1. Introduction

2. Phosphodiesterase-4 inhibitors

3. Roflumilast

4. Anti-inflammatory effects of

roflumilast in patients with

COPD

5. Long-term trials exploring the

effectiveness and safety of

roflumilast in COPD

6. Recent Phase III efficacy studies

7. Expert opinion

Drug Evaluation

Roflumilast in chronic obstructivepulmonary disease: evidence fromlarge trialsMario Cazzola†, Stefano Picciolo & Maria G Matera†Unita di Farmacologia Clinica Respiratoria, Dipartimento di Medicina Interna,

Universita di Roma ‘Tor Vergata’ , Via Montpellier 1, 00133 Rome, Italy

Importance of the field: Chronic inflammation plays a central role in chronic

obstructive pulmonary disease (COPD). Suppression of the inflammatory

response is a logical approach to the treatment of COPD. Corticosteroids

are highly effective as an anti-inflammatory treatment, but patients with

COPD are poorly responsive to these drugs. The phosphodiesterase (PDE)-4

isoenzyme is a major therapeutic target in COPD because its inhibition

increases intracellular cAMP concentrations, which ultimately results in reduc-

tion of cellular inflammatory activity. At present roflumilast is the most

advanced PDE-4 inhibitor undergoing clinical trials for COPD.

Areas covered in this review: In this paper, we describe the importance of

roflumilast as an anti-inflammatory drug and critically review the results of

four large trials with roflumilast in COPD (NCT00297102, NCT00297115,

NCT00313209, NCT00424268).

What the readerwill gain:An unbiased description of trials that have explored

the therapeutic effects of roflumilast in COPD.

Take homemessage: At the moment, roflumilast should only be considered as

a second-line treatment, and the exact indication remains to be determined.

Apparently, it should be reserved for patients who have frequent exacerba-

tions despite treatment with inhaled bronchodilators. However, considering

the high risk of adverse events induced by this drug, the published evidence

seems to indicate limiting its use to the treatment of patients suffering from

very severe COPD.

Keywords: adverse events, COPD, exacerbations, phosphodiesterase-4 inhibitors, roglumilast

Expert Opin. Pharmacother. (2010) 11(3):441-449

1. Introduction

Chronic inflammation plays a central role in chronic obstructive pulmonary disease(COPD). It is characterized by an increase in neutrophils, macrophages and CD8+

T lymphocytes in small and large airways as well as in lung parenchyma andpulmonary vasculature [1]. Other inflammatory cells are routinely observed in thetissues of diseased lung. For example, alveolar macrophages participate in orches-trating the inflammatory progression through the release of proteases such as matrixmetalloproteinase (MMP)-9, inflammatory cytokines such as tumour necrosis factor(TNF)-a and chemokines such as interleukin (IL)-8 that attract neutrophils into theairways. Consequently, suppression of the inflammatory response is a logicalapproach to the treatment of COPD and might improve symptoms and healthstatus, reduce exacerbations and, in the long-term, it should also slow downdisease progression.

Corticosteroids are highly effective as an anti-inflammatory treatment in a widerange of chronic inflammatory diseases. In patients with COPD and a forcedexpiratory volume in the first second of expiration (FEV1) < 50% predicted, inhaled

10.1517/14656560903555201 © 2010 Informa UK Ltd ISSN 1465-6566 441All rights reserved: reproduction in whole or in part not permitted

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corticosteroid (ICS) therapy reduces the frequency of COPDexacerbation [2] and, moreover, in advanced COPD patients,combinations of ICSs and long-acting b2-agonists (LABAs)show an additive effect, suggesting an interaction between thetwo moieties that can have a positive effect [3]. Therefore,current guidelines recommend ICS therapy in addition tobronchodilators for patients with symptomatic COPD, FEV1

< 50% predicted, and repeated exacerbations [4,5].Nonetheless, patients with COPD are poorly responsive to

corticosteroids. This probably happens because cigarettesmoking and oxidative stress impair histone deacetylase 2function [6]. Moreover, their long-term use when administeredby inhalation is associated with a small but significant increasein the risk of pneumonia, which is of clinical concern [2,7], witha risk that may be greatest in patients with the lowest baselineFEV1 and in those receiving the highest ICS dose, shortestduration of ICS therapy and combination therapy [2],although budesonide has not been shown to cause acomparable increase in pneumonia [8].It is clear that there is an unmet need in the current

pharmacotherapy of COPD [9] and, in effect, the AmericanThoracic Society/European Respiratory Society guidelines [4]

identify a pressing need to develop agents that suppress theinflammation associated with COPD and prevent diseaseprogression. Until now, no therapeutic agent has been shownto reduce the number of macrophages, neutrophils and CD8+

lymphocytes in COPD, but further insight into the patho-genesis of the chronic airway inflammation that underliesCOPD has established new therapeutic targets, most of whichare based on components of inflammatory pathways [9].

