New Drug Therapies for COPD Clare L. Ross, MRCP, Trevor T. Hansel, FRCPath, PhD* INTRODUCTION New drugs for chronic obstructive pulmonary dis- ease (COPD) have been largely based on existing classes of current therapies, involving new inhaled combinations of long-acting muscarinic antago- nists (LAMAs), long-acting beta2-agonists (LABAs), and inhaled corticosteroids (ICS) (Table 1). 1 A use- ful reference source for new COPD medicines in development is the Pharmaceutical Research and Manufacturers of America (www.phrma.org). There is also an excellent series of topical articles on “The COPD Pipeline” provided by Nicholas J. Gross in the journal COPD (22 articles as of mid-2012). Although recent increases in knowledge of the inflammatory components contributing to COPD have led to many new targets for COPD treatment, 2 very few new classes of drugs are being licensed, making this a controversial area for new drug development. 3 Clinical studies with new drugs for COPD have been difficult for several reasons 4 : The immunopathology of COPD is complex and variable (Fig. 1). Cigarette smoke has widespread effects beyond the respiratory system, involving the large airways (bron- chitis), small airways (bronchiolitis), lung inter- stitium (emphysema and interstitial lung disease), pulmonary vasculature (pulmonary artery hypertension), and systemic complica- tions. 5–7 Pathologic features such as mucus Imperial Clinical Respiratory Research Unit (ICRRU), Biomedical Research Centre (BMRC), Centre for Respiratory Infection (CRI), National Heart and Lung Institute (NHLI), St Mary’s Hospital, Imperial College, Praed Street, Paddington, London W2 INY, UK * Corresponding author. E-mail address: [email protected]KEYWORDS COPD Pharmacology Bronchodilators Antiinflammatory drugs Antioxidants Protease inhibitors Fibrosis Lung regeneration KEY POINTS It is proving a major challenge to produce new effective drugs for chronic obstructive pulmonary disease (COPD). Improved understanding of COPD pathophysiology, novel clinical trial designs, endpoints, imaging and biomarkers, noninvasive sampling, patient stratification, challenge models, and clinical trial de- signs is necessary to facilitate development of new drugs for COPD. Smoking cessation is fundamental and new approaches include antinicotine vaccines, cannabinoid receptor antagonists, and dopamine D3 receptor antagonists. Novel combinations of inhaled bronchodilators and corticosteroids are being introduced. Antiinfective drugs are important, with a recent focus on the viruses that commonly cause exacerbations. Antiinflammatory drugs are in development, including kinase inhibitors, chemokine receptor antag- onists, inhibitors of innate immune mechanisms, and statins. Biologics used in rheumatoid diseases may also have a role; anti-IL-6 (tocilizumab) is promising. Antioxidants, mucolytics, antiproteases, and antifibrotics are all under active development. Aids to lung regeneration have potential to alter the natural history of COPD, including retinoids and mesenchymal stem cell therapy. Clin Chest Med 35 (2014) 219–239 http://dx.doi.org/10.1016/j.ccm.2013.10.003 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. chestmed.theclinics.com
Transcript
New Drug Therapies for COPDClare L. Ross, MRCP, Trevor T. Hansel, FRCPath, PhD*
INTRODUCTION
New drugs for chronic obstructive pulmonary dis-ease (COPD) have been largely based on existingclasses of current therapies, involving new inhaledcombinations of long-acting muscarinic antago-nists (LAMAs), long-acting beta2-agonists (LABAs),and inhaled corticosteroids (ICS) (Table 1).1 A use-ful reference source for new COPD medicines indevelopment is the Pharmaceutical Research andManufacturers of America (www.phrma.org). Thereis also an excellent series of topical articles on “TheCOPD Pipeline” provided by Nicholas J. Gross inthe journal COPD (22 articles as of mid-2012).Although recent increases in knowledge of theinflammatory components contributing to COPD
have led tomany new targets for COPD treatment,2
very few new classes of drugs are being licensed,making this a controversial area for new drugdevelopment.3
Clinical studies with new drugs for COPD havebeen difficult for several reasons4:
! The immunopathology of COPD is complexand variable (Fig. 1). Cigarette smoke haswidespread effects beyond the respiratorysystem, involving the large airways (bron-chitis), small airways (bronchiolitis), lung inter-stitium (emphysema and interstitial lungdisease), pulmonary vasculature (pulmonaryartery hypertension), and systemic complica-tions.5–7 Pathologic features such as mucus
Imperial Clinical Respiratory Research Unit (ICRRU), Biomedical Research Centre (BMRC), Centre for RespiratoryInfection (CRI), National Heart and Lung Institute (NHLI), St Mary’s Hospital, Imperial College, Praed Street,Paddington, London W2 INY, UK* Corresponding author.E-mail address: [email protected]
! It is proving a major challenge to produce new effective drugs for chronic obstructive pulmonarydisease (COPD).
! Improved understanding of COPD pathophysiology, novel clinical trial designs, endpoints, imagingand biomarkers, noninvasive sampling, patient stratification, challenge models, and clinical trial de-signs is necessary to facilitate development of new drugs for COPD.
! Smoking cessation is fundamental and new approaches include antinicotine vaccines, cannabinoidreceptor antagonists, and dopamine D3 receptor antagonists.
! Novel combinations of inhaled bronchodilators and corticosteroids are being introduced.
! Antiinfective drugs are important, with a recent focus on the viruses that commonly causeexacerbations.
! Antiinflammatory drugs are in development, including kinase inhibitors, chemokine receptor antag-onists, inhibitors of innate immune mechanisms, and statins.
! Biologics used in rheumatoid diseases may also have a role; anti-IL-6 (tocilizumab) is promising.
! Antioxidants, mucolytics, antiproteases, and antifibrotics are all under active development.
! Aids to lung regeneration have potential to alter the natural history of COPD, including retinoids andmesenchymal stem cell therapy.
Clin Chest Med 35 (2014) 219–239http://dx.doi.org/10.1016/j.ccm.2013.10.0030272-5231/14/$ – see front matter ! 2014 Elsevier Inc. All rights reserved. chestm
hypersecretion, small airway fibrosis, and lungdestruction (emphysema) are notoriously diffi-cult to reverse with drugs.
