**2. New bronchodilators for asthma**

#### **2.1 Anticholinergics**

Maintenance treatment to achieve asthma control currently includes inhaled or systemic glucocorticoids (ICS), leukotriene antagonists, LABAs, theophylline, monoclonal antibodies (mAbs) anti-IgE (omalizumab), and recently, newly included in the latest clinical practice guidelines, tiotropium bromide [1, 2]. The parasympathetic or cholinergic system is the most important bronchoconstrictor and hypersecretory neurological mechanism of the airways [11], and blocking specific muscarinic receptors is a therapeutic alternative to reduce the increase in parasympathetic activity that characterizes the main pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the natural alkaloids from the Solanaceae family plants (*Atropa belladonna* and *Datura stramonium*) represent one of the traditional remedies against bronchospasm. Atropine, the prototype nonselective muscar‐ inic receptor antagonist, with "tertiary ammonium" structure, was widely used from the late nineteenth century in oral, parenteral, and inhaled forms for the treatment of asthma; however, its use is constrained by the cardiovascular side effects. Following the introduction of ephe‐ drine and adrenaline, in the early twentieth century, atropine fell into disuse. Later, anticho‐ linergic therapy has returned to the forefront in the treatment of COPD, with the introduction of synthetic quaternary derivatives of atropine, short acting (ipratropium bromide) and long acting (tiotropium, aclidinium, umeclidinium, and glycopyrronium), the latter known under the acronym LAMA (long-acting muscarinic antagonists). The "quaternary ammonium" structure [12] makes them soluble in water and insoluble in lipids, therefore preventing the passage through biological barriers that are easily crossed by "tertiary ammonium" compo‐ nents, such as atropine, hence their lack of central nervous system effects; also they are poorly absorbed from the lung and gastrointestinal tract and do not inhibit the mucociliary clearance [13].

#### *2.1.1 Tiotropium*

of the existence of uniform treatment guidelines, as well as of quite accessible and effective treatments, achieving asthma control often remains a constant challenge. Recent studies indicate that over 50% of patients with asthma are not controlled [3, 4], not even when receiving a combination of inhaled corticosteroids (ICSs) and a long-acting beta-2-agonist (LABA) [5] as controller treatment. These data suggest that the search for alternative treatments is required, particularly for patients with severe uncontrolled a-wrap id="tab1" position="anchor"> sthma.

When searching for new treatment options in asthma, it is important to remember that different drugs, particularly biological agents, act on different pathogenic pathways. So, the individual profile of physiopathological alterations of each patient should be determined to prescribe the

Asthma management, from both a current as well as a future risk perspective, must compre‐ hend the stratification of patients into the recently defined phenotypes (such as clinical, inflammatory, and molecular) [7] and endotypes (such as allergic asthma, aspirin-sensitive asthma, late-onset hypereosinophilic asthma) [8], in the attempt to find a more personalized treatment for each patient. Moreover, in the last 10 years, significant efforts have been made to identify the characteristics that differentiate severe asthma from mild to moderate asthma,

The main goal of the treatment is to achieve and maintain the control of the disease as soon as possible, to prevent chronic airflow obstruction, and to reduce mortality. The goals of the treatment, both in its current control domain and in preventing exacerbations and accelerated loss of lung function (future risk), could be achieved in most of the patients with appropriate

Maintenance treatment to achieve asthma control currently includes inhaled or systemic glucocorticoids (ICS), leukotriene antagonists, LABAs, theophylline, monoclonal antibodies (mAbs) anti-IgE (omalizumab), and recently, newly included in the latest clinical practice guidelines, tiotropium bromide [1, 2]. The parasympathetic or cholinergic system is the most important bronchoconstrictor and hypersecretory neurological mechanism of the airways [11], and blocking specific muscarinic receptors is a therapeutic alternative to reduce the increase in parasympathetic activity that characterizes the main pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the natural alkaloids from the Solanaceae family plants (*Atropa belladonna* and *Datura stramonium*) represent one of the traditional remedies against bronchospasm. Atropine, the prototype nonselective muscar‐ inic receptor antagonist, with "tertiary ammonium" structure, was widely used from the late nineteenth century in oral, parenteral, and inhaled forms for the treatment of asthma; however, its use is constrained by the cardiovascular side effects. Following the introduction of ephe‐ drine and adrenaline, in the early twentieth century, atropine fell into disuse. Later, anticho‐

preparing the ground for the development of new selective treatments.

most appropriate treatment in each case [6].

116 Asthma - From Childhood Asthma to ACOS Phenotypes

**2. New bronchodilators for asthma**

treatment [9, 10].

