Effects of p38 Inhibitor AZD7624 in Corticosteroid Resistant Asthma

In Part A of the study, p38 MAPK activation will be measured in CR asthmatics and compared to CS asthmatics. Assessment of p38 MAPK activation in whole blood samples from 5 CR and 5 CS asthma patients will be performed. After fulfilling all enrollment criteria blood samples will be collected from asthma patients at Visit 1 for the whole blood evaluation of MAPK activation by flow cytometry. After the initial visit, asthmatics will be given oral prednisone for 1 week and patients will return for the spirometry assessment. Patients will be defined as CR if \<10% improvement in FEV1 % predicted is observed and as CS if \>12% improvement in FEV1 % predicted is observed. If at least 2 fold increase in p-p38 MAPK expression in CD14+ cells of CR asthma patients is demonstrated when compared to CS asthmatics, Part B will be triggered. If no difference in p38 MAPK phosphorylation will be observed in monocytes of CR and CS asthmatics by flow cytometry assessment, the study will be terminated. In Part B of the study, CR asthmatics will be randomized for treatment with AZD7624 or placebo for one month in a cross over design; the ability of AZD7624 to inhibit p38 MAPK activity will be assessed in CR patients. Five CR asthma patients from Part A may also take part in Part B. Additional CR (n=10 total patients required) and CS asthmatics (n=5) will be recruited in part B. Baseline levels of p38 MAPK and other biomarkers will also be assessed in CR asthmatics and compared to both CS asthmatics and healthy volunteers. Patients will be enrolled and assessed for baseline p38 MAPK activation as above in peripheral blood. Patients will be re-defined as CR or CS as above based on changes in the lung function after 1 week of oral prednisone burst as above. Levels of p38 MAPK activity and other biomarkers will be compared between CR and CS patients (n=10 in each group based on recruitment for Part A and Part B) and also compared to healthy volunteers (n=10). After 1 week following oral prednisone burst, CR patients will return to undergo bronchoscopy with the collection of BAL and bronchial epithelial brushes. Blood samples will be collected for evaluation of p38 MAPK activation. CS patients will not undergo bronchoscopy, but will give a blood sample one week after oral prednisone burst for the analysis of p38 MAPK activation. Blood samples will also be collected from healthy controls during the initial visit to assess p38 MAPK activation. CR patients will be randomized for treatment with p38 inhibitor AZD7624 or placebo (5 patients per group). After 4 weeks of treatment with AZD7624 or placebo, CR patients will undergo additional bronchoscopy with the collection of BAL, brushes and blood. Patients will be monitored for adverse events during the trial. After completion of first block of cross over treatment, CR patients will undergo a 1 month wash-out period, after which, they will return for induced sputum and blood collection, and then undergo the second crossover period with AZD7624 or placebo. After the second 4 week treatment block, patients will come for sputum induction and blood collection. In CR asthma patients assessment of lung function, asthma control, airway hyperreactivity, p38 MAPK activation in peripheral blood, BAL, induced sputum samples and cellular responsiveness to corticosteroids before and after treatment with AZD7624 will be performed.