30 Current Drug Therapy, 2012, 7, 30-35 Novel Therapies: A Review

Preeti Chopra1, Inderpal Randhawa1,2 and Terry Chin2,*

1Department of Medicine, VA Greater Los Angeles Healthcare System/UCLA, USA; 2Department of Pediatrics, Miller Children’s Hospital, University of California, Irvine, USA

Abstract: Objective: To describe novel medical therapies in asthma. Data Sources: A comprehensive Pub Med search was performed and studies published between 2000 and 2008 were reviewed. Updated studies from 2009 to 2011 were also included. A focus was placed on randomized, controlled studies. Results: , a once daily inhaled long acting beta 2-agonist (LABA) increased forced expiratory volume in 1 sec (FEV1) and resulted in prolonged bronchodilation. , a pro-drug inhaled corticosteroid, has been shown to increase FEV1 as well as improve morning, evening, and site-measured peak expiratory flow (PEF) with fewer adverse effects. / (Flutiform), a combination inhaled corticosteroid and LABA, showed a reduction in severe exacerbations requiring hospitalization, increased FEV1, less rescue use and higher quality of life scores. Extra-fine beclomethasone with formoterol also appears promising. Several immunomodulating drugs are on the horizon. , an oral once-daily PDE-4 inhibitor, improved forced vital capacity (FVC) and reduced the need for rescue medication. There are encouraging results with mepolizumab and reslizumab, anti-leukin-5 monoclonal antibody preparations, in a specific subset of asthmatic patients. Other approaches such as anti-interleukin-5 receptor blockage and anti-interleukin-9 monoclonal antibodies are in the early stages of development. On the other hand, treatment directed toward anti-tumor necrosis factor in asthmatics has been disappointing. Conclusions: Novel therapies for asthma continue to evolve. Inhaled corticosteroids continue to be at the forefront of treatment. However, combination therapies, novel , and PDE4 inhibitors show promise. Many of these therapies still require further study particularly against the current standards in controller therapy. Keywords: Anti-inflammatory , asthma, immunotherapy, inhaled bronchodilators, inhaled corticosteroids, monoclonal antibody.

INTRODUCTION PATHOPHYSIOLOGY Asthma prevalence remains significant as over 22 million Asthma is a chronic obstructive lung disease people are affected and mortality rates approach over 4,000 characterized by variable inflammation. The inflammatory deaths annually in the United States. Poor medication response involves mast cells, T lymphocytes, and eosinophils compliance and a lack of disease education are inculcated resulting in the production of several mediators including [1]. The National Institute of Health (NIH) guidelines from cytokines, leukotrienes, and bradykinins [3]. Subtypes of 2007 focused the therapy of asthma based on age and disease asthma include bronchial, atopic, and nonatopic. Atopic severity [2]. Standardized therapy includes leukotriene asthma, the most common, is caused by hypersensitivity of antagonists, long acting beta 2-agonists (LABA), inhaled the airways to environmental triggers such as mold, dust, corticosteroids, and . The goal of this review is pollens, and other aeroallergens. The type 1 hypersensitivity to summarize novel asthma therapies in recent use or those reaction which ensues after exposure includes bronchiolar that are in development. wall edema, increased mucus secretions, and smooth muscle bronchospasm [1]. These patients often reveal positive allergen A comprehensive search utilizing Pub Med was skin tests and elevated IgE levels [4]. The therapeutic focus performed reviewing studies published between 2000 and for atopic asthma targets the allergic response, smooth 2008. Key words included novel medications, asthma muscle constriction, and airway inflammation. therapy, and allergic asthma. A focus was placed on randomized, controlled trials. Recent American Academy of Bronchial asthma is characterized by inflammation of the Asthma, Allergy, and Immunology meeting abstracts were airway mucosa [5]. The tracheobronchial tree is increasingly also reviewed. The studies were evaluated by all authors and responsive to stimuli, which causes contraction of the summarized in our paper. bronchial airways. Bronchial asthma is a highly ranked chronic health condition in adults and is the most common chronic illness of children. Treatment is dependent on the

severity of the patient’s illness and frequency of symptoms. *Address correspondence to this author at the 2801 Atlantic Avenue, Miller Children’s Hospital, Long Beach, CA 90806, USA; Nonatopic or intrinsic asthma is triggered by respiratory Tel: 562-933-8749, Fax: 562-933-8744; E-mail: [email protected] tract infections, drugs, and chemicals and is not thought to be

