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COPD: Journal of Chronic Obstructive Pulmonary Disease, 7:141153 ISSN: 1541-2555 print / 1541-2563 online Copyright c 2010 Informa

Healthcare USA, Inc. DOI: 10.3109/15412551003758304

CLINICAL REVIEW

Treatment of Chronic Obstructive Pulmonary Disease with Roumilast, a New Phosphodiesterase 4 Inhibitor
Nicholas J. Gross1 (grossnicholas1@gmail.com), Mark A. Giembycz2 (giembycz@ucalgary.ca), and Stephen I. Rennard3 (srennard@unmc.edu)

of Medicine, St. Francis Hospital & Medical Center, Hartford, Connecticut, USA of Physiology & Pharmacology, University of Calgary, Calgary, Canada 3 Pulmonary Critical Care, Allergy and Sleep Medicine, University of Nebraska Medical Center, Nebraska, USA
2 Department

1 Department

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ABSTRACT
Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modication remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efcacy of roumilast available in published reports are considered. The data reviewed here suggest that the clinical efcacy of roumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inammation. Lung function improved with roumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically signicant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roumilast to nd its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.

INTRODUCTION
Our current understanding of the pathophysiology of chronic obstructive pulmonary disease (COPD) and its management

Keywords: Chronic obstructive pulmonary disease, Inammation, Phosphodiesterase 4, Roumilast Correspondence to: Nicholas J. Gross St. Francis Hospital and Medical Center 114 Woodland Street Hartford, CT, 06105-1208, USA email: grossnicholas1@gmail.com

are the subject of several comprehensive, consensus reviews included in the GOLD Guidelines (1) and in Statements from the American Thoracic Society and European Respiratory Society (2, 3). Despite recent advances in treatment that contribute to symptom relief, effective disease-modifying therapies are limited. Smoking cessation, at least early in the course of the disease, slows lung function loss and improves survival. Similarly, oxygen administration in hypoxic patients and volume reduction surgery in selected patients also improve survival. Survival benets from other forms of therapy have been difcult to show. Two large, well-planned, well-conducted international trials, one with the anticholinergic drug, tiotropium and one with the combination of uticasone and salmeterol, have shown trends toward a survival benet (4, 5). Other aspects of COPD
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pathophysiology, however, may also benet from current therapy. Long-acting bronchodilators and inhaled corticosteroids (ICSs) slow the rate of lung function loss, although the effect is less than that achieved by smoking cessation early in the course of the disease and the clinical importance of the effects observed remains uncertain. In addition, several treatments can reduce exacerbation frequency. Thus, disease modication remains our most important unmet need in COPD (6). Acute exacerbations of COPD (AECOPDs) are associated with accelerated disease progression (710). Although not yet established, it is reasonable to conclude that reducing the frequency and severity of AECOPDs would lead to a moderation of disease progression. Apart from that potential outcome, a reduction in AECOPDs is highly desirable in order to reduce the signicant morbidity, mortality, and expense associated with these major events. The achievable reduction in exacerbations is limited with currently available COPD therapies: long-acting 2 agonists ((LABA)s; [3, 11, 12]), long-acting muscarinic antagonists ((LAMA)s; [3, 13]), ICSs (1316), and their combinations. A therapy that further reduces AECOPDs would be desirable. Although the pathophysiological mechanisms of COPD disease progression and the AECOPDs that occur during its course are not fully understood, airway inammation is present and plays an important role at all stages of the disease. Two important features of inammation in established COPD include that it persists long after the inciting event (usually tobacco smoking) has ceased (17, 18), suggesting that the inammatory process is self-propagating. Second, airway inammation in COPD responds poorly to corticosteroid administration (1921), presumably because it is associated with neutrophils, CD8+ T lymphocytes, and CD68+ macrophages, cells that are minimally inhibited by corticosteroids. Clearly the airway inammation of COPD differs from that in asthma in many respects: cell types, inammatory mediators, and response to treatments (2225). A therapy that would effectively address the inammation present in COPD, both in its stable and acute stages, would be a major advance in COPD treatment. To address these three issues, disease modication, reductions in the frequency and severity of acute exacerbations and effective suppression of COPD-type airway inammation, new therapies and/or strategies are required. For purely practical reasons, other unmet needs include a once-daily oral dosing schedule and efcacy without risks of serious systemic side effects. In this regard, not a single new class of pharmacotherapy has been approved for COPD use in more than two decades. Phosphodiesterase (PDE) 4 inhibitors have been in development for many years. Interest in this class of compound arose in the 1980s when it became clear that methylxanthines such as theophylline, which had been widely used for its bronchodilator action since the 1930s, were difcult to use and could be dangerous. As a consequence, safer substitutes were sought. About the same time it was discovered that: theophylline was a nonselective inhibitor of PDEs; there are multiple families of PDEs; one of these families, PDE4, is expressed in airway smooth muscle and in immune and pro-inammatory cells (2629). Inhibitors of PDE4 were synthesized and appropriate candidates
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Figure 1. Structures of roumilast and its primary metabolite roumilast N-oxide.

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entered clinical development. Currently, the most advanced of these agents is roumilast (Daxas), which has been submitted for the approval in Europe and USA as a maintenance treatment for COPD associated with chronic bronchitis in patients at risk of exacerbations. We review here the preclinical and clinical properties of roumilast, its pharmacology, clinical efcacy, and safety as revealed in clinical trials.

PHARMACOLOGY OF PDE4 INHIBITORS


Cyclic nucleotide PDEs are a large family of enzymes that catalyze the inactivation of cyclic adenosine-3 ,5 monophosphate (cAMP) and/or cyclic guanosine-3 ,5 monophosphate (cGMP) to their respective nucleotide 5 monophosphates (30). Eleven families have been discovered with PDE4 representing the desired molecular target for roflumilast and related compounds (30). In humans, PDE4 exists as a large number of variants that are encoded by four genes, PDE 4A, B, C, and D (31). The enzymes have absolute specicity for cAMP, are expressed in immune and pro-inammatory cells, and may, therefore, be of therapeutic potential as targets in COPD for small molecule inhibitors. Roumilast and its primary metabolite, roumilast N-oxide (Figure 1), are very potent and competitive inhibitors of PDE4 (32). Both roumilast and roumilast N-oxide have IC50 values against PDE4 isolated from human neutrophils of 800 pM and 2 nM, respectively. They are highly selective for PDE4 and are essentially inactive against PDEs 1, 2, 3, 5, and 7 at concentrations up to 10 M (33). Roumilast inhibits all PDE4 variants and this might contribute to its improved therapeutic ratio, relative to other development candidates such as cilomilast, which selectively inhibits PDE4D (see section Safety Outcomes). It is, however, approximately 10-fold less potent against PDE4C gene products (33), a property shared with cilomilast (34).

