Profilo di prodotto.

Profilo di prodotto

Il ruolo della PDE4 nell’infiammazione della BPCO
PDE4 inhibition P P PDE4 Speaker Notes Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that catalyse the degradation of cyclic purine (cAMP, cGMP) nucleotides to their corresponding 5’-nucleotide monophosphates.1,2 PDE4 is an enzyme which regulates the cyclic AMP (cAMP) metabolism in pro-inflammatory and immune cells.2 Activation of adenylate cyclase (AC) by cell surface receptors leads to formation of cAMP from ATP. PDE4 catalyses the breakdown of cAMP to its inactive form, AMP.1 By inhibiting the PDE4 enzyme, PDE4 inhibitors reduce the degradation of cAMP, maintaining high levels of cAMP and reducing the pro-inflammatory functions of cells.1,2 References 1. Rabe KF. Roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Rev Resp Med 2010;4:543–555. 2. Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast – A selective oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulmonary Pharm Therapeutics 2010;23:235–256. Inflammation Adapted from Rabe KF. Expert Rev Resp Med 2010;4: 543–555. 2

L’enzima PDE4 è espresso nelle cellule infiammatorie coinvolte nella BPCO
LEUKOCYTE PDE ISOFORM STRUCTURAL CELLS PDE ISOFORM Mast cells , 7 Airway smooth muscle , 2, 3, 4, 5, 7 Eosinophils , 7 Epithelial cells , 2, 3, 4, 5, 7, 8 Neutrophils , 7 Endothelial cells , 3, 4, 5 Monocytes , 3, 4, 7 Speaker notes The PDE superfamily contains 11 isoforms. PDE4 is the cAMP-specific isoform and is the predominant isoform expressed in immune and inflammatory cells. It is the major regulator of cAMP metabolism in almost every pro-inflammatory and structural cell involved in the chronic inflammation underlying COPD. PDE4 was identified as a potential therapeutic target for reducing COPD-specific inflammation many years ago. Reference Giembycz MA. Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis 2002;57:48–64. Sensory nerve , 3, 4 Macrophages , 3, 4, 5, 7 Cholinergic nerves , 3, 4 T-cells (CD4+ and CD8+) , 4, 7 Adapted from: Giembycz MA. Monaldi Arch Chest Dis 2002;57:48-64. 3

I potenziali effetti terapeutici degli inibitori della PDE4
Neutrophil Alveolar Macrophage CD4+ T-Cell PDE4 Inhibitors Pro-inflammatory Cells Eosinophil Epithelial Cell Bronchoconstriction SM Proliferation Speaker notes The mode of action of PDE4 inhibitors is different to that of inhaled bronchodilators. This study in 21 patients with COPD showed the effects of the PDE4 inhibitor cilomilast administered with or without the short-acting bronchodilator salbutamol and/or anti-cholinergic ipratropium. It showed that a single dose of cilomilast had no acute bronchodilator effect. Like cilomilast, roflumilast has no acute bronchodilator effect, but its anti-inflammatory mode of action works over time to improve lung function. Reference Grootendorst DC, Gauw SA, Baan R, et al. Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15mg), induce bronchodilation in patients with chronic obstructive pulmonary disease? Pulm Pharmacol Ther 2003;16: 4

Roflumilast: riduzione dei livelli di marker infiammatori nell’espettorato
Total leukocyte count IL-8 Neutrophil elastase Speaker notes In the 4-week crossover study, sputum samples from patients who received roflumilast had significantly lower leukocyte counts, including eosinophils (p=0.0005) and neutrophils (p=0.0017), than samples from patients treated with placebo. In addition, significantly lower levels of inflammatory mediators, including IL-8 and neutrophil elastase, were observed in sputum from roflumilast-treated patients, compared with placebo-treated patients. Reference Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophils and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62;1081–1087. Placebo Roflumilast Grootendorst DC, Gauw SA, Verhoosel RM, et al. Thorax 2007;62; 5

Concetti chiave PDE4 was identified as a therapeutic target for anti-inflammatory agents many years ago, since it is expressed in many inflammatory cells Early PDE4 inhibitors were limited by low potency and hampered by serious side effects such as nausea and vomiting Current PDE4 inhibitors such as roflumilast have greater affinity for PDE4 and fewer side effects than earlier compounds Roflumilast is the first PDE4 inhibitor to be successfully developed for the reduction of inflammation in COPD 6

Farmacocinetica di roflumilast
Roflumilast N-oxide Roflumilast CYP3A4/ 1A2 Plasma concentrations of roflumilast and roflumilast N-oxide following repeated dosing of 500µg-1 (OD) roflumilast over 7 days in humans Plasma concentration (nM) 4 8 12 16 20 24 0.01 0.1 1 Time (h) Roflumilast Roflumilast N-oxide <50% PDE4 inhibition >50% PDE4 inhibition IC50 (PDE4) Roflumilast N-oxide accounts for clinical efficacy and once daily dosing Hatzelmann A, Morcillo EJ, Lungarella G, et al. Pulmonary Pharm Therapeutics 2010;23: 7

Conclusione degli studi pre-clinici
ROFLUMILAST is an oral, once-daily PDE4 inhibitor Favourable biochemical and PK profile Reduces lung inflammation in various models in vitro and in vivo Reduces oxidative stress in vitro May improve mucociliary clearance in vitro settings Reduces alveolar destruction in vivo 8