**2.1 Anticholinergics**

Tiotropium bromide is the first long-acting anticholinergic agent (24 hours action), widely used for treatment of COPD. At the end of 2014, it was also approved by the FDA as an additional treatment of asthma in patients >12 years in the United States and in adult patients with asthma not controlled by the ICS in the European Union (Spiriva® Respimat). Such approval has been obtained based on sound scientific evidence on the effectiveness and safety of treatment with tiotropium in patients with mild-to-moderate and severe asthma. The major evidence is discussed below and is summarized in Table **1** [14].



**Table 1.** Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].

A study published in 2009 [15] showed additional improvement in lung function in patients with severe asthma when tiotropium was added to conventional treatment, according to the guidelines (LABA/ICS, theophylline, antagonists of leukotriene receptor, and oral steroids). A total of 138 severe asthmatics with decreased lung function were recruited. Tiotropium 18 μg (via HandiHaler) was added once a day, and lung function was assessed every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 mL) in FEV1 that was maintained for at least 8 successive weeks. Of the 138 people with asthma, 46 (33.3%) respond‐ ed to tiotropium.

Peters et al. [16] conducted an independent three-way, double-blind, crossover study in 210 patients with asthma to evaluate the effect of the addition of tiotropium to ICS, when compared with doubling the dose of ICS (primary superiority comparison) or adding salmeterol (secondary comparison of non-inferiority). Use of tiotropium was superior when compared with doubling the dose of ICS; it also demonstrated superiority in the secondary endpoints, including evening PEF, the proportion of asthma control days, prebronchodilator FEV1, and daily symptom scores. The addition of tiotropium was not inferior to the addition of salmeterol on all evaluated results and increased FEV1 prebronchodilator more than salmeterol. In summary, when added to an ICS, tiotropium improved symptoms and lung function in poorly controlled patients with asthma, and its effects appear to be equivalent to those obtained with the addition of salmeterol.

Bateman et al. [17] carried out a double-blind, double-dummy, placebo-controlled trial to compare the efficacy and safety profile of tiotropium (Respimat 5 μg, administered daily in the evening with the Respimat device) with that of salmeterol and placebo added to an ICS, in 16-Arg/Arg patients with asthma that was not controlled by ICS alone. The study population comprised patients aged 18–67 years, with reversibility to bronchodilators and symptoms that were not controlled by regular therapy with ICS (400–1000 μg of budesonide or equivalent maintained throughout the trial). Changes in weekly primary endpoint (PEF) from the last week of the run-in period to the last week of treatment showed that tiotropium was not inferior to salmeterol.

It has been also assessed whether tiotropium could be an effective bronchodilator in patients with severe asthma who remain symptomatic and obstructed despite maximum recommend‐ ed treatment with the combination of ICS and LABA. Kerstjens et al. [18] compared the efficacy and safety profile of two doses of tiotropium (Respimat, 5 and 10 μg daily) with placebo as an add-on therapy in 100 patients with uncontrolled severe asthma despite maintenance treat‐ ment with at least a high dose ICS combined with a LABA, in a randomized, double-blind, crossover study with three treatment periods of 8 weeks each. The PEF was peak FEV1 at the end of each treatment period. Peak FEV1 was significantly higher with 5 μg and 10 μg of tiotropium than placebo, whereas there was no significant difference between the two active doses. Domiciliary PEF values were higher with both tiotropium doses. Adverse events were balanced across groups, except for dry mouth, which was more common in patients taking tiotropium 10 μg. This study shows that the addition of once-daily tiotropium for asthma treatment, including a high-dose ICS combined with a LABA, significantly improves lung function over 24 hours in patients with uncontrolled severe asthma.

**Study Patients' characteristics Main results and Conclusions**

**Table 1.** Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].

A study published in 2009 [15] showed additional improvement in lung function in patients with severe asthma when tiotropium was added to conventional treatment, according to the guidelines (LABA/ICS, theophylline, antagonists of leukotriene receptor, and oral steroids). A total of 138 severe asthmatics with decreased lung function were recruited. Tiotropium 18 μg (via HandiHaler) was added once a day, and lung function was assessed every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 mL) in FEV1 that was maintained for at least 8 successive weeks. Of the 138 people with asthma, 46 (33.3%) respond‐

Peters et al. [16] conducted an independent three-way, double-blind, crossover study in 210 patients with asthma to evaluate the effect of the addition of tiotropium to ICS, when compared with doubling the dose of ICS (primary superiority comparison) or adding salmeterol (secondary comparison of non-inferiority). Use of tiotropium was superior when compared with doubling the dose of ICS; it also demonstrated superiority in the secondary endpoints, including evening PEF, the proportion of asthma control days, prebronchodilator FEV1, and daily symptom scores. The addition of tiotropium was not inferior to the addition of salmeterol on all evaluated results and increased FEV1 prebronchodilator more than salmeterol. In summary, when added to an ICS, tiotropium improved symptoms and lung function in poorly controlled patients with asthma, and its effects appear to be equivalent to those obtained with

