asthma2  

Abstract and Introduction

Abstract

Current therapy for asthma with inhaled corticosteroids and long-acting inhaled β2-agonists is highly effective, safe, and relatively inexpensive, but many patients remain poorly controlled. Most advances have been through improving these drug classes and a major developmental hurdle is to improve existing drug classes. Major unmet needs include better treatment of severe asthma (which has some similarity to chronic obstructive pulmonary disease), as well as curative therapies for mild to moderate asthma that do not result in the return of symptoms when the treatment is stopped. Several new treatments are in development, but many are specific, targeting a single mediator or receptor, and are unlikely to have a major clinical impact, although they may be effective in specific asthma phenotypes (endotypes). Drugs with more widespread effects, such as kinase inhibitors, may be more effective but have a greater risk of side effects so inhaled delivery may be needed. Several new treatments target the underlying allergic/immune process and would treat concomitant allergic diseases. Improved immunotherapy approaches have the potential for disease modification, although prospects for a cure are currently remote.

Introduction

Asthma now affects over 300 million people in the world, and its prevalence is rising, particularly in developing countries. In the past asthma was seen as a disease of bronchoconstriction due to the release of bronchoconstrictor mediators from mast cells and was treated predominantly with bronchodilators. More recently it has been viewed as an inflammatory disease of the airways with a focus on antiinflammatory treatments. Inhaled corticosteroids (ICSs) have revolutionized the management of asthma, leading to better control of symptoms, a marked reduction in hospitalization, and reduced mortality. Current management of asthma is highly effective; most patients are well controlled if they take regular ICSs with or without long-acting β2-agonists (LABAs) in combination inhalers. Yet despite the availability of effective therapies over half of patients with asthma appear to be poorly controlled largely due to poor adherence.[1,2] Most surprising is the fact that over 80% of patients with difficult-to-treat asthma have poor adherence with regular inhaled therapy, and even in patients with corticosteroid-dependent asthma only half take oral corticosteroids regularly.[3] This article discusses some of the new treatments for asthma that are now in preclinical or clinical development.

The Need for New Asthma Therapies

A major problem facing development of new drugs for asthma is that existing therapies, particularly combination inhalers, are highly effective, relatively inexpensive, and safe. There is a strong scientific rationale for this approach to asthma therapy.[4] This poses an enormous challenge in discovering drugs that could improve on existing therapy.[5] Another problem is that small animal models of asthma are poorly predictive of efficacy in asthma; most drugs that are effective in animal models have failed in clinical trials, and drugs that might be effective would not be identified by these models. More useful animal models that more closely follow clinical features of human asthma are now needed.[6]

There is still concern about the use of ICSs because patients fear long-term side effects and they have to be taken by inhalation, whereas oral medications are generally preferred by patients. Although ICSs are very effective, patient adherence with this medication is very poor, even in patients who have troublesome symptoms.[3] Even when taken regularly ICSs do not appear to significantly modify the course of the disease and are not curative, because asthma symptoms and inflammation rapidly recur when the treatment is discontinued. Concern has also been expressed about the long-term safety of LABAs,[7] although when administered in combination with ICSs there does not seem to be a problem.[8]

Approximately 5 to 10% of patients are not controlled despite taking effective inhaled therapy. These patients with severe asthma account for a disproportionate amount of health care spending; they require hospitalization, use a lot of medications, and miss time from work.[9] This has led to a search for novel or improved therapies for asthma, driven by the prospect of large sales for antiasthma medications globally. It is now recognized that different therapeutic approaches may have effects on different aspects of the inflammatory process, resulting in a change in different outcome measurements; for example, some treatments may have a major impact on exacerbation frequency, whereas others may predominantly improve lung function.[10] This means that several outcome measures may be needed in the clinical development of new treatments.