Roflumilast nella BPCO: dal meccanismo d‘azione ai benefici clinici
Rate of Acute Exacerbations Impediment of Expiratory Flow N Cl O F H Mucociliary malfunction Innate defense Small airway thickening Emphysematous destruction COPD Oxidative stress Inflammation ROFLUMILAST Roflimulast reduces the rate of COPD exacerbations and improves airflow clinically. This slide shows the potential impact on the various parts of the inflammatory pathway that may be giving this clinical benefit. This presentation outlines the possible scientific explanations underlying these effects. ROFLUMILAST ROFLUMILAST ? ROFLUMILAST 9

Roflumilast: gli studi registrativi
Early phase III studies1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) Speaker notes The pivotal phase III studies were designed to confirm the effects of roflumilast in the patient population identified in the analysis of the early studies. References Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161. Rennard SI, Calverley PMA, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011,12:18 3 Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. 4 Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. LABA = Long-acting β2-agonist LAMA = Long-acting muscarinic antagonist 1. Calverley PMA, et al. Am J Respir Crit Care Med 2007;176: Rennard et al. Respiratory Research 2011,12: Calverley PMA, et al. Lancet 2009;374:685–694. 4.Fabbri LM, et al. Lancet 2009;374: 10

Gli studi M2-111 e M2-112: disegno dello studio
Follow-up 30 days Roflumilast 500µg o.d. Placebo o.d. Treatment 52 weeks R VE Visit 0 Follow-up Baseline 4 weeks Speaker notes In two replicate randomized, placebo-controlled, double-blind, parallel-group trials, 2686 patients (1173 in M2-111) and 1513 in M2-112) with COPD (post-bronchodilator FEV1 ≤50% predicted; post-bronchodilator FEV1:FVC ratio ≤70%) were randomized to roflumilast or placebo once-daily for 12 months. It is important to note that unlike the pivotal 12-month phase III studies, patients in this study were not required to have symptoms of chronic bronchitis or a history of exacerbations. References Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161. Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Placebo o.d. Allowed concomitant medication: ICSs (≤2000µg BDP or equivalent) Approximately 60% of all patients were on ICS treatment R = randomization ICS = Inhaled corticosteroids VE = Visit end BDP = Beclomethasone dipropionate o.d. = once daily Calverley PMA, Sanchez-Toril F, McIvor A, et al. Am J Respir Crit Care Med 2007;176: 11

Speaker notes The two 12- month, randomized, double-blind, parallel group studies were identical in study design with the exception of the classification used for COPD severity. For M2-111, American Thoracic Society diagnostic criteria were used and for M2-112, the GOLD diagnostic criteria. Each study began with a 4 week, single-blind run-in period during which patients received placebo. Patients were then randomly assigned to roflumilast 500 µg once daily or placebo for 52 weeks. Patients were allowed to continue treatment with SAMA and ICS (≤2000µg beclomethasone dipropionate or equivalent) if taken on a regular basis at a constant daily dose for at least 3 months prior to study entry. About 60% of patients concomitantly received ICS during the studies. The definition of smoking history used in these studies was as follows: Current or ex-smoker (stopped smoking ≥1 year ago) with a smoking history of ≥10 pack years. ‘Clinically stable’ was defined as no exacerbation and no change in COPD treatment within 4 weeks prior to first baseline visit. Some of the main exclusion criteria were: COPD exacerbation indicated by a treatment with systemic glucocorticosteroids not stopped 4 weeks prior to the baseline visit B0 Lower respiratory tract infection not resolved 4 weeks prior to the baseline visit B0 Diagnosis of asthma and/or other relevant lung disease. It is important to note that unlike the pivotal 12-month phase III studies, patients in this study were not required to have symptoms of chronic bronchitis or a history of exacerbations. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011,12:18. Gli studi M2-111 e M2-112 Two 12-month randomized, double-blind, parallel-group studies Following a 4-week, single blind run-in period, patients were randomized to receive roflumilast 500µg or placebo once daily for 52 weeks Allowed concomitant medication: ICS and SAMA (if used at stable doses before study entry) Key inclusion criteria: Patients ≥ 40 years, current or ex-smoker (≥ 10 pack years) COPD as defined by ATS (M2-111) or GOLD (M2-112) Clinically stable with unchanged COPD treatment within 4 weeks of baseline Post-bronchodilator FEV1 ≤ 50% predicted; post-bronchodilator FEV1:FVC ratio ≤ 0.70 No history of exacerbations required ICS = Inhaled corticosteroids - SAMA = Short-acting antimuscarinic antagonists FEV1 = Forced expiratory volume in 1 second - FVC = Forced vital capacity Rennard et al, Respiratory Research 2011; 12: 18. 12

Speaker notes FEV1 reversibility to short-acting beta2-agonists was similar in both treatment groups. As the inclusion criteria of FEV1 reversibility to short-acting beta2-agonists ≤15% was defined only in study M2-112, mean reversibility was lower in M2-112 (11%) than in M2-111 (19%). All other characteristics were comparable between groups. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Studi M2-111 e M2-112: demografia e caratteristiche basali dell’analisi congiunta Data are expressed as mean (SD), unless otherwise stated; SAMA = Short-acting antimuscarinic antagonists FEV1 = Forced expiratory volume in 1 second; FVC = Forced vital capacity Rennard et al, Respiratory Research 2011; 12: 18. 13