! COPD may be caused by the innate immuneresponse to oxidants and microbes, withaccelerated aging and autoimmune features.Bacteria and viruses may become moreimportant in more severe COPD.8
! Preclinical models need to be improved forin vitro and in vivo (animal) studies.9
! COPD patients are often elderly, frail, andhave multiple diseases associated with smok-ing. Cardiovascular diseases, metabolic syn-drome, and malignancies may be present.Hence, these patients may be on a variety ofmedications. These factors may mean that itis difficult to recruit patients when there arestrict entry criteria.
! A new therapy is more likely to be effectivewhen used early in the natural history ofCOPD, before irreversible disease hasoccurred. However, delays in diagnosis arecommon and the disease is notoriouslyunderdiagnosed.
! Small proof-of-concept studies in humans arepoorly predictive of efficacy in clinical practice.Some clinical development plans for COPDhave been discontinued after large-scale clin-ical trials, including Viozan, recombinantDNase (Pulmozyme), and cilomilast (Ariflo).
! Challenge models looking at the effects ofcigarette smoke,10 ozone, or lipopolysaccha-ride have been developed. On the otherhand, smoking cessation is part of COPD pa-tient care, providing an interesting situation ofwithdrawal of the stimulus.10–12 As a model ofCOPD exacerbations, live experimental chal-lenge can be performed with human rhino-virus (HRV) in patients with COPD.13 Novellarge scale clinical trial designs for COPD arealso needed.14
! There is a need to identify and validate end-points that can capture the considerableheterogeneity of pulmonary and systemic fea-tures. Forced expiratory volume in 1 second(FEV1) is a commonly used endpoint in mostclinical COPD trials. However, recently, theEvaluation of COPD Longitudinally to IdentifyPredictive Surrogate Endpoints (ECLIPSE)study has demonstrated that the annual rateof change in FEV1 in COPD is highly variable indifferent subjects.15 In addition, given that theFEV1declinesvery slowly during the natural his-tory of COPD, an estimated 1000 subjects persample group must be followed for a minimumof 3 years to have sufficient power to detect a50% improvement in disease progression.16
! Phenotypes of COPD need to be defined andvalidated in order to tailor drugs to individualpatients; it is becoming increasing clear that“one size does not fit all” in COPD.17 Thiswas demonstrated clearly by recent trialssuch as the National Emphysema TreatmentTrial (NETT), which showed a mortality benefitin only a subgroup of patients undergoing lungvolume reduction surgery.18 Of special inter-est are approaches that use CT.7,19
! Samples of varying invasiveness and fromdifferent compartments are required. Sputumgene expression looks promising,20 althoughexhaled breath condensate has been disap-pointing,21 and there are few studies withexhaled nitric oxide.22 However, assessmentby proteomics of epithelial lining fluid fromthe airway of COPD patients is feasible,23
and bronchial brushings can be carried outto assess gene expression.24
! There is a need to identify and validate bio-markers that may predict potential respondersfor specific therapy.25–27 Gene expression ortranscriptomics of the airway in COPD is ofspecial interest.20,24
! Current therapy is merely palliative; it isbecoming clear that there must be more focuson preventative and regenerative therapies.However, these are ambitious targets for newdrugs.
Smoking cessation is the first priority in the man-agement of a COPD patient who smokes. Todate, it is the only intervention shown to convinc-ingly reduce the accelerated decline in pulmonaryfunction and improve long-term prognosis (seeFig. 1, Table 1).28,29 Success in quitting isincreased by behavioral support in addition to arange of pharmacotherapies.30 However, a recentsystematic review has concluded that, in contrastto non-COPD smokers, neither the intensity ofcounseling nor the type of antismoking drugmake a significant difference in smoking cessationresults.31
The most widely used agents include nicotinereplacement (in a variety of preparations), antide-pressants such as bupropion and nortriptyline,and nicotine partial receptor agonists such asvarenicline (which remains the most efficaciousmonotherapy for smoking cessation32). Cytisine,a partial agonist that binds with high affinity tothe a4b2 subtype of the nicotine acetylcholinereceptor is effective in sustaining abstinence at
12 months.33 Other approaches currently underinvestigation include nicotine vaccines (with theassociated benefits of infrequent dosing and pro-longed effect); however, large trials of the currentfront-runners (NicVAx and NIC002) have beendisappointing.34,35 Both agents stimulate the pro-duction of antibodies that bind to nicotine and pre-vent it from crossing the blood-brain barrier. Novelnicotine products that can be given via the inhaled,topical (in the form of a spray) or orally dissolvingfilm route are also under development, anddetailed in a recent review.36 Compounds arealso being explored to target other neurotransmit-ters implicated in nicotine dependence suchas dopamine, g- aminobutyric acid (GABA), andglutamate.37 These include trials of monoamineoxidase inhibitors such as selegiline.36 The canna-binoid receptor system is thought to inhibitindirectly the dopamine-mediated rewarding prop-erties of food and tobacco, and cannabinoid re-ceptor 1 antagonists are undergoing evaluation,although trials have so far been disappointing.36
There is increasing popularity of electronic ciga-rettes, which deliver nicotine via an electronic
T cell
EmphysemaMucus
Hypersecretion
Obstructive
bronchiolitis
Fibrosis Proteolysis
Fibroblast
Neutrophil
Macrophage Epithelial cells
Transcription Factor inhibitors
Kinase inhibitors
Lung Regeneration
Reversal of Steroid Resistance
Smoking Cessation Aids
Anti-Infectives
Anti-Inflammatories
PDE4 inhibitors
Biologics: mABs
Processes
Anti-oxidants
Anti-fibrotics
Mucolytics
Inflammatory
Cells &
Mediators
Pathology
TriggersCigarette Smoke &
Reactive Oxygen Species, ROS
Systemic
Inflammation
StatinsNew Combinations of Inhaled
Bronchodilators and Steroids
Protease inhibitors
LocalInflammation
Fig. 1. Pathology, targets, and new drugs for COPD. An overview of some of the pathophysiologic processesinvolved in COPD, highlighting potential therapeutic targets for novel therapies. Cigarette smoke contains reac-tive oxygen species, particulates, and chemicals, which lead to a range of inflammatory effects: macrophage,epithelial cell, and CD81 T cell activation. These cells in turn release neutrophil chemotactic factors. Numerouslocal inflammatory mediators are then released, along with proteases, which break down connective tissue inthe lung, causing emphysema. Proteases are also important in stimulating mucus hypersecretion, which may man-ifest as chronic bronchitis. Profibrotic mediators are also released by epithelial cells, contributing to fibroblastproliferation and small airway fibrosis. Novel therapies include those aimed at local as well as systemic inflamma-tion. The most ambitious target is to regenerate lung tissue in response to emphysema. mABs, monoclonal anti-bodies; PDE4, phosphodiesterase 4.
