**6. Therapies for asthma**

Modern treatments for asthma have been tested and used since the early twentieth century [79]. However, the oldest documented drug for asthma dates back to ancient Egypt. Kyphi, an incense mixture drink, was used inside the temples by the priests as a multipurpose lung medicament. There was more than one recipe for Kyphi; each may include as many as 10 herbs [80]. Following this, about 4000 years ago, Atropa Belladonna alkaloids, also called "deadly nightshade" because of their poisonous properties ("Natural Medicinal Herbs"), were derived from the leaves of thorn-apple plant and smoked by the Indians as cough suppressant [82]. Till today, natural and synthesized entities related to the tropane alkaloids class are still widely used. This includes anticholinergics (e.g., natural atropine, hyoscyamine (the levo-isomer of atropine), acopolamine, and the synthetic Ipratropium Bromide and stimulants (e.g., cocaine and hydroxytropacocaine) [83]. In 1872, one of the first papers published on asthma states that rubbing the chest of asthmatics with chloroform liniment can resolve airway constriction [84]. Adrenergic stimulants were in use for asthma over 100 years ago. In 1901, the adrenaline isolated from sheep and oxen adrenal glands was used to treat asthma [85]. The first documented publication of adrenaline as a bronchodilator therapy for asthma was written in 1903 by James Burnett, a physician in Edinburgh [86]. One year later in 1904, adrenaline was synthesized in the laboratories of Friedrich Stolz and Henry Drysdale Dakin, independently [87].

As suggested by the Global Initiative for Asthma (GINA) [88], a five-level step-down approach is widely recognized among the medical practitioners (**Figure 3**). The GINA approach assigns two types of drug classes for managing asthma:


#### Legend:

angiogenic effects, but the exact molecular mechanism linking the increase in the VEGF

Correlation between angiogenesis and asthma severity has also been documented. Dense vascularity occurs in severe asthmatics, followed by moderate, and then finally mild asthmat‐ ics, who experience less angiogenesis events [76]. This pattern was also observed in fatal asthmatics compared with nonfatal asthmatics [77]. While current asthma therapeutics is not directly targeting vascular remodeling, recent trials investigate some anti-angiogenic therapies as a new approach for asthma. Yuksel et al. showed that Bevucizamab, which significantly neutralizes VEGF, results in a reduced thickening of lung epithelium, a reduced ASM, and a reduced basement membrane thickness compared with untreated ovalbumin (OVA)-chal‐

Modern treatments for asthma have been tested and used since the early twentieth century [79]. However, the oldest documented drug for asthma dates back to ancient Egypt. Kyphi, an incense mixture drink, was used inside the temples by the priests as a multipurpose lung medicament. There was more than one recipe for Kyphi; each may include as many as 10 herbs [80]. Following this, about 4000 years ago, Atropa Belladonna alkaloids, also called "deadly nightshade" because of their poisonous properties ("Natural Medicinal Herbs"), were derived from the leaves of thorn-apple plant and smoked by the Indians as cough suppressant [82]. Till today, natural and synthesized entities related to the tropane alkaloids class are still widely used. This includes anticholinergics (e.g., natural atropine, hyoscyamine (the levo-isomer of atropine), acopolamine, and the synthetic Ipratropium Bromide and stimulants (e.g., cocaine and hydroxytropacocaine) [83]. In 1872, one of the first papers published on asthma states that rubbing the chest of asthmatics with chloroform liniment can resolve airway constriction [84]. Adrenergic stimulants were in use for asthma over 100 years ago. In 1901, the adrenaline isolated from sheep and oxen adrenal glands was used to treat asthma [85]. The first documented publication of adrenaline as a bronchodilator therapy for asthma was written in 1903 by James Burnett, a physician in Edinburgh [86]. One year later in 1904, adrenaline was synthesized in the laboratories of Friedrich Stolz and Henry Drysdale Dakin, independently

As suggested by the Global Initiative for Asthma (GINA) [88], a five-level step-down approach is widely recognized among the medical practitioners (**Figure 3**). The GINA approach assigns

**•** *Relievers* (bronchodilators) cause immediate dilatation effects on the airways obstruction,

**•** *Controllers* (preventers) provide long-term control of symptoms, mainly by suppressing the

expression to remodeling of the airways has not been fully understood [75].

lenged mice [78].

[87].

