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International Immunopharmacology xxx (2014) xxx–xxx
INTIMP-03283; No of Pages 5
Contents lists available at ScienceDirect
International Immunopharmacology
j ourna l homepage: www.e lsev ie r .com/ locate / in t imp
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Promising future therapies for asthma
Jeffrey R. StokesDivision of Allergy and Immunology, Creighton University Medical Center, 601 N 30th St, Suite 3M-100, Omaha, NE 68131, United States
E-mail address: [email protected].
http://dx.doi.org/10.1016/j.intimp.2014.05.0321567-5769/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Stokes JR, Promj.intimp.2014.05.032
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Article history:Received 30 March 2014Received in revised form 23 May 2014Accepted 27 May 2014Available online xxxx
Keywords:AsthmaCytokinesLAMALABA
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D PROAsthma affects 300 million people worldwide and that number has been increasing especially in developed
countries. The current standard of care for asthma treatment is based on 2 key pathological features of asthma,airway inflammation and airway obstruction. Improving bronchodilation can be accomplished with ultra-longacting beta2 agonists or long-acting muscarinic agonists used in combination with inhaled corticosteroids.These combinations have already been used effectively for the treatment of COPD. An inhaled phosphodiesteraseinhibitor has been shown to improve bronchodilation and decrease airway inflammation. Directly altering theairway smooth muscle with bronchial thermoplasty in select patients has demonstrated long-term benefitsbut must be measured with immediate post procedure complications. The development of monoclonal antibodiesto directly target specific cytokines has hadmixed results. In eosinophilic asthma blocking IL-4, IL-5 and IL-13 haveimproved asthma outcomes. The promise of more directed therapy for asthma appears closer than ever withincreased options available for the clinician in the near future.
© 2014 Elsevier B.V. All rights reserved.
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1. Introduction
Asthma affects 300 million people worldwide and its prevalenceincreases by 50% every decade [1]. In North America about 10% of thepopulation has asthma while in other developed countries this isgreater than 15% [1]. Asthma is a heterogenetic disorder characterizedby chronic inflammation with variable airflow obstruction and airwayhyperresponsiveness. The asthma inflammatory milieu consists of eo-sinophils, lymphocytes, mast cells, and epithelial cells. [2]. Neutrophilsmay play a key role in sudden onset-fatal asthma, occupational asthmaand asthmatic smokers. Later in the disease airway remodeling occurswith the development of sub-basement fibrosis, goblet cell hyperplasia,smooth muscle hypertrophy and angiogenesis. Atopy, the genetic pre-disposition for the development of IgEmediated allergy, is the strongestpredictor for the development of asthma. Typically allergic inflamma-tion is geared towards a T helper lymphocyte (TH2) profile with thegeneration of cytokines IL-4, IL-5, and IL-13 leading to increased airwayeosinophilia, mast cell activation and IgE production.
Current treatment goals consist of reducing inflammation with in-haled corticosteroids or leukotriene modifying agents, and decreasingairway obstruction via bronchodilation with beta2-agonists or anticho-linergics. Patients with moderate and severe persistent perennial aller-gic asthma are candidates for monoclonal antibody therapy withomalizumab or anti-IgE antibodies. Future therapies will build on ourexpanding understanding of the pathogenesis of asthma and effectivetreatment strategies already in place.
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2. Bronchodilators
2.1. Long-acting beta2-agonist (LABA)
The use of an inhaled corticosteroid (ICS) combined with a long-acting beta2-agonist (LABA) is the standard of care for treatingmoderate–severe asthma [2]. In 2013, a newer ICS/LABA combinationconsisting of fluticasone furoate (FF) and vilanterol (VI) was approvedby the Food and Drug Administration (FDA) of the United States forthe treatment of COPD. This combination has an ultra long actingbeta2-agonist, vilanterol, with 24 h bronchodilator activity, allowingfor once a day dosing. Early studies in asthma patients demonstrated agood safety profile with superiority to inhaled corticosteroidmonother-apy in reducing asthma symptoms [3,4].