New Drug Therapies for COPD 221
battery-powered device resembling a cigarette,despite no formal demonstration of the efficacyand safety of such devices. These devices havethe potential advantage of tackling the psycholog-ical and physical components of nicotine addic-tion; therefore, several large prospective studiesare now underway.38
The development of improved bronchodilators hasfocused on finding better inhaled LABAs andLAMAs (Table 2).39–41 Novel classes of bronchodi-lator have been difficult to develop because theyoften have additional unwanted effects on vascularsmooth muscle, producing postural hypotensionand headaches. Until recently, all LABAs requiredtwice-daily dosing, but newer once-daily agents,ultra-LABAs (ULABAs), such as indacaterol, oloda-terol, vilanterol, and carmoterol are proving tobe effective.39,42–44 Aclidinium bromide is a newLAMA that has an acute onset of action (comparedwith tiotropium’s slower onset of action) but hasdisappointed in trials to date.45,46 Other LAMAswith a more rapid onset of action are in develop-ment. Glycopyrronium bromide/NVA237 has beenshown to provide comparable effects to tio-tropium.47–49 Another company is soon to startphase III trials with nebulized LAMA, EP-101, a gly-copyrrolate solution. Two single-molecule, dual-action bronchodilators, muscarinic antagonist andbeta2-agonists (MABAs), are in phase I and II trials,including GSK961081.Studies looking at the benefits of dual LABA or
LAMA (salmeterol or formoterol with tiotropium)therapyhavedemonstratedgreater bronchodilationand fewer symptomswhen thedrugsare combined,than with either agent alone.50–52 New ULABAsallow for once-daily administration of LABA-LAMAcombination inhaler, anda recent studyhasdemon-strated significant benefits in FEV1 using QVA149(a combination of glycopyrronium bromide and in-dacaterol) versus indacaterol alone or placebo.53
Aclidinium has been combined with formoterol asa LAMA and LABA combination.46
Attempts to combine existing classes of drugswith additional agents have proved less success-ful, as demonstrated by the arrested developmentof the novel D2 dopamine receptor–b2 adrenore-ceptor agonist sibenadet (Viozan). The rationalefor this agent was based on observations thatsensory afferent nerves were key mediators ofCOPD symptoms such as breathlessness, cough,and excess sputum production, and advocates ofViozan hypothesized that that activation of
D2-receptors on such nerves would modulate theiractivity.54 Although initial short-term studies werepromising, the duration of the bronchodilatoreffect diminished as studies progressed and nosustained benefit was reported in a 1-year large-scale trial.55
ICS
Current United Kingdom and international guid-ance, despite little supporting evidence, recom-mend ICS for symptomatic patients with an FEV1
Table 2Inhaled bronchodilators and corticosteroidsand corticosteroid-related approaches
lower than 50% and/or frequent exacerbations.These are usually prescribed in the form of acombination inhaler containing LABA. In realityICS-LABA inhalers may be used inappropriatelyin an excessive number of COPD patients whodo not meet the criteria outlined by the GlobalInitiative for Chronic Obstructive Lung Disease(GOLD) guidelines.56 A Spanish study found arate of inappropriate ICS use of 18.2%.57
A Cochrane review of the role of ICS includedstudies published up until July 2011.58 This reviewconcluded that long-term (>6 months) ICS use didnot consistently reduce the rate of decline in FEV1
in COPD patients. There was no statistically signif-icant effect on mortality in COPD subjects, butlong-term use of ICS did reduce the mean rate ofexacerbations in those studies in which poolingof data was possible. In addition, there was slow-ing of the rate of decline in quality of life (measuredby the St. George’s Respiratory Questionnaire).There was an increased risk of oropharyngealcandidiasis and hoarseness with ICS use and, inthe long-term studies, the rate of pneumonia wasincreased in the ICS group compared with theplacebo group. Although ICS does seem to havesome beneficial effects in COPD, when comparedwith long-acting bronchodilators, the latter agentsseem to provide similar benefits to ICS orICS-LABA combinations in exacerbation reductionwithout the side effects associated with ICS use.59
One alternative may be the use of nonglucocor-ticoid steroids. EPI-12323 is a once-daily, smallmolecule, inhaled nonglucocorticoid steroid andmay not exhibit any of the classic side effects ofglucocorticoid steroids. It may also be possibleto avoid the unwanted side effects of glucocorti-coids by selectively inducing transrepressiongenomic mechanisms (which are responsible formany desirable antiinflammatory and immunomo-dulating effects), whereas transactivation pro-cesses (associated with frequently occurring sideeffects) are simultaneously less affected.60,61 Aninhaled selective glucocorticoid receptor agonistis currently undergoing clinical trials.