**6. Therapies for asthma**

144 Asthma - From Childhood Asthma to ACOS Phenotypes

two types of drug classes for managing asthma:

mainly by acting on lung's smooth muscle.

underlying disease process.

SABA: Short acting beta agonists, ICS: Inhaled corticosteroids (arrow down = low dose, arrow up = high dose), LABA: Long acting beta agoints, LTRA: Leukotriene receptor antagonists, MX: Methylxanthines, OCS: Oral corticosteroids, OZ: Omalizumab

**Figure 3.** Stepwise approach for controlling asthma symptoms and minimizing future morbidity.

β2-agonists and anticholinergics are considered to be bronchodilator relievers. Asthma controllers include corticosteroids, anti-leukotrienes, and anti-IgE. Theophylline is casually classified as both a bronchodilator and a reliever. The following book section will briefly discuss each therapeutic class.

#### **6.1. Corticosteroids**

Nowadays, most popular protocols for managing asthma involve the use of corticosteroids and β-agonists [1]. Anti-inflammatory corticosteroids, which are one of most trusted treat‐ ments for asthma, were introduced in mid-twentieth century [79]. The principle mode of action of corticosteroids in asthma is through their direct anti-inflammatory effect in different white blood cells including T cells, mast cells, and eosinophils. Among leukocytes, corticosteroids suppress chemotaxis and adhesion, and prevent inflammatory cytokines recruitment [89]. *In vitro*, corticosteroids reduce human ASM proliferation directly [90] by stimulating p21 gene expression [91], an important regulator of cell cycle progression. Moreover, corticosteroids improve vast majority of vascular remodeling aspects in asthma, reducing angiogenesis, excess blood flow, and vascular leakage [92]. This is mainly mediated by decreasing VEGF activity within the airway wall cells [93].

Various studies describe contradicting effects of corticosteroids on the lung epithelial abnor‐ malities in asthmatics. Dorscheid et al. [94] reported that Dexamethasone treatment resulted in increased epithelial apoptosis and shedding. Similar results were obtained when treating guinea pigs with Budesonide, which did not improve the tracheal epithelium [95]. By contrast, some *in vivo* studies showed that inhaled corticosteroid (ICS) treatment resulted in improve‐ ment of epithelial damage in severe asthmatics [96,97].

ICS has been used around for the past couple of decades. Its idea dates back to the nineteenth century when the hand-held glass bulb nebulizer was used; however, pressurized metereddose inhaler (pMDI) came to the clinic in 1956. After seeing his daughter's suffering while using the hand-held nebulizer, George Maison, a medical consultant at 3M Pharmaceuticals, had advocated the use of pMDI. In 1959, George Maison and Irvine Porush were awarded a patent on the first pMDI [98].

#### **6.2 β-adrenergic agonists**

Long-acting β-agonists (LABAs), for example, Formoterol [99] and Salmeterol [100], offer a longer period of bronchodilation compared to the short-acting beta agonists (SABAs), for example, Salbutamol [101] and Terbutaline [102]. LABAs persist in the airway tissues for long periods due to their lipophilic nature and they provide a good umbrella of asthma broncho‐ dilation and control, particularly at night [99,100]. However, until recently, the medical literature lacked supporting studies reporting the positive effect of β2 agonists on the chronic airway remodeling [103]. Addition of a β-agonist to the corticosteroid therapy allows a "steroid-sparing" effect, that is, maintains asthma control using lower doses of corticosteroids [104]. LABAs are not used as monotherapies anymore and they must be used in combination with ICS [105], because there have been cases of severe exacerbations and death when LABAs are administrated solely.

#### **6.3. Antimuscarinic agents**

Inhaled antimuscarinic agents, also known as inhaled anticholinergics, are considered another alternative bronchodilator group to β-agonists. The bronchodilation effect is functionally mediated via muscarinic receptor subtypes M1, M2, and M3, although five muscarinic receptors have been revealed in the lungs M1, M2, M3, M4, and M5 [106]. It is widely known that parasympathetic stimulation via the vagus nerve leads to immediate smooth muscle contraction and mucus secretion in the airways [107]. It is also suggested that M receptors interact with β2-adrenergic receptors (ADRB2) on the airways smooth muscle, leading to a reduced bronchodilator response of the β-agonists [108]. For years, in both adults and children, short-acting antimuscarinic agents use, for example, Ipratropium [109], has been limited to acute asthma management, in addition to inhaled SABA [110, 111]. Long-acting antimuscarinic agents, for example, Tiotropium [112], appear to have more benefits in difficult-to-control asthma. Adding Tiotropium to the standard asthma therapy significantly reduces asthma symptoms and highly increases the clinical outcomes [113, 114].

