Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial

Background Airway neutrophilic inflammation is a pathological feature in some patients with severe asthma. Stimulation of the chemokine receptor CXCR2 mediates neutrophil migration into the airways. We investigated the safety and efficacy of AZD5069, a CXCR2 antagonist, as an add-on therapy in patients with uncontrolled severe asthma. Methods In this multicentre, randomised, double-blind, placebo-controlled, dose-finding trial, we enrolled patients aged 18 years or older with uncontrolled asthma despite combination therapy with long-acting beta(2) agonists and medium-dose or high-dose inhaled corticosteroids. Patients were randomised in a 1:1:1:1 ratio via an interactive voice-response or web response system to receive 5,15, or 45 mg oral AZD5069 twice daily or matched placebo. The primary endpoint was the number of severe asthma exacerbations in 6 months. Safety was assessed in the 6-month treatment period and an optional 6-month safety extension. This trial is registered with ClinicalTrials.gov, number NCT01704495. Findings 640 patients with a mean age of 52 (SD 11.8) years were randomised, 478 to receive AZD5069 (5 mg n=160, 15 mg n=156, and 45 mg n=162) and 162 placebo. No dose of AZD5069 reduced the rate of severe exacerbations compared with placebo (rate ratio for 5 mg 1.29, 90% CI 0.79-2.11; for 15 mg 1.53, 0.95-2.46; and for 45 mg 1.56, 0.98-2.49). Treatment with AZD5069 was generally well tolerated. The most commonly reported adverse event overall was nasopharyngitis, seen in 18 (11.5%) receiving 5 mg, 13 (8.5%) receiving 15 mg, and 18 (11.2%) receiving 45 mg AZD5069, and 31 (19.5%) of those receiving placebo. Interpretation Treatment with this selective CXCR2 antagonist did not reduce the frequency of severe exacerbations in patients with uncontrolled severe asthma. These findings bring into question the role of CXCR2-mediated neutrophil recruitment in the pathobiology of exacerbations in severe refractory asthma.