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There is general agreement that chronic obstructive pulmonary disease (COPD) is a global epidemic affecting both developed and, particularly, developing countries. Despite access to the most up-to-date medicine currently available, we all also agree that its management is inadequate in at least two ways; people still smoke cigarettes and, for those who already have COPD, current treatment is inadequate. Patients still suffer and die of COPD. None of our therapies have substantially decreased its mortality or progression in this disease. Similarly, a large proportion of the population world-round suffers from asthma, causing much symptomatology and substantial time lost from school or work as well as mortality. Although effective therapies are available for asthma, the disease in many patients is not adequately controlled. The asthma–COPD overlap syndrome combines the suffering and mortality of both disorders and may require combined therapy. In this Perspective we focus on the drugs currently being developed to address these unmet needs. In fact, the same drug classes are often in development for severe asthma and COPD in parallel, as there are many shared mechanisms of chronic inflammation. In asthma, the greatest need, apart from improving adherence, is the need for therapies that address patients who have severe disease despite using current therapies. In COPD the greatest needs are for treatments that address smoking cessation and the underlying progressive disease process that can continue to damage the airways and parenchyma long after smoking cessation (1).
Although short-acting inhaled bronchodilators (such as albuterol and ipratropium) are still used as rescue therapy, the major development has been in the introduction of long-acting inhaled β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), with several new products and LABA–LAMA combinations now on the market and in clinical development (2). New bronchodilators in development include revefenacin (TD4208), a once-daily LAMA to be delivered by nebulization and abediterol, a once-daily LABA, in addition to existing once-daily LAMAs (tiotropium, glycopyrrolate, umeclidinium) and LABAs (indacaterol, vilanterol, olodaterol). Fixed-dose LABA–LAMA combinations for COPD include once-daily indacaterol–glycopyrrolate, vilanterol–umeclidinium, and olodaterol–tiotropium, and twice-daily formoterol–glycopyrrolate and formoterol–aclidinium. There is little to choose between these drugs in terms of efficacy and safety, but they are delivered by different inhaler devices.
Several twice-daily fixed-dose inhaled corticosteroid (ICS)–LABA combinations are now on the market for asthma and COPD maintenance therapy, including fluticasone propionate–salmeterol, budesonide–formoterol, beclomethasone dipropionate–formoterol, and mometasone–formoterol, with one once-daily combination of fluticasone furoate–vilanterol and another (mometasone–indacaterol) in development.
Fixed combinations of ICS–LABA–LAMA are now in development for COPD and severe asthma. One of the first triple inhalers with beclomethasone dipropionate–formoterol–glycopyrrolate twice daily shows a clinical advantage over the ICS–LABA combination in patients with COPD (3) and several others, including once-daily fluticasone furoate–vilanterol–umeclidinium and mometasone–indacaterol–glycopyrrolate, as well as twice-daily budesonide–formoterol–glycopyrrolate, are currently in clinical development. Triple inhalers have the advantage of convenience and may improve adherence, but there are risks that the three components may interact chemically in the device, and the fixed doses may require several dose combinations.
Muscarinic antagonist–β2 agonists (MABAs), combining two pharmacophores by an inactive spine, are also in development (4). Several MABAs, including batefenterol (GSK961081), AZD2115, and AZD8871, are already in clinical trials. A major problem is that it is difficult to balance the LABA and LAMA activities, so that most MABAs tend to have a predominance of either LABA or LAMA activity. MABAs combined with an ICS are also in development as functional triple combinations.
β2-Agonists act as functional antagonists, which means they counteract all known bronchoconstrictor mechanisms, so it is unlikely that more effective bronchodilators can be discovered. Drugs that relax constricted human airway smooth muscle, such as potassium channel openers and vasoactive intestinal peptide analogs, turned out to be more potent as vasodilators than bronchodilators, so side effects were a problem that was not overcome by inhaled delivery. Bitter taste type-2 receptor agonists, such as chloroquine and quinine, have bronchodilator effects on human airways, but are likely to be less effective than LABAs (5). Calcilytics, which block the calcium-sensing receptor, also have bronchodilator effects and may have additional antiinflammatory actions (6). However, there are concerns about their effects on blood calcium concentrations, so that it would be necessary to develop inhaled formulations without systemic actions.