2212-3903/12 $58.00+.00 ©2012 Bentham Science Publishers Novel Asthma Therapies: A Review Current Drug Therapy, 2012, Vol. 7, No. 1 31

IgE mediated [6]. It is common in adults especially women. mediator release [9]. Several new long acting beta agonists The mechanisms involved are poorly defined and the have been studied recently. importance of mast cells remains unclear [7]. The treatment Indacaterol, a once-daily inhaled long acting beta agonist, is aimed at avoidance of triggers such as perfume, cleaning is currently in phase II trials. Once daily dosing theoretically agents, smoke, etc [8]. improves compliance compared to other long-acting beta agonists. The safety of indacaterol was assessed in a study of DISCUSSION 144 patients with persistent asthma who were randomized to Removal of environmental triggers and other inciting receive 28-days of double-blind treatment with indacaterol agents remain the first step in asthma management. Drug 400 g or 800 g or placebo. Adverse events were similar therapy for asthma may be categorized based upon between the active and placebo groups and were not dose- mechanism. Broad categories include inhibition of smooth- dependent (400 g, 40.7%; 800 g, 37.3%; and placebo, muscle contraction (beta agonists, methylxanthines, and anti- 38.5%) [10]. cholinergics) and control of inflammation (, The efficacy of indacaterol was assessed in numerous phosphodiesterase inhibitors, monoclonal antibodies, studies. One trial of 436 patients with persistent asthma leukotriene inhibitors, and mast cell-stabilizing agents). A receiving inhaled corticosteroids were randomized to a description of novel therapies follows within these categories seven-day treatment course with indacaterol 50, 100, 200, or (see Table 1). 400 g via a multi-dose dry-powder inhaler, indacaterol 400 A. Beta Agonists ug via single-dose dry powder inhaler, or placebo. All doses of indacaterol increased the mean time-standardized area Beta-2 agonists results in smooth muscle relaxation, under the curve of FEV1 compared with placebo (P<0.001) increased mucociliary transport, and decreased mast cell [11]. A second study involved 42 patients with persistent

Table 1. New Drug Therapies

Class/Drugs: Mechanism of Action Phase Trial Efficacy

Long Acting smooth muscle relaxation, increased mucociliary Beta Agonists transport, and decreased mast cell mediator release

Indacaterol II FEV1  with both doses (200 ug and 400 ug)

Carmoterol II Carmoterol is as effective as formoterol

Inhaled not entirely understood but is believed to have an Corticosteroids inhibitory effect on leukocyte recruitment into the airways.

Ciclesonide pro-drug inhaled corticosteroid which remains FDA approved  improvement in FEV1, FVC and PEF inactive until cleaved and activated by esterases in compared to and fluticasone the lung parenchyma.

Combination Drugs inhaled corticosteroid/long acting beta agonist

Flutiform® III Equally as effective as Advair® but more (fluticasone/formoterol) rapid action

Beclomethasone/Formoterol III Reportedly greater small airway effect

Phosphodiesterase inhibits PDE-4, an enzyme with activity in Inhibitors inflammatory cells.

Roflumilast III No clinically significant difference when compared to inhaled beclomethasone.

Oglemilast II Currently being studied

Monoclonal Antibodies

Mepolizumab anti-interleukin-5 monoclonal antibody III Mixed results in exacerbations and quality of life measures

Reslizumab anti-interleukin-5 monoclonal antibody I Well tolerated subcutaneously

Benralizumab anti-IL-5 receptor monoclonal antibody I Well tolerated subcutaneously