A recent randomized, double-blind, double-dummy, parallel groupstudy by Woodcock et al evaluated 806 patients treated with once dailyinhaled FF/VI 100/25 μg compared to twice daily dosing of, fluticasonepropionate (FP)/salmeterol (SAL) 250/50 μg for 24 weeks [5]. Prior totreatment patients in the studywere not optimally controlled onmediumdose ICS alone. Both ICS/LABA therapies equally improved lung function,asthma control, exacerbation rates and quality of life measures. Bothtreatments were well tolerated with no difference in urinary cortisollevels between the two groups. The advantage of daily dosing makesthis a useful alternative to the current twice daily ICS/LABA therapies.
2.2. Long-acting muscarinic agonist (LAMA)
The use of long-acting muscarinic agonist (LAMA) medications asbronchodilators, such as tiotropium, is standard therapy for COPD. The
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addition of these types ofmedications for the treatment of patientswithasthma has been evaluated in several different patient populations. Thetypes of patients evaluated fall into 2 categories, moderate patients notwell controlled on ICS alone and patients symptomatic despite highdose ICS/LABA therapy.
In patients not well controlled on low dose ICS alone currentinterventions include increasing the ICS or adding a LABA. Peters et aldesigned a three-way, double-blind, triple-dummy crossover trial in-volving 210 patients with asthma, evaluating the addition of tiotropiumbromide to an ICS, as compared with doubling the dose of the inhaledglucocorticoid, or the addition of the LABA, salmeterol [6]. Comparedto doubling the ICS, the addition of tiotropium improved lung function(peak flows and FEV1) and symptoms (ACT scores, asthma controldays, and daily symptoms). Similar improvement was noted with theaddition of salmeterol to ICS compared to higher dose ICS. When thetiotropium arm was compared to the salmeterol arm the only signifi-cant difference was a greater improvement in FEV1 with tiotropium. Ina double-blind, double-dummy, placebo-controlled trial 388 asthmaticpatients who had a single nucleotide polymorphism at amino acid 16(B16-Arg/Arg) of the β2-adrenergic receptor gene (ADRB2B16-Arg/Arg) were randomized to 16 weeks of treatment with daily tiotropium,salmeterol administered twice daily through a metered-dose inhaler,or placebo in addition to their regular ICS doses [7]. Tiotropium andsalmeterol were superior to placebo in maintaining lung function,while tiotropium was evaluated noninferior to salmeterol with similarimprovements noted.
An early concept study evaluated the addition of tiotropium to stan-dard ICS/LABA therapy [8]. In this double blind, randomized, placebo-controlled, crossover study evaluating the effects of halving ICS dosageand adding either salmeterol alone, or salmeterol and tiotropium in 18non-smoking severe asthmatics, both the ICS/LABA and ICS/LABA/LAMA treatments were more effective than twice the dose of ICS in im-proving PEF and airway resistance. The addition of tiotropium addition-ally improved FEV1 and FVC while exhaled NO was reduced comparedto double the dose of ICS. In another study comparing 2 differentdoses of tiotropium (5 and 10 μg daily) added to patients uncontrolledon high dose ICS/LABA, both doses of tiotropium improved lungfunction, while the higher dose was associated with more side effectssuch as dry mouth [9]. Based on those results a subsequent 48 weekrandomized, double-blind, placebo-controlled, parallel-group study,was undertaken evaluating the addition of tiotropium (5 μg daily)for asthmatics not well controlled on ICS/LABA [10]. The additionof tiotropium increased the time to first exacerbation by 56 dayscompared to placebo, reducing both exacerbation risks by 21%, andthe total number of severe exacerbations. The median time to the firstepisode of asthma worsening was 315 days with tiotropium comparedto 181with placebo treatment. Again this study demonstrated improve-ment in lung functions, FEV1, FVC and peak flowmeasurements similarto previous studies.
One potential future therapy could be the use of one inhaler with acorticosteroid, ultra-long acting beta agonist, and tiotropium as a oncea day medication for treating moderate to severe asthma.