2. Phosphodiesterase-4 inhibitors

The phosphodiesterase (PDE)-4 isoenzyme was identified as amajor therapeutic target in respiratory diseases because it is thepredominant isoenzyme involved in the metabolism of 3¢, 5¢-cyclic adenosine monophosphate (cAMP) in the majority ofinflammatory cells, including macrophages, neutrophils and

CD8+ lymphocytes [10]. Inhibition of PDE-4 blocks thehydrolysis of cAMP, leading to elevated intracellular cAMPlevels and, thus, suppression of the proinflammatory activityof these cells.

In recent years, there has been a real interest in developingPDE-4 inhibitors because of a wealth of compelling preclinicaldata indicating that inhibition of PDE-4 should alleviatechronic inflammation [11]. The clinical development of first-generation PDE-4-selective inhibitors, such as rolipram, washampered by the dose-limiting side effects of nausea andvomiting [12], and, therefore, various strategies were under-taken to try and improve the side-effect profiles of these drugs.New second-generation PDE-4 inhibitors have been devel-oped with the hope of a wider therapeutic ratio, particularlywith respect to overcoming nausea and vomiting [13]. Atpresent, two PDE-4 inhibitors, cilomilast and roflumilast,have reached Phase III clinical trial stage. The results ofPhase I and Phase II studies demonstrated that cilomilastsignificantly improves lung function and quality of life to aclinically meaningful extent, and suggested a comprehensivePhase III program of research evaluating its efficacy, safety andmechanism of action. However, the results of Phase III studieswere unremarkable and disappointing, which led to theinevitable termination of the development of cilomilast [14].

3. Roflumilast

Roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide; Box 1), which is derivedfrom a series of benzamides, is a selective PDE-4 inhibitordeveloped by Nycomed (Zurich, Switzerland) with a rangeof anti-inflammatory properties and potential for treatmentof COPD.

In terms of selective PDE-4 inhibition of human neutrophilfunction, roflumilast was found to be roughly equipotent to itsmajor metabolite, roflumilast N-oxide, which largely deter-mines the pharmacodynamic activity of roflumilast in rats andin humans; but it showed potency more than 100 timesgreater than cilomilast or rolipram [15]. Intriguingly, thepotency of roflumilast and cilomilast in suppressing neutro-phil elastase release from human neutrophils was significantlyreduced in the presence of TNF-a, and there was a trend ofreduced potency with roflumilast N-oxide and rolipram,though this was not significant [16]. Whatever the casemay be, orally administered roflumilast and its N-oxideinhibited lipopolysaccharide-induced release of TNF-a, awell-characterized cAMP-sensitive pathway in cells of themonocytic/macrophage lineage, in the rat; they were 25 timesmore potent than rolipram and 310 times more potent thancilomilast [17]. Orally administered roflumilast was also ablepartially to ameliorate acute and chronic lung inflammationand to prevent fully parenchymal destruction induced bycigarette smoke in mice [18].

In addition to its established inhibitory effects on the airwayinflammatory cells, roflumilast may exert direct effects on

Box 1. Drug summary.

Drug name Roflumilast

Phase Pre-registration

Indication Chronic obstructive pulmonary disease

Pharmacologydescription

Phosphodiesterase IV inhibitor

Route ofadministration

Alimentary, p.o.

Pivotal trial(s) NCT00297102NCT00297115NCT00313209NCT00424268

Pharmaprojects - Copyright to Citeline Drug Intelligence (an Informa

business). Readers are referred to Informa-Pipeline (http://informa-

pipeline.citeline.com) and Citeline (http://informa.citeline.com).

Roflumilast in COPD

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human airway epithelial cells inhibiting the MUC5AC expres-sion that follows the activation of the epidermal growth factorreceptor (EGFR) signaling cascade [19]. Also in this case, it ismore potent than rolipram and cilomilast. In fact, the potencyorder of their activities (expressed as -log IC50 values) wasroflumilast (~ 7.5) > rolipram (~ 6.5) > cilomilast (~ 5.5).