The types of new drugs needed for asthma include new classes of drug that are effective in severe, poorly controlled asthma; an oral treatment that is as effective as ICSs but without any side effects; and drugs that modify the course or even cure the disease. The approaches that have usually been taken are to improve existing treatments, such as ICSs and LABAs, or to find drugs against novel targets identified through better understanding of the disease process, such as cytokine blockers. An oral therapy may have the advantage that it would treat not only asthma but also rhinitis and atopic dermatitis that are commonly associated, although oral therapies have a much greater risk of side effects.

Another issue of growing importance is the recognition that there are different phenotypes or endotypes of asthma.[11,12] As treatments become more specific, such as blockade of specific cytokines or kinases, the treatments may be effective in only a small proportion of patients, but these need to be identified, and stratification will reduce the market size. For example, anti-immunoglobulin E (anti-IgE) therapy with omalizumab is only effective in a proportion of allergic asthmatic patients with elevated IgE, but it has been difficult to predict based on clinical criteria which patients will benefit. Because new therapies are likely to be very expensive (especially antibodies) it will become increasingly important to recognize responder patients and to select these patients for clinical trials.

New Bronchodilators

Bronchodilators are important for preventing and relieving bronchoconstriction, and the major advance has been the introduction of the LABAs salmeterol and formoterol, which last for over 12 hours. These drugs have complementary actions to corticosteroids, and fixed combination inhalers with a corticosteroid are now the most effective available therapy for asthma. There are now several even longer acting β2-agonists ("ultra-LABAs") in development, including indacaterol, carmoterol, vilanterol, and olodaterol, which have a duration of action > 24 hours and are suitable for once-daily dosing.[13] A once-daily muscarinic antagonist, tiotropium bromide, is less effective as a bronchodilator in asthma than β2-agonists and is used predominantly in chronic obstructive pulmonary disease (COPD) but appears to be a useful add-on therapy in some patients with severe asthma.[14,15] Several other once-daily long-acting muscarinic antagonists (LAMAs) are also in development. Novel classes of bronchodilators have proved difficult to develop, and new drugs, such as vasoactive intestinal peptide analogues and potassium channel openers, have had side effects due to their more potent vasodilator than bronchodilator effects. Recently agonists of bitter taste receptors (TAS2R), including quinine, chloroquine, and saccharine, have been identified as a novel class of bronchodilator.[16]

A case has been made for the development of triple inhalers containing a LABA, LAMA, and ICS. These might be suitable for selected patients with severe asthma who benefit from all three drugs, but the lack of flexibility in dosing may be a disadvantage, and the drug components might interact physically and impair drug deposition.[17]

New Corticosteroids

ICSs are by far the most effective antiinflammatory therapy for asthma and work in almost every patient. However, all currently available ICSs are absorbed from the lungs and thus have the potential for systemic side effects. This has led to a concerted effort to find safer ICSs, with reduced oral bioavailability, reduced absorption from the lungs, or inactivation in the circulation.[18] Dissociated steroids attempt to separate the side-effect mechanisms from the antiinflammatory mechanisms. This is theoretically possible because side effects are largely mediated via transactivation and the binding of glucocorticoid receptors to DNA, whereas antiinflammatory effects are largely mediated via transrepression of transcription factors through a nongenomic effect.[19] Dissociated steroid agonists have a greater effect on the transactivation than transrepression and thus may have a better therapeutic ratio and might even be suitable for oral administration.[20] Nonsteroidal selective glucocorticoid receptor activators (SEGRA), such as AL-438 and maprocorat, are in clinical development. However, some of the antiinflammatory effects of corticosteroids may be due to transactivation of antiinflammatory genes so SEGRAs may not be as efficacious as existing drugs. Corticosteroids switch off inflammatory genes by recruiting the nuclear enzyme histone deacetylase-2 (HDAC2) to the activated inflammatory gene initiation site so that activators of this enzyme may also have antiinflammatory effects or may enhance the antiinflammatory effects of corticosteroids.[19,21]