For patients who remain symptomatic despiteLABA-ICS combination, GOLD recommends tripletherapy with LAMA, LABA, and ICS. The rationalebehind this seems logical because all three agentswork via different mechanisms on different targets,potentially allowing for lower doses of the individualagents to be used, accompanied by improved side-effect profiles. However, there has been a lack ofsufficiently powered studies primarily addressingthe benefits of triple therapy versus LABA-ICStherapy, or, indeed, versus dual LABA-LAMA ther-apy.62,63 A single inhaler combining all three agentsis currently in formational development, although
the ICS to be used has not been confirmed.Once-daily ICS are now in development to allowfuture trials with once-daily triple-therapy com-bined inhalers. These inhalers may well improvecompliance, but titration of individual componentdrug doses may prove difficult, and diseaseseverity seems to affect the drug dose-responsecurve.64
Steroid Resistance
Interestingly, ICS do not seem to suppress inflam-mation in COPD. One hypothesis attributes this tothe marked reduction in histone deacetylase 2(HDAC2), the nuclear enzyme that corticosteroidsrequire to switch off activated inflammatorygenes,65 rendering these patients resistant to theeffects of ICS. The reduction in HDAC2 is thoughtto be secondary to oxidative stress, both indepen-dent of and by way of activation of phosphoinosi-tide-3-kinase-d (PI3Kd).66 Inhibition of PI3Kd hasrecently shown to restore corticosteroid sensitivityin mice66 and may hold therapeutic promise.67,68
One group has shown that formoterol reversesoxidative stress-induced corticosteroid insensi-tivity via PI3Kd.68 Low-dose theophylline hasshown to enhance the antiinflammatory effects ofsteroids during exacerbations of COPD69 andseems to have the capacity to restore the reducedHDAC2 activity in COPD macrophages.70 Morerecently, roflumilast has shown to augment theability of formoterol to enhance glucocorticoid-dependent gene transcription in human airwayepithelial cells.71
ANTIINFECTIVE AND ANTIINFLAMMATORYAGENTSAntibiotics
The Lung Health Study of North America revealedthat lower respiratory tract illnesses promote FEV1
decline in current smokers (Table 3).72 There isgrowing evidence that exacerbations acceleratethe progressive decline in lung function in COPDpatients.73 Several lines of evidence now impli-cate bacteria as an important cause of exacerba-tions74 and bacterial colonization is frequentlyfound in patients with COPD.75 It is associatedwith the frequency of exacerbations.76 Thereseems to be a correlation between bacterialcolonization of lower airways and elevated levelsof inflammatory mediators.77 Finally, patientswith severe COPD who receive inappropriateantibiotic treatment are vulnerable to multidrug-resistant infections.78
It has become increasingly difficult to developnew antibiotics, so that there is a need for noveltypes of therapy. Bacteriophages are bacterial
New Drug Therapies for COPD 223
viruses that are approximately 10 times morenumerous than bacteria in nature. Although theyhave been used in Russia for many decades asantibacterial agents, they have been used less inWestern medicine.79 Lytic phages are highly spe-cific to particular bacteria and are well tolerated,with no risk of overgrowth of intestinal flora. Theymay be administered by inhalation, so may beeffective in the treatment of respiratory bacterialinfections.Antimicrobial peptides, including a-defensins,
b-defensins, and cathelicidins, are producedfrom epithelial and other cells in the respiratorytract and play a key role in innate immunity andstimulating adaptive immune responses.80 Thesepeptides may also be considered potential futuretherapies.Although the molecular mechanisms for these
effects are not fully clear, 14- and 15-memberedring macrolide antibiotics have several antiinflam-matory effects in addition to their antibacterialactions.81 It has been shown that these drugsdecrease the production of cytokines in thelungs.82 A recent large clinical trial, with more
than 1142 volunteers, randomized subjects todaily administration of 250 mg of azithromycin orplacebo for 1 year.83 The median time to the firstacute exacerbation in the azithromycin groupwas increased by 92 days, and the frequency ofexacerbations in the azithromycin group wassignificantly reduced. However, deafness wasobserved in the treatment group as an adverseevent. Another long-term, placebo-controlled clin-ical trial examining macrolides in the prevention ofacute exacerbations used erythromycin at a doseof 250 mg twice daily for 1 year.84 A nonantibioticmacrolide such as EM704, derived from the struc-ture of erythromycin, has been shown to inhibitneutrophilic inflammation, the release of TGF-b,and fibrosis in a bleomycin model of pulmonaryfibrosis.85 Such nonantibiotic macrolides may bedelivered by inhalation during an exacerbationand will not affect antibiotic resistance patterns.Recently, pulsed antibiotic prophylaxis has
been trialed. Moxifloxacin has shown to reducethe odds of exacerbation in stable COPD subjectswhen given once a day for 5 days every 8 weeksfor 48 weeks.86 New pneumococcal vaccines are
also in development that may prove more effectivethan are their current counterparts.
Antivirals
With advances in diagnostic techniques for vi-ruses, such as polymerase chain reaction, thereis evidence that the most COPD exacerbationsare associated with viral infections and that, ofthese, HRV is the most common cause87 andcan directly infect the lower respiratory tract.88
Up-regulation of the HRV receptor, intercellularadhesion molecule 1, on epithelial cells occurs inCOPD patients and this may cause predispositionto infection.89 When infected, COPD primary bron-chial epithelial cells elicit exaggerated antiviraltherapies, especially in relation to HIV, develop-ment of resistance to proinflammatory response.90
Although there have been remarkable strides in thedevelopment of antiviral therapies, especially inrelation to HIV, development of resistance to viraltherapy is a recurrent problem91 and there are noeffective antirhinoviral treatments to date.Recently, an important model of human RV16challenge has been introduced as a model ofexacerbations in patients with COPD.13
Respiratory syncytial virus (RSV) is increasinglyrecognized in adults with COPD92 and it canpersist in stable disease.93 Treatment of RSVinfection remains largely supportive, although amonoclonal antibody (MoAB) therapy againstRSV F protein (palivizumab) is licensed forspecialist use in restricted circumstances.94
Seasonal influenza is another important cause ofexacerbations of COPD and there is the fear thatan influenza pandemic could cause high mortalityin patients with COPD.95 It is important that all pa-tients with COPD have adequate influenza immu-nization and that they be considered for earlytreatment in the event of an influenza-inducedexacerbation of COPD. Apart from vaccines, thereare two licensed antiviral agents against influenza:zanamivir and oseltamivir (Tamiflu).96 Neverthe-less, development of resistance is a major problemand new anti-influenza agents are being activelysought.97
Agents Acting on Innate Immunity
Cigarette smoke has long been known to increasethe permeability of the respiratory epithelium, thuscompromising the barrier function. Respiratory vi-ruses have a particular predilection for respiratoryepithelial cells and these can then initiate nonspe-cific inflammation. Once the respiratory physicalbarrier is penetrated, danger signals meet thenext part of the immune system defense: thepattern recognition receptors (PRRs). Recently,
there has been recent dramatic progress in theunderstanding of the molecular and cellular detailsof how the innate nonspecific immune system isactivated.98 PRRs are thought to be central tothe activation of the innate immune system andthey have the capacity to drive chronic lunginflammation,99 repair processes, fibrosis, andproteolysis. A unified theory can be made of howthe development of mild-to-moderate COPD, aswell as exacerbations of COPD, is mediatedthrough interaction of reactive oxidant species(ROS), viruses, and bacteria with the innate im-mune system.100 Molecular signatures on ROS,viruses, and bacteria, as well as from dead anddamaged cells, cause rapid activation of the fam-ily of PRRs. Pathogen-associated molecular pat-terns (PAMPs) are found especially in the nucleicacid of the viruses that infect the respiratoryepithelium and in various cell wall and cytoplasmiccomponents of bacteria.101 A variety of damage-associated molecular patterns (DAMPs) hasbeen proposed, including high-mobility groupbox 1, S100 proteins, heat shock proteins (HSP),and extracellular matrix hyaluronans.
