Presentation is loading. Please wait.

Presentation is loading. Please wait.

Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011 Clinica di Malattie.

Similar presentations


Presentation on theme: "Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011 Clinica di Malattie."— Presentation transcript:

1 Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011 Clinica di Malattie delApparato Respiratorio Università degli Studi di Modena e Reggio Emilia

2 Paucity of new therapeutics for asthma Holgate et al. Eur Respir J. 2007;29:793-803 Decade Drugs currently available Drugs in development Therapeutics that have failed Ig: immunoglobulin; mAb: monoclonal antibody; PDE: phosphodiesterase; COPD: chronic obstructive pulmonary disease; TNF: tumour necrosis factor; PAF: platelet-activating factor; IL: interleukin; hr: human recombinant; IFN: interferon; VLA: very late antigen. # : Rarely used and uncertain efficacy Decade Drugs currently available Drugs in development Therapeutics that have failed 1960s Short-acting ß 2 -agonists Neuropeptide antagonists 1980s Long-acting ß 2 agonists Type IV PDE inhibitors (mostly targeted for COPD) PAF antagonists 1960s Inhaled and oral corticosteroids Anti-TNF-α Thromboxane inhibitors 1990s Leukotriene receptor antagonists Bradykinin antagonists 1970s (Cytotoxics and immunosuppressants) # Anti-IL-5 mAb 1930sTheophylline hr IL-12 1950sAnti-cholinergics hr IFN- hr IFN- 2000s Anti-human IgE mAb hr IL-10 Soluble IL-4 receptor IL-4 double mutein Allergen-specific IL VLA-4 antagonists P-selectin mAb Antihistamines Mast cell "stabilisers"

3 $ confronto basato sui dati di efficacia Fluticasone Propionato Flunisolide Budesonide Beclometasone Dipropionato HFA Beclometasone dipropionato >500 – 1000 >2000 >800 – 1600 >400 – 800 >1000 – 2000 Dose Alta >250 – 500 >1000 – 2000 >400 – 800 >200 – 400 >500 – 1000 Dose intermedia 100 – 250 500 – 1000 200 – 400 100 – 200 200 – 500 Dose bassa ADULTI $ FARMACO DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA Ciclesonide 80 - 160 160 - 320 320 - 1280 www.ginasma.it Steroidi inalatori per la terapia dell asma Mometasonefuroato 200 - 400 > 400 - 800 >800 - 1200

4 Original Article Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma Stephen P. Peters, N Engl J Med Volume 363(18):1715-1726 October 28, 2010 Peters SP, N Engl J Med 2010;363:1715-26

5 Original Article Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma.When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol.Its effects appeared to be equivalent to those with the addition of salmeterol.

6 Lindacaterolo, nuovo β2 agonista a lunghissima durata dazione (24 ore) è efficace e sicuro nei pazienti con asma persistente non controllato dagli steroidi inalatori. Nuovi broncodilatatori: INDACATEROLO Sugihara N et al. Respir Me2010;104:1629-37 Beeh Km et al. Eur Respir J. 2007;29:871-8

7 omalizumab IgE C 3 Binding site of omalizumab to IgE

8 Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE omalizumab omalizumab placebo placebo Clinically significant Asthma exacerbations rate Severe asthma exacerbations rate 0 0 0.2 0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.68 0.48 0.91 0.24 P=0.042 P=0.002 Humbert M et al; Allergy 2005; 60:309-316

9 Treating to Achieve Asthma Control Step 5 – Reliever medication plus additional controller options Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A) Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A) Addition of anti-IgE treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A) Addition of anti-IgE treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A)

10 Nuove indicazioni AIFA per la prescrizione di omalizumab Lomalizumab è indicato per i pazienti con: - asma grave allergico (test cutaneo o in vitro positivo per - asma grave allergico (test cutaneo o in vitro positivo per allergeni perenni) allergeni perenni) - VEMS < 80% teorico - VEMS < 80% teorico - sintomatici o con frequenti riacutizzazioni gravi nonostante - sintomatici o con frequenti riacutizzazioni gravi nonostante lassunzione quotidiana di alte dosi steroidi e LABA per via lassunzione quotidiana di alte dosi steroidi e LABA per via inalatoria inalatoria - con livelli di IgE totali fino a 1500 IU/ml - con livelli di IgE totali fino a 1500 IU/ml Comunicato AIFA Gazzetta ufficiale n 6 del 10.01.11, pag.58