Several ICSs for twice-daily administration are now on the market and a once-daily ICS, fluticasone furoate, has been introduced in combination with vilanterol. There has been a search for safer corticosteroids and several nonsteroidal selective glucocorticoid receptor agonists (SEGRAs) have been developed, which favor gene repression (antiinflammatory) versus transactivation (mediating side effects) (7). This concept may be too simplistic and so far no advantage of SEGRAs, such as GW870086X, has been shown over conventional ICS in terms of efficacy or safety (8).
The discovery that the bronchodilator and antiinflammatory effects of theophylline are mediated mainly through inhibition of phosphodiesterases (PDEs), which include 11 major families of enzyme, each of which may have several isoforms, led to the development of selective PDE inhibitors in the hope that efficacy may be enhanced and side effects reduced. PDE4 inhibition appears to mediate the antiinflammatory effects of theophylline, and selective PDE4 inhibitors have a wide spectrum of antiinflammatory effects in the lung and are more effective against neutrophilic inflammation than are corticosteroids. Only one PDE4 inhibitor, roflumilast, is currently marketed as an antiinflammatory treatment in COPD, but has a narrow therapeutic window as the dose is limited by side effects that include diarrhea, nausea, and headaches (9). Roflumilast on a maintenance basis is currently indicated for the prevention of severe exacerbations in patients with severe COPD, frequent exacerbations, and chronic bronchitis. It may also have a future role in acute management of exacerbations as they are associated with a flare-up of inflammation (10). Several other oral PDE4 inhibitors have failed in clinical trials because of side effects or lack of efficacy, leading to a search for inhaled PDE4 inhibitors to avoid systemic dose-limiting side effects (11). A potent inhaled PDE4 inhibitor, GSK256066, appears to be well tolerated but has little efficacy in patients with COPD (12); another, CHF6001, is also well tolerated and has a modest inhibitory effect on allergen challenge and reduced sputum eosinophils in patients with asthma (13). The bronchodilator effect of theophylline is mediated predominantly via inhibition of PDE3 in airway smooth muscle cells. A dual PDE3/4 inhibitor, RPL554, given by nebulization, has a bronchodilator effect in patients with asthma and COPD, but no convincing evidence of antiinflammatory activity has been seen (14).
Multiple kinases are known to be involved in driving lung inflammation and remodeling, and several kinase inhibitors have been targeted for the treatment of asthma and COPD, although none have yet come to market (15) (Figure 1). Although many kinases have been shown to be activated in asthma and COPD, relatively few have so far been targeted with drugs. There have been problems with specificity and off-target effects of kinase inhibitors, as well as side effects from target inhibition after oral administration, leading to a search for inhaled formulations.
Figure 1. Kinase inhibitors in development for airway disease. Several classes of kinase are activated in airway diseases as a result of several triggers and lead to multiple downstream effects, especially inflammation, but also corticosteroid resistance, cellular senescence, and cell survival/proliferation. Kinases currently targeted are p38 mitogen-activated protein kinase (p38 MAPK), phosphoinositide 3-kinases (PI3Ks), Janus-activated kinases (JAKs), and spleen tyrosine kinase (Syk).