3. Phosphodiesterase inhibitors
Phosphodiesterases (PDEs) are enzymes associated with airwaysmooth muscle activity and airway inflammation. Inhibitors of PDE3act as bronchodilators while inhibition of PDE4 is anti-inflammatory.Roflumilast, an oral PDE4 inhibitor was shown to increase the FEV1 inpatients already taking salmeterol or tiotropium with COPD. The maindrawback was associated GI side-effects leading to increased studywithdrawals [11]. A novel inhaled PDE3/4 inhibitor RPL554 has beenevaluated in 4 proofs of concept studies involving healthy volunteersand patients with COPD or mild asthma [12]. Treatment was well toler-ated in all study groups with similar adverse reactions with study drugcompared to placebo. In patients with asthma or COPD bronchodilation
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was rapid, and was maintained after 6 days of daily dosing in patientswith asthma. RPL554 significantly reduced total number of neutrophilsand cells in sputum of healthy volunteers after lipopolysaccharidechallenge. Overall RPL55 was well tolerated, not demonstrating thesame GI effects as the oral PDE4 inhibitor.
4. Bronchial thermoplasty
Bronchial thermoplasty (BT) is a novel invasive treatment for severeasthma. Bronchial thermoplasty reduces airway smoothmusclemass bydelivering radiofrequency energy by bronchoscope directly to largerlobar and segmental bronchi (3–10 mm in diameter). Airway smoothmuscle is active in producing and responding to inflammatory cytokinessuch as IL-4 and leukotriene B4. In addition to decreasing the smoothmuscle thickness and leading to fixed airway size other potential mech-anisms include reduction of goblet cell hyperplasia and alteration ofbronchomotor tone [13].
An initial study on 16 patients with mild to moderate asthma toler-ated the standard bronchial thermoplasty of 3 treatments 3 weeks apart[14]. Themost common side effects were airway irritation presenting asincreased cough, dyspnea, wheeze and bronchospasm typically withinthe first day or two post procedure resolving within 5 days. Twelveweeks post treatment patients had significant improvement inpeak flow readings and symptom-free days and 2 years post procedureairway hyperresponsiveness had improved from a mean PC20 of0.92 mg/ml to 3.40 mg/ml.
A larger prospective, randomized, controlled study involving 112moderate–severe asthmatics were treated with 3 BT procedures3 weeks apart and evaluated a year after last treatment [15]. One yearpost therapy the BT group compared to control group had greaterimprovements in morning peak flow readings and symptom scores. Inaddition thermoplasty patients had a reduction in the number of mildexacerbations estimated at 10 fewer mild exacerbations per subjectper year with 86 additional symptom-free days per subject per year.After 5 years no evidence of adverse events due to BT were notedwhile spirometry was stable during this period of time [16].
A more severe subset of refractory asthmatics (32 patients) requir-ing high dose ICS/LABA with and without oral corticosteroids wererandomized to BT (15) or standard therapy (17) [17]. During the bron-choscopy treatment period, the first 6 weeks of the study having 3treatments 3 weeks apart, 4 BT patients were hospitalized a total of 7times while the control group had no hospitalizations. In the post treat-ment period 5 hospitalizations occurred in 3 BT patients while 4 hospi-talizations occurred in one control patient. Bronchial thermoplastypatients had improvements in rescue medication use and quality oflife 52 weeks after treatment compared to the control group.
Castro and colleagues evaluated 288 severe asthmatics symptomaticdespite high dose ICS/LABA who were randomized to thermoplasty orsham control bronchoscopies [18]. A year after treatment completed79% patients treated with BT had improvement in quality of life com-pared to 64% of sham treated patients. In the post treatment period(after the initial 6 weeks of procedures) the BT group had reductionsin severe exacerbations by 32%, ER visits due to respiratory symptomsby 84%, time lost from work/school by 66%, and hospitalizations forrespiratory symptoms by 73% compared to the sham treated group.During the treatment period, the first 6 weeks, 85% of the BT subjectsexperienced adverse events compared to 76% of sham bronchoscopypatients. During this period 8.4% of BT patients (16/190) required 19hospitalizations compared to 2% of sham patients (2/98). One of thethermoplasty patients required bronchial artery embolization for treat-ment of his post procedure hemoptysis. Of the 190 BT treated patients162 (85%) were evaluated 5 years after treatment [19]. These patientshad an average reduction over 5 years in severe exacerbations and ERvisits by 48% and 78% respectively compared to the 12 months priorto BT treatment. Prebronchodilator FEV1 remained unchanged duringthe 5 years even with a decrease in ICS dose by 18%.
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Due to the immediate complications associated with the procedurebronchial thermoplasty may be reserved for the more severe persistentoral steroid dependant patient not responsive to alternative therapies.