11 Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children Busse WW et al. N Engl J Med 2011;364:1005-15

12 Original Article Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma.

13 Paucity of new therapeutics for asthma Holgate et al. Eur Respir J. 2007;29:793-803 Decade Drugs currently available Drugs in development Therapeutics that have failed Ig: immunoglobulin; mAb: monoclonal antibody; PDE: phosphodiesterase; COPD: chronic obstructive pulmonary disease; TNF: tumour necrosis factor; PAF: platelet-activating factor; IL: interleukin; hr: human recombinant; IFN: interferon; VLA: very late antigen. # : Rarely used and uncertain efficacy Decade Drugs currently available Drugs in development Therapeutics that have failed 1960s Short-acting ß 2 -agonists Neuropeptide antagonists 1980s Long-acting ß 2 agonists Type IV PDE inhibitors (mostly targeted for COPD) PAF antagonists 1960s Inhaled and oral corticosteroids Anti-TNFα Thromboxane inhibitors 1990s Leukotriene receptor antagonists Bradykinin antagonists 1970s (Cytotoxics and immunosuppressants) # Anti-IL-5 mAb 1930sTheophylline hr IL-12 1950sAnti-cholinergics hr IFN- hr IFN- 2000s Anti-human IgE mAb hr IL-10 Soluble IL-4 receptor IL-4 double mutein Allergen-specific IL VLA-4 antagonists P-selectin mAb Antihistamines Mast cell "stabilisers"

14 Anti-TNF therapy in asthma Brightling C et al. JACI 2008; 121:5-10

15 Anti-TNF therapy in asthma

16 Anti-TNFa therapy in asthma Small n° of patients Small n° of patients Heterogeneity of response Heterogeneity of response Safety (infections, malignancies) Safety (infections, malignancies)

17 A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma Wenzel SE et al. AJRCCM 2009; 179:549-58 Percent of patients free from severe asthma exacerbation Changes from baseline in prebronchodilator percent- predicted FEV1 through Week 24

18 A randomized, double-blind, placebo- controlled study of tumor necrosis factor-α blockade in severe persistent asthma Wenzel SE et al. AJRCCM 2009; 179:549-58 Overall, treatment with golimumab did not demonstrate a favourable risk-benefit profile in this study population of patients with severe persistent asthma.

19

20 n= 52 n = 49 Asthma control during the year after bronchial thermoplasty Cox G et al N Engl J Med 2007; 356:1327-37

21 Thermoplasty vs control, 12mo Morning PEFp=0.003 Morning PEFp=0.003 FEV 1 n.s. FEV 1 n.s. BHRn.s BHRn.s Rescue medicationp=0.04 Rescue medicationp=0.04 Symptom free daysp=0.005 Symptom free daysp=0.005 Symptom scorep=0.01 Symptom scorep=0.01 AQLQ scorep=0.003 AQLQ scorep=0.003 ACQ scorep=0.001 ACQ scorep=0.001 Asthma control during the year after bronchial thermoplasty Cox G et al N Engl J Med 2007; 356:1327-37

22 Adverse respiratory events thermoplasty vs control thermoplasty vs control up to 6 wk p<0.01 up to 6 wk p<0.01 6 wk-12 mo n.s 6 wk-12 mo n.s Asthma control during the year after bronchial thermoplasty Cox G et al N Engl J Med 2007; 356:1327-37

23 Castro M et al. Am J Respir Crit Care Med 2010;181:116–24. This study demonstrates that BT provides clinically meaningful improvements in severe exacerbations requiring corticosteroids, ED visits, and time lost from work/school during the post-treatment period in patients with severe and inadequately controlled asthma, together with improvements in quality of life. We conclude that the increased risk of adverse events in the short-term after BT is outweighed by the benefit of BT that persists for at least 1 year. BT offers clinicians a novel, procedure-based, add-on therapy beyond the current use of high-dose ICS and LABA to decrease the morbidity of severe asthma. Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Trial