This intriguing preclinical pharmacological profile has ledinterest in developing roflumilast in the treatment of COPD.

4. Anti-inflammatory effects of roflumilast inpatients with COPD

Roflumilast is at present the most advanced PDE-4 inhibitorundergoing clinical trials for COPD. Preliminary clinical dataindicated that it could improve lung function in patients withCOPD while being well tolerated [20]. Moreover, roflumilast500 µg once-daily treatment was associated with an approx-imately 40% reduction in sputum leukocyte number versusplacebo in a 12-week, placebo-controlled crossover study thatincluded 4 weeks in each treatment arm separated by a 4-weekplacebo washout period [21]. The majority of this differencewas accounted for by changes in neutrophil number. Inflam-matory mediator levels were also significantly decreased byroflumilast. With placebo treatment, IL-8 increased by ~ 10%above baseline. However, with roflumilast it decreased by~ 20% (p = 0.044). A similar pattern was observed for cell-freeneutrophil elastase (roflumilast versus placebo; p = 0.028).The differences in effects on inflammatory markers observedwith roflumilast versus placebo were paralleled by changes inpostbronchodilator FEV1. There was a 40-ml increase duringtreatment with roflumilast versus a ~ 20 ml decline during theplacebo treatment period (p = 0.018).

5. Long-term trials exploring the effectivenessand safety of roflumilast in COPD

In an initial placebo-controlled Phase III trial [22] consisting of1411 patients with moderate to severe COPD (GOLD(Global Initiative for Chronic Obstructive Lung Disease)stages II and III) [23]), 24-week treatment with 500 µg oncedaily of roflumilast produced a significant improvement inpostbronchodilator FEV1 (the improvement in FEV1 frombaseline compared with placebo was 97 ml ± 18), whereasexacerbations were reduced by 34% over placebo(p = 0.0029). In the same group of patients, roflumilastwas found to be safe and well tolerated, although diarrheaand nausea, two class-associated side effects, were still appar-ent. These data indicated that roflumilast can improve clinicalsymptoms in patients with COPD but it is unable to elicitdirect bronchodilator activity. The ability of roflumilast toreduce the number of exacerbations was considered veryinteresting but, unfortunately, the signal was generated by astudy that was too short to explore this effect and, in anycase, the primary outcome variables were the changes inpostbronchodilator FEV1 and St George’s respiratory

questionnaire (SGRQ) total score and not the numberof exacerbations.

A second placebo-controlled Phase III trial [24] explored in1513 patients whether improvement in lung function andreduction in exacerbations could persist over 1 year of treat-ment in patients with more severe disease (GOLD stages IIIand IV [23]) than had been studied previously [22]. Data of thissecond trial confirmed and extended the results of the first trialby demonstrating that roflumilast treatment provided a mod-est improvement in lung function (an increase in postbroncho-dilator FEV1 from baseline versus placebo of 39 ml ± 12;p < 0.002) in more advanced COPD over 1 year. However, nochange in the overall exacerbation frequency was observedwith roflumilast (the difference of overall moderate or severeexacerbations versus placebo was -6.6%; p = 0.451), althoughexacerbations were less common in GOLD stage IV patientsin whom the difference of overall moderate or severe exacer-bations versus placebo was -36.1% (p = 0.024). The mostcommon adverse events effects reported with roflumilastincluded diarrhoea (9.3%), headache (6.2%) and nausea(5.0%). The adverse events disappeared with continued usebut they were a major reason why patients discontinued withthe study during the first 3 – 4 weeks of treatment.

All these findings, which were not really exciting, suggested,in any case, that roflumilast might have a role in the treatmentof COPD. However, they did not tell us whether treatmentbenefits with roflumilast could be integrated into currenttherapeutic regimens and, in particular, whether combiningroflumilast with long-acting bronchodilators might providean acceptable alternative to combined inhaled therapy withlong-acting bronchodilators and ICSs in patients with moresevere COPD.

6. Recent Phase III efficacy studies

To give an answer to these important questions, four addi-tional larger trials were designed and recently their results havebeen published [25,26].