MEDI-528 anti-interleukin-9 monoclonal antibody II Decreased exacerbations

Etanercept blocks TNF-alpha III No significant difference in quality of life and FEV1 compared with placebo. 32 Current Drug Therapy, 2012, Vol. 7, No. 1 Chopra et al. asthma who were randomized to indacaterol 50, 100, 200, FEV1 from baseline (416 and 321 ml, respectively; p<0.0001). and 400 g or placebo. All doses resulted in prolonged The increase was more significant in the ciclesonide group bronchodilation. The FEV1 increased 7.6% in those with 95% CI 0.016-0.174, p=0.019 versus budesonide. Both receiving 200 g and 14.9% in those with 400 g [12]. agents also improved FVC and PEF from baseline with Similar results indicating a greater improvement in FEV1 p>0.0001 [20]. In a comparison between ciclesonide and with 400 g dose were found in a smaller study of 33 fluticasone, 474 patients with moderate asthma were patients [13]. Two studies found that doses equal or greater randomized for 12 weeks with ciclesonide 320 g daily or than 200-300 g indacaterol were equal or greater than fluticasone 200 g daily. Both groups showed an formoterol 12 g [14, 15] and with a faster onset of action improvement in FEV1 with p<0.0001. Asthma symptom [15]. scores and rescue medication use was decreased in both groups as well with p<0.0001. The adverse effect profile of Carmoterol is a long-acting beta2- agonist. It is oral candidiasis was non-existent in the ciclesonide group currently undergoing phase II trials. In one study, 118 [21]. Similarly another study involving 528 patients treated patients with persistent asthma were treated with carmoterol patients with ciclesonide 230 g twice a day or fluticasone 2 micrograms daily versus formoterol 12 micrograms twice a 330 g twice a day. The patients were followed for six day versus placebo over eight days. Carmoterol compared months. The results were similar with decreased asthma with placebo showed a p-value of 0.029 while formoterol symptom scores and an improvement in morning, evening, versus placebo had a p-value of 0.039. There was no and site-measured PEF [22]. Finally, in a Cochrane review difference between carmoterol and formoterol on the 1st, of twenty-one trials ciclesonide, beclomethasone, and 2nd, and 8th day of treatment. Thus it appeared that budesonide all provided similar results in PEF rates but carmoterol once a day was as effective as formoterol twice the FVC was higher with ciclesonide. The FEV1 results a day [16]. proved to be inconsistent. A comparison was performed B. Inhaled Corticosteroids with fluticasone and the results of FEV1, FVC, and PEF did not show statistical significance with 95% CI of Ciclesonide is a pro-drug inhaled corticosteroid which 0.11-0.01 [23]. remains inactive until cleaved and activated by esterases in the lung parenchyma. It is a potent anti-inflammatory Studies have been performed in which the allergic medication for asthma patients and is available as 80 response is measured using eosinophils. In one study 21 micrograms or 160 micrograms and is given once daily [17]. patients with atopic asthma were treated with ciclesonide 40 It is activated following oral inhalation. It received FDA g or 80 g for seven days. The 80 g dose reduced the approval on January 10, 2008. The majority of the studies early and late asthmatic response as well as a change in performed compared low dose inhaled corticosteroids rather FEV1, serum eosinophils, and sputum eosinophils with than moderate or high dose inhaled corticosteroids. p<0.025. The 40 g dose reduced the late asthmatic response and sputum eosinophils, p<0.025. Thus, ciclesonide 40 g Ciclesonide has been studied in several trials against was effective in blocking allergen-induced responses. It also placebo and other inhaled corticosteroids. Eight trials were reduced CCL17 release which is often elevated in patients included. One trial was performed in 311 patients with mild- with late asthmatic responses [24, 25]. to-moderate asthma who were given four weeks of beclomethasone dipropionate 400 micrograms/day and then C. Combination Drugs (Beta Agonists/Inhaled Corti- once-daily ciclesonide 100 g, 200 g, 400 g, or placebo costeroids) for eight weeks. The morning PEF was used as an efficacy The benefit of adding LABA to ICS