A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis.
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.
Institute of Cellular Medicine, Newcastle University and Freeman Hospital, Sir William Leech Research Centre, Respiratory Department, Newcastle upon Tyne, UK anthony.de-soyza@ncl.ac.uk.
Anthony
A
De Soyza
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Ian
I
Pavord
Centre for Infection and Immunity, Queens University, Belfast, UK.
J Stuart
JS
Elborn
Respiratory Research Unit, Southmead Hospital, Bristol, UK.
David
D
Smith
Innovative Medicines, Respiratory, Inflammation and Autoimmunity (iMED RIA), AstraZeneca R&D, Mölndal, Sweden.
Heather
H
Wray
Innovative Medicines, Respiratory, Inflammation and Autoimmunity (iMED RIA), AstraZeneca R&D, Mölndal, Sweden.
Margareta
M
Puu
Innovative Medicines, Respiratory, Inflammation and Autoimmunity (iMED RIA), AstraZeneca R&D, Mölndal, Sweden.
Bengt
B
Larsson
Respiratory Department, Queen Elizabeth Hospital, Birmingham, UK.
Robert
R
Stockley
D000328:Adult; D000368:Aged; D001987:Bronchiectasis / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D002452:Cell Count; D054360:Chemokine CXCL1 / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D011743:Pyrimidines / Q000627:therapeutic use*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013183:Sputum / Q000187:drug effects*; D013449:Sulfonamides / Q000627:therapeutic use*; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; C000597960:N-(2-(2,3-difluoro-6-benzylthio)-6-(3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D002097:C-Reactive Protein