6.1 Trials NCT00297102 (M2–124) andNCT00297115 (M2–125)Calverley and colleagues [25] reported the results oftwo placebo-controlled, double-blind, multicenter trials(NCT00297102 or M2–124 and NCT00297115 or M2–125) with identical design, which tested the hypothesis thatroflumilast is able to reduce the rate of exacerbations requiringsystemic corticosteroids in specific subsets of patients withCOPD. Patients with severe to very severe COPD wereenrolled in two different populations in an outpatient setting.They were older than 40 years, with severe airflow limitation,bronchitic symptoms, and a history of exacerbations. Patientswere randomly assigned to oral roflumilast (500 µg onceper day; n = 1537) or placebo (n = 1554) for 52 weeks.They could use short-acting b2 agonists as needed andcould continue treatment with LABAs or short-acting

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anticholinergic drugs at stable doses. However, ICSs and long-acting anticholinergic drugs were not allowed during thestudy. The primary end points were the change in prebroncho-dilator FEV1 during treatment and the rate of COPDexacerbations, defined as moderate if they required oral orparenteral corticosteroids, or severe if they were associatedwith hospital admission or death. Key secondary outcomesincluded the postbronchodilator FEV1 (change from baselineduring treatment), time to death from any cause, natural log-transformed C-reactive protein concentration (change frombaseline to study end), Transitional Dyspnoea Index (TDI)focal score (during treatment) and changes in Euroquol5-dimension (EQ-5D) questionnaire, a measure of healthutility. Additionally, data for the total number of COPDexacerbations (as defined above together with episodes treatedwith antibiotics alone) and a range of spirometry outcomeswere gathered. After randomization, patients were assessedevery 4 weeks up to week 12 and every 8 weeks thereafter. Ateach visit, spirometric measurements were recorded before and15 – 45 min after administration of bronchodilator (inhaledsalbutamol 400 µg). The study was powered on the basis of anassumption of a mean exacerbation rate of 1.25 per patient peryear in the placebo group and 1.00 in the roflumilast group.The pooled analysis of prebronchodilator FEV1 values

generated in the two trials showed that roflumilast wasmore effective than placebo, with a difference (48 ml) thatwas statistically significant (p < 0.0001). The concomitant useof a LABA did not influence the changes in prebronchodilatorFEV1 (mean prebronchodilator FEV1 increase with LABA,46 ml, p < 0.0001; and without LABA: 50 ml, p < 0.0001).The annual rate of moderate or severe exacerbations perpatient was 1.14 in the roflumilast group and 1.37 in theplacebo group, which was a significantly (< 0.0003) reductionof 17% (95% CI 8 – 25) versus placebo. The concomitantadministration of a LABA did not influence the rate ofexacerbations (p = 0.5382). Roflumilast was associated witha reduction in the mean number of exacerbations (excludingsevere events) treated with systemic corticosteroids or anti-biotics, or both (reduction of 16%) in the pooled analysis.Roflumilast was also associated with a significant delay in thetime to the first and second episode of moderate orsevere exacerbation.Hazard ratio for time to death from any cause was > 1 in

both studies. The change in C-reactive protein from baselineto last post-randomization visit was not significant (in thepooled analysis of the two trials, the difference versus placebowas 1.0 mg/liter (0.9 – 1.1; p = 0.8670), but it must bementioned that its baseline concentrations varied widely. TDIfocal score changed significantly from baseline with roflumi-last compared with placebo (in the pooled analysis of the twotrials, the difference versus placebo was 0.3 units [0.1 to 0.4];p = 0.0009), but the change was not clinically significantbecause only a change of 1 unit is associated with a change in aseverity level as assessed by physicians. The two trials did notdocument any significant difference in total EQ-5D scores

(roflumilast versus placebo: p = 0.5331 in the M2–124 trialand p = 0.6712 in the M2–125 trial, respectively).

Sixty-seven per cent of patients in the roflumilast group and62% of patients in the placebo group experienced at least oneadverse event. Diarrhea (the difference versus placebo was4.75% in the M2–124 trial and 5.70% in the M2–125 trial)and weight loss (the difference versus placebo was 8.78% inthe M2–124 trial and 5.82% in the M2–125 trial) were themost common side effects reported with roflumilast. A greaterweight loss was reported by those patients in the roflumilastgroup who also suffered from diarrhea, nausea, vomiting orheadache: 2.60 kg (3.72) vs 2.02 kg (4.01). Inexplicably, themagnitude of weight loss was greater in the first 6 months oftreatment and it declined thereafter.