for maintenance variable and the results showed 4.23 L/min (p<0.001), 3.75 therapy in asthma in adults is well-established by more than L/min (p<0.001), -0.40 L/min (p<0.001), -24.95 L/min in the seventy-seven studies involving over 21,000 patients in a 100 g, 200 g, 400 g, and placebo group, respectively. Cochrane review [26]. It is clear that the addition of LABA Thus it was found to be effective in all doses [18]. to ICS reduced the rate of exacerbations requiring oral A four week trial was done to determine if ciclesonide corticosteroids, decreased the frequency of rescue short- had an effect on the hypothalamic-pituitary-adrenal axis. The acting beta-agonist, increased pulmonary function, and study enrolled 77 patients with moderate-to-severe asthma. improved patient’s symptoms in adults who are symptomatic These patients were randomized to ciclesonide 320 g bid, on low to high doses of ICS therapy. However, the beneficial 640 g bid, 440 g bid, 880 g bid, or effects are less certain in children [27]. There are currently placebo for four weeks. The results of the cosyntropin three LABA/ICS combinations which have been improved stimulation showed no statistically significant difference by the FDA: flucatisone/ (Advair®), budesonde/ between the groups. The group who received ciclesonide 640 formoterol (Symbicort®) and monometasone/formoterol g bid had a higher 24-hour urinary cortisol level when (Dulera®). However, there are two newer combination compared to placebo (p < 0.0224). The fluticasone group preparations which have developed. that received 880 g bid had suppression in mean serum ® Flutiform is a combination inhaler consisting of cortisol as compared to placebo (p < 0.0009) [19]. formoterol (long acting beta-2 agonist) and fluticasone Ciclesonide has been compared to established asthma (inhaled steroid). It is currently in phase III trials, and the therapy. In one randomized study of 399 patients with FDA is reviewing previous studies and is expected to issue a asthma, patients received ciclesonide 320 g or once daily ruling in 2012. One study was conducted in 620 patients who budesonide 400 g for 12 weeks. Both medications increased were randomized to flutiform in a single inhaler in two Novel Asthma Therapies: A Review Current Drug Therapy, 2012, Vol. 7, No. 1 33 different doses versus fluticasone or formoterol alone, and Roflumilast has been compared to inhaled beclomethasone they were treated for 12 weeks. The FEV1 showed as well with no clinically significant difference noted. In one statistically significant differences favoring flutiform [28]. study, 499 patients with asthma received roflumilast 500 g When flutiform was compared with fluticasone/salmeterol once daily or beclomethasone 200 g twice daily for twelve (Advair®) in 202 patients, both were equally effective in weeks. The results of the study showed that both improved increasing FEV1, rescue medication use, asthma FEV1 by 12% and 14%, respectively. They also improved exacerbations and quality of life scores [29]. However, FVC with p<0.0001 and reduced rescue medication use flutiform did have a more rapid onset of action. p<0.0001. Given that compliance is a large problem with asthmatics, roflumilast does differ from beclomethasone A new fixed combination of beclomethasone/formoterol in that it is administered once daily as compared to twice (inhaled corticosteroid and long acting beta agonist) has daily [37]. been developed utilizing extra-fine particles to deliver to both large and small airways [30]. One study examined Oglemilast is similar to roflumilast in that it is a highly 228 patients with moderate to severe asthma who were selective PDE-4 inhibitor and tofimilast is an eosinophil treated for 12 weeks with this agent or fluticasone/salmeterol phosphodiesterase inhibitor. These are currently being two puffs twice a day. It measured lung function, symptom studied for safety and efficacy. scores, and rescue medication use and both groups 2. Monoclonal Antibodies had improvements. However there were no differences in the rate of asthma exacerbations or adverse events Mepolizumab is an anti-interleukin-5 (IL-5) monoclonal (difference -3.32 L/min; 95% CI -17.92 to 11.28). It was antibody. Interleukin-5 stimulates the