ROS activate Toll-like receptor (TLR) 2102 andTLR4 using MyD88 signaling,103,104 but they canalso cause damage to membrane lipids and toDNA and thus activate DAMPs.105,106 The cellwall of gram-negative bacteria contains lipopoly-saccharide that activates cell surface TLR4,whereas various other bacterial components acti-vate different cell surface TLRs. In contrast, viralnucleic acid motifs activate TLR3, 7, and 9, whichare found on the inner surface of the endosomalmembrane.
PRRs undergo extensive cross-talk withTLRs,101 scavenger receptors,107 and receptor foradvanced glycation end-products (RAGE).91,108 Inaddition, there are TLRs on endosomes that recog-nize viral nucleic acids and cytoplasmic PRRs thatconsist of retinoic acid-inducible gene-1 (RIG-1)-like receptors (RLRs), and NOD-like receptors(NLRs). Activation of PRRs takes place in COPDon epithelial cells, neutrophils, macrophages,smooth muscle109 fibroblasts, and other cells ofthe airways. Acute cigarette smoke activatesMyD88, a common adapter protein that is involvedin the signaling of several TLRs (including TLR2, 4,7, 8, and 9).104
Therefore, blocking PRRs, including TLRs thatrecognize and are activated by PAMPs on oxi-dants and infectious agents, may be a potentialway of modulating disease activity in COPD. Thereare now intensive efforts to develop TLR-agonistsand antagonists for treatment of diseases likeCOPD that involve inflammation and infection.110
Eritoran, a synthetic TLR4 antagonist, has been
New Drug Therapies for COPD 225
shown to block influenza-induced lethality inmice, and may well provide a novel therapeuticapproach for other infections.111 PRRs activate avariety of signal transduction pathways, includingNF-kB and mitogen-activated protein (MAP)kinase pathways, as well as type I interferon path-ways in the case of viruses.112 MyD88 offersanother target for therapy.104,113
Chemokine Receptor Antagonists
CXC and CC chemokine receptors are thought tobe involved in COPD inflammation due to theirrole in neutrophil recruitment. The concentrationsof CXC chemokines, including CXCL5 andCXCL8, are increased during exacerbations and,because they all signal through a common recep-tor, CXCR2, specific antagonists of this receptormay be useful in treating exacerbations. A smallmolecule CXCR1/2 antagonist (AZD8309) showspromise in inhibiting sputum neutrophils, afterinhaled endotoxin, by approximately 80%,114
suggesting that this could be useful in exacerba-tions and has the advantage of oral administration.A proof-of-principle study revealed thatSCH527123, a novel, selective CXCR2 antagonist,causes significant attenuation of ozone-inducedairway neutrophilia in healthy subjects.115 How-ever, experimental inflammation by ozone chal-lenge is chiefly CXCL8-dependent, transient, andfully reversible in contrast to the pathologic inflam-mation occurring in the airways of subjects withCOPD, which depends on multiple mediatorsand is chronic and largely irreversible. This high-lights the difficulty with current models. Interest-ingly, SCH527123 has now undergone phase 2studies in subjects with moderate-to-severeCOPD, during which there were beneficial effectson sputum neutrophil counts and FEV1 (reportedat the ERS in 2010).Several other oral CXCR2 antagonists such as
AZD5069 are currently in phase II trials and includesecondary outcome measures of circulating bloodneutrophil levels.CX3CL1 binds exclusively to CX3C chemokine
receptor 1 (CX3CR1), and is unregulated in thelung tissue of smokers with COPD, making thisan attractive target.38
An inhaled CCR1 antagonist (AZD4818) failed toshow benefit in COPD,116 although a CCR2bantagonist (AZD2423) is currently in trials.
Chemoattractant receptor-homologous moleculeexpressed on Th2 cells (CRTH2) is a G-proteincoupled receptor expressed by Th2 lymphocytes,
eosinophils, and basophils. The receptor mediatesthe activation and chemotaxis of these cell typesin response to prostaglandin D2 (PGD2), the majorprostanoid produced by mast cell degranulationtypically in the initial phase of IgE-mediatedreactions but also thought to occur at sites ofinflammation, such as the bronchial mucosa. Assuch, selective PGD2 receptor antagonists(CRTh2 antagonists) are mainly in developmentfor asthma.117
LTB4 Receptor Antagonists
Serum concentrations of LTB4, a potent neutrophilchemoattractant, are increased in patients withCOPD.118 LTB4 activates BLT1-receptors, whichare expressed on neutrophils and T lymphocytes.Although BLT1-antagonists have a relatively smalleffect on neutrophil chemotaxis in response toCOPD sputum119 and they have not proved to beeffective in treating stable COPD, it is possiblethat they would have greater efficacy if usedacutely, due to observations that LTB4 is espe-cially elevated during COPD exacerbations.7
LTA4H has been proposed as another potentialtherapeutic target because it is the enzymeresponsible for generation of LTB4 from leuko-triene A2. However, another role for LTA4H hasbeen observed, whereby it degrades anotherneutrophil chemoattractant, namely proline-glycine-proline (PGP),120 thus therapeutic strate-gies inhibiting LTA4H to prevent LTB4 generationmay not reduce neutrophil recruitment due tosimultaneous elevation in PGP levels, once againdemonstrating the complexity of manipulating in-flammatory processes in COPD.
