CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial

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

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.

Keywords: COPD; CXCR2; Clinical trial; Danirixin.

Conflict of interest statement

ALL, BEM, AD, TK, CA and JR are employees of GSK and own shares in the company. RTS is a former employee of GSK and hold shares in the company. HW reports support from GSK related to the conduct of the study.

Figures

Fig. 1
Fig. 1
Consolidated Standards of Reporting Trials (CONSORT) flow diagram of subject disposition; mITT: modified intent-to-treat
Fig. 2
Fig. 2
Daily mean E-RS: COPD total scores over time. Baseline ERS:COPD Total Scores, Mean (SD): Placebo = 12.01 (6.299), DNX 5 mg = 12.73 (6.232), DNX 10 mg = 11.53 (6.288), DNX 25 mg = 11.70 (6.724), DNX 35 mg = 12.08 (5.804), DNX 50 mg = 11.43 (5.219)

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