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Drug Evaluation

Roflumilast in chronic obstructive pulmonary disease: evidence from large trials 1.

Introduction

Mario Cazzola†, Stefano Picciolo & Maria G Matera

2.

Phosphodiesterase-4 inhibitors

3.

Roflumilast

4.

Anti-inflammatory effects of roflumilast in patients with

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COPD 5.

Long-term trials exploring the effectiveness and safety of roflumilast in COPD

6.

Recent Phase III efficacy studies

7.

Expert opinion

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 reduction 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 reader will gain: An unbiased description of trials that have explored the therapeutic effects of roflumilast in COPD. Take home message: 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 exacerbations 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 and pulmonary vasculature [1]. Other inflammatory cells are routinely observed in the tissues of diseased lung. For example, alveolar macrophages participate in orchestrating the inflammatory progression through the release of proteases such as matrix metalloproteinase (MMP)-9, inflammatory cytokines such as tumour necrosis factor (TNF)-a and chemokines such as interleukin (IL)-8 that attract neutrophils into the airways. Consequently, suppression of the inflammatory response is a logical approach to the treatment of COPD and might improve symptoms and health status, reduce exacerbations and, in the long-term, it should also slow down disease progression. Corticosteroids are highly effective as an anti-inflammatory treatment in a wide range of chronic inflammatory diseases. In patients with COPD and a forced expiratory volume in the first second of expiration (FEV1) < 50% predicted, inhaled 10.1517/14656560903555201 © 2010 Informa UK Ltd ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted

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Roflumilast in COPD

Box 1. Drug summary.

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Drug name

Roflumilast

Phase

Pre-registration

Indication

Chronic obstructive pulmonary disease

Pharmacology description

Phosphodiesterase IV inhibitor

Route of administration

Alimentary, p.o.

Pivotal trial(s)

NCT00297102 NCT00297115 NCT00313209 NCT00424268

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corticosteroid (ICS) therapy reduces the frequency of COPD exacerbation [2] and, moreover, in advanced COPD patients, combinations of ICSs and long-acting b2-agonists (LABAs) show an additive effect, suggesting an interaction between the two moieties that can have a positive effect [3]. Therefore, current guidelines recommend ICS therapy in addition to bronchodilators 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 cigarette smoking and oxidative stress impair histone deacetylase 2 function [6]. Moreover, their long-term use when administered by inhalation is associated with a small but significant increase in the risk of pneumonia, which is of clinical concern [2,7], with a risk that may be greatest in patients with the lowest baseline FEV1 and in those receiving the highest ICS dose, shortest duration of ICS therapy and combination therapy [2], although budesonide has not been shown to cause a comparable increase in pneumonia [8]. It is clear that there is an unmet need in the current pharmacotherapy of COPD [9] and, in effect, the American Thoracic Society/European Respiratory Society guidelines [4] identify a pressing need to develop agents that suppress the inflammation associated with COPD and prevent disease progression. Until now, no therapeutic agent has been shown to reduce the number of macrophages, neutrophils and CD8+ lymphocytes in COPD, but further insight into the pathogenesis of the chronic airway inflammation that underlies COPD has established new therapeutic targets, most of which are based on components of inflammatory pathways [9]. 2.

Phosphodiesterase-4 inhibitors

The phosphodiesterase (PDE)-4 isoenzyme was identified as a major therapeutic target in respiratory diseases because it is the predominant isoenzyme involved in the metabolism of 3¢, 5¢cyclic adenosine monophosphate (cAMP) in the majority of inflammatory cells, including macrophages, neutrophils and 442