Speaker notes For the overall population, pre-bronchodilator and post-bronchodilator FEV1 improved with roflumilast compared to placebo by 51 mL (p<0.0001) and 53 mL (p<0.0001). The improvement was evident at Week 4 (first measured time point) and maintained throughout the 52 weeks of the studies. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Risultati dell’analisi congiunta: miglioramento del FEV1 pre- e post-broncodilatore Pre-bronchodilator FEV1 Post-bronchodilator FEV1 FEV1 = Forced expiratory volume in 1 second Rennard et al, Respiratory Research 2011; 12: 18. 14

Speaker notes No statistically significant differences in exacerbation rate (moderate or severe) were seen between roflumilast and placebo when the early phase III clinical studies were analyzed individually. The pooled analysis revealed a statistically significant reduction of 14.3% (95% CI -25 to -2; p=0.026) in the exacerbation rate. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Risultati dell’analisi congiunta: riduzione del tasso di riacutizzazioni Study M2-111 Study M2-112 Pooled analysis post-hoc *Moderate or severe exacerbations treated with systemic steroids or leading to hospitalization or death Rennard et al, Respiratory Research 2011; 12: 18. 15

Le analisi per identificare i pazienti responsivi
Speaker notes In the pooled analysis of M2-111 and M2-112, the effects of roflumilast on the co-primary endpoints (pre-bronchodilator FEV1 and exacerbation rate) were analyzed based on a number of patient characteristics. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Le analisi per identificare i pazienti responsivi The co-primary endpoints (pre-bronchodilator FEV1 and rate of moderate or severe exacerbations per patient per year) were analyzed additionally in subgroups stratified by: Sex Smoking status Concomitant use of ICS Concomitant use of anticholinergics Study completion status COPD severity (severe, very severe) History of chronic bronchitis or emphysema (investigator diagnosed) Cough/sputum score one week before randomization ICS = Inhaled corticosteroids Rennard et al, Respiratory Research 2011; 12: 18. 16

Roflumilast: riduzione delle riacutizzazoni in base ai sottogruppi
Speaker notes Among the variables analyzed, the presence of chronic bronchitis (symptoms of chronic cough and sputum) was found to correlate with a greater reduction in exacerbation rate compared with the absence of these symptoms Presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001) Presence of cough (20.9% decrease, p = 0.006) Presence of sputum (17.8% decrease, p = 0.03) Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Roflumilast: riduzione delle riacutizzazoni in base ai sottogruppi Rennard et al, Respiratory Research 2011; 12: 18. 17

Patients with chronic brochitis with/without emphysema
Speaker notes Among the variables analyzed, the presence of chronic bronchitis (symptoms of chronic cough and sputum) was found to correlate with a greater reduction in exacerbation rate compared with the absence of these symptoms. Overall, patients with chronic bronchitis experienced a 26.2% reduction in exacerbations compared with 1.1% reduction in patients with emphysema only and no chronic bronchitis. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18 . L’effetto di roflumilast sulle riacutizzazioni nei pazienti con bronchite cronica (tosse ed espettorato) Patients with emphysema Patients with chronic brochitis with/without emphysema All patients Rennard et al, Respiratory Research 2011; 12: 18. 18

L’evoluzione del programma di sviluppo clinico
IDENTIFICATION OF TARGET PATIENT POPULATION Confirmatory 1-yr pivotal studies M2-124, M2-125 Subgroup analyses of early phase III studies M2-111, M2-112 Speaker notes Based on findings from the early clinical studies, patients with chronic bronchitis were identified as the target patient population for the pivotal phase III studies. Patients also had severe airflow limitation and a history of exacerbations, two additional factors known to increase the risk of exacerbations in patients with COPD. Hypothesis Generation Severe/very severe patients History of chronic cough and sputum History of exacerbations 19

Early phase III studies1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) Speaker notes The pivotal phase III studies were designed to confirm the effects of roflumilast in the patient population identified in the analysis of the early studies. References Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161. Rennard SI, Calverley PMA, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011,12:18 3 Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. 4 Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. LABA = Long-acting β2-agonist LAMA = Long-acting muscarinic antagonist 1. Calverley PMA, et al. Am J Respir Crit Care Med 2007;176: Rennard et al. Respiratory Research 2011,12: Calverley PMA, et al. Lancet 2009;374:685–694. 4.Fabbri LM, et al. Lancet 2009;374: 20

Gli studi M2-124 e M2-125 (12 mesi di durata)
Single-blind Double-blind, randomized, parallel group Follow-up 4 weeks Run-in 4 weeks Roflumilast 500µg o.d. Treatment 52 weeks Visit 0 R VE Follow-up Speaker notes Patients were randomly assigned to receive roflumilast (500μg once daily) (n=1537) or placebo (n=1554) for 52 weeks. After randomization, patients were assessed every 4 weeks up to week 12, and every 8 weeks thereafter. Patients could use short-acting β2-agonists as needed and could continue treatment with long-acting β2-agonists (LABA) or short-acting anti-cholinergic drugs at stable doses. However, inhaled corticosteroids (ICS) and long-acting anti-cholinergic drugs were not allowed during the study. Analysis was by intention to treat. Patients were stratified according to smoking status, previous use of inhaled corticosteroids (stopped before study start) and treatment with LABAs. Data from the two studies were analyzed separately and in a pooled analysis. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Placebo o.d. Concomitant medication: LABA or short-acting anticholinergics Targeting a proportion of ~ 50% of all patients on LABA R = randomization VE = Visit end o.d. = Once daily LABA = Long-acting β2-agonist Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 21