Pharmacodynamics of PDE4 inhibitors


The rationale for developing selective PDE4 inhibitors is based on three critical ndings: PDE4 is a primary regulator of cAMP degradation in essentially all immune and proinammatory cells; PDE4 inhibitors suppress a myriad of responses that are considered to be pro-inammatory; and PDE4

COPD: Journal of Chronic Obstructive Pulmonary Disease

inhibitors are efcacious in animal models of pulmonary inammation (26, 27, 35, 36). With the exception of platelets, all immune and proinammatory cells express PDE4 (37). In most cases, these cells co-express multiple PDE4 variants derived from PDE4A, PDE4B, and PDE4D (36). Currently, the isoforms that must be inhibited for the anti-inammatory actions of PDE4 inhibitors to be realized largely are unknown. There is extensive in vitro data describing the inhibitory effect of roumilast and PDE4 inhibitors on a variety of responses that, in vivo, are considered to be pro-inammatory (33, 3842). Similarly, in preclinical animal models that reproduce specic facets of COPD pathophysiology, roumilast is efcacious, suggesting that this drug might be disease modifying in human COPD (4346). PDE4 is also expressed in structural cells including broblasts, raising the possibility that targeting PDE4 could arrest the airway remodeling that is a dening characteristic of COPD and is thought to compromise long-term lung function. The mechanism of action of roumilast has not unequivocally been established. In animals, roumilast does not protect against leukotriene D4 - or 5-hydroxytryptamine-induced bronchoconstriction (47, 48). Similarly, there is no evidence that PDE4 inhibitors evoke bronchodilation in patients with COPD (49). Thus, benecial effects on pro-inammatory/immune cell function rather than on airway smooth muscle tone may account, in part, for the clinical efcacy of this compound in COPD. However, data supporting an anti-inammatory effect of roumilast in human subjects are limited. In a double-blind, cross-over, placebo-controlled study involving 38 patients with COPD who were minimally responsive to inhaled albuterol and whose mean post-bronchodilator FEV1 was 61% of predicted, roumilast (500 g/day for 4 weeks) reduced, at the end of the study, the absolute number of neutrophils, eosinophils, and lymphocytes in induced sputum by 36% (p < 0.0017), 50% (p < 0.0005), and 35% (p < 0.022), respectively, relative to placebo (50). Signicant reductions in eosinophil cationic protein, interleukin8, neutrophil elastase, and 2 -macroglobulin (a marker of microvascular leak) relative to placebo were also reported (50). The ex vivo generation of TNF induced by lipopolysaccharide (LPS) in whole blood (a biomarker of systemic inammation) was reduced by 10.4% (p < 0.047). These actions of roumilast on indices of inammation were accompanied by a signicant improvement in pre- and post-bronchodilator FEV1 (mean change 79.5 ml and 68.7 ml, respectively, compared to placebo; p < 0.0001). The concern with these data is that the statistical signicance for most inammatory endpoint measures was driven by the placebo. Thus, at the end of the placebo arm of the study, the absolute number of neutrophils and eosinophils was increased by 2040% relative to baseline (50). Similar effects were also seen for neutrophil elastase and 2 -macroglobulin. Therefore, the anti-inammatory activity of roumilast may have been overestimated. The mechanism responsible for this rapid apparent worsening in inammatory status after placebo is unclear and, while identied by the investigators, was not discussed. A possible explanation could be regression to the mean, because subjects were selected to have been stable

and exacerbation-free for one month preceding enrollment. Although the mechanisms are not established, the available data are consistent with an anti-inammatory effect of roumilast. Despite difculties interpreting the aforementioned results, independent studies with roumilast and evidence obtained with other PDE4 inhibitors (e.g. cilomilast, Bay 198004) support an anti-inammatory mechanism of action for this class of compound in airway inammatory diseases. Thus, roumilast signicantly inhibited the appearance of neutrophils in the bronchoalveolar lavage uid of healthy subjects following segmental challenge with LPS (51) and reduced LPS-induced TNF generation ex vivo (52). Similar anti-inammatory effects have been reported with other PDE4 inhibitors (49, 53).

Pharmacokinetics of roumilast and roumilast N-oxide


The absorption, distribution, metabolism, and excretion (clearance [CL]) of roumilast have been studied in adults, adolescents, and children following oral administration (5456). In an open-label, randomized, two-period cross-over study involving 12 healthy, fasted, white adult subjects, the absorption of roumilast (2 250 g immediate release tablets) was rapid and complete after oral administration, with the time to achieve peak plasma concentration (Tmax ) of approximately 1 hr (55). Roumilast given orally is highly bioavailable (F = 0.79), bound extensively (98.9%) to plasma proteins, achieves steady-state levels within 4 days of once-daily dosing, has an elimination half-life (t1/2 ) of 725 hr (mean 17 hr), and is subject to negligible rst pass hepatic metabolism (38, 5457). Furthermore, after a single intravenous dose (120 g) of roumilast to healthy adult subjects, the CL and volume of distribution (Vd ) were 13 L/hr and 2.92 L/kg, respectively, indicating pronounced distribution in tissues (58). A further study in 15 healthy subjects using an open-label, randomized, two-period, two-sequence crossover design established that oral administration (both single and repeat doses) of roumilast (250 g and 500 g) provided dose-proportional systemic exposure with no difference between the single and repeat dose regimens. Similar dose proportionality data also were observed for roumilast N-oxide (the primary metabolitesee below) indicating that both compounds display linear pharmacokinetics (54). In humans, after oral administration, the major metabolic pathway for the elimination of roumilast is N-oxidation (Figure 1). This process is catalyzed primarily by the mixed function oxidases, cytochrome (CYP) 3A4, and CYP1A2 to yield roumilast N-oxide (Figure 1). Signicantly, this metabolite retains appreciable inhibitory activity against PDE4. The pharmacokinetics of roumilast N-oxide generally are distinct from the parent compound. Thus, the Tmax is between 4 hr and 12 hr and the maximum observed plasma concentration (Cmax ) is typically one- to two-fold higher (54, 57, 5961). Steady-state plasma levels of roumilast N-oxide are usually achieved within 6 days of once-daily oral administration and the elimination t1/2 is approximately 27 hr, which is signicantly prolonged relative
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COPD: Journal of Chronic Obstructive Pulmonary Disease