#### **6.4. Targeted therapies**

in increased epithelial apoptosis and shedding. Similar results were obtained when treating guinea pigs with Budesonide, which did not improve the tracheal epithelium [95]. By contrast, some *in vivo* studies showed that inhaled corticosteroid (ICS) treatment resulted in improve‐

ICS has been used around for the past couple of decades. Its idea dates back to the nineteenth century when the hand-held glass bulb nebulizer was used; however, pressurized metereddose inhaler (pMDI) came to the clinic in 1956. After seeing his daughter's suffering while using the hand-held nebulizer, George Maison, a medical consultant at 3M Pharmaceuticals, had advocated the use of pMDI. In 1959, George Maison and Irvine Porush were awarded a

Long-acting β-agonists (LABAs), for example, Formoterol [99] and Salmeterol [100], offer a longer period of bronchodilation compared to the short-acting beta agonists (SABAs), for example, Salbutamol [101] and Terbutaline [102]. LABAs persist in the airway tissues for long periods due to their lipophilic nature and they provide a good umbrella of asthma broncho‐ dilation and control, particularly at night [99,100]. However, until recently, the medical literature lacked supporting studies reporting the positive effect of β2 agonists on the chronic airway remodeling [103]. Addition of a β-agonist to the corticosteroid therapy allows a "steroid-sparing" effect, that is, maintains asthma control using lower doses of corticosteroids [104]. LABAs are not used as monotherapies anymore and they must be used in combination with ICS [105], because there have been cases of severe exacerbations and death when LABAs

Inhaled antimuscarinic agents, also known as inhaled anticholinergics, are considered another alternative bronchodilator group to β-agonists. The bronchodilation effect is functionally mediated via muscarinic receptor subtypes M1, M2, and M3, although five muscarinic receptors have been revealed in the lungs M1, M2, M3, M4, and M5 [106]. It is widely known that parasympathetic stimulation via the vagus nerve leads to immediate smooth muscle contraction and mucus secretion in the airways [107]. It is also suggested that M receptors interact with β2-adrenergic receptors (ADRB2) on the airways smooth muscle, leading to a reduced bronchodilator response of the β-agonists [108]. For years, in both adults and children, short-acting antimuscarinic agents use, for example, Ipratropium [109], has been limited to acute asthma management, in addition to inhaled SABA [110, 111]. Long-acting antimuscarinic agents, for example, Tiotropium [112], appear to have more benefits in difficult-to-control asthma. Adding Tiotropium to the standard asthma therapy significantly reduces asthma

symptoms and highly increases the clinical outcomes [113, 114].

ment of epithelial damage in severe asthmatics [96,97].

146 Asthma - From Childhood Asthma to ACOS Phenotypes

patent on the first pMDI [98].

**6.2 β-adrenergic agonists**

are administrated solely.

**6.3. Antimuscarinic agents**

Over the last 40 years, there has been a marked increase in the development of targeted treatments for asthma—anti-leukotrienes, anti-IgE, anti-interleukins, and anti-TNF-α [115]. Obviously, as more of the biological basis of asthma is uncovered, more effective targeted asthma treatments might be developed. The list of most recently published clinical trials covering the period from 1 January 2013 to 1 January 2016, as well as the list of currently ongoing registered clinical trials that has started since 2013 for the new asthma medications are summarized in **Tables 1** and **2**, respectively.




**Clinical Trial Identifier**

**Publication Title**

148 Asthma - From Childhood Asthma to ACOS Phenotypes

NCT01007149 A proof-of-concept, randomized, controlled trial of omalizumab in patients with severe, difficult-to-control, nonatopic asthma.

NCT00971035 Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids.

NCT00873860 A phase II placebo-

asthma.