Studi M2-124 e M2-125: popolazione in studio ed endpoint clinici
TWO PIVOTAL 12-MONTH STUDIES PATIENTS (POOLED STUDY POPULATION N=3091): COPD associated with chronic bronchitis* History of exacerbations Severe airflow limitation (FEV1 ≤50% of predicted) TREATMENTS: Once-daily roflumilast 500µg or placebo Concomitant use of LABAs or regular short-acting bronchodilators allowed PRIMARY ENDPOINTS: Pre-bronchodilator FEV1 Exacerbation rate (moderate to severe) Speaker notes In response to observations from the early clinical studies, the pivotal 12-month studies2 were designed to investigate the effects of roflumilast in patients with severe COPD, symptoms of chronic cough and sputum, and a history of exacerbations. Patient inclusion criteria included diagnosed COPD, severe airflow limitation, age ≥40 years, bronchitic symptoms, and a history of exacerbations. Patients were randomly assigned to receive roflumilast (500μg once daily) (n=1537) or placebo (n=1554) for 52 weeks. Primary endpoints were change in pre-bronchodilator FEV1 and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. Patients were stratified according to smoking status, previous use of inhaled corticosteroids (ICS, stopped before study start) and treatment with LABAs. Data from the two studies were analyzed separately and in a pooled analysis. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. *Chronic productive cough for 3 months in each of the 2 years prior to baseline visit LABA: Long-acting β2-agonist FEV1 = Forced expiratory volume in one second Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 22

Demografia e caratteristiche dei pazienti al basale
Speaker notes Patients in the roflumilast and placebo groups of the 12-month clinical studies had similar characteristics at baseline. Around 60% of patients had severe COPD, with around 30% having very severe COPD, as defined by GOLD stages. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Demografia e caratteristiche dei pazienti al basale Data are expressed as mean (SD), unless otherwise stated FEV1 = Forced expiratory volume in 1 second FVC = Forced vital capacity Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 23

Speaker notes In a pooled analysis of the two 12-month clinical studies, roflumilast was associated with a mean 48mL improvement in pre-bronchodilator FEV1 levels compared with placebo (p<0.0001). This was the co-primary endpoint in the two 12-month clinical studies. In addition, roflumilast significantly improved post-bronchodilator FEV1 levels compared with placebo (mean change of 55mL, p<0.0001). The anti-inflammatory mode of action of roflumilast is different to that of bronchodilators. This means that roflumilast offers additional benefits for patients when added to bronchodilator therapy. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Roflumilast: aumento significativo della funzionalità respiratoria dopo 12 mesi di terapia con roflumilast Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 24

Co-primary endpoint: Exacerbation rate
Roflumilast: riduzione significativa del tasso di riacutizzazioni moderate e gravi Co-primary endpoint: Exacerbation rate Speaker notes In a pooled analysis of the total population of the two 12-month clinical studies, roflumilast significantly reduced the rate of moderate or severe exacerbations by 17% compared with placebo (p=0.0003). In addition to a significantly lower rate of exacerbations following roflumilast treatment, the time to onset of an exacerbation was significantly longer in patients receiving roflumilast than in patients receiving placebo (Hazard ratio 0.89, p=0.0185). Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 25

Speaker notes These data were calculated in a post hoc analysis of pooled data from the 12-month roflumilast clinical studies. Roflumilast significantly reduced the mean exacerbation rate (per patient per year) in all patient groups. However, the effects of roflumilast were greatest in patients with ≥2 exacerbations in the previous year (1.51 with roflumilast vs 1.95 with placebo, a difference of -22.3%). These data confirm that roflumilast has the greatest benefits in patients with a history of frequent exacerbations. Reference Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011, erj d; accepted manuscript, DOI: / Roflumilast: vantaggi clinici superiori nei pazienti con storia di frequenti riacutizzazioni M2-124 and M2-125 pooled post hoc analysis Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560 26

Gli studi M2-124 e M2-125: roflumilast nei pazienti trattati con LABA
Single-blind Double-blind, randomized, parallel group Follow-up 4 weeks Run-in 4 weeks Roflumilast 500µg o.d. Treatment 52 weeks Visit 0 R VE Follow-up Speaker notes Patients enrolled in these 12-month studies were allowed concomitant medications, including short-acting anticholinergics at regular dosing and LABAs, in order to reflect common clinical practice. Patients were stratified according to treatment with LABAs. Approximately 50% of patients used a LABA concomitantly with study medication. Approximately 40% of patients in both treatment arms used a short-acting bronchodilator. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Placebo o.d. Concomitant medication: LABA or short-acting anticholinergics Targeting a proportion of ~ 50% of all patients on LABA R = randomization VE = Visit end o.d. = Once daily LABA = Long-acting β2-agonist Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 27

Miglioramento della funzionalità respiratoria nei pazienti trattati con roflumilast in aggiunta a LABA Speaker notes In addition, analysis of pooled data from M2-124 and M2-125 pivotal 12-month clinical studies revealed the effects of roflumilast on lung function in the LABA subgroup. Compared with placebo, treatment with roflumilast resulted in a significant improvement in pre- and post-bronchodilator FEV1 in all patients, irrespective of whether they were also receiving a concomitant LABA, suggesting that the beneficial effect of roflumilast on lung function is additive to that achieved with bronchodilators. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. LABA = Long-acting β2-agonist FEV1 = Forced expiratory volume in one second Calverley PMA, Rabe,KF, Goehring UM et al. Lancet 2009;374:685–694. 28 28