[More] [Minimize]Mitogen-activated protein kinases (MAPKs) play an important role in activating inflammatory and immune genes. p38 MAPK is activated in cells from patients with severe asthma and COPD, and several selective inhibitors are effective in reducing lung inflammation in experimental models of asthma and COPD (16). These inhibitors are also effective against corticosteroid-resistant inflammation in cells from patients with COPD and severe asthma, making them attractive therapies (17). However, clinical studies with oral p38 MAPK inhibitors have so far been disappointing in patients with COPD. Losmapimod has no effect on symptoms, leads to little improvement in lung function, but has a trend toward reduced exacerbations (18), whereas another oral inhibitor, PH-797804, had inconsistent effects on symptoms and lung function (19). Side effects are dose-limiting, so there has been a search for inhaled inhibitors. Inhaled PF-03715455 is well tolerated but no antiinflammatory effects in healthy subjects have been seen (20). No studies in asthma have been reported and clinical studies with this class of drug have now been largely abandoned.
Phosphoinositide 3-kinase (PI3K) plays an important role in cell signaling and is involved in cell survival, differentiation, activation, cellular senescence, and corticosteroid resistance (21). PI3K and downstream kinases are activated in the lungs of patients with COPD (22, 23) and in animal models of asthma (24). Nonselective PI3K inhibitors have dose-limiting adverse effects, so isoenzyme-selective inhibitors have been developed. The PI3Kδ isoenzyme has been implicated in corticosteroid resistance in severe asthma and COPD and is selectively inhibited by low concentrations of theophylline (22). Oral PI3Kδ inhibitors developed for the treatment of B-cell leukemia have considerable adverse effects, so there has been a search for inhaled inhibitors of PI3Kδ or PI3Kγ/δ, such as GSK2269557, which is in clinical development for asthma and COPD (25, 26).
Janus-activated kinases (JAKs) regulate many inflammatory and immune genes involved in asthma and COPD, which has led to the development of JAK inhibitors (Jakinibs). Several oral Jakinibs are in development for other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, but have frequent side effects, including hematological effects, that are dose-limiting. Pan-JAK inhibitors are effective in inhibiting inflammatory cytokine release from airway epithelial cells of patients with COPD (27). Inhaled pan-JAK inhibitors are now in development for asthma and COPD and show some efficacy in animal models of these diseases (28).
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that plays an important role in regulating innate and adaptive immunity. Syk inhibitors are effective in experimental asthma models (29) and inhaled LAS189386 inhibits allergen responses and mast cell degranulation in mice (30). Inhaled Syk inhibitors are in development for asthma, but so far clinical efficacy has not been reported.
Many inflammatory mediators, including lipid mediators, cytokines, chemokines, and peptides, are involved in the complex inflammation of asthma and COPD (Figure 2). These mediators account for the recruitment and activation of inflammatory cells and the structural changes that occur over time. However, because of redundancy of mediators, antagonists of single mediators have usually proved to be ineffective. Nevertheless, cysteinyl-leukotriene receptor antagonists have been widely used in the treatment of asthma as they are well tolerated by mouth, even though less effective than ICS.
Figure 2. Targeting inflammation in airway disease. Eosinophilic inflammation is regulated by helper T type 2 (Th2) lymphocytes through allergen-induced activation of dendritic cells (DCs) and release of thymic stromal lymphopoietin (TSLP). Innate type 2 lymphoid (ILC2) cells may be important in nonallergic asthma and some patients with chronic obstructive pulmonary disease and are regulated by IL-25 and IL-33; all of these upstream cytokines may be targeted by blocking antibodies. Both types of T cell release IL-5 and IL-13, which may be blocked by monoclonal antibodies or by inhibiting GATA3 or by blocking their receptors (IL-5Rα, IL-4Rα). Mast cells release prostaglandin D2 (PGD2), which acts on a chemotactic receptor (CRTh2 [chemoattractant receptor–homologous molecule expressed on Th2 cells], also known as DP2 receptor) for which small-molecule antagonists have been developed. Neutrophilic inflammation may be driven by release of chemokines such as CXC chemokine ligand 8 (CXCL8) from epithelial cells in response to external triggers or by IL-17 from Th17 or ILC3 cells, which may be regulated by IL-23 from macrophages. IL-1 is produced from NLRP3 (NOD-like receptor [NLR] family, pyrin domain–containing protein 3) inflammasome activation, and these cytokines and NLRP may be inhibited. CXCL8 recruits neutrophils via CXC motif chemokine receptor 2 (CXCR2), which can be antagonized by small-molecule antagonists. Neutrophilic inflammation may also be inhibited by macrolides, p38 mitogen-activated protein kinase inhibitors (MAPKi), and phosphodiesterase-4 inhibitors (PDE-4I). Reactive oxygen species (ROS) may further drive neutrophil inflammation and may be inhibited by antioxidants. Neutrophils and other cells release proteases, such as neutrophil elastase (NE) and matrix metalloproteinases (MMPs), which may be blocked by small-molecule inhibitors. Therapeutic interventions are shown in green boxes. Antag = antagonist; CCL17 and CCL22 = C-C motif chemokine ligand 17 and 22, respectively; Inflam inhib = inflammasome inhibitor.