Selectin Antagonism
The selectin family is a group of adhesion mole-cules involved in the initial activation and adhesionof leukocytes on the vascular endothelium, whichfacilitates their migration into the surrounding tis-sue. In a phase II trial in 77 COPD subjects,28 days of bimosiamose (an inhaled pan-selectinantagonist) led to a significant decrease in thesputum macrophage count, and decreasedCXCL8 and matrix metalloprotease (MMP)-9,whereas most lung function parameters alsoshowed a small numeric increase with no differ-ence in adverse events.121 Trials with longertreatment durations are now required and an anti-selectin MoAB (EL246) is currently underpredevelopment.122
Phosphodiesterase Inhibitors
Theophylline has some PDE inhibitor activities andit as been used in the treatment of COPD for more
Ross & Hansel226
than 75 years. However, its use is limited by itsnarrow therapeutic range, side-effect profile, anddrug interactions. Newer selective PDE inhibitorsare anticipated to exhibit the beneficial effects oftheophylline with an improved side-effect profile.PDE4 inhibitors have a broad spectrum of antiin-flammatory effects and are effective in animalmodels of COPD. However, in human studies theireffectiveness has been limited by side effects,such as nausea, diarrhea, and headaches.123,124
Development of selective orally active PDE4 in-hibitors has predominantly involved cilomilast(Ariflo), roflumilast, and tetomilast in inflammatorybowel disease.125 Cilomilast has been studied infive phase III studies: involving 2088 subjects oncilomilast and 1408 on placebo for 24 weeks.126
Although an initial study was very encouraging in424 patients with COPD assessed for 6 weeks,127
benefits were not as great in a larger study for6 months,128 and cilomilast failed to convince inother phase III studies. As a result, the entire cilo-milast program was terminated, providing acautionary example of the difficulties in developingnew drugs for COPD.
In contrast, roflumilast has proved more effec-tive in long-term studies,129–132 especially indecreasing exacerbations, and is now the first inthis new class of agents licensed for treatment ofsevere COPD with bronchitis.133,134 Roflumilast isgiven once daily (500 mg), but gastrointestinaladverse effects and weight loss are common onstarting therapy. The Roflumilast in the Preventionof COPD Exacerbations While Taking AppropriateCombination Treatment (REACT) study aims toassess whether or not roflumilast will provide addi-tional benefit when added to dual or triple ther-apy.135 This will also go some way to confirmingthe safety of the drug and it’s future use, althoughit may be that newer inhaled PDE4 inhibitors willprove preferable in terms of reduced side effects.To date, inhaled PDE4 inhibitors have been foundto be ineffective.
Avoidance of targeting certain isoforms shouldhelp limit side effects because mouse studieshave suggested that emesis is the result ofPDE4D inhibition,136 whereas PDE4B is the pre-dominant subtype present in monocytes and neu-trophils and is implicated in the inflammatoryprocess. This insight has led to the design ofPDE4 inhibitor modulators, which have one to twoorders of magnitude less affinity for the PDE4D iso-form, while maintaining other PDE4 inhibitory activ-ities. However, more work is needed to confirmwhether targeting specific subtypes really is morebeneficial. In addition, mixed PDE4/7 inhibitorsare under development that may have synergisticbenefits. TPI 1100, which comprises two antisense
oligonucleotides targeting the mRNA for thePDE4B/4D and PDE7A isoforms, has been shownto reduce neutrophil influx and key cytokines in anestablished smoking mouse model.137 A finalapproach may be use of a PDE4 inhibitor in combi-nation with other antiinflammatory drugs such asglucocorticoids138 based on recent findings thatthese drugs together may impart clinical benefitbeyond that achievable by an ICS or a PDE4alone.71
Kinase Inhibitors
After decades of research on oral kinase inhibitors,a JAK inhibitor has been licensed in 2012 for thetreatment of rheumatoid arthritis.139 There is alsoprogress with orally active Syk inhibitors in autoim-mune disease. p38 (p38 MAP kinase) is activatedby bacteria and viruses, as well as other inflamma-tory signals and, therefore, is another target for in-hibition.140,141 These phosphorylases are involvedin cell-signaling cascades, which often result in theactivation of proinflammatory nuclear transcriptionfactors such as NF-kB. Several p38 MAP kinaseinhibitors are now in clinical development, andthe results of a phase II trial with losmapimod (anoral p38 MAP kinase inhibitor) were publishedlast year. Although losmapimod did not have an ef-fect on sputum neutrophils or lung function, therewas a significant reduction in plasma fibrinogenlevels after 12 weeks, and improvements in lunghyperinflation were noted.142
Other broad-spectrum antiinflammatory drugs indevelopment include inhibitors of NF-kB and PI3K.However, there is much interaction betweensignaling pathways and it may be that a multi-pronged approach is required.125,143 NF-kB inhibi-tion can be attempted through a variety ofapproaches; namely by inhibiting the degradationof the inhibitor of NF-kB family of proteins (IkB),gene transfer of IkB or IkB kinase (IKK) inhibition.Several IKK inhibitors are in development.38 PI3Kinhibitors also have therapeutic potential,144,145
and selective inhibition may restore glucocorticoidsensitivity.146 There are drugs directed againstboth the d- and g-isoforms of PI3K,147,148 as wellas an inhaled dual g/d inhibitor.149 In addition,peroxisome proliferator-activated receptor gamma(PPAR-g) antagonists such as rosiglitazone maytreat airway mucus hypersecretion.150 Finally, newformulations of cyclosporine A (inhaled) are beingdeveloped for asthma and COPD.151
Statins
COPD is associated with a complex list of sys-temic manifestations, including systemic inflam-mation associated with cachexia and skeletal
New Drug Therapies for COPD 227
muscle weakness.152,153 COPD also has an exten-sive association with comorbidities, such as car-diovascular diseases,154 and it is recognized thatnew drugs are required for COPD and thesecomorbidities.155 This subset of patients withpersistent systemic inflammation has been associ-ated with poor clinical outcomes, irrespective oftheir lung impairment.156 It is recognized that skel-etal muscle weakness and wasting may also beamenable to therapy.157,158
This has encouraged the use of statins in COPDbecause they have a range of systemic antiinflam-matory effects.159 Statins increase survival inpatients with peripheral arterial disease andCOPD,160 and may reduce COPD exacerba-tions.161 Furthermore, retrospective studies haveshown that statins reduce the risk of death in pa-tients with COPD.162–164 The benefit on all-causemortality depends on the level of underlyingsystemic inflammation, as assessed using high-sensitivity C-reactive protein (hsCRP) measure-ments.165 Various academic institutions are
currently conducting studies looking at the effectof statins on the frequency of COPD exacerbationsin patients with moderate-to-severe COPD whoare prone to exacerbations, but may not haveother indications for statin treatment. In addition,statins have been associated with a reduced riskof extrapulmonary cancers in patients withCOPD.166
Each inhalation of cigarette smoke contains alarge burden of ROS,167 as well as many differentchemical components that cause lung toxicity(Table 4).168 In addition, oxidants are generatedendogenously from activated inflammatory cells.Manipulation of the oxidant–antioxidant balance,therefore, seems to be a logical therapeutic strat-egy and there is a range of novel targets.169,170 Re-sveratrol is a cardioprotective antioxidant in red
Table 4Miscellaneous additional classes of new drugs
wine, whereas stilbenes are dietary antioxidantsfrom tomatoes, but may not achieve sufficientlevels in established COPD. Interestingly, resvera-trol is also a sirtuin (SIRT) activator and this prop-erty has been proposed to account for antiagingeffects.171 There are theories that COPD repre-sents an accelerated form of lung aging,172,173
and this concept suggests that antiaging mole-cules may have potential in COPD.174 Other die-tary components such as sulforaphanes andchalcones are potential therapeutic antioxidantsin COPD.175
N-acetyl-cysteine (NAC) is a potent reducingagent capable of increasing intracellular gluta-thione levels. In addition, its mucolytic propertiescan improve sputum clearance in COPD. In pre-clinical studies, NAC attenuated elastase-induced emphysema in rats,176 but later clinicalstudies have yielded mixed results. A Cochrane re-view reported the beneficial effects on exacerba-tion frequency of NAC in chronic bronchitis,177
but this was later followed by a large multicentertrial in which NAC had no effect on exacerbationfrequency or FEV1 decline.178 Carbocysteine maybe more promising. The PEACE study revealed asignificant decline in COPD exacerbations using500 mg carbocysteine three times a day daily inChinese patients with COPD.179 Both of theseagents are undergoing further studies in COPD.
