CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine 2015-05, Vol.191 (9), p.1001-1011
• Main Authors: Rennard, Stephen I, Dale, David C, Donohue, James F, Kanniess, Frank, Magnussen, Helgo, Sutherland, E Rand, Watz, Henrik, Lu, Susan, Stryszak, Paul, Rosenberg, Elizabeth, Staudinger, Heribert
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anti-Inflammatory Agents - administration & dosage; Benzamides - administration & dosage; Bronchodilator Agents - administration & dosage; Cyclobutanes - administration & dosage; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume - drug effects; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils - drug effects; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - physiopathology; Receptors, Interleukin-8B - antagonists & inhibitors; Surveys and Questionnaires
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201405-0992oc

An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. 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. 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. 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).