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

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.

Fig. 1

Consolidated Standards of Reporting Trials (CONSORT) flow diagram of subject disposition; mITT: modified intent-to-treat

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)