5. Monoclonal antibodies
Blocking specific targets along the asthma inflammatory pathwayholds promise as a future treatment option (Fig. 1). Currently the onlyFDA approved immunomodulator for the treatment of allergic asthmais omalizumab, a humanized anti-IgE antibody that binds to the Fc por-tion of the IgE molecule. In a review of 8 clinical trials involving nearly3500 patients subcutaneous omalizumab reduced asthma exacerba-tions, hospitalizations due to asthma, rescue inhaler use, and ICS dosage.Additionally more patients were able to discontinue inhaled corticoste-roids with omalizumab treatment [20]. Omalizumab may be moreeffective for patients with more severe asthma [21].
Cytokines are a natural target site for directed therapeutic interven-tions. Cytokines associated with asthma include TNF-α, IL-4, IL-5, IL-9,IL-13 and IL-17.
5.1. Tumor necrosis factor (TNF)-α
Tumor necrosis factor (TNF)-α is a proinflammatory chemoattractantthat recruits neutrophils and eosinophils into the airway and thus con-tributes to airway hyperresponsiveness [22]. Etanercept, a monoclonalantibody that directly binds to TNF-α, was evaluated in a phase II trialinvolving 132 patients with moderate–severe asthma [23]. Etanerceptwas administered subcutaneously twice weekly for 12 weeks and waswell tolerated. Overall treatment with etanercept was no more clinicallyeffective than placebo. Another human monoclonal antibody to TNF-α,golimumab, was evaluated in 309 patients with severe uncontrolledasthma [24]. An unfavorable risk-to-benefit profile leads to early discon-tinuation of the study. At that point no significant improve was noted inlung function or exacerbations with golimumab compared to placebo.Severe adverse reactions were noted in 30% of the golimumab treatedgroup, with eight malignancies and one death. Given these results, it is
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Fig. 1. Cytokine-b
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unlikely that blocking the effects of TNF-α will be a viable option forfuture asthma therapy.
5.2. IL-9
IL-9 is produced by lymphocytes and mast cells. In animal modelsIL-9 regulates airway inflammation, mucus production, and airwayhyperresponsiveness [25]. An anti-IL-9 monoclonal antibody wasevaluated in asthmatics whose symptoms were uncontrolled despiteICS therapy. A phase II randomized, double-blind, placebo controlled,parallel group study with 3 different doses of subcutaneous MEDI-528found no significant improvement with any doses of anti-IL-9 on ACQ,exacerbations or lung function [26].
5.3. IL-17
Lymphocytes producing IL-17 have demonstrated the ability torecruit eosinophils and neutrophils to the airway. The IL-17 receptor Aantibody brodalumab did not demonstrate any clinical effect on agroup of 302 poorly controlled moderate–severe asthmatics in a phaseIIa study [27]. When 9 subgroups were analyzed those patients withgreater FEV1 reversibility (N20%) did demonstrate significant improve-ment in ACQ scores with brodalumab treatment.
5.4. IL-5
Interleukin 5 (IL-5) is required for thedifferentiation andmaturationof eosinophils. In the treatment of asthma mepolizumab is the moststudied anti-IL-5 monoclonal antibody. Flood-Page et al evaluated 362uncontrolled moderate–severe symptomatic asthmatics despite ICStreated with 250 or 750 mg mepolizumab intravenously monthly for3 months in a randomized, double-blind placebo-controlled study[28]. Overall lung function, beta-agonist use, symptoms, exacerbationrates and quality of life were unaffected by either dose of mepolizumabcompared to placebo. Mepolizumab treatment did decrease blood andsputum eosinophils.
ased therapy.
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Subsequent studies have focused on specific patient populationsthat have evidence of eosinophilic based asthma. A randomized,double-blind, parallel-group trial of 20 prednisone dependent asth-matics with persistent sputum eosinophils and asthma symptomswere treated with either monthly 750 mepolizumab or placebo for5 months [29]. Mepolizumab treatment reduced their prednisonedose by 84% of their maximum possible dose compared to 48% forplacebo. Asthma control and lung function were increased whileblood and sputum eosinophils were decreased for 8 weeks after lastmepolizumab dose. In 61 patients with refractory eosinophilic asthmaand a history of recurrent severe exacerbationsmepolizumab treatmentfor 50 weeks reduced exacerbations to a mean of 2.0 while the placebopatients averaged 3.4 exacerbations per subject [30]. Blood and sputumeosinophils were again decreased, symptoms were improved whilelung function was not altered with treatment. A follow-up unblinded,prospective observational study of these patients noted that afterdiscontinuation of mepolizumab exacerbation frequency, sputum andblood eosinophils reverted back to pretreatment levels [31].