[More] [Minimize]CRTh2 (chemoattractant receptor–homologous molecule expressed on Th2 cells) mediates chemotaxis of helper T type 2 (Th2) cells, innate lymphoid type 2 cells, and eosinophils in response to prostaglandin D2 released from mast cells and other cells. Because this is a G-protein–coupled receptor it has been possible to develop small-molecule antagonists, such as fevipiprant, that are effective after oral administration. Preliminary studies show that these drugs may be effective in allergic eosinophilic asthma and are well tolerated (31) but have no effect on symptoms or lung function, except in patients with severe disease (32). Long-term clinical studies in patients with asthma are currently underway.
Complex cytokine networks are involved in maintaining chronic inflammation in asthma and COPD, and many of these cytokines may now be inhibited by antibodies to either the cytokine itself or its receptor. In patients with refractory eosinophilic asthma, blocking antibodies to IL-5 have been developed, including mepolizumab and reslizumab that target IL-5 and benralizumab, which targets its receptor (IL-5Rα). These anti–IL-5 therapies markedly reduce exacerbations, with only modest improvements in lung function and symptoms in patients with refractory eosinophilic inflammation, despite maximal treatment with ICS and LABA (33). Another Th2 cytokine that has been targeted is IL-13, with usually disappointing clinical results, apart from dupilumab, an antibody that blocks the common receptor for IL-4 and IL-13 (IL-4Rα). Dupilumab is effective in reducing exacerbations, improving symptoms; unexpectedly, its efficacy seems to be independent of eosinophil count in patients with moderate to severe asthma (34). These strategies may also be useful in patients with COPD who have increased eosinophils and in some patients with asthma–COPD overlap syndrome (35). Th2 cytokines are regulated by the transcription factor GATA3, which had been targeted by an inhaled oligonucleotide (SB010), with some reduction in the response to inhaled allergen in patients with mild asthma, although it is challenging to inhibit this transcription factor intracellularly (36).
Targeting noneosinophilic inflammation has proved to be more difficult. Anti–tumor necrosis factor-α and anti–IL-1 antibodies have been ineffective in asthma and COPD, despite their efficacy in other chronic inflammatory diseases (33, 35). Th17 cells have been implicated in neutrophilic inflammation in asthma and COPD. However, blocking IL-17 receptors (IL-17Rα) with brodalumab proved to be ineffective in patients with severe asthma, although the subjects were not selected for neutrophilic inflammation (37).
Chemokines play a key role in recruiting inflammatory cells from the circulation into the lungs. They activate G-protein–coupled receptors on targeted cells that may be blocked by small-molecule antagonists. CCR3 are involved in eosinophil chemotaxis to chemokines, such as CCL11 (eotaxin), but CCR3 antagonists proved difficult to develop clinically. Most attention has focused on CXCR2 antagonists that are involved in neutrophil recruitment in response to CXCL8 and related CXC chemokines. CXCR2 antagonists have so far been disappointing in clinical studies of patients with neutrophilic asthma (38) and COPD (39), despite marked efficacy against sputum neutrophilia induced by inhaled ozone and lipopolysaccharide in normal subjects (40, 41). One problem in taking these drugs forward is the reduction in circulating neutrophils (neutropenia) that is sometimes marked.
