Identificazione del sottogruppo di pazienti responsivi 1

Fenotipi clinici della BPCO “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, and rate of disease progression or death)” predictive value prospectively validated for each of the outcomes to which they may relate able to classify patients into distinct subgroups that provide prognostic information and allow physicians to better determine the most appropriate therapy to improve clinically meaningful outcomes Han MK et al., AJRCCM 2010

Definizione delle riacutizzazioni della BPCO COPD EXACERBATIONS WERE CLASSIFIED IN CLINICAL STUDIES AS FOLLOWS: ‘Severe’ COPD exacerbation Requiring hospitalisation and/or leading to death ‘Moderate’ COPD exacerbation Initiation of oral or parenteral glucocorticosteroid therapy required Speaker notes The rate of moderate to severe exacerbations was measured in the roflumilast phase III clinical studies.1-4 This ‘event-based’ classification of exacerbations defines the severity of each exacerbation according to the change in medication needed.5 This type of classification does not capture exacerbations that do not require a change in medications, but is more useful in clinical studies than alternative approaches that use patients’ symptoms to define exacerbation severity.5 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. Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. 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. 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. Pauwels R, Calverley P, Buist AS, et al. COPD exacerbations: the importance of a standard definition. Respir Med 2004;98:99–107. 3

Gli studi M2-111 e M2-112 R VE Treatment 52 weeks Visit 0 Follow-up Roflumilast 500µg o.d. Follow-up 30 days Placebo o.d. Treatment 52 weeks VE Visit 0 R 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;176:154-161. 4

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. 5

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. 6

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. 7

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 8