Targeting Allergic Inflammation in Asthma

Airway inflammation in asthma is characterized by activation of mast cells, infiltration of eosinophils, and increased activated T-helper 2 (Th2) cells, which orchestrate allergic inflammation through the release of multiple cytokines.[22-24] Chronic inflammation may lead to structural changes in the airways, including increased airway smooth muscle mass, fibrosis, neovascularization, and mucus gland hyperplasia, particularly in patients with poorly controlled disease. These structural changes may underlie the irreversible component of airway narrowing that may increase over many years, particularly in patients with severe disease. Some patients, especially those with severe asthma, may also have increased numbers of neutrophils in the airways and T cells more reminiscent of patients with COPD, with increased numbers of Th1 and Th17 cells.[22] Better understanding of the pathophysiology of allergic inflammation has identified novel targets for asthma therapy, particularly in severe disease.[24]

Targeting Lipid Mediators

Over 100 mediators are involved in the complex inflammatory process in asthma,[25] so blocking the synthesis or receptor for a single mediator seems unlikely to be very effective. The only mediator antagonists currently used in asthma therapy are antileukotrienes, which block cysteinyl-leukotriene CysLT1-receptors, but these drugs are much less effective than ICSs. Several other drugs that inhibit receptors or synthesis of lipid mediators are currently in development. Phospholipase A2(PLA2) inhibits the generation of lipid mediators from membrane phospholipids so theoretically should be effective in asthma, although there is uncertainty about whether to block the secretory or cytosolic isoforms of PLA2, and it has been difficult to discover safe and selective inhibitors.[26] The enzyme 5-lipoxygenase (5'-LO) works through 5'LO-activating protein (FLAP), and several novel 5'-LO and FLAP inhibitors are currently in clinical development. These drugs could be more effective in patients with neutrophilic inflammation because they block the production of leukotriene (LT)B4. However, an LTB4 receptor (BLT1) antagonist had no effect in mild asthma.[27]

Prostaglandin (PG)D2 is released from mast cells, Th2 cells, and dendritic cells and activates DP2-receptors, also known as chemoattractant homologous receptor expressed on Th2 cells (CRTh2), which mediate chemotaxis of Th2 cells and eosinophils (Fig. 1).[28] Many CRTh2 antagonists are now in clinical development for asthma, including AMG-853 OC000459 and MK-2746, which have shown early clinical efficacy as oral treatments for asthma and rhinitis. PGD2 also activates DP1-receptors, which mediate vasodilatation and enhance Th2 cell polarization by dendritic cells, so that a dual DP1/DP2-antagonist may be more effective, whereas an inhibitor of PGD synthase would block PGD2synthesis and also prevent the bronchoconstrictor effects of PGD2 that are mediated via thromboxane prostanoid (TP)-receptors on airway smooth muscle.

774255-fig1  

Figure 1.

Prostaglandin D2 (PGD2) may play an important role in asthma. It is synthesized mainly in mast cells by PGD synthase (PGDS) and acts on DP1-receptors on vessels to mediate vasodilatation and on dendritic cells to enhance their activation, via DP2 (prostaglandin D)-receptors, also known as chemoattractant homologous receptor expressed on Th2 cells (CRTh2), to attract Th2 lymphocytes and eosinophils, and on thromboxane prostanoid (TP) receptors to cause bronchoconstriction. Antagonists of DP1, DP2 receptors, and inhibitors of PGDS are now in clinical development for asthma therapy.

Cytokine Modulators

Cytokines play a critical role in orchestrating chronic inflammation and in remodeling airway structure and have become important targets for blockade in asthma.[29] Over 50 cytokines have been implicated in asthma, and some have already been targeted in clinical studies (Table 1, Fig. 2).

774255-fig2  

Figure 2.

Several inhibitors of cytokines and chemokines are in clinical development.