production, activation, noted, however, that beclomethasone/formoterol had a and maturation of eosinophils. Since eosinophilic asthma faster onset of bronchodilation [31]. In another study represent approximately 40-60% of asthmatics, blocking beclomethasone/formoterol was compared with budesonide/ eosinophils may alleviate asthmatic symptoms. Three formoterol in 219 patients for 12 weeks. This study monoclonal antibodies have been developed to target IL-5 also showed no difference between both groups in similar and its receptor. Mepolizumab and reslizumab both end-point parameters [32]. neutralize IL-5; and benralizumab (MEDI-563) blocks IL- D. Other Inflammatory Medications 5R. In a study of 362 asthmatics, patients were treated with intravenous infusions of 250 mg or 750 mg mepolizumab at 1. Phosphodiesterase Inhibitors monthly intervals and were followed for 12 weeks. Blood Phosphodiesterase 4 (PDE-4) is a cyclic adenosine-3’,5’ and sputum eosinophils were reduced in both treatment monophosphate-metabolizing enzyme that has activity in groups with p<0.001. There were no statistically significant inflammatory cells including T cells, eosinophils, and changes in morning PEF, FEV1, daily beta agonist use, macrophages. Thus, by inhibiting PDE-4, inflammation is symptom scores, exacerbation rates, or quality of life suppressed. Roflumilast is an oral, once-daily PDE-4 measures [38]. However, two later studies did find clinical inhibitor which has been approved for use in humans and is improvement in severe refractory esoinophilic asthmatics available in Canada and Europe since 2011 [33]. It is with fewer severe exacerbations and quality of life currently in phase III trials in the United States. improvements after a 50-week treatment period [39] and improvement in FEV1 with subsequent reduction in steroid There have been several trials in allergic asthmatic use [40]. Reslizumab (formerly SCH55700) is another anti- patients. In one trial, 13 patients with mild allergic asthma IL-5 antibody which has shown some promise in severe were randomized to receive a single dose of oral roflumilast asthma in 18 patients with severe persistent asthma [41] and or placebo. The patients were given the drug one hour prior in a 15-week study [42] with improvement in FEV1. Finally, to an allergen challenge and the asthmatic response was benralizumab (formerly MEDI-563), which binds to the assessed by changes in FEV1. The results showed that IL-5R, thereby blocking IL-5 function and inducing roflumilast did not have activity sixty eosinophilic apoptosis, has been studied in a phase 2 minutes after being adminisered however it did affect multiple dose safety study using a subcutaneous formulation allergen-induced airway hyperresponsiveness as compared to [43]. There are two phase 2 studies in adult asthmatics which placebo (p=0.002) [34]. The results were similar to another are ongoing. study of 23 patients with mild asthma who were treated with roflumilast 250 g, 500 g, or placebo. These patients MEDI-528 is an anti-IL-9 monoclonal antibody. Safety participated in three treatment periods which were separated of the medication as well as tolerability was performed in 10 by washout periods. An allergen challenge was done at the patients with atopic asthma. The adverse events were noted end of each treatment period and the results showed that the in five patients and included chills, erythema, and headache. late asthmatic reactions were reduced by 27% (p=0.0110) However, the adverse events were found to be mild and 43% (p=0.0009) in those treated with 250 g and 500 to moderate and thus the medication was well tolerated. g, respectively as compared to placebo [35]. These results [44]. Another phase I study compared intravenous and supported a much larger study involving 693 patients taking subcutaneous doses in 24 and 29 subjects, respectively [45]. roflumilast for 12 weeks [36]. They showed a superior Early results from phase 2 studies are encouraging with improvement in FEV1 with the dose of 500 g per day. evidence of decreased asthma exacerbations and decreased There were no significant adverse effects in all the doses exercise-induced bronchospasm [46]. Further phase 2 trials tested. are pending. 34 Current Drug Therapy, 2012, Vol. 7, No. 1 Chopra et al.