Inflammasomes are protein complexes that mediate the coordinated expression of proinflammatory cytokines IL-1 and IL-18 through the regulation of caspase-1, which releases the active cytokine from inactive precursors. There is evidence that the NLRP3 (NOD-like receptor [NLR] family, pyrin domain–containing protein 3) inflammasome is activated in severe asthma and COPD, particularly during exacerbations (42), and selective small-molecule NLRP3 inhibitors, such as cytokine release inhibitory drug (CRID)-3, have now been discovered (43).
Several proteases from neutrophils, macrophages, and epithelial cells show increased expression in COPD and may be important in the breakdown of elastin fibers in the lung parenchyma of patients with emphysema. Although several neutrophil elastase inhibitors have been in clinical development, none have shown safety and/or efficacy in COPD. Matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12, are also involved in elastin degradation, and an MMP9/12 inhibitor (AZ11557272) was effective in a cigarette smoke–induced model of emphysema in guinea pigs; however, this drug and related compounds turned out to have toxicology problems (44).
Oxidative stress is important in driving the pathophysiology of COPD and severe asthma, suggesting that antioxidants should be effective therapies (45). Existing antioxidants, such as N-acetylcysteine and carbocysteine, are largely ineffective in clinical studies, as they are inactivated by high levels of oxidative stress. This has prompted a search for different (nonthiol) classes of antioxidants. Reactive oxygen species (ROS) may be generated by NADPH oxidases (NOX) in activated inflammatory cells in the airways, and selective NOX4 inhibitors are now in clinical development for various diseases (46). Mitochondria are a major source of ROS in COPD, and selective mitochondria-targeted antioxidants, such as mitoquinone, which accumulates selectively in mitochondria, are now in clinical studies (47). Another approach is to activate the transcription factor Nrf2, which regulates many antioxidant genes and is impaired in COPD. Nrf2 activators, such as sulforaphane and bardoxolone methyl, are poorly selective and have toxicity, so there is a search for novel activators (48).
Asthma and COPD are often associated with diseases outside the lung that could also be targeted by new therapies.
Many patients with asthma suffer from rhinitis and atopic dermatitis that may be treated with additional topical therapies, such as corticosteroid nasal spray or skin cream, but systemic therapies may be developed to target all allergic disease. These therapies may include anti-IgE and Th2 cytokine–blocking antibodies that may also prove to be effective against concomitant rhinitis, rhinosinusitis, atopic dermatitis, and food allergy. Alternatively, novel, more effective approaches to immunotherapy may be developed (49).
Cachexia secondary to severe COPD is largely refractory to dietary supplements but new therapies to target skeletal muscle wasting (sarcopenia) are beginning to show promise in clinical studies (50). These dugs include anamorelin (a ghrelin agonist), bimagrumab (an activin type II receptor-blocking antibody), and tesamorelin (a growth hormone–releasing factor).
The most effective drug therapies for asthma and COPD are delivered by inhalation to improve the therapeutic window, and in the case of bronchodilators give a more rapid onset of action. However, many patients have problems in using conventional metered dose and dry powder inhalers correctly, and there are now several approaches to improving inhaler devices by making them more user-friendly, with dose counters and reminders to take the therapy. In recognition of the fact that inhaled drugs need to reach small airways in patients with COPD and severe asthma, several devices deliver smaller particles to peripheral airways (51). One novel inhaler uses “cosuspension technology.” Drug particles are loaded on “porous particles” which, after deposition in the lungs, release one or more drugs onto the airway surface, providing a more even and potentially longer duration of action (52).
