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Novel Asthma Therapies: a Review

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Novel Asthma Therapies: a Review 30 Current Drug Therapy, 2012, 7, 30-35 Novel Asthma 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: Indacaterol, a once daily inhaled long acting beta 2-agonist (LABA) increased forced expiratory volume in 1 sec (FEV1) and resulted in prolonged bronchodilation. Ciclesonide, 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. Fluticasone/formoterol (Flutiform), a combination inhaled corticosteroid and LABA, showed a reduction in severe exacerbations requiring hospitalization, increased FEV1, less rescue medication use and higher quality of life scores. Extra-fine beclomethasone with formoterol also appears promising. Several immunomodulating drugs are on the horizon. Roflumilast, 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 bronchodilators, and PDE4 inhibitors show promise. Many of these therapies still require further study particularly against the current standards in controller therapy. Keywords: Anti-inflammatory medications, 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 omalizumab. 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 (glucocorticoids, 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 budesonide 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
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