24 Asthma Management and Prevention Program Goals of Long-term Management Achieve and maintain control of symptoms Maintain normal activity levels, including exercise Maintain pulmonary function as close to normal levels as possible Prevent asthma exacerbations Avoid adverse effects from asthma medications Prevent asthma mortality Achieve and maintain control of symptoms Maintain normal activity levels, including exercise Maintain pulmonary function as close to normal levels as possible Prevent asthma exacerbations Avoid adverse effects from asthma medications Prevent asthma mortality

25 GOAL: design of the study Sal/Flu 50/100 or FP 100 8- week control assessment 4- week control assessment Phase I Phase II Sal/Flu 50/250 or FP 250 Sal/Flu e 50/500 or FP 500 Visit123456789 Week-404122436485256 Step 1 Step 2 Step 3 Bateman E et al Am J Respir Crit Care Med 2004;170:836-44.

26 GOAL: Exacerbation rate in Phase II GOAL: Exacerbation rate in Phase II Mean exacerbation rate per patient per year per patient per year Bateman E et al Am J Respir Crit Care Med 2004;170:836-44. n = 592 n = 1512 n = 1378

27 Run-in SMILE: Study Design Formoterol/Budesonide + Terbutaline 0.4 mg as reliever Formoterol/Budesonide + Terbutaline 0.4 mg as reliever n=1141 n=1141 Formoterol/Budesonide + Formoterol 4.5 µg as reliever Formoterol/Budesonide + Formoterol 4.5 µg as reliever n=1140 n=1140 Formoterol/Budesonide + Formoterol/Budesonide 160/4.5 µg as reliever (SMART) n=1113 Visit:1 2 3 4 5 6 Month: -0.5 0 1 4 8 12 (All patients received Form/Bude 160/4.5 µg bid both during run-in and following Randomisation) Form/Bude + Terbutaline as reliever R Enrolled: n=3829 Randomised: n=3394 Rabe KF et al, Lancet. 2006;368:744-53

28 Total No. events Hospitalisations/ ER treatment TerbutalFormoterolForm/Bude Maintenance Form/Bude + prn p<0.001 20 60 100 140 194 296 377 p<0.01 p<0.001 p<0.05 300 200 100 400 70 98 115 SMILE Study: Severe Exacerbations Rabe KF et al, Lancet. 2006;368:744-53

29 MILD ASTHMA: an expert review on epidemiologiy, clinical characteristics and treatment Intermittent and mild persistent asthma Intermittent and mild persistent asthma 50-75% of all asthmatic patients 50-75% of all asthmatic patients 0.12-0.77 severe exacerbations per patient-year 0.12-0.77 severe exacerbations per patient-year Associated with inflammation/remodeling Associated with inflammation/remodeling Dusser D et. al. Allergy 2007; 62:591-604 Permanent low-dose ICS reference treatment

30 Stepwise Approach to Asthma Therapy Controlled by low-dose inhaled steroids Controller Daily inhaled cortico-Daily inhaled cortico- steroid (200-500 mcg) steroid (200-500 mcg) Consider LeukotrieneConsider Leukotriene Modifiers Modifiers Reliever Inhaled beta2-agonistInhaled beta2-agonist prn prn Step 2: Mild Persistent Asthma Avoid or Control Triggers

31 REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMA Boushey H.A. et al, NEJM 2005;352:1519-1528 Mild persistent asthma may not require regular treatment and may be controlled with a short intermittent course of inhaled corticosteroids (400 mcg budesonide bid x 10 days) taken when symptoms worsen

32 10-Day course of intense combined therapy 411 Enrolled 225 Randomized WeekVisit-43-25061372683911481252135414 200 µg of budesonide b.i.d. + placebo tablets 20 mg of zafirlukast b.i.d. + placebo inhaler b.i.d. + placebo inhaler to placebo tablets + placebo inhaler Budesonide 800 g bid x 10 days Run-in period 10-Day course of intense combined therapy REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMA Boushey H.A. et al, NEJM 2005;352: 1519-28 Budesonide 800 g bid x 10 days