CD8+ lymphocytes [10]. Inhibition of PDE-4 blocks the hydrolysis of cAMP, leading to elevated intracellular cAMP levels and, thus, suppression of the proinflammatory activity of these cells. In recent years, there has been a real interest in developing PDE-4 inhibitors because of a wealth of compelling preclinical data indicating that inhibition of PDE-4 should alleviate chronic inflammation [11]. The clinical development of firstgeneration PDE-4-selective inhibitors, such as rolipram, was hampered by the dose-limiting side effects of nausea and vomiting [12], and, therefore, various strategies were undertaken to try and improve the side-effect profiles of these drugs. New second-generation PDE-4 inhibitors have been developed with the hope of a wider therapeutic ratio, particularly with respect to overcoming nausea and vomiting [13]. At present, two PDE-4 inhibitors, cilomilast and roflumilast, have reached Phase III clinical trial stage. The results of Phase I and Phase II studies demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, and suggested a comprehensive Phase III program of research evaluating its efficacy, safety and mechanism of action. However, the results of Phase III studies were unremarkable and disappointing, which led to the inevitable 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 derived from a series of benzamides, is a selective PDE-4 inhibitor developed by Nycomed (Zurich, Switzerland) with a range of anti-inflammatory properties and potential for treatment of COPD. In terms of selective PDE-4 inhibition of human neutrophil function, roflumilast was found to be roughly equipotent to its major metabolite, roflumilast N-oxide, which largely determines the pharmacodynamic activity of roflumilast in rats and in humans; but it showed potency more than 100 times greater than cilomilast or rolipram [15]. Intriguingly, the potency of roflumilast and cilomilast in suppressing neutrophil elastase release from human neutrophils was significantly reduced in the presence of TNF-a, and there was a trend of reduced potency with roflumilast N-oxide and rolipram, though this was not significant [16]. Whatever the case may be, orally administered roflumilast and its N-oxide inhibited lipopolysaccharide-induced release of TNF-a, a well-characterized cAMP-sensitive pathway in cells of the monocytic/macrophage lineage, in the rat; they were 25 times more potent than rolipram and 310 times more potent than cilomilast [17]. Orally administered roflumilast was also able partially to ameliorate acute and chronic lung inflammation and to prevent fully parenchymal destruction induced by cigarette smoke in mice [18]. In addition to its established inhibitory effects on the airway inflammatory cells, roflumilast may exert direct effects on

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human airway epithelial cells inhibiting the MUC5AC expression that follows the activation of the epidermal growth factor receptor (EGFR) signaling cascade [19]. Also in this case, it is more potent than rolipram and cilomilast. In fact, the potency order of their activities (expressed as -log IC50 values) was roflumilast (~ 7.5) > rolipram (~ 6.5) > cilomilast (~ 5.5). This intriguing preclinical pharmacological profile has led interest in developing roflumilast in the treatment of COPD.

Anti-inflammatory effects of roflumilast in patients with COPD

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4.

Roflumilast is at present the most advanced PDE-4 inhibitor undergoing clinical trials for COPD. Preliminary clinical data indicated that it could improve lung function in patients with COPD while being well tolerated [20]. Moreover, roflumilast 500 µg once-daily treatment was associated with an approximately 40% reduction in sputum leukocyte number versus placebo in a 12-week, placebo-controlled crossover study that included 4 weeks in each treatment arm separated by a 4-week placebo washout period [21]. The majority of this difference was accounted for by changes in neutrophil number. Inflammatory mediator levels were also significantly decreased by roflumilast. 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-free neutrophil elastase (roflumilast versus placebo; p = 0.028). The differences in effects on inflammatory markers observed with roflumilast versus placebo were paralleled by changes in postbronchodilator FEV1. There was a 40-ml increase during treatment with roflumilast versus a ~ 20 ml decline during the placebo treatment period (p = 0.018).

Long-term trials exploring the effectiveness and safety of roflumilast in COPD

5.

In an initial placebo-controlled Phase III trial [22] consisting of 1411 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 once daily of roflumilast produced a significant improvement in postbronchodilator FEV1 (the improvement in FEV1 from baseline compared with placebo was 97 ml ± 18), whereas exacerbations were reduced by 34% over placebo (p = 0.0029). In the same group of patients, roflumilast was found to be safe and well tolerated, although diarrhea and nausea, two class-associated side effects, were still apparent. These data indicated that roflumilast can improve clinical symptoms in patients with COPD but it is unable to elicit direct bronchodilator activity. The ability of roflumilast to reduce the number of exacerbations was considered very interesting but, unfortunately, the signal was generated by a study that was too short to explore this effect and, in any case, the primary outcome variables were the changes in postbronchodilator FEV1 and St George’s respiratory