Tumor necrosis factor (TNF)-alpha is a cytokine that is a tobacco avoidance. The goal of new drug therapies currently target in chronic inflammatory disease. Etanercept is a drug are to assist in disease modification; and the goal of future which blocks this cytokine and has been used in rheumatoid therapies is to offer definitive control of asthma. arthritis, Crohn’s disease, and psoriasis and is currently CONFLICT OF INTEREST being studied as a treatment modality in asthma patients as bronchoalveolar lavage has shown elevated levels of TNF- None of the authors have any financial connections to alpha in patients with severe asthma [47]. In a double-blind, any pharmaceutical companies nor have they conducted any placebo controlled study of 39 patients with corticosteroid of the research described in this manuscript. refractory asthma patients were given etanercept once a week for 12 weeks. The results were minimally significant in ACKNOWLEDGEMENT reducing asthma control questionnaire scores between Declared none. treatment and placebo (-1.11 (95% CI -1.56, -0.75) and -0.52 (95% CI -0.97, -0.07) respectively, p=0.030) and had no REFERENCES significant difference in asthma quality of life between both [1] Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. WB groups (p=0.084). There was, however, a significant Saunders Company 2001. reduction in CRP and sputum macrophages following [2] National Asthma Guidelines Updated. National Institute of Health. treatment. There were only minor adverse events which http://www.nih.gov/news/pr/aug2007/nhbli-29.htm. August 27, 2007. included pain at the injection site and skin rashes [48]. A [3] Andreoli TE, Carpenter CCJ, Griggs RC, et al. Cecil Essentials of larger study of 132 patients with moderate-to-severe asthma Medicine. 5th ed. WB Saunders Company 2001. taking 35 mg subcutaneously twice a week also did not find [4] Kasper D, Braunwald E, Fauci A, et al. Harrison’s Manual of th any differences [49]. Although etanercept has been well- Medicine. 16 ed. McGraw-Hill Professional 2005. [5] Shunsuke S. Bronchial Asthma Up-To-Date: Repair and tolerated in these studies, it is known to cause reactivation of Remodeling of Bronchial Mucosa. Jap J Natl Med Services 1999; latent tuberculosis (TB). There were 25 reports in the first 40 53: 239-245. months after the drug had been marketed [50]. A subsequent [6] Robbins S, Cotran R, Kumar V, et al. Pathologic Basis of Disease. study was performed in 48 patients with a positive PPD who 6th ed. Saunders/Elsevier 1999. had a mean follow-up period of 17 months and none of these [7] Kraneveld AD, Hanneke PM, Mirjam K, et al. Key Role for Mast Cells in Nonatopic Asthma. J Immunol 2002; 169: 2044-2053. patients developed active TB [51]. [8] Busse WW, Holgate ST, Reed CE. Asthma & Rhinitis. 2nd ed. Blackwell Publishing 2000. CONCLUSION [9] Bai, TR. Beta-2 adrenergic receptors in asthma: A current The classes of medications used most frequently in perspective. Lung 1992; 170: 125-141. [10] Yang WH, Martinot JB, Pohunek P, et al. Tolerability of asthma management continue to remain beta-2 agonists, indacaterol, a novel once-daily beta2-agonist, in patients with inhaled corticosteroids, combination beta-2 agonists/inhaled asthma: a randomized, placebo-controlled, 28-day safety study. corticosteroids, and anti-inflammatory medications. Within Ann Allergy Asthma Immunol 2007; 99: 555-561. these broad categories, efforts are made to produce novel [11] LaForce C, Alexander M, Deckelmann R, et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in