 

Cytokine Blockade

Inhibition of another Th2 cytokine interleukin (IL)-4 by using inhaled soluble receptors proved to be disappointing, but there is continued interest in blocking IL-13, a related cytokine that regulates immunoglobulin E (IgE) formation, particularly in severe asthma. Pitrakinra, a mutated form of IL-4 that blocks IL-4Rα, the common receptor for IL-4 and IL-13, significantly reduces the late response to inhaled allergen in mild asthmatics when given by nebulization,[30] and clinical trials are currently in progress. Several IL-13 and IL-4Rα blocking antibodies are now in clinical development, but so far clinical studies in severe asthma have been disappointing. Careful selection of patients may be needed to find responder phenotypes, such as patients with high IL-13 concentrations in sputum. IL-4 and IL-13 signal through STAT6 (signal transduction-activated transcription factor), and small molecule inhibitors, such as AS1517499, have been developed that are active in a murine model of asthma.[31]

IL-5 is of critical importance for eosinophilic inflammation, and a blocking antibody to IL-5 (mepolizumab) depletes eosinophils from the circulation and sputum of asthmatic patients but disappointingly has no effect on the response to inhaled allergen, airway hyperresponsiveness, symptoms or lung function, or exacerbation frequency in asthmatic patients.[32,33] However, more recent studies show that mepolizumab reduces exacerbations in highly selected patients who have persistent sputum eosinophilia despite high doses of ICSs, although there is no improvement in symptoms, lung function, or airway hyperresponsiveness.[34,35] An antibody against the IL-5 receptor (IL-5Rα) is also being studied in clinical trials. Inhaled antisense oligonucleotides that block the common β chain of IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors together with the chemokine receptor CCR3 (TPI ASM8) has a small effect in reducing allergen responses and airway inflammation.[36]

Another cytokine targeted in asthma is tumor necrosis factor (TNF)-α, which may play a significant role in severe asthma. Several uncontrolled or small studies suggested that anti-TNF therapies (TNF blocking antibody infliximab or soluble receptor etanercept) may be useful in reducing symptoms, exacerbations, and airway hyperresponsiveness in patients with severe asthma, but a recent large multicenter trial with an antibody golimumab showed no beneficial effect on lung function, symptoms, or exacerbations, and there were increased reports of pneumonia and cancer.[37]

Several other cytokine blockers are currently being studied in asthma patients, including IL-9, IL-17, IL-25, IL-33, GM-CSF, and thymic stromal lymphopoietin (TSLP). IL-17 has attracted interest as a target in severe asthma because it may be a mediator of neutrophilic inflammation in severe asthma.[38]

Cytokines as Therapy

Other cytokines are inhibitory to the inflammatory process in asthma and therefore might be considered as therapy. For example, IL-10 has a broad spectrum of antiinflammatory effects, and its secretion is defective in asthma, especially in more severe disease.[39] IL-10 is effective in animal models, but its efficacy has not yet been demonstrated in asthma. Other members of the IL-10 superfamily may also have antiinflammatory potential in asthma but so far have not been investigated. IL-12 regulates the balance between Th1 and Th2 cells and should suppress Th2 cells, thereby reducing eosinophilic inflammation and IgE. Although repeated IL-12 injections decrease circulating eosinophils in asthmatic patients, this does not reduce the response to inhaled allergen or airway hyperresponsiveness, as with IL-5 inhibitors.[40] In addition, this cytokine has unacceptable side effects, including malaise and occasional dangerous cardiac arrhythmias. Interferon (IFN)-γ also suppresses Th2 cells but has unacceptable side effects.

Type I (IFNα, IFNβ) and type III (IFNλ1/IL-29) interferons have antiviral and antiinflammatory effects, and their secretion may be defective in asthma, resulting in increased susceptibility and response to upper respiratory tract viruses, such as rhinovirus and respiratory syncytial virus, which are the commonest causes of severe exacerbations.[41] Inhaled IFNβ or IFNγ may therefore be of benefit in treating or preventing viral exacerbations of asthma.