to the parent compound. Finally, total systemic exposure estimated from the area under the concentration-time curve (AUC) exceeds that of roumilast by approximately 10-fold (58). Taken together, these data strongly suggest that the N-oxide accounts for about 90% of the biological action of roumilast and produces a long-lasting, competitive inhibition of PDE4 over a 24-hr period such that roumilast may be administered once daily. Roumilast N-oxide is dealkylated (inactivated) primarily by CYP3A4 (with a small contribution by CYP2C19 and extrahepatic CYP1A1) (57), glucuronidated and eliminated via the kidney (59). Very low amounts of roumilast and roumilast N-oxide are excreted unchanged in urine.

Polyaromatic hydrocarbons, which are constituents of tobacco smoke, are known to induce drug-metabolizing enzymes including CYP1A1 and CYP1A2 (6870). Although CYP1A2 contributes to the metabolism of roumilast and, as such, may enhance the rate at which the N-oxide is produced in smokers (see above), the N-oxide itself is not a substrate for CYP1A2 (40). Accordingly, no dose adjustments are likely to be required in patients with COPD who smoke tobacco.

CLINICAL EFFICACY
The clinical efcacy of roumilast has been explored in six large prospective, randomized, double-blind, placebocontrolled studies that provide the majority of the efcacy and safety data that we now review (Table 1). A study by Rabe and colleagues (71) was performed in 1,411 patients with moderateto-severe COPD (mean post-bronchodilator FEV1 50% of predicted) and a documented absence of signicant improvement of FEV1 (reversibility) following inhalation of albuterol 400 g. Subjects were randomized to receive either 250 or 500 g of roflumilast, or matching placebo, orally, once daily for 24 weeks. Two co-primary outcomes were specied: the change from baseline in post-bronchodilator FEV1 and the Saint Georges Respiratory Questionnaire (SGRQ). The study was completed by 82% of subjects, withdrawals being somewhat higher in the active treatment arms. At the 24-week endpoint, the postbronchodilator FEV1 dose-related increases over placebo were 74 ml and 97 ml in the roumilast 250 and 500 g groups, respectively (p < 0.0001), and both also signicantly greater than baseline values. The pre-bronchodilator FEV1 and FVC similarly improved. The changes from baseline in SGRQ were 3.4 and 3.5 units for 250 and 500 g of roumilast, respectively, and both were statistically signicant (p < 0.0001). However, when compared to placebo, which also improved, but to a lesser degree, neither of these improvements was statistically signicant. Among secondary outcomes, fewer subjects in each of the active treatment arms experienced an AECOPD, the mean numbers of AECOPDs being 1.13, 1.03, and 0.75 per patient/year in the groups that received placebo, 250, and 500 g of roumilast, respectively. The results for both treatment groups for acute exacerbations were statistically signicant compared to placebo (p = 0.0029, one-sided), the greatest effect being in the 500 g roumilast arm in which a 34% reduction was seen. A 1-year study of similar design was performed with only the 500 g dose of roumilast and published by Calverley and colleagues (72). The other main difference to the Rabe study was that enrollees were required to have more severe disease, with the actual mean post-bronchodilator FEV1 of enrollees reported as 41% of predicted. The primary efcacy variables were the change from baseline to endpoint in post-bronchodilator FEV1 (as in the Rabe study), and the number of moderate or severe exacerbations per patient per year, instead of SGRQ. Again, study dropouts were higher in the active treatment arm. The mean improvement with roumilast in post-bronchodilator

Contraindications, effect of food and drugdrug interactions


No potential contraindications have, thus far, been identied. Although the metabolism of roumilast is signicantly arrested in patients with mild and moderate hepatic insufciency leading to increased systemic exposure (AUC024 = 51% and 92% higher in patients meeting Child-Pugh A and Child-Pugh B criteria, respectively, when compared to healthy subjects), changes to the pharmacokinetics of roumilast N-oxide are relatively modest (62). Since the primary metabolite is believed to account for approximately 90% of the pharmacodynamic impact of roumilast, the small pharmacokinetic changes reported are not believed to be clinically relevant. Thus, no dose adjustments are predicted to be required in patients with mild and moderate liver compromise (62). Similarly, although a high fat meal decreases Cmax and delays Tmax of roumilast versus the fasted state, the same pharmacokinetic parameters are not changed for roumilast N-oxide (55). Thus, again, because the primary metabolite mediates most of the pharmacological effects of roumilast, these data strongly suggest that the parent drug can be taken with or without food. Patients with COPD typically have multiple co-morbidities for which they may receive other medications. The possibility that roumilast and/or its N-oxide could interact unfavorably with drugs commonly used in COPD has, therefore, been evaluated. Neither roumilast nor roumilast N-oxide by themselves inhibit CYP3A4 or CYP1A2 (40). Other data suggest a low potential for roumilast to interact adversely with other drugs including montelukast, erythromycin, ketoconazole, budesonide, albuterol, midazolam (40), and antacids containing magnesium hydroxide or aluminium hydroxide (5961, 6367). This is important to determine because inducers of CYP3A4 and CYP1A2 have the potential to increase the CL of roumilast thereby lowering its efcacy. Conversely, xenobiotics that are metabolized by the same enzyme(s) could compete with roumilast, delay its inactivation and so increase systemic exposure, with the potential for adverse events. Thus far, only rifampicin, an antibiotic used to treat pulmonary tuberculosis, has been shown to signicantly limit the efcacy of roumilast due to its ability to induce xenobiotic-metabolizing enzymes that include CYP3A4, CYP2C19, and extrahepatic CYP1A2 (57).