6.2 Trials NCT00313209 (M2–127) andNCT00424268 (M2–128)In their paper, Fabbri and colleagues [27] described the resultsof other two double-blind, multicentre trials done in anoutpatient setting, the NCT00313209 (M2–127) study inwhich after a 4-week run-in, patients older than 40 years withmoderate-to-severe COPD were randomly assigned to oralroflumilast 500 µg (n = 466) or placebo (n = 467) once a dayfor 24 weeks, in addition to salmeterol, and theNCT00424268 (M2–128) study in which after a 4-weekrun-in, patients still older than 40 years and suffering frommoderate to severe COPD were randomly assigned to oralroflumilast 500 µg (n = 371) or placebo (n = 372) once a dayfor 24 weeks, in addition to tiotropium. By contrast with thesalmeterol plus roflumilast trial, patients recruited to thetiotropium plus roflumilast trial were more symptomaticbecause they had to have chronic cough and sputum produc-tion, and frequent use of as-needed short-acting b2 agonists (atleast 28 puffs/week) during the run-in period while they werebeing treated with tiotropium for at least 3 months beforeenrolment. In both trials, change in prebronchodilator FEV1

was the primary end point. Secondary end points in both trialsincluded postbronchodilator FEV1 and forced vital capacity(FVC), TDI score, Shortness of Breath Questionnaire(SOBQ), rate of COPD exacerbations, and use of rescuemedications. Patients attended the clinics at randomizationand after 4, 8, 12, 18 and 24 weeks of treatment. Spirometricmeasurements were carried out before and 30 min afteradministration of inhaled salbutamol 400 µg at visits. Thestudy was powered on the basis of an assumption of adifference of 50 ml in FEV1 between roflumilast and placeboas treatment effect.

Mean prebronchodilator FEV1 increased by 49 ml (p< 0.0001) in patients treated with roflumilast plus salmeterol,and 80 ml (p < 0.0001) in those treated with roflumilast plustiotropium versus placebo, whereas postbronchodilator FEV1

increased by 60 ml (p < 0.0001) in patients treated withroflumilast plus salmeterol, and 81 ml (p < 0.0001) in thosetreated with roflumilast plus tiotropium versus placebo. Also,FVC improved significantly in both trials, with an increase in

Roflumilast in COPD

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prebronchodilator values of 47 ml (p < 0.0128) in patientstreated with roflumilast plus salmeterol, and 97 ml(p < 0.0001) in those treated with roflumilast plus tiotropiumversus placebo, and an improvement in postbronchodilatorvalues of 58 ml (p = 0.0028) in patients treated withroflumilast plus salmeterol, and 101 ml (p < 0.0001) in thosetreated with roflumilast plus tiotropium versus placebo. Base-line characteristics of patients, such as sex, current smokingstatus, COPD severity and use of rescue medications, did notinfluence the improvement in prebronchodilator FEV1.

The tiotropium plus roflumilast combination seemed to bemore effective than the salmeterol plus roflumilast combina-tion in improving some patient-centered end points, such asTDI, SOBQ and use of rescue medication.

The proportion of patients reporting adverse events washigher in both of the groups that received roflumilast com-pared with the placebo groups (63% of patients assigned tosalmeterol plus roflumilast and 46% patients in the tiotro-pium plus roflumilast group versus 59% of patients assignedto salmeterol plus placebo and 41% of patients in thetiotropium plus placebo group, respectively, suffered fromat least one adverse event). As expected, the most commonlyreported serious events associated with roflumilast affected thegastrointestinal and respiratory tracts. Again, diarrhea (thedifference vs placebo was 4.73% in the M2–127 trial and8.28% in the M2–128 trial) and weight loss (the difference vsplacebo was 7.51% in the M2–127 trial and 5.07% in theM2–128 trial) were the most common side effects reportedwith roflumilast.

7. Expert opinion

The treatment of the inflammatory component of COPDremains an unmet meet and, therefore, any new drug able tointerfere with this component is really welcome. The onlylimits set for the development of a new anti-inflammatorycompound to be used in COPD are real effectiveness andsafety profile. Extensive Phase III clinical trials allow us toassess the true efficacy and safety of each new drug. This isespecially true if the trial design includes the correct end pointsand meets not only the regulatory requirements but also thescientific ones.

