CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial
Authors: Lazaar Aili L. , Miller Bruce E. , Donald Alison C. , Keeley Thomas , Ambery Claire , Russell John , Watz Henrik , Tal-Singer Ruth ,   for 205724 Investigators, Bardin Philip , Bremner Peter , Langton David , Southcott Anne-Marie , Thomas Paul S. , Wheatley John , Chapman Kenneth R. , Ferguson Murdo , Homik Lawrence A. , Maltais Francois , Pek Bonavuth , St-Amour Eric , Eckermann Tamara , Eich Andreas , Ern Guido , Foerster Karin , Forster Andreas , Hoffmann Martin , Keller Claus , Linnhoff Anneliese , Nischik Ruth , Schenkenberger Isabelle , Schmidt Olaf , Ahn Joong Hyun , Chung Hee Soon , Kim Do-Jin , Kim Jae Yeol , Lee Sang Haak , Oh Yeon-Mok , Park Myung Jae , Yong Suk Joong , Van der Sar Simone , Wielders Pascal L. M. L. , Olech-Cudzik Anna , Wytrychowski Krzysztof , Apti Ghiulten , Balta Andreia Madalina , Didita Doru , Filip Livia , Mincu Bogdan Mihai , Mincu Viorica , Nemes Roxana Maria , Scridon Maria Elena , Trofor Antigona Carmen , Ungurean Dragos G. , Balbín Ramon Agüero , Ferrero Miguel Barrueco , Echave-Sustaeta José Maria , Trigo José María Marín , Mola Eduardo Monso , Guardia Sergi Pascual , Romero Germán Peces-Barba , Abrahams Roger A. , Hyers Thomas M. , Kerwin Edward M. , Magee Shawn M. , Ramaswamy Murali , Wells James Michael 
Published: June 2020

Abstract
Background
Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD.

Methods
This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C).

Results
A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg.

Conclusions
The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD.

Trial registration
This study was registered with clinicaltrials.gov, NCT03034967.