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Table 1: Six Long-term, Placebo-controlled Studies of Roflumilast vs. Placebo Mean Baseline Post-bronchodilator FEV1, % of 10 Outcome Measures Predicted 54% Post-bronchodilator FEV1 54% SGRQ 55% 41% Post-bronchodilator FEV1 41% Acute Exacerbations /yr 38% 37% 35% 35% 55% 55% 56% Pre-bronchodilator FEV1 Acute Exacerbations /yr Pre-bronchodilator FEV1 Acute Exacerbations /yr Pre-bronchodilator FEV1 Pre-bronchodilator FEV1

Citation Rabe KF et al
Lancet 2005; 366: 563-71 M2-107 Study

Calverley PMA et al
AJRCCM 2007; 176: 154-61 M2-112 Study

Treatments ROF 250 g, ROF 500 g PBO Rof 500 g Pbo ROF 500 g PBO ROF 500 g PBO ROF 500 g + SAL PBO + SAL ROF 500 g + TIO

N 576 555 280 760 753 765 758 772 796 466 467 371

Duration 24 weeks

10 Outcome Achieved? Yes -74-97 mL P<0.0001 No Yes - 39 mL P=0.001 No Yes - 39 mL P=0.0003 Yes -RR=0.85 P=0.0278 Yes - 58 mL P<0.0001 Yes- RR=0.82 P=0.0035 Yes - 49 mL P<0.0001 Yes - 80 mL P<0.0001

1 year 1 year 1 year 24 weeks 24 weeks

Calverley PMA et al
Lancet 2009; 374: 685-94 M2-124 Study

Calverley PMA et al
Lancet 2009; 374: 685-94 M2-125 Study

Fabbri LM et al
Lancet 2009; 374: 695-703 M2-127 Study

Fabbri LM et al

Lancet 2009; 374: 695-703 372 56% PBO + TIO M2-128 Study PBO indicates placebo, ROF indicates roflumilast, SAL indicates salmeterol, TIO indicates tiotropium, RR indicates rate ratio for treatment:placebo

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FEV1 from baseline compared with placebo was 39 ml (p < 0.001). The overall rate of moderate or severe exacerbations was not signicantly different between roumilast- and placebotreated patients, 0.86 versus 0.92 exacerbations/patient/year. However, a post-hoc subgroup analysis showed that exacerbations were less frequent among GOLD stage IV subjects in the roumilast group compared to the placebo-treated arm, 1.01 versus 1.59 exacerbations/patient/year, respectively (p = 0.024). The SGRQ, a secondary outcome, deteriorated similarly in both groups. In the subgroup with very severe disease, GOLD stage IV, there was a better, but still non-signicant (p = 0.086), improvement in SGRQ in the roumilast arm. To expand on the ndings above, an identical pair of studies (M2124 and M2125) in more select populations was performed and reported by Calverley and colleagues. The results were combined into a single publication (73). Although similar in design to the previous studies (71, 72), the Calverley 2009 report differed by specifying the pre-bronchodilator (rather than post-bronchodilator) FEV1 as a co-primary outcome. The rate of moderate or severe acute exacerbations was the other co-primary outcome. Entry criteria, which were designed to reproduce the subset that responded in the rst two studies, included a postbronchodilator FEV1 of 50% or less of predicted and a history of at least one acute exacerbation requiring corticosteroids or hospitalization in the previous year. Enrollees were allowed to continue use of a long-acting bronchodilator, but corticosteroids were withheld throughout the studies. A total of 3,091 subjects with a mean FEV1 of 36% of predicted were recruited and, after a 4-week run-in, randomized to receive either 500 g of roumilast or matching placebo, orally, once daily for 1 year. Subject withdrawals were marginally higher in the active treatment arm at the endpoint versus placebo (35% vs. 31% in M2124 and 32% vs. 31% in M2125; Figure 2). Both primary outcomes were achieved (Table 2). The pre-bronchodilator FEV1

increased by a mean of 48 ml more in the treatment arm than placebo arm (p < 0.0001) (Figure 3); and the rate of moderate or severe acute exacerbations was less in the roumilast group than placebo arm in each of the individual studies, the pooled result being 1.14 versus 1.37 exacerbations/patient/year, respectively, a reduction of 17% (p = 0.0003). The time to rst exacerbation in the roumilast group was also signicantly prolonged (p = 0.0185), but only in the pooled analysis. Of the secondary outcomes, only the Transition Dyspnea Index focal score was signicantly improved (p = 0.0009) in the treatment compared to the placebo group, although the difference was less than the generally accepted clinically important difference. To summarize the efcacy results of these four Phase III studies, they each have two coprimary outcomes, one of which is an FEV1 outcome. Initially, it was the post-bronchodilator that was specied; later, the pre-bronchodilator FEV1 . The latter is probably a more appropriate outcome for an anti-inammatory agent that may have some bronchodilator effect. However, in either case, whether pre- or post-bronchodilator, the FEV1 improvement with roumilast is statistically signicant in each case, although modest at 40100 ml. While this is less than the 100150 ml often considered to be the minimum clinically important difference for FEV1 (74), one notes that only patients with little or no response to inhaled albuterol were admitted to the trials, that LABAs were permitted during the studies, and that the amount of spirometric improvement that nevertheless occurred was similar to that achieved by the corticosteroid components when added to a LABA in both of the two COPDapproved combinations, Advair and Symbicort. The second coprimary endpoint was the health-related quality of life outcome, SGRQ, in the rst pivotal study (71). This only reached statistical signicance when compared to the original baseline value, not when compared to placebo. However, the improvements in SGRQ, although modest, were also similar in magnitude to those
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Figure 2. Probability of treatment discontinuation in roumilast and placebo groups in trials M2124 (A) and M2125 (B). Reproduced from Calverley PMA et al Lancet 2009;374:68594 with permission. Number of patients still at risk at the beginning of the respective week; number at risk might be different from the number completing the study because the protocol allowed patients to nish the study up to 7 days before the end of week 52.