The largest study to date of eosinophilic asthmatics included 616patients in 81 centers and 13 countries with a history of recurrentsevere exacerbations treated with 3 different doses of mepolizumab[32]. Patients were treated with 13 intravenous doses every 4 weeks.All three doses reduced exacerbation events ranging from 39 to 52%,as well as time to first exacerbation, ER visits, exacerbation-inducedhospitalizations and eosinophil counts in blood and sputum. Efficacyof mepolizumab may be related to baseline blood eosinophil countsand the number of exacerbations the preceding year.
In a meta-analysis of 7 randomized placebo-controlled trials with1131 subjects the use of mepolizumab in the treatment of eosinophilicasthma reduced the risk of exacerbations and improves quality of lifein patients [33]. In this analysis no significant differences were notedin FEV1, PEF and PC20 in mepolizumab patients compared to placebo.
Benralizumab is a new humanized monoclonal antibody thatbinds to the IL-5α receptor. In an early phase I study in 13 eosinophilicasthmatics benralizumab reduced airway mucosal, sputum, blood andbone marrow eosinophils with a good safety profile [34].
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NCORRE5.5. IL-13
Il-13 has been directly implicated in airway inflammation,hyperresponsiveness, fibrosis, and increased mucus production. Piperet al evaluated 194 asthmatics with uncontrolled moderate to severeasthma on the IL-13 antibody, tralokinumab in a phase IIa study [35].Tralokinumab (150, 300 or 600 mg) or placebo was administered sub-cutaneously every 2 weeks for 12 weeks with subsequent 12 weekfollow-up. None of the active therapy doses altered the primary end-point of asthma symptoms (ACQ-6questionnaire) compared to placebo.Lung function measured by FEV1 was significantly improved in adose response fashion with tralokinumab from baseline compared toplacebo. No serious AEs were associated with tralokinumab treatmentbut those patients treated with tralokinumab had increased overall
U
Table 1Summary of future therapies.
Ultra-long acting beta2-agonists Likely will be available foLong acting muscarinic agonists Likely will be available foPhosphodiesterase inhibitors Early study favorable as inBronchial thermoplasty Significant complicationsCytokine specific therapy TNF-alpha Risk benefit ratio not favo
IL-9 One study, not effectiveIL-17 One study, not effectiveIL-5 Effective for select patienIL-13 Effective for a select patieIL-4 (IL-13) Early studies look promis
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AEs (48%) compared to placebo (36%) with the most frequent beingasthma, headache and nasopharyngitis.
Lebrikizumab is another monoclonal antibody directed at IL-13.Corren et al. compared lebrikizumab to placebo in 219 adults withasthma inadequately controlled despite ICS usage in a randomized,double-blind, placebo-controlled study [36]. Patients were treatedwith either 250mg of lebrikizumab or placebo subcutaneouslymonthlyfor 6 months. Lebrikizumab treatment improved FEV1 by 5.5% com-pared to the placebo group. Periostin, a matrix protein induced by IL-4and IL-13, was used as a marker to compare two subgroups, high andlow periostin at baseline. In the high periostin group lebrikizumabimproved FEV1 by 8.2% compared to 1.6% in the low group. Theimprovement was noted within a week of treatment and persisted for12 weeks after the last dose. Patients with increased baseline FeNOlevels demonstrated greater improvement in FEV1 with lebrikizumab.Despite these findings no significant improvement in asthma symptomsor exacerbations was noted.
A subsequent phase II study randomized 212 asthmatics not receiv-ing any ICS therapy to receive 125, 250, or 500 mg of lebrikizumab orplacebo subcutaneously monthly for 12 weeks with an 8-week follow-up period [37]. No significant change in FEV1, PEF, ACQ, or albuterolusage was demonstrated with lebrikizumab. Although patients onactive therapy were less likely to have a treatment failure (6%)compared to placebo (27%). The high and low periostin groups did notdemonstrate any differences but the percentages of patients in eachgroup did not correlate well in the treatment and placebo patients soit was difficult to compare.
