CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease

Abstract

Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).

Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist

“…These are in different stages of drug development and have been shown to have an effect on neutrophil recruitment to the lung in clinical studies (Holz et al, 2010;Lazaar et al, 2011;Virtala et al, 2012;Pavord et al, 2013). In addition, the effect of inhibiting neutrophil recruitment has been shown for clinical biomarkers and endpoints indicative of disease efficacy as investigated in cystic fibrosis, severe asthma, and COPD (Nair et al, 2012;Moss et al, 2013;Rennard et al, 2015). Despite a strong association of chemokine involvement in disease, to date, there are only two marketed products targeting chemokine receptors: plerixafor, a small-molecule antagonist of CXCR4, and maraviroc, an antagonist of CCR5 (Bachelerie et al, 2014).…”

The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates

“…6 However, further subanalysis in current smokers on high dose MK-7123 showed a statistically and clinically significant increase in FEV 1 (by up to 168 ml) and a reduction in sputum neutrophils, relative to placebotreated patients. 6 Although these data suggest that oral CXCR2 antagonists may offer a new treatment avenue for current smokers with COPD, further long-term follow-up studies in larger cohorts will be needed to determine the absolute therapeutic index of these neutrophildirected agents.…”

The double-edged sword of neutrophilic inflammation in bronchiectasis

“…Thus, STOCKLEY et al [6] recently evaluated the effectiveness and safety of a neutrophilic elastase inhibitor (AZD9668) in bronchiectasis patients and found a significant functional improvement and a trend toward a reduction in inflammatory biomarkers. Furthermore, recent clinical studies have evaluated the efficacy and safety of blockers of CXCR2 receptors in diseases with marked neutrophilic inflammation, such as COPD [8], neutrophilic asthma [9], cystic fibrosis [10] and some interstitial diseases [11], but no study has yet focussed on the effect of these new molecules on bronchiectasis patients.…”

“…It will be necessary to find a balance between a strong anti-inflammatory action ( preventing bronchial damage due to inflammation) and an excessive one that weakens the defences against infection (commonly found in bronchiectasis patients, sometimes to a serious degree). This necessity is even more pertinent when we consider that these products could induce neutropenia [8,13] and that CXCR2 has been shown to play a role in the host pulmonary immune response to Pseudomonas [14], Aspergillus [15] and Nocardia [16] infections (all very frequent microorganisms in bronchiectasis). This has led some authors to postulate that any successful approach would require a selective blockade of CXCR2 (the main cause of the chemotaxis of neutrophils) as opposed to CXCR1 (responsible for activation against infections) [3].…”

“…It will also be important to make a long-term evaluation of adverse effects ( particularly neutropenia, which some of these products are capable of triggering); pharmacological interactions; synergic action with other previously known anti-inflammatory drugs; the patient groups that would most benefit; the effect of smoking on the efficacy of the product; and the variable(s) that need to be monitored to best evaluate efficacy. We must also find explanations for the paradoxical effects observed when these molecules are put to use, such as the increase in some acute-phase reactants and pro-inflammatory molecules [8]. Until all this is achieved, AZD-5069 will occupy a place among molecules that show promise in the management of bronchiectasis but require further studies before any significant clinical impact can be demonstrated.…”