Riduzione delle riacutizzazioni moderate e gravi
M2-124 & M2-125 – pooled analysis All LABA: Yes LABA: No 2  = % (CI -25;-8) p =  = % (CI -31;-9) p=0.0011  = % (CI -26;-1) p=0.0387 Mean rate of exacerbations (moderate or severe) per patient per year 1 Key Message: Roflumilast reduced the rate of moderate or severe exacerbations compared with placebo in all patients irrespective of concomitant treatment with long acting bronchodilators. LABAs were used by 749 (49%) patients in the roflumilast group and 793 (51%) patients in the placebo group in the pooled data set. The change in exacerbation rate with roflumilast vs placebo was –16.9% in the overall population and was not influenced by LABA use, with changes in exacerbation rates of –20.7% and –14.6% in the subgroups of LABA users and non-LABA users, respectively. The larger decrease in exacerbations for the patients who received LABA could be explained by these patients being more symptomatic and therefore were at higher risk of exacerbations. This is also indicated by the higher exacerbation rate in the placebo group in LABA-treated patients versus non LABA-treated patients (1.55 versus 1.17) and thus, treatment effects on exacerbations are easier to demonstrate in these patients. 1.37 1.14 1.55 1.23 1.17 1.00 n: placebo roflumilast Rabe KF BrJ Pharmacol 2011. 29 29

Pre-specified analysis of exacerbation rate in LABA subgroup
Speaker notes Approximately 50% of patients in the two 12-month studies continued to use LABAs throughout the roflumilast treatment period.1 Roflumilast reduced the rate of exacerbations irrespective of whether patients were taking concomitant LABA.1 A pre-specified analysis of the effects of roflumilast in the LABA subgroup, revealed approximately 21% lower exacerbation rate in patients receiving roflumilast relative to placebo (p=0.0011).2 R e f e r e n c e s C a l v e r l e y P M A , R a b e K F , G o e h r i n g U M , e t a l . R o f l u m i l a s t i n s y m p t o m a t i c c h r o n i c o b s t r u c t i v e d i s e a s e : t w o r a n d o m i z e d c l i n i c a l t r i a l s . L a n c e t ; : – R a b e K F . U p d a t e o n r o f l u m i l a s t , a p h o s p h o d i e s t e r a s e 4 i n h i b i t o r f o r t h e t r e a t m e n t o f c h r o n i c o b s t r u c t i v e p u l m o n a r y d i s e a s e . B r J P h a r m ; : Roflumilast e LABA: maggiore riduzione delle riacutizzazioni moderate e gravi Pre-specified analysis of exacerbation rate in LABA subgroup LABA = Long-acting β2-agonist Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560. 30

Early phase III studies1,2 M2-111 (n=1173) M2-112 (n=1513) Pivotal studies3 M2-124 (n=1523) M2-125 (n=1568) Supplementary 6-month studies4 M2-127 add on to LABA (n=933) M2-128 add on to LAMA (n=743) Speaker notes The supplementary phase III studies were designed to examine the effects of roflumilast when taken on top of long-acting bronchodilators for treatment of COPD. References Calverley PMA, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154–161. Rennard SI, Calverley PMA, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011;12:18. 3 Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. 4 Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. LABA = Long-acting β2-agonist LAMA = Long-acting muscarinic antagonist 1. Calverley PMA, et al. Am J Respir Crit Care Med 2007;176: Rennard et al. Respiratory Research 2011,12: Calverley PMA, et al. Lancet 2009;374:685– Fabbri LM, et al. Lancet 2009;374: 31

Studio M2-127: roflumilast e salmeterolo
Speaker notes P a t i e n t s w e r e r a n d o m l y a s s i g n e d t o r e c e i v e r o f l u m i l a s t ( μ g ) o r p l a c e b o o n c e d a i l y o n t o p o f s a l m e t e r o l ( a L A B A ) , f o r w e e k s . Reference Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. Studio M2-127: roflumilast e salmeterolo Single-blind Double-blind, randomized, parallel group Follow-up 4 weeks Run-in 4 weeks Salmeterol 50µg b.i.d. + roflumilast 500µg o.d. Treatment 24 weeks Visit 0 R VE Follow-up Salmeterol 50µg b.i.d. + placebo o.d. R = randomization VE = Visit end b.i.d. = twice daily o.d. = Once daily Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 32

Studio M2-128: roflumilast e tiotropio
Speaker notes P a t i e n t s w e r e r a n d o m l y a s s i g n e d t o r e c e i v e r o f l u m i l a s t ( μ g ) ( n = ) o r p l a c e b o ( n = ) o n c e d a i l y o n t o p o f t i o t r o p i u m , f o r w e e k s . Reference Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. Studio M2-128: roflumilast e tiotropio Single-blind Double-blind, randomized, parallel group Follow-up 4 weeks Run-in 4 weeks Tiotropium 18µg + roflumilast 500µg o.d. Treatment 24 weeks Visit 0 R VE Follow-up Tiotropium 18µg + placebo o.d. R = randomization VE = Visit end b.i.d. = twice daily o.d. = Once daily Fabbri LM, Calverley PMA, Izquierdo-Alonso JL , et al. Lancet 2009;374: 33