medications with better efficacy, improved compliance, and asthma: a 7-day dose-ranging study. Allergy 2008; 63: 103-111. fewer adverse effects. [12] Beeh KM, Derom E, Kanniess F, et al. Indacaterol, a novel inhaled beta2-agonist, provides sustained 24-h bronchodilation in asthma. According to the 2007 National Institute of Health Eur Respir J 2007: 29: 871-878. guidelines for asthma recommendations from the Expert [13] 15. Sugihara N, Kanada S, Haida M, et al. 24-h bronchodilator Panel Report 3 (EPR-3), the key components of asthma care efficacy of single doses of indacaterol in Japanese patients with remain: assessment and monitoring, patient education, asthma: a comparison with placebo and salmeterol. Respir Med 2010; 104: 1629-1637. control of environmental triggers, and medications. The [14] Kanniess F, Boulet LP, Pierzhala W, et al. Efficacy and safety of EPR-3 continues to reaffirm that inhaled corticosteroids indacaterol, a new 24-hour beta2-agonist, in patients with asthma: a are the most effective controller medications. It is also dose-ranging study. J Asthma 2008; 45: 887-92. recommended that leukotriene receptor antagonists, cromolyn, [15] Pearlman DS, Greos L, LaForce C, et al. Bronchodilator efficacy of and long acting beta agonists be used as an adjunct therapy indacaterol, a novel once-daily beta2-agonist in patients with persistent asthma. Ann Allergy Asthma Immunol 2008; 101: 90-95. with inhaled corticosteroids [2]. The challenge for any [16] Kottakis I, Nandeuil A, Raptis H, et al. Efficacy of the novel very new drug is to prove similar or superior efficacy with long-acting beta-2 agonist carmoterol following 7 days once daily a comparable adverse effect profile. Several medications dosing: comparison with twice daily formoterol in patients with are demonstrating this standard including indacaterol, persistent asthma. Eur Respir J Suppl 2006. Poster 3858. [17] Dahl R. Ciclesonide for the treatment of asthma. Ther Clin Risk ciclesonide, and several LABA/ICS combinations. Other Manag 2006; 2: 25-38. reviewed medications still require further studies in a larger [18] Adachi M, Ishihara K, Inoue H, et al. Efficacy and safety of once- cohort of patients. daily inhaled ciclesonide in adults with mild to moderate asthma: a double-blind, placebo-controlled study. Respirology 2007; 12: 566- The control of asthma is defined as an absolute reduction 572. of rescue medication use, exacerbation rates, limitation of [19] Szefler S, Shashank R, James W, et al. Ciclesonide, A novel activity, and improvement in the decline of lung function inhaled steroid, does not affect hypothalamic-pituitary-adrenal axis function in patients with moderate-to-severe persistent asthma. [52]. Unfortunately to date, no single or combination therapy Chest 2005; 128: 1104-1114. has achieved this level of control. Compliance and a lack of [20] Ukena D, Biberger C, Steinijans V, et al. Ciclesonide is more patient education continue to remain the leading cause of effective than budesonide in the treatment of persistent asthma. asthma exacerbations and hospitalizations. Thus, practitioners Pulm Pharmacol & Ther 2007; 20: 562-570. should focus on symptom education, proper usage of [21] Boulet LP, Bateman ED, Voves R, et al. A randomized study comparing ciclesonide and fluticasone propionate in patients with medications, avoidance of environmental exposures, and moderate persistent asthma. Respir Med 2007; 101: 1677-1686. Novel Asthma Therapies: A Review Current Drug Therapy, 2012, Vol. 7, No. 1 35