questionnaire (SGRQ) total score and not the number of exacerbations. A second placebo-controlled Phase III trial [24] explored in 1513 patients whether improvement in lung function and reduction in exacerbations could persist over 1 year of treatment in patients with more severe disease (GOLD stages III and IV [23]) than had been studied previously [22]. Data of this second trial confirmed and extended the results of the first trial by demonstrating that roflumilast treatment provided a modest improvement in lung function (an increase in postbronchodilator FEV1 from baseline versus placebo of 39 ml ± 12; p < 0.002) in more advanced COPD over 1 year. However, no change in the overall exacerbation frequency was observed with roflumilast (the difference of overall moderate or severe exacerbations versus placebo was -6.6%; p = 0.451), although exacerbations were less common in GOLD stage IV patients in whom the difference of overall moderate or severe exacerbations versus placebo was -36.1% (p = 0.024). The most common adverse events effects reported with roflumilast included diarrhoea (9.3%), headache (6.2%) and nausea (5.0%). The adverse events disappeared with continued use but they were a major reason why patients discontinued with the 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 treatment of COPD. However, they did not tell us whether treatment benefits with roflumilast could be integrated into current therapeutic regimens and, in particular, whether combining roflumilast with long-acting bronchodilators might provide an acceptable alternative to combined inhaled therapy with long-acting bronchodilators and ICSs in patients with more severe COPD. 6.

Recent Phase III efficacy studies

To give an answer to these important questions, four additional larger trials were designed and recently their results have been published [25,26]. Trials NCT00297102 (M2–124) and NCT00297115 (M2–125)

6.1

Calverley and colleagues [25] reported the results of two placebo-controlled, double-blind, multicenter trials (NCT00297102 or M2–124 and NCT00297115 or M2– 125) with identical design, which tested the hypothesis that roflumilast is able to reduce the rate of exacerbations requiring systemic corticosteroids in specific subsets of patients with COPD. Patients with severe to very severe COPD were enrolled 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. Patients were randomly assigned to oral roflumilast (500 µg once per day; n = 1537) or placebo (n = 1554) for 52 weeks. They could use short-acting b2 agonists as needed and could continue treatment with LABAs or short-acting

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Roflumilast in COPD

anticholinergic drugs at stable doses. However, ICSs and longacting anticholinergic drugs were not allowed during the study. The primary end points were the change in prebronchodilator FEV1 during treatment and the rate of COPD exacerbations, defined as moderate if they required oral or parenteral corticosteroids, or severe if they were associated with hospital admission or death. Key secondary outcomes included the postbronchodilator FEV1 (change from baseline during treatment), time to death from any cause, natural logtransformed C-reactive protein concentration (change from baseline to study end), Transitional Dyspnoea Index (TDI) focal score (during treatment) and changes in Euroquol 5-dimension (EQ-5D) questionnaire, a measure of health utility. Additionally, data for the total number of COPD exacerbations (as defined above together with episodes treated with antibiotics alone) and a range of spirometry outcomes were gathered. After randomization, patients were assessed every 4 weeks up to week 12 and every 8 weeks thereafter. At each visit, spirometric measurements were recorded before and 15 – 45 min after administration of bronchodilator (inhaled salbutamol 400 µg). The study was powered on the basis of an assumption of a mean exacerbation rate of 1.25 per patient per year 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 was more effective than placebo, with a difference (48 ml) that was statistically significant (p < 0.0001). The concomitant use of a LABA did not influence the changes in prebronchodilator FEV1 (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 per patient was 1.14 in the roflumilast group and 1.37 in the placebo group, which was a significantly (< 0.0003) reduction of 17% (95% CI 8 – 25) versus placebo. The concomitant administration of a LABA did not influence the rate of exacerbations (p = 0.5382). Roflumilast was associated with a reduction in the mean number of exacerbations (excluding severe events) treated with systemic corticosteroids or antibiotics, or both (reduction of 16%) in the pooled analysis. Roflumilast was also associated with a significant delay in the time to the first and second episode of moderate or severe exacerbation. Hazard ratio for time to death from any cause was > 1 in both studies. The change in C-reactive protein from baseline to last post-randomization visit was not significant (in the pooled analysis of the two trials, the difference versus placebo was 1.0 mg/liter (0.9 – 1.1; p = 0.8670), but it must be mentioned that its baseline concentrations varied widely. TDI focal score changed significantly from baseline with roflumilast compared with placebo (in the pooled analysis of the two trials, the difference versus placebo was 0.3 units [0.1 to 0.4]; p = 0.0009), but the change was not clinically significant because only a change of 1 unit is associated with a change in a severity level as assessed by physicians. The two trials did not document any significant difference in total EQ-5D scores 444