Studi M2-127 e M2-128: aumento del FEV1 post-broncodilatore
M2-127 salmeterol M2-128 tiotropium 100  = 60 ml (CI 38;82) p <  = 81 ml (CI 51;110) p < 80 n=364 n=452 60 Mean change in postFEV1 [ml] 40 Key Message Significant improvements in lung function (post-bronchodilator FEV1) were achieved when roflumilast was used concomitantly with salmeterol or tiotropium as underlying maintenance treatment, compared with either long-acting bronchodilator alone Roflumilast used concomitantly with salmeterol or tiotropium significantly increased post-bronchodilator FEV1 compared with salmeterol or tiotropium alone in the respective studies. The mean change for roflumilast in M2-127 and M2-128 was 68ml and 74ml respectively which resulted in a treatment difference between roflumilast and placebo of 60ml in study M2-127 and 81ml in study M2-128 Study medication was to be withheld in the morning of study visit days, as was salmeterol for 10 hours and tiotropium for 20 hours, respectively, and reliever medication for at least 4 hours prior to pulmonary function tests. The post-bronchodilator measurement was performed directly after the pre-bronchodilator test by spirometry 30 minutes after inhalation of 4 inhalations of 100 microgram of salbutamol/albuterol (total dose 400 microgram). This test would be discriminative of whether the effect of roflumilast on lung function was independent of bronchodilation by smooth muscle relaxation. 20 n=460 8 68 n=363 74 -20 -7 salmeterol or tiotropium + placebo salmeterol or tiotropium + roflumilast 500 µg Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703. 34 34

Speaker notes In each study, roflumilast had an additive effect, improving lung function on top of the benefits already achieved with bronchodilator therapy. Reference Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharm 2011;163:53-67. Miglioramento della funzionalità respiratoria con roflumilast in aggiunta ai broncodilatatori a lunga durata d’azione LABA = Long-acting β2-agonist SAMA = Short-acting muscarinic antagonist Rabe KF. Br J Pharm 2011;163:53-67. 35

Studi M2-111 e M2-112: analisi del sottogruppo di pazienti trattati con ICS
Speaker notes In the pooled analysis of M2-111 and M2-112, 1622 patients were taking concomitant Inhaled corticosteroids. Patient baseline characteristics were similar in both groups. The ICS-treated patients had slightly more severe COPD, indicated by lower lung function. This may be partially explained by the fact that concomitant ICS treatment selects for patients with a more advanced stage of the disease. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. Data are expressed as mean (SD), unless otherwise stated FEV1 = Forced expiratory volume in 1 second FVC = Forced vital capacity Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. 36

Roflumilast e ICS: riduzione del tasso di riacutizzazioni
M2-111 and M2-112 pooled post hoc analysis Speaker notes In the pooled analysis of studies M2-111 and M2-112, roflumilast reduced the rate of moderate or severe exacerbations by 18.8% in patients with concomitant ICS. This supports that the anti-inflammatory mechanism of roflumilast is different to that of ICS. The trend for a higher benefit in patients on ICS may be partially explained by the fact that concomitant ICS treatment selects for patients with a more advanced stage of COPD. These patients are at a higher risk of exacerbation, indicated by the higher exacerbation rate in the placebo group in ICS-treated patients versus non ICS-treated patients (0.89 versus 0.46) and thus, treatment effects on exacerbations are easier to demonstrate in these patients. Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. ICS = Inhaled corticosteroids Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. 37

Roflumilast e ICS: maggiore riduzione delle riacutizzazioni nei pazienti con bronchite cronica
M2-111 and M2-112 pooled post hoc analysis of sub-group with chronic bronchitis +/- ICS Speaker notes In patients with severe COPD associated with chronic bronchitis, roflumilast reduced the rate of moderate or severe exacerbations compared with placebo in patients taking concomitant ICS by -30.2% Reference Rennard SI, Calverley PMA, Goehring, UM, et al. Exacerbation reduction by roflumilast – the importance of defining different subsets of patients with COPD. Respiratory Research 2011;12:18. ICS = Inhaled corticosteroids Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. 38

Roflumilast: il profilo di tollerabilità emerso dagli studi clinici
Side effects associated with roflumilast therapy were typically mild to moderate They occurred mainly within the first weeks of therapy and mostly resolved on continued treatment Changes in weight, and neuropsychiatric events should be monitored Most commonly reported adverse reactions* Diarrhoea 5.9% Weight decrease 3.4% Nausea 2.9% Abdominal pain 1.9% Headache 1.7% Speaker notes In clinical studies, approximately 16% of patients taking roflumilast experienced adverse reactions compared to 5% of patients taking placebo. The most commonly reported adverse reactions were diarrhoea, weight decrease, nausea, abdominal pain and headache. The majority of these adverse reactions were mild or moderate. They occurred mainly within the first weeks of therapy and mostly resolved with continued treatment. Changes in weight and neuropsychiatric events should be monitored when taking roflumilast. Body weight of underweight patients should be checked at each visit. Patients should be advised to check their body weight on a regular basis and record the results on the patient information card. In the event of an unexplained and clinically concerning weight decrease, intake of roflumilast should be discontinued and body weight should be further followed up. Physicians and patients should be informed of the higher incidence of neuropsychiatric events associated with roflumilast, including rare events of suicidal behaviour. Patients should be monitored for changes in neuropsychiatric events. Reference Daxas® European Summary of Product Characteristics. Available at the end of this slide kit and at *Expressed as percent of total study population Daxas® EU SmPC. Available at 39

Concetti chiave Adverse events were frequently reported but there was no overall difference in the number of events between treatment arms There were no differences in the SAE event rate or in mortality with roflumilast More people withdrew from the studies while taking roflumilast (5%) mainly due to GI effects 40