Stable glutathione compounds, superoxide dis-mutase (SOD) analogues, and radical scavengersare in development. Enzyme mimetics are beingdeveloped that enhance the activity or expressionof antioxidant enzymes such as SOD and gluta-thione peroxidase, which can neutralize cellularROS. Nitrone spin-traps are potent antioxidants,which inhibit the formation of intracellular ROS byforming stable compounds, whereas thioredoxinis a redox sensor inhibitor. Hydrogen sulfide(H2S) is a potent antioxidant and GYY4137 is anovel H2S-releasing molecule that protectsagainst endotoxic shock in the rat180; however,all these agents are still being assessed in animalmodels.
Mucoactive Drugs
Secretions can accumulate in airway lumens,exacerbating airflow obstruction and increasingsusceptibility to infections in COPD. A variety ofdrugs has been developed to treat airway mucushypersecretion, as well as mucoactive drugs,181
in addition to NAC and carbocysteine mentionedabove. These agents combat targets such asepidermal growth factor receptor, tyrosine kinaseinhibitors, and human calcium-activated chloridechannel (hCACL2). PPAR-g is an exciting target
for drugs to treat airway mucus hypersecretion.150
Surfactant protein B has recently been found to beassociated with COPD exacerbations.182 It isimportant to stress that mucus can be both pro-tective and harmful in different situations inCOPD. In a study using inhaled recombinantDNAse to treat acute exacerbations of COPD,the study was terminated due to a trend towardincreased mortality in the treatment arm.183
Proteases
a1-Antitrypsin deficiency is a genetic disease thatillustrates the importance of proteases in causing asubtype of COPD.134,135 There have been recentadvances in provision of augmentation therapyfor a1-antitrypsin deficiency.184 Neutrophil elas-tase (NE),136 MMP-9,137 and MMP-12185 havebeen implicated in the pathogenesis of COPD,and provide targets for novel therapies.186
A novel oral inhibitor of NE, AZD9668, under-went a 12-week dose-finding study in subjectswith COPD treated with tiotropium, but failed toshow benefit.187,188 An inhibitory effect of heparinhas been shown on neutrophil elastase release,which is independent of the anticoagulant activityof this molecule.189 However, a phase II trial ofO-desulfated heparin in subjects with exacerba-tions of COPD was terminated at the end of lastyear due to a lack of efficacy. Interestingly, heparinis also a known inhibitor of selectin-mediated in-teractions, but a phase II trial in COPD exacerba-tion patients with PGX-100 (2-O, 3-O desulfatedheparin) also failed to demonstrate efficacy andwas terminated early.122
Attempts to readdress theprotease-antiproteaseimbalancewith syntheticMMP inhibitors have beenattempted,190 but the development of musculo-skeletal syndrome with marimastat is a prominentadverse effect.191 AZD1236, a novel more selectiveinhibitor of MMP-9 and MMP-12, has failed todemonstrate convincing clinical efficacy in twostudies over 6 weeks.192,193 The role of other prote-ases in COPD remains unclear, but inhibitors ofcysteine proteases are under development.
Fibrosis and Remodeling
There have been dramatic advances in the under-standing of lung injury and idiopathic pulmonaryfibrosis (IPF).194–196 This has resulted in a flurry ofdrug development, for which excellent reviewsare available.197,198 Inflammation and fibrosis arerelated processes, and COPD and IPF havesome common features.199,200 Airway inflamma-tion, resulting in tissue injury can result in peribron-chial fibrosis when lung injury exceeds the lung’sability to repair. The resulting airways become
New Drug Therapies for COPD 229
narrowed, leading to airway obstruction. However,although these processes, inflammation, andfibrosis, may be closely related, it has also beenpostulated that fibrosis may occur alone inCOPD. For example, in IPF there can be very littleinflammation.201 The process of fibrosis is promi-nent in the small airways as obstructive bronchio-litis, but excessive fibrosis may also contribute toemphysema. It has been recently recognized thatfibroblasts and myofibroblasts may be residentcells, derived from bone marrow stem cells andblood-borne fibrocytes, or may be derived byepithelial to mesenchymal transition (EMT).202,203
Therefore, strategies used to treat IPF (eg, pirfeni-done) may be of benefit in COPD, but moreresearch is needed in this area.194,204
A recent study has demonstrated that cigarettesmoke induces EMT in differentiated bronchialepithelial cells via release and autocrine action oftransforming growth factor-b1 (TGF-b1) as wellas by enhancing oxidative stress, thus suggestingthat EMT could participate in the COPD remodel-ing process of small bronchi such as peribronchio-lar fibrosis.205 Small-molecule inhibitors of TGF-b1receptor tyrosine kinase have been developed:SD-208, however, has been shown to inhibitairway fibrosis in a model of asthma.206
Biologics: MoABs
Tumor necrosis factor a (TNF-a) has been impli-cated in the pathogenesis of COPD and seemsto be a good therapeutic target. Indeed, an obser-vational study in rheumatoid arthritis patientsdemonstrated that etanercept (a TNF-receptorantagonist) led to a reduction of 50% in the rateof hospitalization due to COPD exacerbations.207
Although blocking TNF-a was not effective in sta-ble COPD patients,208–210 it is possible that admin-istration during an acute exacerbation might beeffective in view of the acutely increased TNF-aconcentrations. However, there are major con-cerns that the TNF antibody infliximab increasedthe incidence of respiratory cancers in a COPDstudy (although this was not statistically signifi-cant),208 and increased other types of cancer aswell as infections in a study in severe asthma.211
Future efforts may consider a more tailoredapproach using these agents in a subset of pa-tients defined by an increased TNF-a axis. In addi-tion, cachectic patients were found to have a smallimprovement in exercise capacity in post hocanalysis.208 Inhibition of TNF-a production by inhi-bition of TNF-a converting enzyme is an alternativestrategy.38 A prominent effect of NF-kB and p38MAP kinase inhibitor is the downstream inhibitionof TNF-a synthesis.