33 Kaplan–Meier Estimates of the Time to a First Exacerbation of Asthma Days since Randomization Percentage without Exacerbation Daily budesonide Daily zafirlukast Intermittent therapy P=0.39 Boushey H.A. et al, NEJM 2005;352:1519-1528

34 Papi A et al. N Engl J Med 2007;356:2040-52 In patients with mild asthma, the symptom- driven use of inhaled beclomethasone/albuterol combination in a single inhaler is as effective as regular use of inhaled beclomethasone and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid RESCUE USE OF BECLOMETHASONE AND ALBUTEROL IN A SINGLE INHALER FOR MILD ASTHMA

35 Papi A et al. N Engl J Med 2007;356:2040-52 Study design Inhaled placebo b.i.d. plus p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination Inhaled placebo b.i.d. plus p.r.n. inhaled 100 µg salbutamol Inhaled 250 µg beclomethasone/100 µg salbutamol combination b.i.d. plus p.r.n. inhaled 100 µg salbutamol Inhaled 250 µg beclomethasone b.i.d. plus p.r.n. 100 µg salbutamol Beclomethasone(500µg/day) Visit 1 (screening) Visit 2 (randomization) Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 (end of treatment) 6-month Treatment Period 4-Week Run-in Period

36 Papi A et al. N Engl J Med 2007;356:2040-52 0 0,5 1 1,5 2 As needed combination albuterol Regular beclomethasone Regular combination Number of exacerbations per patients/year Papi A et al. N Engl J Med 2007;356:2040-52 EFFECT OF EXACERBATIONS

37 Papi A et al. N Engl J Med 2007;356:2040-52 0 20 40 60 80 100 prn BDP/S prn S regular BDP regular BDP/S ****mg CUMULATIVE DOSE OF BECLOMETHASONE (BDP)

38 Original Article Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma Pranabashis Haldar, M.R.C.P., Christopher E. Brightling, Ph.D., F.R.C.P., Beverley Hargadon, R.G.N., Sumit Gupta, M.R.C.P., William Monteiro, M.Sc., Ana Sousa, Ph.D., Richard P. Marshall, Ph.D., M.R.C.P., Peter Bradding, D.M., F.R.C.P., Ruth H. Green, M.D., F.R.C.P., Andrew J. Wardlaw, Ph.D., F.R.C.P., and Ian D. Pavord, D.M., F.R.C.P. N Engl J Med Volume 360(10):973-984 March 5, 2009

39 Original Article Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma N Engl J Med Volume 360(10):973-984 March 5, 2009 Background Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations

40 Mepolizumab and exacerbations of refractory eosinophilic asthma Haldar P. NEJM 2009;360:973-84 Study Design Randomized, double – blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations Mepolizumab (anti-IL-5 monoclonal AB) for 50 weeks Primary outcome: n° of severe exacerbations Secondary outcomes: QoL, FEV 1, use of SABA, PC 20

41 Haldar P. et al., N Engl J Med 2009; 360: 973-984. Severe Exacerbations during the Study 0 20 40 60 80 100 120 123456789101112 Month Cumulative No. of exacerbations Start of treatment Placebo Mepolizumab 4 14 25 34 47 58 69 79 85 97 10 8 10 9 3 7 13 21 27 33 36 40 44 49 55 57 No. of subjects 0 1 2 3 4 5 6 7 8 9 10 0123456789 No. of exacerbations MepolizumabPlacebo 31% vs 16% had no EX

42 Mepolizumab and exacerbations of refractory eosinophilic asthma Haldar P. et al. NEJM 2009;360:973-84 P< 0.001 P = ns P = 0.002 P< 0.02 P = ns

43 Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. Mepolizumab and exacerbations of refractory eosinophilic asthma Haldar P. et al NEJM 2009;360:973-84

44 Original Article Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia Parameswaran Nair, M.D., Ph.D., Marcia M.M. Pizzichini, M.D., Ph.D., Melanie Kjarsgaard, R.R.T., Mark D. Inman, M.D., Ph.D., Ann Efthimiadis, M.L.T., Emilio Pizzichini, M.D., Ph.D., Frederick E. Hargreave, M.D., and Paul M. O'Byrne, M.B. N Engl J Med Volume 360(10):985-993 March 5, 2009