(roflumilast versus placebo: p = 0.5331 in the M2–124 trial and p = 0.6712 in the M2–125 trial, respectively). Sixty-seven per cent of patients in the roflumilast group and 62% of patients in the placebo group experienced at least one adverse event. Diarrhea (the difference versus placebo was 4.75% in the M2–124 trial and 5.70% in the M2–125 trial) and weight loss (the difference versus placebo was 8.78% in the M2–124 trial and 5.82% in the M2–125 trial) were the most common side effects reported with roflumilast. A greater weight loss was reported by those patients in the roflumilast group who also suffered from diarrhea, nausea, vomiting or headache: 2.60 kg (3.72) vs 2.02 kg (4.01). Inexplicably, the magnitude of weight loss was greater in the first 6 months of treatment and it declined thereafter. Trials NCT00313209 (M2–127) and NCT00424268 (M2–128)

6.2

In their paper, Fabbri and colleagues [27] described the results of other two double-blind, multicentre trials done in an outpatient setting, the NCT00313209 (M2–127) study in which after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 µg (n = 466) or placebo (n = 467) once a day for 24 weeks, in addition to salmeterol, and the NCT00424268 (M2–128) study in which after a 4-week run-in, patients still older than 40 years and suffering from moderate to severe COPD were randomly assigned to oral roflumilast 500 µg (n = 371) or placebo (n = 372) once a day for 24 weeks, in addition to tiotropium. By contrast with the salmeterol plus roflumilast trial, patients recruited to the tiotropium plus roflumilast trial were more symptomatic because they had to have chronic cough and sputum production, and frequent use of as-needed short-acting b2 agonists (at least 28 puffs/week) during the run-in period while they were being treated with tiotropium for at least 3 months before enrolment. In both trials, change in prebronchodilator FEV1 was the primary end point. Secondary end points in both trials included postbronchodilator FEV1 and forced vital capacity (FVC), TDI score, Shortness of Breath Questionnaire (SOBQ), rate of COPD exacerbations, and use of rescue medications. Patients attended the clinics at randomization and after 4, 8, 12, 18 and 24 weeks of treatment. Spirometric measurements were carried out before and 30 min after administration of inhaled salbutamol 400 µg at visits. The study was powered on the basis of an assumption of a difference of 50 ml in FEV1 between roflumilast and placebo as 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 plus tiotropium versus placebo, whereas postbronchodilator FEV1 increased by 60 ml (p < 0.0001) in patients treated with roflumilast plus salmeterol, and 81 ml (p < 0.0001) in those treated with roflumilast plus tiotropium versus placebo. Also, FVC improved significantly in both trials, with an increase in

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prebronchodilator values of 47 ml (p < 0.0128) in patients treated with roflumilast plus salmeterol, and 97 ml (p < 0.0001) in those treated with roflumilast plus tiotropium versus placebo, and an improvement in postbronchodilator values of 58 ml (p = 0.0028) in patients treated with roflumilast plus salmeterol, and 101 ml (p < 0.0001) in those treated with roflumilast plus tiotropium versus placebo. Baseline characteristics of patients, such as sex, current smoking status, COPD severity and use of rescue medications, did not influence the improvement in prebronchodilator FEV1. The tiotropium plus roflumilast combination seemed to be more effective than the salmeterol plus roflumilast combination in improving some patient-centered end points, such as TDI, SOBQ and use of rescue medication. The proportion of patients reporting adverse events was higher in both of the groups that received roflumilast compared with the placebo groups (63% of patients assigned to salmeterol plus roflumilast and 46% patients in the tiotropium plus roflumilast group versus 59% of patients assigned to salmeterol plus placebo and 41% of patients in the tiotropium plus placebo group, respectively, suffered from at least one adverse event). As expected, the most commonly reported serious events associated with roflumilast affected the gastrointestinal and respiratory tracts. Again, diarrhea (the difference vs placebo was 4.73% in the M2–127 trial and 8.28% in the M2–128 trial) and weight loss (the difference vs placebo was 7.51% in the M2–127 trial and 5.07% in the M2–128 trial) were the most common side effects reported with roflumilast. 7.