Chemokine Antagonists

Chemokines are small cytokines that attract inflammatory cells, including mast cells, eosinophils, and Th2 cells into the airways and are therefore appropriate targets for therapy, particularly as they signal through G-protein coupled receptors for which small molecule inhibitors may be developed.[42] The major focus of interest has been the chemokine receptor CCR3, which is predominantly expressed on eosinophils and mediates the chemotactic response to CXCL11 (eotaxin), which is secreted in asthma. CCR3 are also expressed on mast cells and some Th2 cells. Several small molecule inhibitors of CCR3 have been in clinical development, but their effects in asthma have not yet been reported because they have usually been discontinued as a result of toxicology problems. An inhaled antisense oligonucleotide that targets CCR3 has some effect in reducing sputum eosinophils, but results are difficult to interpret because IL-5 and GM-CSF β chain antisense was coadministered.[43] Other chemokine receptors that are targeted for asthma therapy are CCR2 on monocytes and T cells, CXCR2 on neutrophils and monocytes, and CCR4, CCR8, and CXCR4 on Th2 cells. Blocking antibodies to CCR4 result in marked and prolonged depletion of Th2 cells and reduced lung inflammation in animal models. Some patients with severe asthma have a predominance of neutrophils and increased concentrations of CXCL8 (IL-8), which acts through CXCR2. Several small molecule CXCR2 antagonists, such as SCH527123, have now been developed for COPD but might also be effective in neutrophilic asthma. For example, oral SCH527123 very effectively prevents the increases in sputum neutrophils induced by ozone.[44]

Novel Antiinflammatory Treatments

Although ICSs are effective in most patients with asthma, they have to be given in high doses in the 5 to 10% of patients with severe disease, and there are still concerns about systemic side effects of high-dose ICSs. Approximately 1% of patients also require maintenance oral corticosteroids with their high risk of adverse effects. This has prompted a search for alternative antiinflammatory therapies, particularly treatments that may be effective by mouth, because this could then treat associated allergic diseases such as rhinitis. In severe asthma many patients appear to have reduced responsiveness to corticosteroids.[45] Corticosteroids are not effective against neutrophilic inflammation, so antiinflammatory treatments that target neutrophils may also be useful, particularly in patients with severe asthma.[46] Several new classes of treatment that inhibit intracellular targets, such as kinases and transcription factors, are in development (Fig. 3).

774255-fig3  

Figure 3.

Inhibition of signal transduction pathways that amplify inflammatory gene expression in asthmatic airways. Selective inhibitors have been developed for phosphodiesterase-4 (PDE4), which degrades cyclic adenosine monophosphate (cAMP); inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK2), which activates NF-κB; and p38 mitogen-activated protein kinase (MAPK), which activates MAP kinase activated protein kinase 2 (MAPKAPK2); Jun kinase (JNK), which activates activator protein-1 (AP-1); and phosphoinositide-3-kinase (PI3K), which activates Akt. Selective inhibitors have now been developed for all of these enzyme targets.

Patients with severe asthma are poorly responsive to the antiinflammatory effects of corticosteroids, and a few patients are completely resistant, indicating a need for nonsteroidal antiinflammatory therapies.[45] The molecular mechanisms of corticosteroid resistance in asthma are now being elucidated, and it is clear that there may be several different mechanisms so that different therapies may be needed. For some molecular pathways of corticosteroid resistance there may be new treatments that are able to reverse the corticosteroid resistance.

Phosphodiesterase Inhibitors

The most advanced of the nonsteroidal antiinflammatory therapies are phosphodiesterase (PDE)-4 inhibitors, which have a wide spectrum of antiinflammatory effects, inhibiting T cells, eosinophils, mast cells, airway smooth muscle, epithelial cells, and nerves and are highly effective in animal models of asthma.[47,48] An oral PDE4 inhibitor, roflumilast, has an inhibitory effect on allergen-induced responses in asthma and also reduces symptoms and lung function similar to low doses of ICSs.[49] However, a major limitation to this class of drugs is the mechanism-based side effect profile, including nausea, headaches, and diarrhea, which limit the dose. However, most of the antiinflammatory effects appear to be mediated by PDE4B, whereas nausea and vomiting are mediated via PDE4D, suggesting that PDE4B-selective inhibitors might be better tolerated.[50] Another approach is to deliver PDE4 inhibitors by inhalation, but so far these drugs have had no efficacy. Inhaled PDE3/4 inhibitors are also in development and may have the advantage of bronchodilatation through PDE3 inhibition.[51]