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1.35 1.25 1.15

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764 743 667 625 758 744 694 667 757 728 661 622 753 733 691 662 604 633 598 626 571 600 569 597 542 566 540 562 517 537 510 532 499 521 497 513 772 730 669 637 796 762 725 708 769 725 666 635 793 761 723 706

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Figure 3. Prebronchodilator and postbronchodilator forced expiratory volumes in 1 s (FEV1 ) over 52 weeks in patients in roumilast and placebo groups in trials M2124 (A) and M2125 (B), and changes in prebronchodilator and postbronchodilator FEV1 over 52 weeks in patients in roumilast and placebo groups in trials M2124 (C) and M2125 (D). Error bars are SE. Reproduced from Calverley PMA et al Lancet 2009;374:68594 with permission.

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Table 2. Pooled Results for Lung Function Variables, Exacerbations and Other Clinical Outcomes from the M2-124 and M2-125 Studies Roflumilast vs. Roflumilast Placebo Placebo Lung function* 40 (6); 9 (5); Difference 48 Change in pre-bronchodilator n=1475 n=1511 (35 to 62); P<.0001 FEV1 (mL) Change in post-bronchodilator FEV1 (mL) Change in pre-bronchodilator FVC (mL) Change in Post-bronchodilator FVC (mL) Change in pre-bronchodilator FEV1/FVC (%) Change in post-bronchodilator FEV1/FVC (%) Change in pre-bronchodilator FEF2575 (mL/s) Change in post-bronchodilator FEF2575 (mL/s) Change in pre-bronchodilator PEF (L/min) Change in post-bronchodilator PEF (L/min) Exacerbations Moderate or severe (mean rate, per patient per year [95% CI]) Severe (mean rate, per patient per year [95% CI]) Moderate (mean rate, per patient per year [95% CI]) Treated with systemic corticosteroids, antibiotics, or both (mean rate, per patient per year [95% CI]) Median time to first exacerbation (moderate or severe; days [IQR]) Median time to second exacerbation (moderate or severe; days [IQR]) Further pre-specified secondary analyses TDI focal score* Change in C-reactive protein from baseline to last postrandomization visit (mg/L)* Time to mortality (days; mean, SD) Health utility assessment EQ-5D total score* 50 (6); n=1453 64 (10); n=1475 67 (10); n=1453 0.247 (0.147); n=1475 0.517 (0.141); n=1453 16 (4); n=1475 21 (4); n=1453 3.69 (1.02); n=1475 4.93 (1.05); n=1453 1.14 (1.051.24); n=717 0.12 (0.100.16); n=157 0.99 (0.911.08); n=624 1.13 (1.041.23); n=700 80.0 (28.0190.0) 177.0 (92.0262.0) 4 (6); n=1500 34 (10); n=1511 35 (10); n=1500 0.146 (0.1439); n=1511 0.090 (0.138); n=1500 4 (4); n=1510 2 (4); n=1499 0.17 (0.99); n=1511 0.22 (1.02); n=1500 1.37 (1.281.48); n=821 0.15 (0.120.19); n=198 1.19 (1.101.29); n=723 1.35 (1.261.46); n=798 71.0 (28.0160.0) 148.0 (85.0236.0) Difference 55 (41 to 69); P<.0001 Difference 98 (73 to 123); P<.0001 Difference 101 (77 to 126); P<.0001 Difference 0.393 (0.028 to 0.758); P=.0350 Difference 0.426 (0.077 to 0.776); P=.0169 Difference 20 (12 to 29); P<.0001 Difference 19 (10 to 29); P<.0001 Difference 3.53 (1.01 to 6.04); P=.0060 Difference 4.72 (2.13 to 7.30); P=.0004 RR 0.83 (0.75 to 0.92); P=.0003 RR 0.82 (0.63 to 1.06);P=.1334 RR 0.83 (0.75 to 0.92); P=.0007 RR 0.84 (0.76 to 0.92); P=.0003

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HR 0.89 (0.80 to 0.98); P=.0185 HR 0.79 (0.69 to 0.91); P=.0014

0.7 (0.1); n=1470 1.1; n=1371 206.1 (116.4); n=1537 0.0072 (0.0043); n=1470

0.4 (0.1); n=1514 1.1; n=1390 211.7 (125.1); n=1554 0.0049 (0.0042); n=1504

Difference 0.3 (0.1 to 0.4); P=0.0009 Difference 1.0 (0.9 to 1.1); P=0.8670 HR 1.1 (0.7 to 1.8); P=0.5452 Difference 0.0023 (0.0083 to 0.0129); P=0.6712

Data are mean (SE), mean difference (95% CI), or point estimate (95% CI), unless otherwise indicated. n=number of patients with data available (or, for exacerbations, number of patients with at least one exacerbation). Changes are from baseline. FEV1=forced expiratory volume in 1 s. FVC=forced vital capacity. FEF=forced expiratory flow. PEF=peak expiratory flow. RR=rate ratio. HR=hazard ratio. TDI=transition dyspnea index. EQ-5D=Euroquol 5-dimension. *Least squares means (SE). Estimated exacerbation rates were based on a Poisson regression model and HRs were based on a Cox proportional hazards model. Since patients might have had more than one type of exacerbation, the total of moderate and severe exacerbations is different from the total of exacerbations that were moderate or severe. Reproduced in part from Calverley PMA et al Lancet 2009;374:685-94 with permission

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147

Table 3.