Eventi avversi gastrointestinali: la maggior parte si risolve in 4 settimane
Diarrhoea Nausea 69% resolved 74% resolved % patients Speaker notes Safety data from 14 placebo-controlled, double-blind, phase II/III studies of roflumilast 500µg once daily (n=5766) versus placebo (n=5491), in subjects with moderate to very severe COPD, were pooled and analyzed. Apart from decreased weight, the majority of the most frequently reported AEs (such as diarrhoea and nausea) resolved within 4 weeks. Reference Gross N, Calverley P, Fabbri LM et al. Characterization of safety with roflumilast, an oral phosphodiesterase-4 inhibitor for the treatment of COPD Chest. 2010; 138:466A (Abstract+ Poster). Roflumilast Placebo GI=Gastrointestinal Adapted from Gross N, Calverley P, Fabbri LM, et al. Chest. 2010; 138:466A (Abstract+ Poster). 41

La perdita di peso si manifesta nei primi 6 mesi di trattamento
Speaker notes The average weight change in 12-month clinical studies was a loss of 2.09kg in patients taking roflumilast and a gain of 0.08kg in patients taking placebo. This was a mean difference of 2.17kg more weight lost in patients taking roflumilast compared with patients taking placebo (95% CI -2.4 to -1.9, p<0.0001).1 Most of the weight decrease occurred in the first 6 months of treatment and was attenuated thereafter.1 In a 12-week follow-up study, patients who experienced weight decrease during the treatment phase were monitored for further changes in weight (n=126; roflumilast, 91; placebo, 35). Most of the patients who were treated with roflumilast regained weight in the follow-up period, demonstrating that the weight decrease was reversible upon discontinuation of roflumilast treatment.2 References Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. Martinez FJ, Rabe KF, Wouters EFM, et al. Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase inhibitor. Am J Respir Crit Care Med 2010;181:A4441. Calverley PMA, Rabe KF, Goehring UM, et al. Lancet 2009;374:685–694. 42

La perdita di peso è più evidente nei pazienti obesi
Speaker notes In a pooled analysis of the two 12-month clinical studies, patients were categorised based on body-mass index (BMI) as follows: Underweight ≤18 Normal 18 to ≤25 Overweight 25 to ≤30 Obese >30 kg/m2. The largest absolute weight decrease was observed in obese patients (BMI over 30 kg/m2) treated with roflumilast. Reference Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. (Supplementary webappendix) Calverley PMA, Rabe,KF, Goehring, UM, et al. Lancet 2009;374:685–694. (supplementary webappendix). 43

La perdita di peso è a carico della massa grassa
Speaker notes In the 6-month clinical study in which patients received roflumilast or placebo in addition to tiotropium, the mean weight decrease was 2.1kg more in the roflumilast group compared with placebo group (95% CI -2.5, -1.7; p<0.0001).1,2 BMI fell gradually in roflumilast-treated patients, until reaching a plateau at 18 weeks of treatment (mean decrease 0.73 kg/m2). No significant change in BMI was observed in patients taking placebo during the 24-week treatment period (mean decrease 0.03 kg/m2).2 The overall mean difference in BMI between roflumilast-treated and placebo-treated patients was –0.76 kg/m2 (95% CI –0.89, –0.62; p<0.0001).2 Bioimpedance measurements indicated only minimal changes in fat free mass index (FFMI) following roflumilast or placebo treatment. There was an initial decline in FFMI in the roflumilast group, but after approximately 4 weeks of treatment, no obvious further large (>0.2 kg) change was noted for either group. There was no significant difference between the change in FFMI in roflumilast-treated and placebo-treated patients (mean difference kg/m2, 95% CI to ; p=0.0059).2 These data indicate that the weight decrease associated with roflumilast was primarily fat mass and probably not owing to continued loss of muscle mass. References Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703. Wouters EFM, Teichmann P, Brose M, et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:A4473. FFMI = Fat Free Mass Index BMI = Body Mass Index Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473. 44

Mean change in body weight [kg]
Studi M2-124 e M2-125: recupero del peso corporeo alla sospensione del trattamento Double blind treatment period FU period Mean change in body weight [kg] Speaker notes Safety data from 14 placebo-controlled, double-blind, phase II/III studies of roflumilast 500µg once daily (n=5766) versus placebo (n=5491), in subjects with moderate to very severe COPD, were pooled and analyzed. Apart from decreased weight, the majority of the most frequently reported AEs (such as diarrhoea and nausea) resolved within 4 weeks. Reference Gross N, Calverley P, Fabbri LM et al. Characterization of safety with roflumilast, an oral phosphodiesterase-4 inhibitor for the treatment of COPD Chest. 2010; 138:466A (Abstract+ Poster). Time (weeks) roflumilast, n= placebo, n= 91 35 90 34 88 34 87 33 84 32 83 31 Martinez FM, et al. Am J Respir Crit Care Med 2010;181:A4441. 45

Concetti chiave Early clinical studies conducted in a broad patient population suggested clear potential for roflumilast as a treatment for COPD Post hoc analyses indicated that the greatest benefits were seen in patients with severe COPD associated with chronic bronchitis Pivotal phase III studies confirmed the efficacy of roflumilast in this patient population, demonstrating improved lung function and reduced exacerbation rate when added to maintenance therapy with bronchodilators or ICS 46

Il trattamento con roflumilast
Terapia di mantenimento in aggiunta ai broncodilatatori a lunga durata d’azione nel paziente con: FEV1 post-broncodilatatore < 50% del teorico storia di riacutizzazioni frequenti sintomi di bronchite cronica (tosse ed espettorato)