Kinase Inhibitors

Kinases play a critical role in regulating the expression of inflammatory genes in asthma.[52] The transcription factor nuclear factor-κB (NF-κB) regulates many of the inflammatory genes that are abnormally expressed in asthma and is activated in asthmatic airways. Small molecule inhibitors of the key enzyme IKK2/IKKβ (inhibitor of κB kinase) block inflammation induced by NF-κB activation and are now in preclinical testing.[53] p38 mitogen-activated protein kinase (MAPK) activates similar inflammatory genes to NF-κB and is activated in cells from patients with severe asthma.[54] Several small molecule inhibitors are now in clinical development for the treatment of inflammatory diseases.[55]An antisense that blocks p38 MAP kinase demonstrated efficacy in a murine asthma model.[56] p38 MAPK plays a key role in activation of GATA3, a transcription factor that regulates Th2 cell differentiation and expression of Th2 cytokines.[57] Corticosteroids block GATA3 activation and are mimicked by p38 MAPK inhibitors.[58]

Phosphoinositide-3-kinase (PI3K) also regulates inflammation and has several isoforms.[59] PI3Kγ is important in chemotactic responses, and selective inhibitors are in development, whereas PI3Kδ activation results in reduced steroid responsiveness through reducing HDAC2 activity, so that PI3Kδ inhibitors may potentially reverse corticosteroid resistance in severe asthma.[60] Theophylline is a selective inhibitor of PI3Kδ, and theophylline derivatives that lack PDE inhibition or selective PI3Kδ inhibitors may therefore be of therapeutic value. The tricyclic antidepressant nortriptyline also targets PI3Kδ and reverses corticosteroid resistance.[61] Several selective PI3Kδ inhibitors are now in clinical development for asthma.

A general concern about novel kinase inhibitors is that they may have side effects because they target mechanisms that found in many cell types. It may therefore be necessary to develop inhaled formulations for use in asthma in the future, as proved to be necessary for corticosteroids.

Adhesion Molecule Blockade

Another approach to inhibiting inflammation is to block the adhesion molecules that are involved in the recruitment of inflammatory cells from the circulation into the airways.[62] Small molecule inhibitors of very late antigen-4 (VLA-4, α4β1), which is involved in the recruitment of eosinophils and T cells, were effective in animal models but so far have been ineffective in asthma patients.[63] Inhaled bimosiamose, a pan-selective selectin inhibitor, has some inhibitory effect in allergen challenge in asthma patients, but further clinical studies have not been reported.[64] Nebulized bimosiamose is also effective against sputum neutrophilia induced by ozone, suggesting that it may be potentially useful in neutrophilic asthma.[65]

PPARγ Agonists

Peroxisome proliferator-activated receptor gamma agonists have a wide spectrum of antiinflammatory effects, including inhibitory effects on macrophages, T cells, and neutrophilic inflammation, and polymorphisms of the PPARγ gene have been linked to increased risk of asthma.[66] A PPARγ agonist rosiglitazone gave a small improvement in lung function in smoking asthmatic patients in whom inhaled corticosteroids were ineffective,[67] and a modest (15%) reduction in late response to inhaled allergen in mild asthmatics.[68] This suggests that PPARγ agonists, such as thiazolidinediones, have little therapeutic potential in asthma therapy.

Antiallergy Treatments

The majority of asthmatic patients are allergic, and treatments that target the underlying allergic inflammation are therefore a logical approach, particularly because this may also treat associated allergic conditions.[24] Indeed, even in patients with nonatopic (intrinsic) asthma the same inflammatory mechanisms are found.

