXCR2 antagonist with potential as a therapeutic agent in inflammatory conditions.

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Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis

Cited by 106 publications

References 19 publications

The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions

The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions

Neutrophils in cystic fibrosis

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

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