NCT01018186 Safety and tolerability

NCT00393952 Efficacy and safety

of fluticasone/ formoterol combination

of the novel inhaled corticosteroid fluticasone furoate in combination with the β2-agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomized trial.

controlled study of tralokinumab in moderate-to-severe **Phase Drugs Outcome Responsible**

Phase 3 Omalizumab (anti-IgE)

Phase 2 Lebrikizumab (anti-IL-13)

Phase 2 Tralokinumab (anti-IL-13)

Phase 3 Fluticasone

Phase 3 Fluticasone propionate (ICS)

furoate (ICS) + Vilanterol (LABA)

marrow and peripheral blood in asthmatic patients.

Omalizumab may have a therapeutic potential for treatment of severe nonatopic asthma.

Blocking IL-13 alone was insufficient to improve lung function in asthmatic

patients.

Safety profile of tralokinumab was acceptable with no serious

adverse effects. Although tralokinumab treatment was associated with improved lung function, no improvement in

asthma control questionnaire score was

Fluticasone furoate/ Vilanterol (100/25 μg or 200/25 μg) administered once daily over 52 weeks was well tolerated by asthmatic patients aged ≥12

The overall safety profile of Fluticasone furoate/ Vilanterol did not reveal any serious adverse effects.

Fluticasone/formoterol combination therapy was an efficient alternative treatment option for

observed.

years.

**Party**

Novartis Pharmaceuticals

Genentech, Inc. [5]

GlaxoSmithKline [7]

SkyePharma AG [8]

MedImm une

LLC

**Reference**

[4]

[6]



**Clinical Trial Identifier**

**Publication Title**

in asthma: a doubleblind, randomized, dose-ranging study in adult patients with moderate asthma.

150 Asthma - From Childhood Asthma to ACOS Phenotypes

Phase 2 Tiotropium (LAMA)

Phase 2 huMAb OX40L (anti-OX40L)

Phase 2 Benralizumab (Anti-IL-5)

Phase 1 Anakinra

(Anti-IL-1)

NCT01233284 Tiotropium Respimat®

NCT00983658 OX40L blockade and

asthma.

NCT00768079 A randomized trial of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, after acute asthma.

NCT01369017 IL-1 receptor

antagonist reduces endotoxin-induced airway inflammation in healthy volunteers.

allergen-induced airway responses in subjects with mild

**Phase Drugs Outcome Responsible**

Administration of tiotropium Respimat®

(Once-daily) add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma, and the largest improvement was with a dose of 5 μg.

Anti-OX40L MAb decreased serum total IgE and airway eosinophils at 16 weeks post dosing, but there was no effect on allergen-induced airway responses. This may be due to the treatment duration or dose of antibody was insufficient to have an effect on the airway

responses.

acute asthma.

Anakinra effectively reduced airway neutrophilic inflammation with no serious adverse

A dose of benralizumab when added to usual care reduced the rate and severity of asthma exacerbations experienced over 12 weeks by subjects who presented to the emergency department with

**Party**

Boehringer Ingelheim

Genentech, Inc. [14]

MedImmune LLC

University of North Carolina, Chapel Hill

[15]

[16]

**Reference**

[13]

Abbreviations: **IL**: Interleukin; **IgE**: Immunoglobulin E; **TNF-α**: Tumor necrosis factor – α; **PDE**: Phosphodiesterase enzyme; **ICS**: Inhaled corticosteroids; **OCS**: Oral corticosteroids; **SABA**: Short-acting β-agonists; **LABA**: Long-acting βagonists; **LAMA**; Long-acting muscarinic antagonists.

**Table 1.** Summary of recent published clinical trials for new drugs used in the treatment of asthma (from 1 January 2013 to 1 January 2016).



Genetics of Allergic Asthma and Current Perspectives on Therapeutic Management http://dx.doi.org/10.5772/63651 153


**Clinical Trial Identifier**

NCT018 36471

NCT019 55512

NCT017 05964

NCT018 68061

NCT018 67125

with placebo in inadequately controlled asthma subjects with high bronchodilator reversibility

A study to assess the effect of QAW039 in nonatopic asthmatic patients

Effect of Clopidogrel on allergen challenge in asthma

Intramuscular epinephrine as an adjunctive treatment for severe pediatric asthma exacerbation

A study of Lebrikizumab in patients with uncontrolled asthma on inhaled corticosteroids and a second controller medication

A study of Lebrikizumab in patients with uncontrolled asthma who are on inhaled

**Title Phase Drugs Start**

152 Asthma - From Childhood Asthma to ACOS Phenotypes

Phase 2 Placebo QAW039 ICS

Phase 2 Placebo

Phase 4 Epinephrine (IM)

Phase 3 Placebo

Phase 3 Placebo

Lebrikizumab (anti-IL-13)

Lebrikizumab (anti-IL-13)

Clopidogrel (platelets P2Y12 receptor blocker)

**Date**

May 2013 Assessment of the clinical effect of QAW039 in nonatopic asthmatics taking lowdose ICS as background therapy.