Expert opinion

The treatment of the inflammatory component of COPD remains an unmet meet and, therefore, any new drug able to interfere with this component is really welcome. The only limits set for the development of a new anti-inflammatory compound to be used in COPD are real effectiveness and safety profile. Extensive Phase III clinical trials allow us to assess the true efficacy and safety of each new drug. This is especially true if the trial design includes the correct end points and meets not only the regulatory requirements but also the scientific ones. The development of roflumilast in COPD is the clear documentation of the changes in regulatory and scientific requirements that have taken in recent years. The first large trial of roflumilast in COPD was that published by Rabe and colleagues [22]. In that trial, the changes in postbronchodilator FEV1 and SGRQ total score were the primary end points and the duration of the trial was 6 months according to what was requested by CPMP-Guideline CPMP/EWP562/98: ‘Points to consider on clinical investigation of medicinal products in the chronic treatment of patients with chronic obstructive pulmonary disease (COPD)’ [28]. FEV1 is a lung function parameter that is routinely used to evaluate the efficacy of new drugs for COPD regardless of whether they are bronchodilators. Therefore, the

choice of using FEV1 as a primary end point was not surprising, although there was documentation that roflumilast has no direct bronchodilating properties, at least in animal models [17]. In any case, the authors honestly acknowledged that their study was not designed specifically to assess the antiinflammatory activity of roflumilast. Nevertheless, they reported that roflumilast reduced the overall mean number of exacerbations and suggested that the ability of roflumilast to target the underlying pulmonary inflammation might translate into a reduction of COPD exacerbations. Taking into account that an evaluation of exacerbation frequency requires a period of ‡ 1 year because of seasonal variation, and, in any case, the timing of the study treatment is important (e.g., capturing winter cold season in the majority of patients) [29], Calverley and colleagues [24] correctly explored whether reduction in exacerbations would persist over 1 year of treatment with roflumilast. Although they enrolled patients suffering from severe to very severe COPD and it is well known that exacerbation frequency increases with progressive airflow obstruction [30], PDE-4 inhibition with roflumilast was unable to change the exacerbation rate. However, it must be mentioned that inhaled corticosteroids of 2000 µg or less beclomethasone dipropionate or equivalent were allowed at a constant daily dose if they were used before study entry and, consequently, we cannot exclude that these medications may have influenced the likelihood of exacerbations [31], regardless of treatment with roflumilast. Nonetheless, since the study of Calverley and colleagues [24] also documented that roflumilast treatment reduced the frequency of exacerbations requiring systemic corticosteroids, as well as that of exacerbation rates in a subset of very severely impaired patients in whom exacerbations occur more frequently, another trial specifically designed to investigate whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD was mandatory. The trials NCT00297102 and NCT00297115 have tried to give an answer to this question. These two trials [25] have been well designed. All patients had postbronchodilator FEV1 £ 50% than the predicted value and at least one recorded COPD exacerbation requiring systemic corticosteroids or treatment in hospital, or both, in the previous year. The treatment duration of 1 year was certainly appropriate. Moreover, drugs that could influence exacerbations, such as inhaled corticosteroids and long-acting anticholinergic agents, were not allowed during the study, although it must be highlighted that patients were allowed to continue treatment with long-acting b2 agonists, and a recent meta-analysis has documented that single treatment with longacting b2 agonists is able to prevent exacerbations [32]. Nonetheless, the results of these two trials have shown that the difference in the frequency of exacerbations between treatments was independent of concomitant long-acting b2 agonist use [25]. This finding indicates that roflumilast is capable of reducing exacerbation rate.