5.6. IL-4
The potential of blocking both IL-13 and IL-4 induced inflammationhas been addressed with dupilumab, a monoclonal antibody to theIL-4 receptor alpha subunit. This inhibits both IL-4 and IL-13 signaling.A phase IIa study by Wenzel et al evaluated duplimab in 104moderate-severe eosinophilic asthma adults [38]. Patients weretreated subcutaneously with 300mg duplimab (52 patients) or placebo(52 patients) weekly and LABAs were discontinued after 4 weeks oftreatment and ICS was tapered during weeks 6 through 9. Patientswere treated for 12 weeks or until first exacerbation, the primaryendpoint of the study. Treatment with duplimab significantly reducedexacerbations by 89% compared to placebo as well as time to first exac-erbation. At the onset of duplimab therapy FEV1 increased and wasmaintained despite the elimination of LABA and ICS. Significant im-provements were noted for asthma control and symptoms with reduc-tions in TH2 biomarkers. Decreases in FeNO levels with duplimabtreatment correlated with the improvement noted in the FEV1.
Pitrakinra is another IL-4 alpha receptor antagonist and has beenevaluated in 2 phase IIa clinical trials, in one administration was bysubcutaneous injection and the other nebulization [39]. Both studiesmeasured lung function after inhaled allergen challenge. There wasa decrease in FEV1 of 17% with subcutaneous pitrakinra comparedto 23% with placebo after challenge but this was not a significant
References
r asthma treatment in the near future, effective for COPD [3–5]r asthma treatment in near future, effective for COPD [6–10]haled preparation [11,12]immediately after procedure, may be effective for select patients [14–19]rable [23,24]
[26][27]
ts with eosinophilic based asthma [28–34]nt population with high periostin levels [35–37]ing. [38,39]
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difference. While the FEV1was only reduced by 4.4% after allergen chal-lenge with inhaled pitrakinra compared to 15.9% in the placebo arm,this was a significant difference. Less asthma related rescue medicationuse was demonstrated in the pitrakinra subcutaneous group while theinhaled study had too few adverse events to compare to placebo.
6. Conclusion
New therapeutic options are continually being investigated to treatasthma (Table 1). Some may become gold standard therapy whileothers don't make it beyond phase I studies. Currently the use of ultra-long acting beta2-agonists and LAMAs are currently treatment optionsfor COPD. It is possible that a three medication inhaler of ICS/LABA/LAMA will be the end result for once a day asthma treatment. Theearly development of an inhaled PDE3/PDE4 inhibitor shows promise.Bronchial thermoplasty decreases exacerbations in severe asthmaticslong term, but the high complication rate post-procedure makes thisunlikely to be a mainstream treatment. The cytokine specific therapiestarget specific patient populations, generally those with eosinophilicbased inflammation, making their universal use unlikely. As we contin-ue to find outmore about the pathogenesis of asthmawewill likely findmore options for specific interventions to decrease symptoms andimprove the quality of life for those patients.
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[3] Bateman ED, O'Byrne PM, Busse WW, Lötvall J, Bleecker ER, Andersen L, et al.Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbationsin asthma versus FF alone. Thorax Apr. 2014;69(4):312–9 [Epub 2013 Nov 19].
[4] Busse WW, O'Byrne PM, Bleecker ER, Lötvall J, Woodcock A, Andersen L, et al. Safetyand tolerability of the novel inhaled corticosteroid fluticasone furoate in combina-tion with the β2 agonist vilanterol administered once daily for 52 weeks in patientsN=12 years old with asthma: a randomised trial. Thorax Jun. 2013;68(6):513–20[Epub 2013 Feb 25].
[5] Woodcock A, Bleecker ER, Lötvall J, O'Byrne PM, Bateman ED, Medley H, et al.Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone pro-pionate/salmeterol combination in adult and adolescent patients with persistentasthma: a randomized trial. Chest Oct. 2013;144(4):1222–9.
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sthma, Int Immunopharmacol (2014), http://dx.doi.org/10.1016/