The development of roflumilast in COPD is the cleardocumentation of the changes in regulatory and scientificrequirements that have taken in recent years. The first largetrial of roflumilast in COPD was that published by Rabe andcolleagues [22]. In that trial, the changes in postbronchodilatorFEV1 and SGRQ total score were the primary end points andthe duration of the trial was 6 months according to what wasrequested by CPMP-Guideline CPMP/EWP562/98: ‘Pointsto consider on clinical investigation of medicinal products in thechronic treatment of patients with chronic obstructive pulmonarydisease (COPD)’ [28]. FEV1 is a lung function parameter that isroutinely used to evaluate the efficacy of new drugs for COPDregardless of whether they are bronchodilators. Therefore, the

choice of using FEV1 as a primary end point was notsurprising, although there was documentation that roflumilasthas no direct bronchodilating properties, at least in animalmodels [17]. In any case, the authors honestly acknowledgedthat their study was not designed specifically to assess the anti-inflammatory activity of roflumilast. Nevertheless, theyreported that roflumilast reduced the overall mean numberof exacerbations and suggested that the ability of roflumilastto target the underlying pulmonary inflammation mighttranslate into a reduction of COPD exacerbations.

Taking into account that an evaluation of exacerbationfrequency requires a period of ‡ 1 year because of seasonalvariation, and, in any case, the timing of the study treatmentis important (e.g., capturing winter cold season in themajority of patients) [29], Calverley and colleagues [24] cor-rectly explored whether reduction in exacerbations wouldpersist over 1 year of treatment with roflumilast. Althoughthey enrolled patients suffering from severe to very severeCOPD and it is well known that exacerbation frequencyincreases with progressive airflow obstruction [30], PDE-4inhibition with roflumilast was unable to change the exacer-bation rate. However, it must be mentioned that inhaledcorticosteroids of 2000 µg or less beclomethasone dipro-pionate or equivalent were allowed at a constant daily dose ifthey were used before study entry and, consequently, wecannot exclude that these medications may have influencedthe likelihood of exacerbations [31], regardless of treatmentwith roflumilast.

Nonetheless, since the study of Calverley and colleagues [24]also documented that roflumilast treatment reduced thefrequency of exacerbations requiring systemic corticosteroids,as well as that of exacerbation rates in a subset of veryseverely impaired patients in whom exacerbations occurmore frequently, another trial specifically designed to inves-tigate whether roflumilast would reduce the frequency ofexacerbations requiring corticosteroids in patients withCOPD was mandatory. The trials NCT00297102 andNCT00297115 have tried to give an answer to this question.

These two trials [25] have been well designed. All patientshad postbronchodilator FEV1 £ 50% than the predicted valueand at least one recorded COPD exacerbation requiringsystemic corticosteroids or treatment in hospital, or both,in the previous year. The treatment duration of 1 year wascertainly appropriate. Moreover, drugs that could influenceexacerbations, such as inhaled corticosteroids and long-actinganticholinergic agents, were not allowed during the study,although it must be highlighted that patients were allowed tocontinue treatment with long-acting b2 agonists, and a recentmeta-analysis has documented that single treatment with long-acting b2 agonists is able to prevent exacerbations [32]. None-theless, the results of these two trials have shown that thedifference in the frequency of exacerbations between treat-ments was independent of concomitant long-acting b2 agonistuse [25]. This finding indicates that roflumilast is capable ofreducing exacerbation rate.

