title: CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease.
abstract: BACKGROUND
  An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD).
  
  
  OBJECTIVE
  To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD.
  
  
  METHODS
  This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1.
  
  
  RESULTS
  A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups.
  
  
  CONCLUSIONS
  Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).
authors.affiliation: 1 University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: David C
authors.initials: DC
authors.lastname: Dale
authors.forename: James F
authors.initials: JF
authors.lastname: Donohue
authors.forename: Frank
authors.initials: F
authors.lastname: Kanniess
authors.forename: Helgo
authors.initials: H
authors.lastname: Magnussen
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.forename: Henrik
authors.initials: H
authors.lastname: Watz
authors.forename: Susan
authors.initials: S
authors.lastname: Lu
authors.forename: Paul
authors.initials: P
authors.lastname: Stryszak
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Heribert
authors.initials: H
authors.lastname: Staudinger
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D003503:Cyclobutanes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D011795:Surveys and Questionnaires
chemical_list: C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D001993:Bronchodilator Agents; D003503:Cyclobutanes; D023063:Receptors, Interleukin-8B
keywords: CXCR2 antagonist; chemokine receptor antagonist; chronic obstructive pulmonary disease; neutrophils; smokers