Journal Article

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

Watz, Henrik, Miller, Bruce E., Keeley, Thomas, Tal-Singer, Ruth, Lazaar, Aili L., Ambery, Claire, Russell, John, Donald, Alison C.

2020

Overview

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 .

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Administration, Oral / Adolescent / Adult / Aged / Aged, 80 and over / Antagonists (Biochemistry) / Bioavailability / Biomarkers / Cell activation / Chemokines / Chronic obstructive lung disease / Chronic obstructive pulmonary disease / Clinical trial / COPD / CXC chemokines / CXCR2 / CXCR2 protein / Danirixin / Disease / Disease Progression / Dose-Response Relationship, Drug / Double-Blind Method / Female / Follow-Up Studies / Forced Expiratory Volume / Health aspects / Humans / Inflammation / Leukocyte migration / Leukocytes (neutrophilic) / Lung - physiopathology / Lung diseases / Male / Medicine / Medicine & Public Health / Middle Aged / Mucus / Mucus - metabolism / Neutrophils / Obstructive lung disease / Patients / Physiological aspects / Piperidines - administration & dosage / Placebo effect / Placebos / Pneumology/Respiratory System / Population / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - metabolism / Pulmonary Disease, Chronic Obstructive - physiopathology / Quality of life / Randomization / Receptors, Interleukin-8B - antagonists & inhibitors / Respiratory tract diseases / Retrospective Studies / Risk assessment / Signs and symptoms / Sulfones - administration & dosage / Surveys and Questionnaires / Young Adult