Bateman et al. [17] carried out a double-blind, double-dummy, placebo-controlled trial to compare the efficacy and safety profile of tiotropium (Respimat 5 μg, administered daily in the evening with the Respimat device) with that of salmeterol and placebo added to an ICS, in 16-Arg/Arg patients with asthma that was not controlled by ICS alone. The study population comprised patients aged 18–67 years, with reversibility to bronchodilators and symptoms that were not controlled by regular therapy with ICS (400–1000 μg of budesonide or equivalent maintained throughout the trial). Changes in weekly primary endpoint (PEF) from the last week of the run-in period to the last week of treatment showed that tiotropium was not inferior

It has been also assessed whether tiotropium could be an effective bronchodilator in patients with severe asthma who remain symptomatic and obstructed despite maximum recommend‐ ed treatment with the combination of ICS and LABA. Kerstjens et al. [18] compared the efficacy and safety profile of two doses of tiotropium (Respimat, 5 and 10 μg daily) with placebo as an

– The addition of tiotropium (409 patients) compared with placebo (405 patients) significantly increased the time to the first severe exacerbation and provided a modest but

sustained bronchodilation.

Nine hundred and twelve patients (814 finished the study) with uncontrolled asthma in spite of ICS/LABA (studies

PrimoTinAsthma 1 and 2).

118 Asthma - From Childhood Asthma to ACOS Phenotypes

*ICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists.*

Kerstjens et al. 2012 [19]

ed to tiotropium.

the addition of salmeterol.

to salmeterol.

Subsequently, Kerstjens et al. [19] have evaluated the influence of add-on treatment with tiotropium on exacerbations, an important marker, as is well known, of asthma control. Two parallel, randomized, double-blind placebo-controlled trials (PrimoTinAsthma 1 and Primo‐ TinAsthma 2) were conducted between October 2008 and July 2011 in 15 countries, involving 912 patients with severe asthma and fixed airflow obstruction, who were randomized for tiotropium (Respimat, 5 μg) or placebo once daily for 48 weeks.

It was concluded that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided a modest but sustained bronchodilation.

As mentioned in the introduction, we once more insist on the importance of determining the asthma phenotype: a small study (17 patients) showed that tiotropium is more effective in asthmatic smokers or non-smokers treated with medium-to-high doses of ICS if the inflam‐ matory phenotype according to induced sputum is non-eosinophilic [20]. This suggests that perhaps early phenotyping poorly controlled asthmatic patients with high doses of ICS and even systemic corticosteroids (SC) could give tiotropium a corticosteroid-sparing effect in patients who turn out to have steroid-resistant asthma phenotypes. In fact, given its mecha‐ nism of action, the bronchodilator additive effect of tiotropium makes most sense in the following circumstances [21]: patients with asthma–COPD overlap syndrome (ACOS) [12], asthma of psychogenic origin, bronchospasm triggered by beta blockers, asthma with chronic airflow limitation, and severe asthmatics with Arg/Gly variation in codon 16 of the ADRB2 gene [15].

However, it seems that the effect of tiotropium goes beyond the bronchodilation because it has significant anti-inflammatory and antiproliferative capacities, such as reduction of hyperplasia of bronchial smooth muscle and inhibition of proliferation of fibroblasts and myofibroblasts [22]. Furthermore, in vitro studies using experimental models of asthma (ovalbumin-sensi‐ tized guinea pigs) have shown that tiotropium inhibits airway remodeling induced by allergens in a similar way to budesonide [23, 24], so its role in the management of allergic asthma may be more important than it seems at first glance.

Regarding adverse effects, tiotropium is a safe drug and is generally well tolerated, the most common side effect being dry mouth. The heart rhythm disturbances are rare (atrial fibrillation, atrial sinus, or supraventricular tachycardia). The TIOSPIR [25] study concluded that tiotropi‐ um Respimat was safe in COPD patients with ischemic heart disease and/or stable arrhyth‐ mias. The study excluded patients with myocardial infarction in the past 6 months, class III– IV NYHA heart failure, potentially fatal arrhythmias, and chronic renal failure.