Although there have been great successes in developing long-acting bronchodilators and ICS–LABA combinations, there have been few advances in finding more effective treatments for the underlying disease process, particularly in COPD. This suggests that we need to understand the origins and natural history of these diseases and the mechanisms of susceptibility. We also need to identify new therapeutic targets and to develop biomarkers to more effectively select patients and to monitor the results of long-term therapy.
A poor response to the antiinflammatory effects of corticosteroids is a major barrier to effective therapy in severe asthma and COPD, but understanding the molecular mechanisms involved in corticosteroid resistance in these diseases has identified new therapeutic targets, with the prospect that drugs to reverse corticosteroid resistance may be developed in the future (53). Existing drugs, including theophylline, nortriptyline, and macrolides, already have this property in vitro, and therefore could be repurposed; some large clinical trials are already underway with low-dose oral theophylline.
Both asthma and COPD are associated with inflammation that fails to resolve, even when the driving mechanisms (e.g., cigarette smoking, occupational sensitizers) are removed, resulting in abnormal repair and probably irreversible structural changes and fibrosis. Enhancing resolution of inflammation by increasing endogenous mechanisms of resolution (such as efferocytosis) and with mediators (such as resolvins) is being explored (54). Inhibitors of fibrosis are also needed, although it has proved difficult to find antifibrotic therapies that are well tolerated in the clinic (55). Another approach is through the development of stem cell therapy, including mesenchymal stem cells, to repair damaged tissue, such as alveolar wall destruction (56).
There is increasing evidence that COPD represents acceleration of lung aging by oxidative stress through identified molecular targets that are shared with many comorbidities, including cardiovascular and metabolic diseases (57). Understanding these pathways of cellular senescence has identified several novel therapeutic approaches, including sirtuin activators and PI3K inhibitors that may prevent the accelerated aging process and also potentially treat comorbidities that are also driven by accelerated aging through shared molecular pathways (58).
Respiratory medicine is the least developed of all major therapeutic areas, with fewer new classes of drug in development or marketed (59). This may reflect low investment by pharmaceutical companies in respiratory diseases (despite the high prevalence in the community), lack of funding for basic research, poor and nonpredictive animal models, and a lack of helpful biomarkers. The drugs that are the most widely used today and in the near future are largely based on natural compounds, such as epinephrine, herbal anticholinergics, and adrenal corticosteroids. Unfortunately, new classes of drugs in asthma (leukotriene receptor antagonists, anti-IgE) and COPD (roflumilast) have not been effective.
Current therapy for asthma is effective in the majority of patients with asthma, yet asthma remains poorly controlled in the real world, probably due to poor adherence with regular ICS therapy. Using an ICS–formoterol combination inhaler as a rescue as well as a maintenance therapy (so-called maintenance and reliever therapy) effectively addresses this issue, and has improved asthma control and reduced exacerbations. Severe asthma is still problematic, and it is now recognized that it is important to phenotype these patients and personalize their therapy. Thus, severe asthma with persistent eosinophils despite high doses of inhaled/oral steroids may be treated with anti–IL-5 therapies, whereas neutrophilic asthma may respond to anti-neutrophil therapies, although apart from macrolides, these have been difficult to develop. Some patients with severe asthma may have little inflammation but may require bronchial thermoplasty to reduce airway smooth muscle bulk that obstructs airflow.
The unmet needs in COPD are much greater as there are no safe and effective antiinflammatory or disease-modifying therapies. This inflammation is usually corticosteroid-resistant, although patients with COPD with increased eosinophils may show an effect of ICS to prevent exacerbations (60). It is likely that there are other therapeutic phenotypes of COPD, but so far it has been difficult to recognize these clinically or with biomarkers. Although targeting inflammation in COPD has been the primary approach, it is possible that this inflammatory response is secondary to cellular senescence and that this would be a better therapeutic target in the future.
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Originally Published in Press as DOI: 10.1164/rccm.201610-2074PP on December 6, 2016
Author disclosures are available with the text of this article at www.atsjournals.org.
