The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

Abstract

Backgroundp38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.ObjectivesThese studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.MethodsThe p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18–55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40–85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations.ResultsThe p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38β isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout.ConclusionAlthough p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.

<p>Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD</p>

“…Although we report a significant upregulation at the protein level of the MEK pathway in GOLD 4 lung sections obtained from COPD transplant patients with end-stage disease, we have not examined pathway activation in mild or moderate COPD lung sections; therefore, it is unclear whether pathway activation could be a driver of disease progression and this important aspect warrants further investigation. Expression of other MAPK, particularly p38, has been reported in alveolar macrophages and bronchial epithelia of COPD patients [8][9][10] implicating the importance of other MAPK pathways in driving inflammation. Enhanced p-ERK1/2 and p-p38 expression was also reported in airway epithelium in biopsy specimens from asthmatics compared to non-asthmatic subjects, indicating that the activation of these signaling pathways may have a broader implication in airway inflammatory diseases.…”

“…Amongst the modules of the MAPK cascade, p38 drew considerable interest as elevated levels of activated p38 were detected in alveolar macrophages from COPD patients. [8][9][10] MAPK inhibitors particularly those targeting p38 MAPK pathway have been tested in COPD. [9][10][11][12] Oral p38 inhibitors have shown marginal effects on lung function in early clinical development.…”

“…[8][9][10] MAPK inhibitors particularly those targeting p38 MAPK pathway have been tested in COPD. [9][10][11][12] Oral p38 inhibitors have shown marginal effects on lung function in early clinical development. 11,12 However, targeting of this kinase pathway in the lung using an inhaled p38 inhibitor AZD7624 failed to show clinical efficacy by reducing exacerbations in patients.…”

“…11,12 However, targeting of this kinase pathway in the lung using an inhaled p38 inhibitor AZD7624 failed to show clinical efficacy by reducing exacerbations in patients. 9 There is emerging indirect evidences linking the activation of another MAPK, the MEK pathway in COPD. Smoking is associated with increased expression of Epidermal Growth Factor Receptor (EGFR) in the bronchial epithelium 13,14 and EGFR, through the MEK1/2-ERK1/2 pathway activation has been shown to contribute to the secretion of IL-8/CXCL8, a potent neutrophil chemoattractant and secretory mucin MUC5AC and its regulators.…”

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

“…In the trial, AZD7624 decreased sputum neutrophils after inhaled LPS challenge. However, p38 inhibition failed to show any benefit in patients with COPD in a 3‐month COPD exacerbation study (Patel et al, ).…”