Adverse events occurring in at least 25% of patients in one of the treatment groups of the M2124 and M2125 studies M2124 Placebo Roumilast vs. placebo (n = 755) (difference, 95% CI) 82 (11%) 26 (3%) 24 (3%) 50 (7%) 21 (3%) 17 (2%) 15 (2%) 22 (3%) 40 (5%) 15 (2%) 28 (4%) 8 (1%) 2 (< 1%) 18 (2%) 1.76% (4.90 to 1.38) 4.75% (2.28 to 7.21) 8.78% (6.04 to 11.53) 0.79% (1.91 to 3.49) 0.70% (2.38 to 0.98) 1.13% (0.66 to 2.92) 0.22% (1.35 to 1.79) 0.60% (1.30 to 2.50) 0.75% (3.05 to 1.56) 3.34% (1.34 to 5.35) 1.11% (2.99 to 0.78) 1.41% (0.04 to 2.86) 2.47% (1.13 to 381) 1.13% (0.70 to 2.95) M2125 Placebo Roumilast vs. placebo (n = 790) (difference, 95% CI) 122 (15%) 23 (3%) 20 (3%) 47 (6%) 38 (5%) 8 (1%) 16 (2%) 13 (2%) 24 (3%) 15 (2%) 20 (3%) 12 (2%) 5 (< 1%) 20 (3%) 4.26% (7.74 to 0.78) 5.70% (3.28 to 8.12) 5.82% (3.46 to 8.18) 1.45% (3.78 to 0.88) 0.57% (2.75 to 1.62) 2.20% (0.65 to 3.75) 1.19% (0.52 to 2.90) 1.31% (0.30 to 2.92) 0.34% (2.12 to 1.44) 0.80% (0.81 to 2.41) 0.22% (1.87 to 1.43) 0.79% (0.69 to 2.28) 1.30% (0.05 to 2.54) 0.99% (2.51 to 0.53)

Roumilast (n = 769) COPD Diarrhea Weight loss Nasopharyngitis Upper respiratory tract infection Headache Pneumonia Back pain Acute bronchitis Nausea Hypertension Insomnia Decreased appetite Inuenza 70 (9%) 63 (8%) 92 (12%) 57 (7%) 16 (2%) 26 (3%) 17 (2%) 27 (4%) 35 (5%) 41 (5%) 20 (3%) 19 (2%) 21 (3%) 27 (4%)

Roumilast (n = 778) 87 (11%) 67 (9%) 65 (8%) 35 (5%) 33 (4%) 25 (3%) 25 (3%) 23 (3%) 21 (3%) 21 (3%) 18 (2%) 18 (2%) 15 (2%) 12 (2%)

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Data are number (%), unless otherwise indicated. Adverse events were reported independently of the investigator causality assessments. Patients might have had more than one adverse event. COPD = chronic obstructive pulmonary disease. Incidence of adverse events in roumilast-treated patients in study M2125 is in a descending order. One patient was randomized twice and included twice in the safety analysis but only once in the efcacy analysis; four patients assigned to placebo were given roumilast instead and were included in the roumilast group for the safety analysis; 765 patients in the roumilast group and 758 in the placebo group were included in the efcacy analysis. Six patients assigned to placebo were given roumilast instead and were included in the roumilast group for safety analysis; 772 patients in the roumilast group and 796 in the placebo group were included in the efcacy analysis. Reproduced from Calverley PMA et al Lancet 2009;374:68594 with permission.

reported in efcacy studies of ICS in COPD (75). In each of the three most recent efcacy studies, the coprimary outcome was frequency of acute exacerbations. Signicant reductions of 34% were observed for roumilast 500 g in the Rabe study (71), in which it was not a primary outcome, and of 15% and 18% in each of the two studies reported by Calverley, in which it was a primary outcome (73). In the earlier study published by Calverley et al. in 2007, no reduction in exacerbations was seen in the roumilast-treated population as a whole (72). However, the exacerbation rate in the placebo-treated population in this study was unexpectedly low (only 0.92 exacerbations/patient/year). Furthermore, post hoc analysis suggested that severe exacerbations, namely those requiring systemic corticosteroids, were signicantly less common in the roumilast-treated arm (18.4% vs. placebo; p = 0.029). Moreover, in the very severe subgroup of patients, GOLD stage IV, roumilast-treated patients experienced 36% fewer exacerbations (p = 0.024). Thus, the exacerbation studies suggest that important reductions in both the frequency and severity of acute exacerbations can be achieved with the 500 g dose of roumilast, particularly in patients with more severe COPD, and that these reductions are similar to those that have been seen with other COPD treatments. Two additional efcacy and safety studies have recently been reported (76). These explored the effect of roumilast in patients who were concomitantly treated with other long-acting bronchodilators, namely salmeterol and tiotropium. The protocols, which were similar to each other as well as to the previously discussed long-term roumilast studies, enrolled patients with moderate-to-severe COPD, and called for a 4-week run-in period followed by random assignment of subjects to receive roumi148 April 2010

last 500 g plus salmeterol inhalation b.i.d. or matching placebo plus salmeterol inhalation b.i.d. in one study. In the other, subjects received roumilast 500 g plus tiotropium inhalation once daily or placebo plus tiotropium inhalation once daily. In this study, subjects were also required to have a history of using 28 puffs or more per week of a short-acting bronchodilator and symptoms of chronic bronchitis. Mean post-bronchodilator FEV1 was 55% of predicted in the roumilast plus salmeterol study and 56% in the roumilast plus tiotropium study (moderate to severe COPD). The studies concluded after 24 weeks and the primary outcome was the change in pre-bronchodilator FEV1 from the original baseline. A total of 744 subjects completed the salmeterol study; 642 completed the tiotropium study. In the salmeterol study, roumilast augmented the pre-bronchodilator FEV1 by a mean of 49 ml over subjects who received only salmeterol plus placebo; in the tiotropium study, the corresponding mean increase was 80 ml, both results being signicant at p < 0.0001. Other spirometric outcomes were similarly improved. In both studies, there were trends toward improvement in the number, severity, and time to rst acute exacerbation in the roumilast-treated subjects and these were sometimes statistically signicant, although neither study had been powered for the analysis of acute exacerbation outcomes. Similar trends toward improvement were seen in other efcacy outcomes. These two studies provide useful and practical information. Many patients with GOLD stage II or worse COPD will already be treated with a long-acting bronchodilator in accordance with the GOLD guidelines. If these do not provide sufcient clinical benet, the patient and practitioner should consider what additional treatments to use. It is therefore important to know

COPD: Journal of Chronic Obstructive Pulmonary Disease

that roumilast can provide further improvements in lung function and possibly reduce the frequency of acute exacerbations in patients already using a long-acting bronchodilator.