Anti-IgE Therapy

A monoclonal antibody that blocks IgE (omalizumab) is now used in the treatment of selected patients with severe asthma. It is expensive, so patients must be selected carefully for a trial of therapy. More potent anti-IgE antibodies that may have a broader spectrum of effects are in development. Allergens bind to a low-affinity IgE receptor (FcεRII, CD23) as well as the high-affinity receptor FcεRI on several immune cells, including T- and B-lymphocytes.[69] An anti-CD23 antibody (lumiliximab) is well tolerated and reduces IgE concentrations in patients with mild asthma, but its clinical efficacy has not been reported.

Mast Cell Inhibitors

Mast cell activation through the release of bronchoconstrictor mediators is very important for the symptoms of asthma so mast cell inhibitors have long been a target of drug discovery (Fig. 4). Cromones (sodium cromoglycate and nedocromil sodium) were very effective in blocking indirect challenges, such as allergen, cold air and allergen, which work through mast cell activation but because of their short duration of action (1 to 2 h) they were not very effective as long-term controllers. The molecular mechanism of action has never been clearly established, although they work on the cell surface, are mimicked by the diuretic furosemide, and may modulate chloride ion channels. Further study of their molecular mechanism may be rewarding because this might allow development of longer-acting drugs.

774255-fig4  

Figure 4.

Inhibition of mast cells in asthma. Mast cell activation may be inhibited by blocking immunoglobulin E (IgE) binding to the high-affinity IgE receptor (FcεRI) by inhibiting c-Kit, which is activated by stem cell factor (SCF) or by inhibiting Syk kinase. Mast cell stabilizers such as cromones and furosemide may work through specific ion channels for which novel modulators may be developed.

Stem cell factor (SCF) is a key regulator of mast cell survival in the airways and acts via the receptor c-Kit on mast cells.[70] Blockade of SCF or c-Kit is very effective in animal models of asthma, suggesting that this pathway may be a good target for new asthma therapies. Masitinib is a potent tyrosine kinase inhibitor that blocks c-Kit (as well as platelet-derived growth factor receptors) and provides some symptomatic benefit in patients with severe asthma.[71] More selective c-Kit inhibitors are in development.

Syk Kinase Inhibitors

Spleen tyrosine kinase (Syk) that is involved in activation of mast cells and other immune cells and several small molecule Syk kinase inhibitors are in development.[72] An antisense inhibitor of Syk kinase is effective in an animal model of asthma,[73] and the small molecule inhibitor R112 given nasally reduces nasal symptoms in hay fever patients.[74] More potent inhibitors, such as R343 and Bay 61–3606, are in development for inhalation in asthma. Because Syk is widely distributed in immune and neuronal cells there are concerns about side effects. As with other kinase inhibitors, there may be side effects with systemic administration so that inhalation may be preferred.

Improved Immunotherapy

Treatments that target the immune deviation in asthma have attracted considerable interest because they may hold the prospect of disease modification or even long-term cure. However, this promising approach has to be considered in the context of potential long-term adverse effects.

Specific Immunotherapy

Specific immunotherapy by subcutaneous injection of allergen is not very effective in controlling asthma, and there is a risk of anaphylaxis. Sublingual immunotherapy with house dust mite extracts has shown some efficacy in asthma and is well tolerated, but longer-term studies and comparison with ICSs are needed.[75] Immunotherapy with peptides derived from T cell epitopes from cat allergen reduce allergen sensitization (measured by skin-prick test) and provide greater tolerance to cat exposure. A mouse model shows that this involves IL-10 secretion from regulatory T cells (Treg).[76] Several approaches use vaccination to shift from Th2 to Th1 dominance, including vaccination with nonpathogenic bacteria such as Mycobacterium vaccae, or CpG oligodeoxynucleotides, which target toll-like receptor (TLR)-9.[77] Although these strategies have been effective in animal models of asthma a clinical study with an immunostimulatory CpG motif (1018 ISS) increased IFNγ and IFNγ-regulated genes but had no effect on the allergic response in asthmatic patients.[78] Conjugation of a TLR9 agonist to an allergen has some clinical efficacy in ragweed-sensitive rhinitis, but this immunotherapy approach has not been extended to asthma with house dust mite allergen.[79]