#### **2.2. New combinations: ICS/LABA, LABA/LAMA, and triple therapy LABA/LAMA/ICS**

Because combination therapy with ICS and LABA is the usual therapeutic option for the treatment of asthma, there is great interest in developing combinations of administration once a day, in an attempt to simplify treatment and improve treatment compliance [26], a currently achievable challenge with the new ICSs (such as ciclesonide, mometasone, and fluticasone furoate) and the emergence of new ultra-LABAs (such as indacaterol, vilanterol, and oloda‐ terol), which can be administered in a single-daily dose. Currently, new combination therapies of ultra-LABA/ICS have been developed, are in clinical trial phases II–III, or have even recently marketed (vilanterol/fluticasone furoate), like several other LAMA–LABA combinations for the treatment of COPD: tiotropium/ olodaterol, aclidinium/ formoterol, umeclidinium / indacaterol, vilanterol / umeclidinium, and so on [27]. However, the use of some of these drugs in asthma is still being investigated (see also Table **2** ).

#### **Long-acting muscarinic antagonists (LAMA):**

**•** Aclidinium bromide (approved for treatment of COPD)

#### **Ultra-long-acting muscarinic antagonists (ultra-LAMA):**


#### **Ultra–long-acting beta-2-agonists (ultra-LABA):**


#### **New combinations of ultra–long-acting beta-2-agonists (ultra-LABA) and inhaled corticosteroids (ICS):**


#### **New combinations of LAMA or ultra-LAMA and LABA or ultra-LABA:**


**Triple therapy of ultra-long-acting beta-2-agonists (ultra-LABA), inhaled corticosteroids (ICS), and ultra–longacting muscarinic antagonists (ultra-LAMA):**

**•** Vilanterol trifenatate/fluticasone furoate/umeclidinium bromide

um Respimat was safe in COPD patients with ischemic heart disease and/or stable arrhyth‐ mias. The study excluded patients with myocardial infarction in the past 6 months, class III–

**2.2. New combinations: ICS/LABA, LABA/LAMA, and triple therapy LABA/LAMA/ICS**

Because combination therapy with ICS and LABA is the usual therapeutic option for the treatment of asthma, there is great interest in developing combinations of administration once a day, in an attempt to simplify treatment and improve treatment compliance [26], a currently achievable challenge with the new ICSs (such as ciclesonide, mometasone, and fluticasone furoate) and the emergence of new ultra-LABAs (such as indacaterol, vilanterol, and oloda‐ terol), which can be administered in a single-daily dose. Currently, new combination therapies of ultra-LABA/ICS have been developed, are in clinical trial phases II–III, or have even recently marketed (vilanterol/fluticasone furoate), like several other LAMA–LABA combinations for the treatment of COPD: tiotropium/ olodaterol, aclidinium/ formoterol, umeclidinium / indacaterol, vilanterol / umeclidinium, and so on [27]. However, the use of some of these drugs

IV NYHA heart failure, potentially fatal arrhythmias, and chronic renal failure.

in asthma is still being investigated (see also Table **2** ).

**•** Tiotropium bromide (approved for treatment of asthma and COPD)

**•** Carmoterol hydrochloride, milveterol hydrochloride, olodaterol hydrochloride

**New combinations of LAMA or ultra-LAMA and LABA or ultra-LABA:**

**•** Umeclidinium bromide / vilanterol trifenatate (approved for COPD)

**•** Vilanterol trifenatate / fluticasone furoate (approved for treatment of asthma and COPD)

**New combinations of ultra–long-acting beta-2-agonists (ultra-LABA) and inhaled corticosteroids (ICS):**

**•** Glycopyrronium bromide (approved for treatment of COPD)

**•** Indacaterol maleate (approved for treatment of COPD)

**Long-acting muscarinic antagonists (LAMA):**

120 Asthma - From Childhood Asthma to ACOS Phenotypes

**Ultra–long-acting beta-2-agonists (ultra-LABA):**

**•** Indacaterol maleate / mometasone (MGC-149)

**•** Tiotropium bromide / olodaterol hydrochloride

**•** Formoterol/ aclidinium (approved for COPD)

**•** Indacaterol maleate / glycopyrronium bromide (QVA149)

**•** Indacaterol maleate / QAE 397

**•** Aclidinium bromide (approved for treatment of COPD) **Ultra-long-acting muscarinic antagonists (ultra-LAMA):**

*COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists; LAMA = long-acting muscarinic antagonists.*

**Table 2.** New bronchodilators, either available or under clinical development, with probable upcoming indication for asthma (monotherapy and combinations).

When talking about the triple combination, it refers to ICSs, such as beta-2-agonist and inhaled anticholinergics, but mainly to long-acting drugs (LAMA–LABA–ICS). The possibility of associating these three drugs can contribute to better compliance, better control of the symp‐ toms, and improved quality of life, as well as to a decrease in exacerbations. There are several clinical studies in development: fluticasone/salmeterol/tiotropium and budesonide/formoter‐ ol/tiotropium [28]. The first triple combination formoterol/tiotropium/ciclesonide (Triohale®, Cipla) is now available in India [29], and its probable effectiveness in asthma is yet to be proven in future clinical trials.