SAFETY OUTCOMES
The therapeutic precursor of synthetic PDE4 inhibitors, theophyllinea nonselective inhibitor of PDEs, has some major safety issues. It suffers from a narrow therapeutic margin, such that nausea and emesis occur at blood levels that are only marginally higher than those that are therapeutic. At only slightly higher levels than these therapeutic levels, serious and sometimes fatal adverse events such as tachyarrhythmias and convulsions are not rare. Of further concern, there is uncertainty about dosing as the metabolism and inactivation of theophylline varies substantially among patients and can also be altered by cigarette smoking, viral infections, and drugdrug interactions with many other agents that are commonly used in COPD patients. It is therefore necessary to measure blood levels of the drug from time to time. The seizures and arrhythmias with theophylline treatment are thought to be due to effects distinct from its PDE inhibition, and these side effects have not been seen in studies with selective PDE4 inhibitors to date. Nevertheless, because of this history, the safety prole of roumilast has been carefully scrutinized in each of the long-term clinical studies. The safety data reviewed here are taken from the reports of clinical trials, which include only the events that are relatively common. Less-common events that may be ascertained from pooled analysis of all studies were not possible from the review of published data. The total number of subjects that reported adverse events was nearly always greater in the roumilast group than the placebo group and, where different doses were employed, was dose-related. Diarrhea was always among the most signicant and frequently reported adverse effects, typically occurring in 89% of patients receiving 500 g of roflumilast, or two to four times more commonly than in patients receiving placebo (Table 3). Nausea also tended to be reported more often, in 35% of the roumilast-treated patients versus about 2% in the placebo arm. Studies in mice have provided indirect evidence that some of the gastrointestinal (GI) events of concern are due to the inhibition of PDE4D in the brain (77, 78). In this respect, it is interesting that cilomilast, whose development was discontinued due to a lack of consistent efcacy (adverse-effects were dose limiting), is 10-fold more selective for PDE4D than the other isoforms (34, 79). In contrast, roumilast (and the N-oxide) does not selectively target PDE4D (33) and this could explain, at least in part, why it is better tolerated. Weight loss was also a relatively frequent adverse event in the 1-year paired studies, occurring in 612% of roumilast subjects versus 13% in the placebo arm. The mean weight changes in that report were 2.09 kg and +0.08 kg in the roumilast and placebo groups, respectively, with most of the change occurring in the rst 6 months. The weight loss may be related to decreased appetite because this adverse event was also reported more commonly by patients in the active treat-

ment arm, as well as nausea and diarrhea. Other adverse events that were reported by more than 2.5% of patients, but not occurring more frequently (2.5%) in the roumilast arm were nasopharyngitis, inuenza, upper respiratory infection, acute bronchitis, back pain, pneumonia, hypertension, insomnia, and headache. (Acute exacerbations were recorded as adverse events, but have been addressed as an efcacy outcome in this review). Most adverse events that could be attributed to roumilast were said to have resolved during the course of the trial. However, it is likely that they contributed to withdrawals from the trials because withdrawals were frequently greater in the active treatment arms, the overall differences in withdrawal rates being almost entirely explained by withdrawals due to adverse events. One notes that withdrawal rates also tended to diverge in the rst month of a trial, suggesting that adverse events became evident shortly after subjects entered the treatment phase so that those subjects who were unable or unwilling to tolerate the adverse event withdrew. In the paired 1-year pivotal studies (73), withdrawals due to adverse events were more common in the active treatment arm than placebo group (101 for roumilast vs. 83 for placebo). By the end of the trial, the number of withdrawals due to GI adverse events was almost entirely compensated for by a similar reduction in withdrawals due to acute exacerbations in the active treatment group (49 for roumilast vs. 66 for placebo), thus, overall withdrawals were almost identical in the two arms. Among the safety concerns of theophylline are the dangerous neurologic and cardiovascular side effects, so it was important to include records of any such events in clinical trials of a PDE4 inhibitor. Mortality rates in the 1-year roumilast trials (73) were virtually identical in the treatment and placebo groups, both about 2%. Cardiovascular events were not different between active and placebo groups, being 7% and 8%, respectively. Similarly, arrhythmias were uncommon being reported in 1% and 0.4% of subjects, respectively. Headache and insomnia tended to be more common in the active treatment than placebo arms. Pneumonia has not been a frequent adverse event in any of the long-term studies and has not been more frequently reported with roumilast than with placebo administration. In preclinical animal toxicity studies, mesenteric vasculitis was seen in some rodents and cynomolgus monkeys following administration of relatively high doses of a PDE4 inhibitor (80). A similar pathology has been observed with inhibitors of other PDEs and with a variety of non-PDE vasodilators (80). There is uncertainty, therefore, whether these instances of arterial disease are species-specic or drug-specic. In humans, Merck withdrew a PDE4 inhibitor in development because of adverse GI effects and there were a few cases of fecal occult blood with GlaxoSmithKlines cilomilast. These events have resulted in requirements for extra vigilance including routine occult blood studies and colonoscopies in the development programs of some PDE4 inhibitors. Instances of GI disturbance are increased following the use of roumilast, as mentioned above, but none have reached the severity of serious bowel disease or malfunction. Nevertheless, clinical experience with roumilast exposure in patients with COPD has been relatively brief, 1 year
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or less, and conned to a relatively small number of patients in comparison with the number of patients who might receive it after approval, so caution is warranted. A nal safety question concerns the potential for unfavorable interaction of roumilast with other drugs. Patients with COPD are known typically to have multiple co-morbidities for which they may receive other medications. Roumilast is metabolized by the CYP3A4 and CYP1A2, and its primary metabolite is also pharmacologically active. Thus, inducers of these systems, for example, rifampicin, have the potential to increase roumilast CL lowering its efcacy. Correspondingly, agents that are metabolized by the same system could compete with roumilast and delay its inactivation, in effect raising its level. A number of studies have been performed to evaluate such drugdrug interactions and their potential for adverse reactions (5967). The results published so far indicate that there is not a substantial effect of a range of potential agents and conditions on roumilast levels. Thus, no dose adjustments of roumilast are likely to be needed when co-administered with other drugs commonly used in COPD or in patients with liver failure. Equally, roumilast blood levels are unaffected by meals or smoking (40).