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Since roflumilast is an anti-inflammatory drug, it is rea-sonable to wonder whether it is as active as an inhaledcorticosteroid in COPD. In the first paper published byCalverley and colleagues [24], the mean rate of moderate orsevere exacerbations per patient per year was 0.86 in theroflumilast group and 0.92 in the placebo group in patientswith a mean baseline postbronchodilator FEV1 of 41%, with a6.6% reduction versus placebo, but in GOLD IV patients themean rate of moderate or severe exacerbations per patient peryear was 1.01 in the roflumilast group and 1.59 in the placebogroup with a 36.1% reduction versus placebo. In the secondpaper published by Calverley and colleagues [25], the mean rateof moderate or severe exacerbations per patient per year was1.14 in the roflumilast group and 1.37 in the placebo group,in patients with a mean baseline postbronchodilator FEV1 of36.1 and 36.4% of the predicted value, respectively, with a17% reduction versus placebo. Three large studies that lasted1 year have examined the effects of a combination of long-acting b2 agonist and inhaled corticosteroid on the risk ofdeveloping exacerbation in COPD. The first of these studiesexplored the effect of salmeterol/fluticasone combination. Themean rate of exacerbation/patient/year was 0.97 with combi-nation, 1.05 with fluticasone alone, and 1.30 with placebo [33].The rate of exacerbations fell by 25% in the combinationgroup and by 19% in the fluticasone group, respectively,compared with placebo in patients with a pretreatmentFEV1 of 44.8, 45.0 and 44.2% of the predicted value,respectively. The formoterol/budesonide combination wasinvestigated in a more severe population. In the study ofSzafranski and colleagues [34], patients with a pretreatmentFEV1 of 36, 27 and 36% of the predicted value were treatedwith combination, budesonide alone and placebo, respec-tively. Mean exacerbation rates were 1.42, 1.59 and 1.87exacerbations/patient/year in the budesonide/formoterol,budesonide, and placebo treatment groups, respectively,with a reduction of 24% and a 15% reduction versus placebo.However, in patients with a pretreatment FEV1 of 36% of thepredicted value, whose treatment was initially intensified withthe oral steroid prednisolone (30 mg once daily) and inhaledformoterol Turbuhaler (4.5 µg twice daily) for 2 weeks, in anattempt to optimize their health status, Calverley and collea-gues [35] reported 1.38, 1.60 and 1.80 exacerbations/patient/year in the budesonide/formoterol, budesonide, and placebotreatment groups, respectively. Formoterol/budesonide ther-apy reduced the risk of exacerbation by 23.6%, and budeso-nide by 11.1% versus placebo. Although indirect comparisonis not the correct method for understanding differencesbetween drugs, and despite some difference in the studiedpopulations, apparently roflumilast seems to be as effectiveas an inhaled corticosteroid in preventing exacerbations inCOPD patients, and even more active in very severe COPD.However, it is noteworthy that the combination of a long-acting b2 agonist and an inhaled corticosteroid amplifies theprotection induced by the inhaled corticosteroid alone [3],whereas, apparently, the combination of a long-acting b2

agonist with roflumilast does not modify the effect inducedby roflumilast alone [25].

Considering that inhaled corticosteroids are recommendedin combination with long-acting bronchodilators for patientswith severe to very severe COPD who have recurrent exacer-bations [4,5], the obvious next step was to determine whetherroflumilast provides benefit to patients who are regularlytreated with long-acting inhaled bronchodilators. Also thetrials NCT00313209 and NCT00424268 were well designedand the treatment duration of 24 weeks was appropriate [27].

The addition of roflumilast to salmeterol in the trial M2–127 improved mean prebronchodilator FEV1 by 49 ml [27].This is less than what reported when fluticasone was added tosalmeterol (73 ml) [33]. A comparison with the budesonide/formoterol combination is questionable because of substantialdifferences between salmeterol and formoterol, but it must bementioned that trials NCT00297102 and NCT00297115documented that the addition of a long-acting b2 agonistdid not change the mean prebronchodilator FEV1 increaseobserved with roflumilast in monotherapy [25].

The addition of roflumilast to tiotropium in the trial M2–128 induced a larger improvement in prebronchodilator FEV1

(80 ml) [27], and this was not an unexpected finding consid-ering the mechanism of actions of the two drugs. Unfortu-nately, no clinical trial has explored the effect of the additionof an inhaled corticosteroid to tiotropium. Nonetheless,Hodder and colleagues [36], who retrospectively analyzedthe relative efficacy of tiotropium and salmeterol as a functionof the concomitant use of inhaled corticosteroids in patientswith moderately advanced COPD using the pooled results oftwo 6-month studies of tiotropium 18 µg q.d. compared withsalmeterol 50 µg b.i.d., reported that after 169 days oftreatment, the mean improvement above placebo in troughFEV1 was 110 ml for tiotropium and 80 ml for salmeterol.

It is clear that roflumilast is not a bronchodilator, althoughit is also possible, as suggested by Celli [37], that it may reachthe distal airways because of its systemic distribution, wherebydecreasing inflammation around the small airways it couldhave more important changes in resting lung volumes than inabsolute FEV1. Unfortunately, this hypothesis cannot beconfirmed because lung volumes were not tested in theexamined trials. In any case, improvements in lung functioninduced by roflumilast are similar to those observed withinhaled corticosteroids. The improvement in prebronchodi-lator FEV1 from baseline with roflumilast versus placebo was36 ml in the first study of Calverley and colleagues [24], and40 ml in their second study [25]. In the TRISTAN study [33],the improvement in prebronchodilator FEV1 from baselinewas 38 ml with fluticasone versus placebo. According to an oldmeta-analysis of the original data sets of several randomizedcontrolled trials the estimated 2-year difference in prebroncho-dilator FEV1 was 34 ml/year in the inhaled corticosteroidgroup versus placebo [38]. Most randomized, more recent,trials did demonstrate a small, sustained improvement inthe FEV1 from inhaled corticosteroid alone. Average

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improvements were usually in the range of 50 – 75 ml.Bronchodilation was apparent shortly after initiating inhaledcorticosteroid treatment, and it persisted for the duration oftherapy, albeit declining at the same rate as placebo in theseindividual studies [39].