May 2013 Determination if the drug Clopidogrel reduces inflammation following breathing in house dust mite in people with mild asthma.

Jun 2013 Determination if IM epinephrine is an effective adjunct to inhaled β2-agonists for children with severe asthma exacerbation.

Jul 2013 Evaluation

Jul 2013 Evaluation of the efficacy and safety of Lebriki zumab in patients with

of the efficacy and safety of Lebrikizumab in patients with uncontrolled asthma despite daily administration of ICS therapy and at least 1-s controller medication.

**Purpose Study**

**Type**

Interve ntional

Interve ntional

Interve ntional

Interve ntional

Interve ntional Recr uiting

Recr uiting

Recr uiting

Recr uiting

Recr uiting

**Recruit ment Status**

**Respon sible Party**

Novartis Pharmaceuticals

University of Southampton

University of Louisville

Hoffmann-La Roche

Hoffmann-La Roche


Genetics of Allergic Asthma and Current Perspectives on Therapeutic Management http://dx.doi.org/10.5772/63651 155


**Clinical Trial Identifier**

NCT019 87492

NCT020 75008

NCT020 75255

NCT021 35692

A Phase 3a, repeat dose, open-label, long-term safety study of Mepolizumab in asthmatic subjects

eosinophilic bronchitis

A study of Lebrikizumab In patients with severe asthma who depend on oral corticosteroids

Long-term safety study of QGE031 in patients with allergic asthma who completed study CQGE031 B2201

Efficacy and safety study of Benralizumab to reduce OCS use in patients with uncontrolled asthma on high-dose inhaled corticosteroid plus LABA and chronic OCS therapy

**Title Phase Drugs Start**

154 Asthma - From Childhood Asthma to ACOS Phenotypes

Phase 2 Placebo

Phase 3 Placebo

Phase 3 Mepolizumab (anti-IL-5) Standard of Care

Benralizumab (anti-IL-5)

Lebrikizumab (anti-IL-13)

**Date**

Phase 2 QGE031 Mar 2014 Assessment

and eosinophilic bronchitis.

Mar 2014 Evaluation of the efficacy of Lebrikizumab compared with placebo as measured by the ability of patients to achieve lower daily doses of OCS in patients with severe corticosteroiddependent asthma.

> of long-term safety of QGE031 during 12 months of treatment in asthma patients who completed study CQGE031B2201.

Apr 2014 This trial is to confirm if Benralizumab can reduce OCS dependence (after dose optimization) in patients who are uncontrolled on high-dose ICS-LABA, and chronically dependent on OCS as part of their regular asthma controller regimen.

May 2014 Collection of clinical data for long-term use and further assessment of efficacy in patients

**Purpose Study**

**Type**

Interve ntional

Interve ntional

Interve ntional

Interve ntional Recr uiting

Recr uiting

Recr uiting Novartis Pharmaceuticals

AstraZeneca

GlaxoSmithKline

**Recruit ment Status**

Recr uiting **Respon sible Party**

Hoffmann-La Roche


Genetics of Allergic Asthma and Current Perspectives on Therapeutic Management http://dx.doi.org/10.5772/63651 157


**Clinical Trial Identifier**

NCT022 58542

NCT022 96411

NCT022 93265

NCT022 81318

Crosssectional study for identification and description of severe asthma patients

Efficacy and safety

A safety extension study to evaluate the safety and tolerability of Benralizumab (MEDI-563) in asthmatic adults and adolescents on inhaled corticosteroid plus LABA (BORA)

Efficacy of LAMA added to ICS in treatment of asthma (ELITRA)

99656 evaluating the effects of Lebrikizumab on airway eosinophilic inflammation in patients with uncontrolled asthma

**Title Phase Drugs Start**

156 Asthma - From Childhood Asthma to ACOS Phenotypes

Phase 3 Benralizumab (anti-IL-5)

Phase 2 Placebo CHF 5259 Glycopyrrolate bromide (LAMA)

Phase 3 Mepolizumab (anti-IL-5)

Phase 3 Placebo

Mepolizumab

Omalizumab (anti-IgE) Reslizumab (anti-IL-5)

Lebrikizumab (anti-IL-13)

**Date**

of the effects of Lebrikizumab on airway eosinophilic inflammation in patients with uncontrolled asthma on inhaled corticosteroids and a second controller medication.

