CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease

Stephen I. Rennard, David C. Dale, James F. Donohue, Frank Kanniess, Helgo Magnussen, E. Rand Sutherland, Henrik Watz, Susan Lu, Paul Stryszak, Elizabeth Rosenberg, Heribert Staudinger

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Rationale: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). Objectives: 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 severeCOPD(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. Measurements and Main 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 1.53109/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).

Original languageEnglish (US)
Pages (from-to)1001-1011
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number9
DOIs
StatePublished - May 1 2015

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Chronic Obstructive Pulmonary Disease
Placebos
Neutrophils
Sputum
2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide
Cytokine Receptors
Bronchodilator Agents
Metalloproteases
Chemotaxis
Double-Blind Method
C-Reactive Protein
Fibrinogen
Peroxidase
Blood Proteins
Anti-Inflammatory Agents
Therapeutics
Biomarkers
Clinical Trials
Inflammation
Safety

Keywords

  • CXCR2 antagonist
  • Chemokine receptor antagonist
  • Chronic obstructive pulmonary disease
  • Neutrophils
  • Smokers

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Rennard, S. I., Dale, D. C., Donohue, J. F., Kanniess, F., Magnussen, H., Sutherland, E. R., ... Staudinger, H. (2015). CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 191(9), 1001-1011. https://doi.org/10.1164/rccm.201405-0992OC

CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. / 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.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 191, No. 9, 01.05.2015, p. 1001-1011.

Research output: Contribution to journalArticle

Rennard, SI, Dale, DC, Donohue, JF, Kanniess, F, Magnussen, H, Sutherland, ER, Watz, H, Lu, S, Stryszak, P, Rosenberg, E & Staudinger, H 2015, 'CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, vol. 191, no. 9, pp. 1001-1011. https://doi.org/10.1164/rccm.201405-0992OC
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. / CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. In: American Journal of Respiratory and Critical Care Medicine. 2015 ; Vol. 191, No. 9. pp. 1001-1011.
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abstract = "Rationale: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). Objectives: 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 severeCOPD(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. Measurements and Main 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 1.53109/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).",
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AU - Dale, David C.

AU - Donohue, James F.

AU - Kanniess, Frank

AU - Magnussen, Helgo

AU - Sutherland, E. Rand

AU - Watz, Henrik

AU - Lu, Susan

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AU - Staudinger, Heribert

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N2 - Rationale: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). Objectives: 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 severeCOPD(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. Measurements and Main 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 1.53109/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).

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