We must now establish whether roflumilast has a role in thetreatment of COPD and, if so, what this role is. It is ouropinion that, at the moment, roflumilast should only beconsidered as a second-line treatment, and the exact indicationremains to be determined. Apparently, it should be reservedfor patients who have frequent exacerbations despitetreatment with inhaled bronchodilators. However, consider-ing the high risk of adverse events induced by this drug, webelieve that the published evidence indicates limiting its use tothe treatment of patients suffering from very severe COPD.Obviously, this is only an initial and, therefore, partialopinion. A solid opinion may be made only when roflumilastis compared, alone or in combination, with other therapies suchas long-acting anticholinergic drugs (e.g., tiotropium), combi-nation inhalers (e.g., fluticasone/salmeterol or budesonide/formoterol), or theophylline, which are treatmentsrecommended in current guidelines [4,5].

In any case, it must be mentioned that Spina has correctlyhighlighted that targeting PDE-4 alone may not fully resolveairway inflammation, in that other PDE types exist in struc-tural and inflammatory cells in the lung and, therefore,targeting multiple PDE enzymes may be required for optimalanti-inflammatory action [40]. For example, the macrophage isviewed as a critical cell type in the pathogenesis of COPD [41];however, the activity of this cell is only inhibited to a smalldegree by PDE-4 inhibitors [15] and the potential functionalinvolvement of PDE-7 cannot be completely ignored. Ineffect, the expression of PDE-7 in inflammatory cells hasbeen acknowledged and, while inhibition of this enzyme alonedoes not suppress inflammatory cell function, however,

combined use of PDE-4 with PDE-7 inhibitors provides agreater inhibition than PDE-4 alone. Actually, the inhibitoryaction of PDE-4 inhibitors on the cellular activity ofCD8+ T lymphocytes and macrophages is significantlyincreased in the presence of PDE-7 selective inhibitors [47].Similarly, combined PDE-3 and PDE-4 inhibitor in a singlemolecule offers the advantage of delivering a bronchodilatorand anti-inflammatory substance. There is documentationthat PDE-4 is also present alongside the PDE-3 isoenzymein airway smooth muscle; the PDE-3 isoenzyme is consideredto predominate in airway smooth muscle, and inhibition ofthis enzyme, rather than PDE-4, leads to airway smoothmuscle relaxation [13]. This clearly indicates that the inhibitionof PDE-4 isoenzyme can only elicit a really weak broncho-dilation and there is documentation that substances thatprevent the degradation of cAMP by inhibiting the activityof PDE-4 are virtually inactive as bronchodilators whenadministered prophylactically, but act synergistically withsubstances that inhibit PDE-3 to prevent LTD4 orhistamine-induced bronchospasm [43]. In any case, it islikely that retention of the inhibitor within the lung maybe required to maintain anti-inflammatory activity within theairways [44].

All these findings indicate that we must not lose interestin PDE inhibitors. However, we believe that only thedevelopment of drugs capable of interfering with multiplePDE isoenzymes administered by inhalation, instead ofjust blocking PDE-4 isoenzyme with drugs administered byoral route, will represent a real progress in the treatmentof COPD.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

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AffiliationMario Cazzola†1, Stefano Picciolo2 &

Maria G Matera3

†Author for correspondence1Unita di Farmacologia Clinica Respiratoria,

Dipartimento di Medicina Interna,

Universita di Roma “Tor Vergata”,

Via Montpellier 1,

00133 Rome, Italy

Tel: +39 348 6412311; Fax: +39 06 7259 6621;

E-mail: mario.cazzola@uniroma2.it2Sezione di Malattie Respiratorie e

Fisiopatologia Respiratoria,

Dipartimento Clinico Sperimentale di

Medicina e Farmacologia,

Universita di Messina,

Messina, Italy3Unita di Farmacologia,

Dipartimento di Medicina Sperimentale,

Seconda Universita di Napoli,

Naples, Italy

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