Nov 2014 Characterization of safety profile of Benralizumab administration in asthma patients who have completed one of the three predecessor studies: D3250C00017, D3250C00018, or D3250C00020.

Nov 2014 Evaluation of the safety and superiority of the glycopyrrolate bromide (CHF 5259 pMDI) versus placebo on top of QVAR® pMDI, in terms of lung functions parameters.

Dec 2014 The

potential overlap of patients eligible for treatment with Mepolizumab

, Omalizumab and/or Reslizumab will be estimated.

Dec 2014 Evaluation of the

**Purpose Study**

**Type**

Interve ntional

Interve ntional

Interve ntional

Interve ntional Recr uiting

Recr uiting

Recr uiting Chiesi Farmaceutici S.p.A.

GlaxoSmithKline

GlaxoSmithKline

Recr uiting

**Recruit ment Status**

ntional uiting La Roche

**Respon sible Party**

AstraZeneca


Abbreviations denote: **IL**: Interleukin; **IgE**: Immunoglobulin E; **PDE**: Phosphodiesterase enzyme; **ICS**: Inhaled corticosteroids; **OCS**: Oral corticosteroids; **SABA**: Short-acting β-agonists; **LABA**: Long-acting β-agonists; **LAMA**; Long-acting muscarinic antagonists.

**Table 2.** Summary of recent ongoing clinical trials for new drugs used in the treatment of asthma (started in the past 3 years).

#### *6.4.1. Anti-leukotrienes*

Leukotrienes are lipid eicosanoids with a wide range of biological activities. They are derived from arachidonic acid through the enzymatic action of 5-lipooxygenase, and play a crucial role in asthma inflammatory pathogenesis, and in other allergic diseases such as allergic rhinitis, rhinosinusitis, atopic dermatitis, and urticaria [116]. Leukotrienes class includes three main types: cysteinyl leukotrienes (CysLTs), LTB4, and LTG4. LTG4 is the metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an α-keto-acid [117]. Since, very little is known about the LTG4-putative leukotriene, most clinical research studies focus on CysLTs and LTB4. CysLTs are strong bronchoconstrictors that powerfully affect airway remodeling, whereas LTB4 is a strong chemoattractant for most leukocyte subsets [118]. Over the last 20 years, since leukotriene antagonists were introduced to the clinic for asthma management, Montelukast [119, 120] and Zafirlukast [121] are the most frequently used drugs in this class.

### *6.4.2. Anti-IgE*

**Clinical Trial Identifier**

NCT023 36425

NCT024 27165

NCT024 22121

NCT025 71660

years).

Effect of RNS60 on the late-phase asthmatic response to allergen challenge

Efficacy of vitamin D on the clinical management of pediatric patients with asthma

Long-acting muscarinic antagonists.

*6.4.1. Anti-leukotrienes*

Efficacy and safety of QGE031 compared with placebo in patients aged 18–75 years with asthma

Comparison of RPL554 With placebo and Salbutamol in asthmatic patients

**Title Phase Drugs Start**

158 Asthma - From Childhood Asthma to ACOS Phenotypes

Phase 2 Placebo QGE031

Phase 2 Placebo RPL554 (PDE-3/4 inhibitor) Salbutamol

Phase 2 Placebo RNS60 Budesonide

Phase 3 Vitamin D (Lowand highsupplemen tation doses)

**Date**

**Purpose Study**

eosinophilic asthma.

Apr 2015 The study will assess the safety and efficacy of different dose levels of QGE031 in asthma patients.

Apr 2015 Assessment of the effects of RPL554 compared with Salbutamol and placebo in patients with chronic asthma.

May 2015 Evaluation of the effects of multiple doses of inhaled RNS60 and Budesonide on the

Oct 2015 Evaluation of vitamin D supplemen tation on exacerbation and clinical control of asthma.

