Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis

Stockley, Robert A.; Soyza, Anthony De; Gunawardena, K A; Perrett, John; Forsman‐Semb, Kristina; Entwistle, Neil; Snell, Noel

doi:10.1016/j.rmed.2012.12.009

Cited by 159 publications

(121 citation statements)

References 31 publications

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“…Therefore, not surprisingly, therapeutic manipulation of elastase has been proposed in bronchiectasis. In a proof of concept study, Stockley and colleagues tested an oral NE inhibitor for 4 weeks in 38 patients with bronchiectasis (41). Although the primary outcome of a reduction in sputum neutrophils was not achieved, the study showed a clinically important and significant improvement in FEV 1 of 100 ml versus placebo, and a more than 4-point improvement in the SGRQ, which did not reach statistical significance (41).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Chalmers

Moffitt²,

Suárez-Cuartín

et al. 2017

Am J Respir Crit Care Med

278

202

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Rationale: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.Methods: This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomographyconfirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years.Measurement and Main Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P , 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P , 0.0001), FEV 1 % predicted (r = 20.33; P , 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P , 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P , 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV 1 decline (b coefficient, 20.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P , 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline.Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Chalmers

Moffitt²,

Suárez-Cuartín

et al. 2017

Am J Respir Crit Care Med

278

202

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“…Given the previously noted importance of neutrophil elastase in pathogenesis [104], this represents a promising therapeutic target. Phase II studies of oral neutrophil elastase inhibitors have been reported while others are ongoing [105]. Data show the ability to inhibit elastase activity but without clear clinical benefits yet.…”

Section: A Stepwise Approach To Treatmentmentioning

confidence: 99%

Management of bronchiectasis in adults

2015

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Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis.The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life.Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation.This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials. @ERSpublications Bronchiectasis is a rapidly developing field: review of recent RCTs and progress towards developing new therapies

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“…In the context of recent studies with other agents for the treatment of bronchiectasis, the reduction in sputum neutrophils observed in this study indicates some clinical potential for CXCR2 antagonism in the management of bronchiectasis [13,30,31,37,38]. Current treatment options such as long-term macrolide antibiotics and corticosteroids are either of limited effectiveness or have a number of potential drawbacks, such as development of bacterial resistance and adrenal suppression [13,30,31,38,39].…”

Section: Discussionmentioning

confidence: 68%

“…Furthermore, CXCR2 antagonism may have additional beneficial effects on airway goblet cell hyperplasia and mucus production, independent of the modulation of neutrophil migration [15]. However, as with other novel approaches in development, larger studies of a longer duration with careful phenotyping of participants will be needed to determine the clinical utility of CXCR2 antagonism in bronchiectasis [37]. The concept that treatment responses to CXCR2 antagonism relate to the cause of neutrophilic airway inflammation is supported by a recent trial of another compound in patients with COPD showing an important reduction in exacerbation frequency in smokers but an increase in non-and ex-smokers [41].…”

Section: Discussionmentioning

confidence: 99%

A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis

et al. 2015

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This randomised double-blind placebo-controlled parallel-group multicentre phase IIa study evaluated the effect of the CXCR2 antagonist AZD5069 on sputum neutrophil counts in adults with bronchiectasis.Patients were randomised 1:1 to receive AZD5069 80 mg or placebo orally twice daily for 28 days. Assessments included blood cell counts, inflammatory markers in blood, morning spontaneous sputum, lung function, safety and tolerability and patients completed daily BronkoTest diary cards. The primary outcome measure was the change in absolute sputum neutrophil count.Of 52 randomised patients, 45 completed treatment, 20 (76.9%) out of 26 receiving AZD5069 and 25 (96.2%) out of 26 receiving placebo. AZD5069 reduced the absolute neutrophil cell count in morning sputum by 69% versus placebo ( p=0.004); percentage sputum neutrophil count was reduced by 36% ( p=0.008). The number of infections/exacerbations was similar with AZD5069 and placebo (nine versus eight), but these led to more study discontinuations with AZD5069 (four versus zero). Sputum interleukin (IL)-6 and growth-regulated oncogene (GRO)-α and serum GRO-α, IL-1ß and IL-8 levels increased with AZD5069 versus placebo (all p<0.001), while serum high-sensitivity C-reactive protein levels did not change. AZD5069 was well tolerated.AZD5069 markedly reduced absolute sputum neutrophil counts in bronchiectasis patients, although this was not associated with improvements in clinical outcomes in this exploratory study. @ERSpublications CXCR2 antagonist AZD5069 reduced sputum neutrophil counts in patients with bronchiectasis over 4 weeks of treatment

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Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis

Abstract: NCT00769119.

Cited by 159 publications

References 31 publications

Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Management of bronchiectasis in adults

A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis

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