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NEW MOLECULES TO TREAT ASTHMA AND COPD

Significant advances in our understanding of the pathogenesis of asthma and COPD have identified new molecular targets. This offers great hope for the development of new, targeted therapies for patients with asthma and COPD who are poorly managed with current treatments. This chapter aims to discuss some of the most promising new therapeutic targets and the current status of the development of anti-inflammatory drugs for asthma and COPD (Table 4.1).

Chemokine and Cytokine Inhibitors

Disease progression in asthma and COPD is driven by a multitude of inflammatory mediators, including chemokines, cytokines, lipids, and growth factors. Inhibiting or preventing their synthesis would seem a logical therapeutic approach to improve the underlying inflammation, as observed in rheumatoid arthritis (RA) [21]. Currently,

TABLE 4.1

Novel Anti-Inflammatory Treatments in the Development for Asthma and Chronic Obstructive Pulmonary Disease

Drug Class

Drugs under Development

PDE4 inhibitors

Roflumilast

GSK256066

RPL554

p38 MAPK inhibitors

SD-282

Dilmapimod

PH797804

NF-kB inhibitors

BMS-345541

PS-1145

Chemokine and cytokine antagonists

ADZ8309 (CXCR2 antagonist)

Navarixin (CXCR2 antagonist)

CXCR3 antagonist

Infliximab (TNF-a inhibitor)

Mepolizumab

Lebrikizumab

Tocilizumab

Phosphoinositide-3-kinase inhibitors

TG100-115

AS605240

Antiproteases

AZ11557272 MMP-9 inhibitors AZD1236

Antimicrobials

Moxifloxacin

Ciprofloxacin

EM-703

Antioxidants

Sulforaphane Bardoxolone methyl Dimethyl fumarate

Antiageing molecules

SIRT2172

Resveratrol

Abbreviations: PDE4, phosphodiesterase-4; MAPK, mitogen-activated protein kinase; MMP, matrix metalloprotease; NF, nuclear factor; TNF, tumor necrosis factor.

several inhibitors of inflammatory mediators are in early clinical development, including antagonists of CXCR2, a receptor that mediates the chemotactic roles of chemokine ligand (CXCL)-8, CXCL-1, and CXCL-5 on monocytes and neutrophils [22]. Potentially, blockade of chemokine receptors would inhibit leukocyte recruitment (a process that is corticosteroid resistant in COPD patients) and therefore dampen down the inflammatory response that drives asthma and COPD.

Several asthma subphenotypes prone to exacerbations and associated with sputum eosinophilia have considerable levels of IL-5, the most potent chemoattractor for eosinophils [23]. In patients with severe asthma and evidence of eosinophilic inflammation, mepolizumab, a humanized monoclonal antibody against IL-5, significantly reduced exacerbation rates, although no improvement in lung function was observed [24]. In healthy volunteers challenged with lipopolysaccharide (LPS), oral administration of ADZ8309, a CXCR-1/2 receptor antagonist, inhibited neutrophil inflammation in the lungs [25]. Additionally, in ozone-induced sputum neutrophilia in healthy volunteers, navarixin, an allosteric antagonist of CXCR2, effectively inhibited sputum neutrophilia, although in several large clinical studies in COPD, navarixin had no beneficial effect [26]. Another chemokine receptor, CXCR3, is increased in the sputum of COPD patients compared with nonsmokers. It mediates the role of CXCL-9, CXCL-10, and CXCL-11 chemokines, which may be involved in T-lymphocyte recruitment in the small airways and lung parenchyma. CXCR3 antagonists are currently under development for COPD [3,27].

Several antibodies inhibiting cytokines or their receptors are under development for asthma and COPD [28-31]. These include humanized monoclonal antibodies against IL-4 and IL-13, cytokines central to disease progression in asthma. In asthmatic patients with high levels of serum periostin, a biomarker of IL-13 activation, lebrikizumab, a monoclonal antibody against IL-13, significantly improved lung function, compared to patients with low serum levels of periostin [31]. The cytokines tumor necrosis factor (TNF)-a and IL-6 are both found in increased levels in sputum and in the systemic circulation of patients with asthma and COPD. TNF-a is important in propagating the inflammatory response in patients with severe asthma and COPD. Infliximab, an effective TNF-a inhibitor in RA, has no beneficial effect on clinical outcomes in severe asthma and COPD [32]. More worry ingly in this study, patients on infliximab developed severe lung infections and lung cancer. A study of tocilizumab, a potent IL-6 inhibitor that is currently used in patients with RA, is planned and may be effective in patients with severe respiratory disease (<50% forced expiratory volume in 1 second (FEVj)/forced vital capacity (FVC)) as it will also target the autoimmune component of COPD [33]. Finally, novel therapeutic inhibitors of IL-17, a family of cytokines that are involved in numerous immune regulatory functions, such as inducing and mediating pro-inflammatory responses and neutrophil recruitment, are also currently under development for COPD [34]. Indeed, targeting a single mediator may have little or no major clinical benefit in asthma and COPD as both diseases are characterized by a plethora of inflammatory mediators.

 
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