[22] Buhl R, Vinkler I, Magyar P, et al. Comparable efficacy of [38] Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate ciclesonide once daily versus fluticasone propionate twice daily in safety and efficacy of mepolizumab in patients with moderate asthma. Pulm Pharmacol & Ther J 2006; 19: 404-412. persistent asthma. Am J Respir Crit Care Med 2007; 176: 1062- [23] Manning P, Gibson PG, Lasserson TJ. Ciclesonide versus other 1071. inhaled steroids for chronic asthma in children and adults. [39] Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and Cochrane Database Syst Rev 2008; 2. exacerbations of refractory eosinophilic asthma. New Eng J Med [24] Gauvreau GM, Boulet LP, Postma DS, et al. Effect of low-dose 2009; 360: 973-84. ciclesonide on allergen-induced responses in subjects with mild [40] Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for allergic asthma. J Allergy Clinl Immunol 2005; 116: 285-291. prednisone-dependent asthma with sputum eosinophilia. New Eng J [25] Heijink I, Kauffman H, Vellenga E, et al. Effect of Ciclesonide Med 2009; 360: 985-93. Treatment on Allergen-Induced Changes in T Cell Regulation in [41] Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a Asthma. Intl Arch Allergy Immunol 2008; 145: 111-121. humanized anti-human interleukin-5 antibody, in severe persistent [26] Ducharme FM, NiChroinin M, Greenstone I, et al. Addition of asthma: a pilot study. Am J Respir Crit Care Med 2003; 167: long-acting beta2-agonists to inhaled corticosteroids versus same 1655-9. dose inhaled corticosteroids for chronic asthma in adults and [42] Castro M, Mathur S, Hargreave F, et al. Ann Allergy Asthma children. Cochrane Database Syst Rev 2010; 5:CD005535. Immunol 2010; 105: A43 (Abstract P64)]. [27] Sears MR. The addition of long-acting beta-agonists to inhaled [43] Busse WW, Katial R, Gossage D, et al. Safety profile, corticosteroids in asthma. Curr Opin Pulm Med 2011; 17: 23-8. pharmocokinetics, and biologic activity of MEDI-563, an anti-IL-5 [28] Bodzenta-Lukaszk A, Pulka G, Dymek A, et al. Efficacy and safety receptor alpha antibody, in a phase I study of subjects with mild of fluticssone and formoterol in a single pressurized metered dose asthma. JACI 2010; 125: 1237-44.e2 inhaler. Respir Med 2011; 105: 674-82. [44] O’Byrne P, Boulet LP, Gauvreau G, et al. A single dose of Medi- [29] Bodzenta-Lukaszk A, Dymek A, McAulay K, et al. 528, a monoclonal antibody against interleukin-9, is well tolerated Fluticasone/formoterol combination therapy is as effective as in mild and moderate asthmatics in the phase II trial. CHEST: fluticasone/salmeterol in the treatment of asthma, but has a more Chest Meeting Abstracts 2007; 132: 478. rapid onset of action: an open-label, randomized study. BMC Pulm [45] White B, Leon F, White W, et al. Two first-in-human, open-label, Med 2011; 11: 28. phase I dose-escalation safety trials of MEDI-528, a monoclonal [30] Scichilone N, Battaglia S, Sorino C, et al. Effects of extra-fine antibody against interleukin-9, in healthy adult volunteers. Clin beclomethasone/formoterol on both large and small airways in Ther 2009; 31: 728-40. asthma. Allergy 2010; 65: 897-902. [46] Parker JM, Oh CK, LaForce C, et al. Safety profile and clinical [31] Papi A, Paggiaro P, Nicolini G, et al. Beclomethasone/formoterol activity of multiple subcutaneous doses of MEDI-528, a humanized vs. fluticasone/salmeterol inhaled combination in moderate to anti-interleukin-9 monoclonal antibody, in two randomized phase severe asthma. Allergy 2007; 62: 1182-1188. 2a studies in subjects with asthma. BMC Pulm Med 2011; 11: 14. [32] Papi A, Paggiaro PL, Nicolilni G, et al. Beclomethasone/formoterol [47] Kim J, Remick DG. Tumor necrosis factor inhibitors for the versus budesonide/formoterol combination therapy in asthma. Eur treatment of asthma. Curr Allergy Asthma Reports 2007; 7: 151- Respir J 2007; 29: 682-9. 156. [33] Giembycz MA, Newton R. Harnessing the clinical efficacy of [48] Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual- TNF-a receptor fusion protein (Etanercept) in corticosteroid selective phosphodiesterase inhibitors and novel combination refractory asthma: a double blind, randomized placebo-controlled therapies. Handbook Exp Pharmacol 2011; 204: 415-46. trial. Thorax 2008; 63: 584-91. [34] Louw C, Williams Z, Venter L, et al. Roflumilast, a [49] Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness etanercept in moderate-to-severe asthma: a randomized, controlled after allergen challenge. Respiration 2007; 74: 411-417. trial. Eur Respir J 2011; 37: 1352-9. [35] Van Schalkwyk E, Strydom K, Williams Z, et al. Roflumilast, an [50] Mohan AK, Cote TR, Block JA, et al. Tuberculosis following the oral, once-daily phosphodiesterase 4 inhibitor , attenuates allergen- use of etanercept, a tumor necrosis factor inhibitor. Clinl Infectious induced asthmatic reactions. J Allergy Clin Immunol 2005; 116: Disease 2004; 39: 295-299. 292-298. [51] Manadan, AM, Joyce K, Sequeira W, et al. Etanercept therapy in [36] Bateman ED, Izquierdo JL, Harnest U, et al. Efficacy and safety of patients with a positive tuberculin skin test. Clin Exp Rheumatol roflumilast in the treatment of asthma. Ann Allergy Asthma 2007; 25: 743-745. Immunol 2006; 96: 679-86. [52] The Childhood Asthma Management Program Research Group. [37] Bousquet J, Aubier M, Sastre J, et al. Comparison of roflumilast, Long-term effects of budesonide or in children with an oral anti-inflammatory, with beclomethasone dipropionate in the asthma. New Eng J Med 2000; 343: 1054-1063. treatment of persistent asthma. Allergy 2006; 61: 72-78.

Received: November 28, 2011 Revised: December 01, 2011 Accepted: January 06, 2012