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Roflumilast in COPD

Since roflumilast is an anti-inflammatory drug, it is reasonable to wonder whether it is as active as an inhaled corticosteroid in COPD. In the first paper published by Calverley and colleagues [24], the mean rate of moderate or severe exacerbations per patient per year was 0.86 in the roflumilast group and 0.92 in the placebo group in patients with a mean baseline postbronchodilator FEV1 of 41%, with a 6.6% reduction versus placebo, but in GOLD IV patients the mean rate of moderate or severe exacerbations per patient per year was 1.01 in the roflumilast group and 1.59 in the placebo group with a 36.1% reduction versus placebo. In the second paper published by Calverley and colleagues [25], the mean rate of moderate or severe exacerbations per patient per year was 1.14 in the roflumilast group and 1.37 in the placebo group, in patients with a mean baseline postbronchodilator FEV1 of 36.1 and 36.4% of the predicted value, respectively, with a 17% reduction versus placebo. Three large studies that lasted 1 year have examined the effects of a combination of longacting b2 agonist and inhaled corticosteroid on the risk of developing exacerbation in COPD. The first of these studies explored the effect of salmeterol/fluticasone combination. The mean rate of exacerbation/patient/year was 0.97 with combination, 1.05 with fluticasone alone, and 1.30 with placebo [33]. The rate of exacerbations fell by 25% in the combination group and by 19% in the fluticasone group, respectively, compared with placebo in patients with a pretreatment FEV1 of 44.8, 45.0 and 44.2% of the predicted value, respectively. The formoterol/budesonide combination was investigated in a more severe population. In the study of Szafranski and colleagues [34], patients with a pretreatment FEV1 of 36, 27 and 36% of the predicted value were treated with combination, budesonide alone and placebo, respectively. Mean exacerbation rates were 1.42, 1.59 and 1.87 exacerbations/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 the predicted value, whose treatment was initially intensified with the oral steroid prednisolone (30 mg once daily) and inhaled formoterol Turbuhaler (4.5 µg twice daily) for 2 weeks, in an attempt to optimize their health status, Calverley and colleagues [35] reported 1.38, 1.60 and 1.80 exacerbations/patient/ year in the budesonide/formoterol, budesonide, and placebo treatment groups, respectively. Formoterol/budesonide therapy reduced the risk of exacerbation by 23.6%, and budesonide by 11.1% versus placebo. Although indirect comparison is not the correct method for understanding differences between drugs, and despite some difference in the studied populations, apparently roflumilast seems to be as effective as an inhaled corticosteroid in preventing exacerbations in COPD patients, and even more active in very severe COPD. However, it is noteworthy that the combination of a longacting b2 agonist and an inhaled corticosteroid amplifies the protection induced by the inhaled corticosteroid alone [3], whereas, apparently, the combination of a long-acting b2 446

agonist with roflumilast does not modify the effect induced by roflumilast alone [25]. Considering that inhaled corticosteroids are recommended in combination with long-acting bronchodilators for patients with severe to very severe COPD who have recurrent exacerbations [4,5], the obvious next step was to determine whether roflumilast provides benefit to patients who are regularly treated with long-acting inhaled bronchodilators. Also the trials NCT00313209 and NCT00424268 were well designed and 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 to salmeterol (73 ml) [33]. A comparison with the budesonide/ formoterol combination is questionable because of substantial differences between salmeterol and formoterol, but it must be mentioned that trials NCT00297102 and NCT00297115 documented that the addition of a long-acting b2 agonist did not change the mean prebronchodilator FEV1 increase observed 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 considering the mechanism of actions of the two drugs. Unfortunately, no clinical trial has explored the effect of the addition of an inhaled corticosteroid to tiotropium. Nonetheless, Hodder and colleagues [36], who retrospectively analyzed the relative efficacy of tiotropium and salmeterol as a function of the concomitant use of inhaled corticosteroids in patients with moderately advanced COPD using the pooled results of two 6-month studies of tiotropium 18 µg q.d. compared with salmeterol 50 µg b.i.d., reported that after 169 days of treatment, the mean improvement above placebo in trough FEV1 was 110 ml for tiotropium and 80 ml for salmeterol. It is clear that roflumilast is not a bronchodilator, although it is also possible, as suggested by Celli [37], that it may reach the distal airways because of its systemic distribution, whereby decreasing inflammation around the small airways it could have more important changes in resting lung volumes than in absolute FEV1. Unfortunately, this hypothesis cannot be confirmed because lung volumes were not tested in the examined trials. In any case, improvements in lung function induced by roflumilast are similar to those observed with inhaled corticosteroids. The improvement in prebronchodilator FEV1 from baseline with roflumilast versus placebo was 36 ml in the first study of Calverley and colleagues [24], and 40 ml in their second study [25]. In the TRISTAN study [33], the improvement in prebronchodilator FEV1 from baseline was 38 ml with fluticasone versus placebo. According to an old meta-analysis of the original data sets of several randomized controlled trials the estimated 2-year difference in prebronchodilator FEV1 was 34 ml/year in the inhaled corticosteroid group versus placebo [38]. Most randomized, more recent, trials did demonstrate a small, sustained improvement in the FEV1 from inhaled corticosteroid alone. Average