An anti-CXCL8 (IL-8) MoAB was tested inCOPD, but no improvement in health status orlung function was seen, possibly because theactive bound form of CXCL8 was not recognizedby the MoAB.38 There is now special interest in as-sessing MoABs directed against IL-6, IL-1b, IL-17,IL-18, IL-1R, TGF-b, and granulocyte-macrophagecolony-stimulating factor for effects in COPD. Ahumanized antibody against IL-6 receptors (tocili-zumab) is effective in several other inflammatorydiseases,212 but there are no studies in COPD.Canakinumab, a MoAB to IL-1b, is already usedin rare autoimmune diseases and is now in trialsin COPD.213 Th17 cells have recently been identi-fied as a separate cell population that produceIL-17, which causes neutrophilia214,215 and induceloss of HDAC2 and steroid insensitivity,216 thusimplicating another potential target, and phase IItrials in psoriasis have been encouraging.217,218
Finally, omalizumab, the anti-IgE MoAB approvedfor severe allergic asthma, has also now entered astudy in a subgroup of COPD patients withelevated IgE levels.
Aging and Autoimmunity
COPD may be considered a disease of acceler-ated aging and geroprotectors are a novel thera-peutic strategy.219 SIRT1 and SIRT6 areattractive targets220,221 because they can possessHDAC2 activity, protect against oxidative stress,and permit stabilization and repair of DNA. Anotherinsight is that autoimmunity may have a role inCOPD222 and the immune systemmay be targetedagainst elastin223 or epithelial cells.224
Lung Regeneration
Approaches to aid lung regeneration aim to cor-rect the defect of emphysema and to replace de-stroyed lung interstitium. Human lungs haveregenerative capacity, as demonstrated in Nepal-ese children given maternal vitamin A supple-ments.225 This is not exclusive to children asdemonstrated in an adult patient after pneumo-nectomy.226 Attempts have been made to exploitthis potential with new drugs to cause lung regen-eration in COPD.227–229
Retinoids are known to promote alveolar septa-tion in the developing lung and to stimulatealveolar repair in some animal models of emphy-sema. However, despite abrogation of elastase-induced emphysema in rats using all-trans retinoicacid,230 subsequent attempts with retinoids andg-retinoic acid receptor agonists in humans havebeen less promising.231,232 The REPAIR studyevaluated the effects of palovarotene (an oralg-selective retinoid agonist) on lung density in
Ross & Hansel230
emphysema secondary to a1-antitrypsin defi-ciency. Although effects on the primary endpointwere not significant, there was a trend toward animprovement in most functional parameters insubjects taking palovarotene for a year. Anothergroup conducted a 2-year trial with this agentand reported their findings at the ATS in 2011.There was no overall improvement in FEV1 inCOPD subjects on the drug; however, subgroupanalysis revealed a significant reduction in therate of decline in FEV1 and TLCO in subjects withlower lobe emphysema.
Mesenchymal stem cells (MSCs) also offerexciting regenerative potential.228,233 MSCsexhibit potent antiinflammatory and immunomod-ulatory activities both in vitro and in vivo. Thisfinding has led to a trial assessing the safety andefficacy of an IV preparation of allogenic MSCs(Prochymal).234 The therapy was well toleratedand, although there were no significant differencesin lung function tests or quality of life indicators, anearly significant decrease in levels of circulatingC-reactive protein was observed in some subjects.Another approach taken with MSCs was to popu-late a biologic connective tissue scaffold (whichhas been stripped of HLA-antigen expressingcells), which can then be used to grow autologoustissue before surgical implantation.235
SUMMARY
For the future treatment of COPD, it should bepossible to have improved current drugs, antiin-fective and antioxidant therapy, coupled withnovel approaches directed against the innate im-mune system. In terms of the processes involvedin COPD, there is rapid advancement of knowl-edge of viral responses and fibrosis, steroid-insensitive inflammation, autoimmunity, aberrantrepair, accelerated aging, and appreciation ofsystemic disease and comorbidities. There is theneed to develop validated noninvasive biomarkersfor COPD and to have novel challenge models inanimals and humans.71 More interest has recentlyfocused on cigarette-challenge models in anattempt to understand the exact immunologic re-sponses to an acute smoke exposure event, to un-derstand better the chronic changes that resultfrom smoking.68 In terms of clinical trial designs,these are adapted for bronchodilation, the naturalhistory, and the prevention and treatment of COPDexacerbations and comorbidities. As is the casewith many diseases, combinations of therapiesmay be the key to effective COPD treatment andprevention, and they may need to be given earlyin the disease. To develop novel drugs forCOPD, it is clear that long-term studies in specific
phenotypic groups, giving targeted therapy basedon companion biomarkers, are needed. This wouldideally use inhaled agents delivered directly to theintended site of action, with minimal unwantedside effects.35 Overall, there is need for extensivecollaboration between scientists, clinicians, thepharmaceutical industry, and drug regulators toidentify and provide better therapy for patientswith COPD.
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