BACKGROUND: It is hypothesized that a CXCR2 receptor antagonist would inhibit the recruitment and activation of neutrophils and other inflammatory cells into the lung in subjects with cystic fibrosis. The objective of this study was to evaluate the safety, tolerability and pharmacodynamics of SB-656933, an oral CXCR2 antagonist. METHODS:146 adult CF patients were randomized to receive either placebo or SB-656933 20mg or 50mg once daily for 28days. The primary endpoint was safety; secondary endpoints included pharmacokinetics, blood and sputum biomarkers, sputum microbiology, pulmonary function and respiratory symptoms. RESULTS:SB-656933 was generally well tolerated. The most frequent adverse event was headache. Five subjects were withdrawn due to adverse events. In subjects receiving SB-656933 50mg, sputum neutrophils and elastase were reduced compared to baseline (probability of a true reduction, 0.889 and 0.882 respectively), and free DNA reduced compared to placebo (probability of a true reduction, 0.967), while blood levels of fibrinogen, CRP and CXCL8 were increased. There were no changes in lung function or respiratory symptoms. Average plasma concentrations of SB-656933 were lower than predicted based on previous studies, only breaching IC50 for ~4h at the 50mg dose. CONCLUSIONS:SB-656933 was well-tolerated in adult patients with cystic fibrosis. Patients receiving a daily dose of 50mg showed trends for improvement in sputum inflammatory biomarkers despite potential blunting of effects by lower than expected plasma concentrations. Although the increase in systemic inflammatory markers requires further evaluation, CXCR2 antagonism may be a useful approach for modulating airway inflammation in patients with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT00903201).
RCT Entities:
BACKGROUND: It is hypothesized that a CXCR2 receptor antagonist would inhibit the recruitment and activation of neutrophils and other inflammatory cells into the lung in subjects with cystic fibrosis. The objective of this study was to evaluate the safety, tolerability and pharmacodynamics of SB-656933, an oral CXCR2 antagonist. METHODS: 146 adult CFpatients were randomized to receive either placebo or SB-656933 20mg or 50mg once daily for 28days. The primary endpoint was safety; secondary endpoints included pharmacokinetics, blood and sputum biomarkers, sputum microbiology, pulmonary function and respiratory symptoms. RESULTS:SB-656933 was generally well tolerated. The most frequent adverse event was headache. Five subjects were withdrawn due to adverse events. In subjects receiving SB-656933 50mg, sputum neutrophils and elastase were reduced compared to baseline (probability of a true reduction, 0.889 and 0.882 respectively), and free DNA reduced compared to placebo (probability of a true reduction, 0.967), while blood levels of fibrinogen, CRP and CXCL8 were increased. There were no changes in lung function or respiratory symptoms. Average plasma concentrations of SB-656933 were lower than predicted based on previous studies, only breaching IC50 for ~4h at the 50mg dose. CONCLUSIONS:SB-656933 was well-tolerated in adult patients with cystic fibrosis. Patients receiving a daily dose of 50mg showed trends for improvement in sputum inflammatory biomarkers despite potential blunting of effects by lower than expected plasma concentrations. Although the increase in systemic inflammatory markers requires further evaluation, CXCR2 antagonism may be a useful approach for modulating airway inflammation in patients with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT00903201).
Authors: Dominik Hartl; Rabindra Tirouvanziam; Julie Laval; Catherine M Greene; David Habiel; Lokesh Sharma; Ali Önder Yildirim; Charles S Dela Cruz; Cory M Hogaboam Journal: J Innate Immun Date: 2018-02-13 Impact factor: 7.349