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improvements were usually in the range of 50 â&#x20AC;&#x201C; 75 ml. Bronchodilation was apparent shortly after initiating inhaled corticosteroid treatment, and it persisted for the duration of therapy, albeit declining at the same rate as placebo in these individual studies [39]. We must now establish whether roflumilast has a role in the treatment of COPD and, if so, what this role is. It is our opinion that, 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 exacerbations despite treatment with inhaled bronchodilators. However, considering the high risk of adverse events induced by this drug, we believe that the published evidence indicates limiting its use to the treatment of patients suffering from very severe COPD. Obviously, this is only an initial and, therefore, partial opinion. A solid opinion may be made only when roflumilast is compared, alone or in combination, with other therapies such as long-acting anticholinergic drugs (e.g., tiotropium), combination inhalers (e.g., fluticasone/salmeterol or budesonide/ formoterol), or theophylline, which are treatments recommended in current guidelines [4,5]. In any case, it must be mentioned that Spina has correctly highlighted that targeting PDE-4 alone may not fully resolve airway inflammation, in that other PDE types exist in structural and inflammatory cells in the lung and, therefore, targeting multiple PDE enzymes may be required for optimal anti-inflammatory action [40]. For example, the macrophage is viewed as a critical cell type in the pathogenesis of COPD [41]; however, the activity of this cell is only inhibited to a small degree by PDE-4 inhibitors [15] and the potential functional involvement of PDE-7 cannot be completely ignored. In effect, the expression of PDE-7 in inflammatory cells has been acknowledged and, while inhibition of this enzyme alone does not suppress inflammatory cell function, however,

combined use of PDE-4 with PDE-7 inhibitors provides a greater inhibition than PDE-4 alone. Actually, the inhibitory action of PDE-4 inhibitors on the cellular activity of CD8+ T lymphocytes and macrophages is significantly increased in the presence of PDE-7 selective inhibitors [47]. Similarly, combined PDE-3 and PDE-4 inhibitor in a single molecule offers the advantage of delivering a bronchodilator and anti-inflammatory substance. There is documentation that PDE-4 is also present alongside the PDE-3 isoenzyme in airway smooth muscle; the PDE-3 isoenzyme is considered to predominate in airway smooth muscle, and inhibition of this enzyme, rather than PDE-4, leads to airway smooth muscle relaxation [13]. This clearly indicates that the inhibition of PDE-4 isoenzyme can only elicit a really weak bronchodilation and there is documentation that substances that prevent the degradation of cAMP by inhibiting the activity of PDE-4 are virtually inactive as bronchodilators when administered prophylactically, but act synergistically with substances that inhibit PDE-3 to prevent LTD4 or histamine-induced bronchospasm [43]. In any case, it is likely that retention of the inhibitor within the lung may be required to maintain anti-inflammatory activity within the airways [44]. All these findings indicate that we must not lose interest in PDE inhibitors. However, we believe that only the development of drugs capable of interfering with multiple PDE isoenzymes administered by inhalation, instead of just blocking PDE-4 isoenzyme with drugs administered by oral route, will represent a real progress in the treatment of COPD.

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

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Affiliation

Mario Cazzola†1, Stefano Picciolo2 & Maria G Matera3 † Author for correspondence 1 Unita` 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.it 2 Sezione di Malattie Respiratorie e Fisiopatologia Respiratoria, Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Universita` di Messina, Messina, Italy 3 Unita` di Farmacologia, Dipartimento di Medicina Sperimentale, Seconda Universita` di Napoli, Naples, Italy

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