Targeting Tregs

Specific immunotherapy increases Treg numbers and their expression of IL-10, which suppresses Th1 and Th2 responses with marked suppression of IgE synthesis.[80] Treg cells for patients with corticosteroid resistance produce less IL-10, but this can be restored in vitro with vitamin D3. In a pilot study of corticosteroid-resistant asthmatic patients oral administration of vitamin D3 for a week enhanced IL-10 secretion by Tregs in response to dexamethasone.[81] Vitamin D3 appears to selectively increase TLR9 expression on these IL-10-secreting Tregs.[82] Longer trials of vitamin D3and its analogue 1α,25-vitamin D3 (calcitriol) are now in progress.

Targeting Dendritic Cells

Dendritic cells play a critical role in orchestrating chronic inflammation in asthma through the release of cytokines and chemokines and are an important target for therapy. Several classes of drug have been shown to suppress myeloid dendritic cell activation, and this suppress eosinophilic inflammation in animal models, including prostacyclin (PGI2) acting on IP-receptors and PDD2 acting on DP1-receptors.[83] The inhaled stable prostacyclin analogue iloprost inhibits airway inflammation in a murine model of asthma by preventing myeloid dendritic cells from migrating to regional lymph nodes.[84]Sphingosine-1-phosphate (S1P) is a lysophospholipid that is released by activated immune cells. Inhalation of S1P or its stable analogue fingolimod (FTY-720) markedly suppresses allergen-induced inflammation in sensitized mice and prevents migration of dendritic cells to regional lymph nodes.[85]Fingolimod is currently used as an immunosuppressive treatment, so that inhalation may avoid potential immunosuppressive side effects

Future Directions

None of the currently available treatments for asthma have long-term effects on airway inflammation or remodeling and therefore are not disease-modifying or curative. ICSs are very effective, but symptoms usually rapidly return when treatment is discontinued. The prospects for a cure seem remote until the molecular and genetic causes of asthma are better understood, but there is a possibility that vaccination approaches have the potential to reverse the abnormal immune regulation found in asthma. However, the long-term consequences of these approaches need to be carefully evaluated, particularly given that they would probably need to be applied in children at the onset of disease.

It has proved difficult to discover novel classes of therapy for asthma, despite intense effort and investment. Asthma is a highly complex disease, so it is unlikely that targeting a single receptor or mediator will be highly effective. Corticosteroids are effective because they suppress multiple inflammatory mechanisms in parallel. It is possible that a key target that is upstream in the complex inflammatory process might be effective, such as anti-TNF therapy in rheumatoid arthritis, but these targets are usually only identifiable by trial and error in the disease. More selective targeting of drugs to patients with particular subphenotypes (endotypes) of asthma may be possible in the future with development of discriminatory biomarkers and genetic profiling.[12] Animal models have proved to be misleading, and there is now pressure to do earlier proof of concept studies in humans. A major unmet need in asthma is to more effectively treat patients with severe asthma who are relatively corticosteroid resistant. These patients share several characteristics of patients with COPD who are steroid resistant.[22] This means that drugs in discovery for COPD may also be effective in treating severe asthma.[86] The mechanism of corticosteroid resistance in COPD appears to be defective function of HDAC2, and similar abnormalities may also be found in severe asthma.[54,87] HDAC2 activity may be restored by low doses of theophylline,[60,88] and identification of the pathways involved may lead to new approaches to restoration of steroid sensitivity on severe asthma.[45] The other unmet need in asthma is to develop an effective oral therapy for patients with mild and moderate disease, but this has proved to be a major challenge because it is likely that any effective therapy is likely to have side effects and would therefore be less useful than the current inhaled therapy.

 

 

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