Strategie globali per la diagnosi, gestione e prevenzione della BPCO Valutazione combinata della BPCO 4 (C) (D) > 2 3 Rischio (Storia di esacerbazioni) dell’ostruzione al flusso aereo) (Classificazione GOLD Rischio 2 (A) (B) 1 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Sintomi (mMRC o CAT score) 48

Esacerbazioni per anno
Strategie globali per la diagnosi, gestione e prevenzione della BPCO Gestione della BPCO stabile: Terapia Farmacologica Prima scelta C D GOLD 4 ICS + LABA or LAMA ICS + LABA or LAMA > 2 GOLD 3 Esacerbazioni per anno A B GOLD 2 Impostazione prognostica shifta da fev1 a sintomi e esacerbazioni Aspettiamoi dati di react Positivo per roflumilast SAMA prn or SABA prn LABA or LAMA 1 GOLD 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 49

Farmacologica Seconda scelta
Strategie globali per la diagnosi, gestione e prevenzione della BPCO Gestione della BPCO stabile: Terapia Farmacologica Seconda scelta C D GOLD 4 LAMA and LABA ICS and LAMA or ICS + LABA and LAMA or ICS + LABA and PDE4-inh or LAMA and LABA or LAMA and PDE4-inh > 2 GOLD 3 Esacerbazioni per anno A B GOLD 2 LAMA or LABA or SABA and SAMA LAMA and LABA 1 GOLD 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 50

Esacerbazioni per anno
Strategie globali per la diagnosi, gestione e prevenzione della BPCO Gestione della BPCO stabile: Terapia Farmacologica Scelte alternative C D GOLD 4 PDE4-inh. SABA and/or SAMA Theophylline Carbocysteine SABA and/or SAMA Theophylline > 2 GOLD 3 Esacerbazioni per anno A B GOLD 2 SABA and/or SAMA Theophylline 1 Theophylline GOLD 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 51

Un nuovo paradigma per la ‘cura ottimale’ del paziente con BPCO
PATIENT CHARACTERISTICS MANAGEMENT PLAN FUTURE RISK REDUCTION BEST CURRENT CONTROL Exacerbations Speaker notes Very recently a new paradigm for the management of COPD has been proposed. This is based on the concept that ‘here-and-now’ goals to minimise current impact on an individual patient should be integrated with goals to achieve better long-term outcomes and reduce future risks. The terminologies introduced in this concept paper are – ‘optimal COPD care’, ‘best current control’, and ‘future risk reduction’ reflecting the concept that , to a COPD patient, prevention of future risk is of equal importance to the immediate impact of treating symptoms. The impact an intervention may have on long-term disease progression is sometimes independent of any effect it may have on current symptoms. Clinicians already apply this broader approach to risk factors such as hypertension and hypercholesterolaemia. Treatments that reduce high blood pressure and serum cholesterol are nowadays prescribed independently of any acute effects on current symptoms. It has now been suggested that this approach should also be considered in COPD. Exacerbations can be used as an example of the link between best current control and future risk reduction. Exacerbation frequency has been linked to increased disease progression in COPD. Recent studies suggest that future exacerbation risk is related to previous exacerbation history. Current therapies are known to decrease the frequency of these future exacerbation events. Thus, treatment reducing exacerbation-frequency can exemplify why current treatment is warranted independent of its impact on ‘best current control’ and rather as a target for ‘future risk reduction’. Reference Postma D, Anzueto A, Calverley P, et al. A new perspective on optimal care for patients with COPD. Prim Care Respir J 2011; 20: Postma D, et al. Prim Care Respir J 2011; 20: 52

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Roflumilast: riduzione dell‘infiammazione polmonare in topi esposti al fumo di tabacco
Inflammatory cells [on the x-axis] respond to toxins such as tobacco smoke. Roflumilast [ROF] inhibits this inflammatory response. The higher dose [ROF5] is more effective overall than the lower dose ROF1 Martorana PA, et al. BMC Pulm Med 2008;8:17. 54

Roflumilast: effetto favorevole sulla funzione mucociliare in vitro
Ciliary Beat Frequency MUC5AC Mucin Protein Mucocillary dysfunction is a feature of COPD. In this slide, Roflumilast [ROF] is demonstrating, in vitro, a potential to improve mucus clearance, in different possible ways. Human nasal epithelial cells (biopsies) Human bronchus Milara J, et al. Eur Respir J Suppl S, P3691. Mata M, et al. Thorax 2005;60: 55

Roflumilast: inibizione della progressione enfisematosa nei topi
Air Tobacco Smoke (TS) ROFLUMILAST (ROF) * TS or Air TS + TS + ROF5 Mean Linear Intercept Mucocillary dysfunction is a feature of COPD. In this slide, Roflumilast [ROF] is demonstrating, in vitro, a potential to improve mucus clearance, in different possible ways. Air Air ROF 5 – Roflumilast 5 mg kg-1 d-1 Lungarella & Mortorana, unpublished. 56

Speaker notes The time to onset of each exacerbation also increased significantly in patients treated with LAMA+ roflumilast compared with LAMA placebo. Reference Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. Eur Respir J 2011, erj d; accepted manuscript, DOI: / Roflumilast e LABA: significativo aumento dell’intervallo di tempo tra riacutizzazioni LABA = Long-acting β2-agonist Bateman ED, Rabe KF, Calverley PMA, et al. Eur Respir J 2011, 38: 553–560. 57

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