Abbreviations denote: **IL**: Interleukin; **IgE**: Immunoglobulin E; **PDE**: Phosphodiesterase enzyme; **ICS**: Inhaled corticosteroids; **OCS**: Oral corticosteroids; **SABA**: Short-acting β-agonists; **LABA**: Long-acting β-agonists; **LAMA**;

**Table 2.** Summary of recent ongoing clinical trials for new drugs used in the treatment of asthma (started in the past 3

Leukotrienes are lipid eicosanoids with a wide range of biological activities. They are derived from arachidonic acid through the enzymatic action of 5-lipooxygenase, and play a crucial role

late-phase asthmatic response to allergen challenge in patients with mild asthma.

**Type**

Interve ntional

Interve ntional

Interve ntional

Interven tional

Not yet recruiting

**Recruit ment Status**

Not yet recruiting

Not yet recruiting

Not yet recruiting **Respon sible Party**

Novartis Pharmaceuticals

Verona Pharma plc

Revalesio Corporation

Hospital General Naval de Alta Especialidad - Escuela Medico Naval

At the moment, Omalizumab, which is the only approved targeted monoclonal antibody against IgE, is used to treat allergic asthma in clinical practice. It can significantly decrease serum IgE levels (up to 99%) within 2 h following subcutaneous administration, and diminish serum, sputum, and tissue eosinophilia [122]. Recently, Omalizumab has also been reported to have steroid-sparing effect, reducing the rate of asthma exacerbations up to 50%, and hence improving the quality of life [123]. However, nearly 45% of patients treated with Omalizumab had adverse reaction at the local injection site, which is considered the most commonly observed adverse event for Omalizumab. Some other minor upper respiratory tract infections and sinusitis have also been reported as well. Patients treated with Omalizumab display a very low (0.09%) frequency of anaphylaxis reaction. Importantly, there are no data reporting any correlation between cancer and Omalizumab treatment [124].

#### *6.4.3. Anti-ILs*

Three interleukin pathways are of physiological importance for asthma: IL-5, IL-9, and IL-4/ IL-13 pathways. IL-5 is pivotal for both eosinophil differentiation and maturation in the bone marrow. Subsequently, it controls eosinophil mobilization, activation, and survival [125]. Hence, antagonizing IL-5 has been proposed to be beneficial for asthma therapy, particularly for predominantly eosinophilic asthma. A number of anti-IL-5 and anti-IL-5 receptor mono‐ clonal antibodies are in the process of development for allergic diseases: Reslizumab [126], Mepolizumab [127], and Benralizumab [128]. IL-9 is one of the T-helper 2 (Th2) pro-inflam‐ matory cytokines that promote mast cell proliferation and T-cell growth [129]. In mouse models, IL-9 causes several common features of chronic asthma: excessive mucus production, eosinophilic airway inflammation, smooth-muscle cell hyperplasia, and aryl hydrocarbon receptor (AHR) [130]. Currently, a phase IIb clinical trial evaluates the efficacy and safety of subcutaneous Medi-528, a humanized IgG1 anti-IL-9 mAb, in adults with uncontrolled asthma (NCT00968669). Activated mast cells, eosinophils, basophils, and dendritic cells secrete IL-4 and IL-13. IL-4 and IL-13 both play an important role in asthma mainly by enhancing IgE production. They also control mast cells' growth and development, eosinophil recruitment, and AHR [131]. The first trial aimed at antagonizing the IL-4 used a soluble recombinant human IL-4 receptor antagonist (IL-4RA), altrakincept, which blocked the binding of IL-4 to its cellular receptors [132]. Several humanized IL-13-neutralizing antibodies have entered asthma phase I/II clinical trials—anrukinzumab [133], QAX576 [134], and CAT354 [135].

#### *6.4.4. Anti-TNF-α*

TNF-α, a cytokine produced by Th1 cells and macrophages, has diverse biological functions. TNF-α shows crucial, and previously extensively documented, role in Crohn's disease, rheumatoid arthritis, and psoriasis pathogenesis. The association between TNF-α increase and these disease progressions had inspired studies aiming to extend anti-TNF-α therapies also for the treatment of severe asthma and COPD [136]. Infliximab and Golimumab, two anti-TNFα mAbs, and Etanercept, a decoy soluble TNF-α receptor, are both able to biologically neutralize TNF-α cytokine, and blunt the immune response, thereby abolishing TNF-α effects in asthma [137].