DISCUSSION
The clinical studies reviewed here strongly suggest that roumilast has clinical efcacy in COPD by a mechanism unrelated to bronchodilation. It is likely, therefore, that the mechanism of action of roumilast is due to the suppression of lung inammation which, if so, would suggest it may be disease modifying in COPD. The clearest evidence of this would be a reduction in mortality or a decrease in the rate of decline of lung function. Conclusive demonstration of either of these outcomes generally requires a large prospective study carried out over several years. The Lung Health Study, for example, enrolled 5,887 subjects and followed them for 5 years. Before roumilast will be subjected to such a study, highly suggestive indications of its anti-inammatory potential and disease modication will be needed. In support of the anti-inammatory properties of roumilast, we have cited evidence that roumilast, like some other PDE4 inhibitors, suppresses the release of a broad range of inammatory mediators from cells in vitro and reduces the recovery of inammatory mediators and cells from the airways after challenges with pro-inammatory agents. Roumilast does not cause signicant short-term relaxation of airways smooth muscle in vitro or rapid bronchodilation in humans with COPD. Yet airway function does improve with roumilast following regular administration over a period of days or weeks and declines over a similar period when withdrawn. These ndings can be most readily explained by an anti-inammatory effect. Of the clinical studies reviewed here, those outcomes that are most supportive of an anti-inammatory action are the improvement in pre-bronchodilator FEV1 and the reduction in the incidence of acute exacerbations, both of which were primary outcomes in the most recent roumilast studies (73,
150 April 2010

76) and both outcomes met predetermined goals. Pre-treatment FEV1 has been developed as an anti-inammatory outcome in other studies, particularly those of LABA-ICS combinations in which the FDAs combination rule requires demonstration that each component contributes to the overall efcacy. As stated earlier, the magnitude of the increase in FEV1 due to roumilast, between 40 and 100 ml, is not as great as would be required for a bronchodilator to be considered effective. But in the context of a study population that was sometimes selected for their non-responsiveness to albuterol and that was allowed to use long-acting bronchodilators, the result can be considered to indicate a meaningful improvement in lung function. The reduction in the incidence of acute exacerbations, while not seen in every study, was substantial and statistically signicant in both long-term studies that were powered for AECOPD as a co-primary outcome. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and with more severe exacerbations. A reduction in AECOPDs has been reported for LABAs, LAMAs, ICSs, and their combinations, as well as theophylline (3, 1116, 81). We do not have a clear understanding of the mechanism by which any of these agents affects the frequency of AECOPDs. However, as inammation is intensied during AECOPD events, a reduction in their frequency and severity would seem to be a requirement for an anti-inammatory agent. Concerning the safety of roumilast, early study dropouts have nearly always been more frequent in the active treatment group compared to the placebo arm and this can be largely attributed to adverse GI events. In contrast, dropouts after the rst few weeks were more common in the placebo groups and may be related to the lack of efcacy with control treatments. Adverse effects associated with roumilast more commonly than control and their approximate frequencies include diarrhea (9%), nausea (5%), and weight loss (12%). The latter two events are a feature of PDE4 inhibition, possibly of the PDE4D isoform, and have been problematic with theophylline and all subsequent non-selective PDE4 inhibitors that have entered clinical trials. While the clinical developments of several PDE4 inhibitors have been discontinued because of GI adverse events, roumilast appears to be among the least problematic in this respect. We have recently reviewed strategies that are being employed by pharmaceutical companies to increase the therapeutic ratio of PDE4 inhibitors (82). With the recent elucidation of the cocrystal structure of the PDE4 active site (83), it may become possible to design agents that avoid the GI problems altogether. Roumilast has two distinct advantages over theophylline. First, it lacks the dangerous induction of seizures and proarrhythmic side effects of theophylline (84). Second, its elimination and pharmacokinetics are not signicantly altered by food, tobacco smoking, and by the many drugs that alter the pharmacokinetics of theophylline (84). Rifampicin is the only drug known to accelerate the inactivation of roumilast. The phenomenon of fast- and slow-inactivators of the drug does not occur, nor are dose adjustments required when fever occurs. Measurements of blood levels are not required. Indeed, the mechanisms of action of roumilast and theophylline differ

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to such an extent that the former should not be considered a novel formulation of the latter. If roumilast is approved for routine use in COPD, we expect it to nd its role initially as a substitute or alternative for ICSs in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations. It may be used as a supplementary drug when symptoms are not adequately controlled by a long-acting bronchodilator alone. Whether it will have a role as a supplement to an ICS-LABA combination therapy, or indeed to supplant it, remains to be determined.

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ACKNOWLEDGEMENTS
Dr. Nicholas Gross has received honoraria from Nycomed and Forest, the manufacturers of roumilast. He also received honoraria from Dey LP, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Pzer, Novartis, and Almirall. Dr. Mark Giembycz has received honoraria from Nycomed and Forest, the manufacturers of roumilast. He also received honoraria and/or unrestricted educational grants from AstraZeneca, Gilead Sciences, GlaxoSmithKline, Otsuka, Proctor and Gamble, SanoAventis, Schering-Plough and the GSK (Canada)/Collaborative Innovation Research Fund. Dr. Stephen Rennard has received honoraria from Nycomed and Forest, the manufacturers of roflumilast. He has also received honoraria and grants from American Board of Internal Medicine, American College of Chest Physicians, Almirall, APT Pharma/Britnall, AstraZeneca, American Thoracic Society, Boehringer Ingelheim, California Allergy Society, Chiesi, COPDForum, Creative Educational Concept, France Foundation, Gerson, GlaxoSmithKline, Hoffmann LaRoche, Information TV, Novartis (Horsham), Oriel Therapeutics, Pearl Therapeutics, Pulmatrix, Schering Plough and UBC.

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Declaration of interest
The authors were responsible for the content and writing of the paper. Each of the authors contributed equally to the writing of the manuscript. Editorial assistance was provided by Young Yoo, Autumn Kelly, Jennifer Jaworski, and Biplob Dass of Prescott Medical Communications Group. The manuscript was submitted to Nycomed and Forest, the manufacturers of roumilast, for review of its factual content only.

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