45 Mepolizumab and exacerbations of refractory eosinophilic asthma Nair P. NEJM 2009;360: 985-93 Study Design Randomized, double – blind, placebo-controlled, parallel- group study of 20 subjects with persistent sputum eosinophilia and symptoms despite prednisone treatment Mepolizumab (anti-IL-5 monoclonal AB) for up to 26 weeks Primary outcomes: n° of exacerbations and steroid reduction Secondary outcomes: QoL, FEV 1, use of SABA, PC 20, sputum and blood eos.

46 Nair P. et al., N Engl J Med 2009; 360: 985-993. Prednisone dose reduction Randomization Mepolizumab (750 mg) Placebo 0 Washout 8 wk 0 2 2 4 6 6 10 8 14 10 18 12 22 14 26 Visit Week Starting doses of Prednisone 25.020.017.515.012.510.07.55.020.015.012.510.07.57.55.02.515.010.07.57.55.05.02.50.010.07.55.05.02.52.50.00.07.55.05.05.02.52.50.00.05.05.05.0 5.0 2.5 2.5 0.0 0.0 Run in 6 wk Protocol for reduction in the dose of prednisone

47 Analysis of the Proportion of Patients without an Asthma Exacerbation during the Study. 0 10 20 30 40 50 60 70 80 90 100 02468101214161820222426 Weeks Patients without exacerbation (%) Randomization Placebo Mepolizumab No. At risk MepolizumabPlacebo9 99101099101099877775747372 Nair P. et al NEJM 2009;360:985-93

48 Nair P. et al., N Engl J Med 2009; 360: 985-993. Nair P. et al., N Engl J Med 2009; 360: 985-993. Eosinophils in Sputum 0 10 20 30 40 50 60 70 V1 V4 W/ExV12 2 Sputum Eosinophils 0 10 20 30 40 50 60 70 V1 V4 W/ExV12 2 MepolizumabPlacebo

49 Nair P. et al., N Engl J Med 2009; 360: 985-993. Eosinophils in Blood Blood Eosinophils (per mm 3 ) Mepolizumab 0 300 400 600 900 1200 1500 1800 V1 V4 W/ExV12 Placebo 0 300 400 600 900 1200 1500 1800 V1 V4 W/ExV12

50 Mepolizumab for prednisone-dependent asthma with sputum eosinophilia Nair P. et al NEJM 2009;360:985-93 Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment Conclusions

51 new therapies (severe/refractory asthma): new therapies (severe/refractory asthma): – anti-IgE – anti-TNF-α – thermoplasty – anti- IL5 new strategies new strategies – GOAL vs SMART – Adding tiotropium bromide – BEST – eNO or EOS guided NEW TREATMENTS FOR ASTHMA

52 Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri, Corso di Aggiornamento per Medici Internisti Modena, 29-30 Marzo 2011 Clinica di Malattie delApparato Respiratorio Università degli Studi di Modena e Reggio Emilia

53 Add inhaled glucocorticosteroids if repeated exacerbations IV: Very Severe IV: Very Severe III: Severe III: Severe II: Moderate II: Moderate I: Mild I: Mild Therapy at Each Stage of COPD FEV 1 /FVC < 70% FEV 1 > 80% predicted FEV 1 /FVC < 70% 50% < FEV 1 < 80% predicted FEV 1 /FVC < 70% 30% < FEV 1 < 50% predicted FEV 1 /FVC < 70% FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add long term oxygen if chronic respiratory failure. Consider surgical treatments

54 Nuovi trattamenti per la BPCO Indacaterolo Indacaterolo è il primo Ultra-LABA approvato dallAgenzia Regolatoria Europea (EMEA) nel dicembre 2009 indicato come terapia broncodilatatrice di mantenimento nellostruzione del flusso aereo in pazienti adulti con broncopneumopatia cronica ostruttiva (BPCO). Indacaterolo è il primo Ultra-LABA approvato dallAgenzia Regolatoria Europea (EMEA) nel dicembre 2009 indicato come terapia broncodilatatrice di mantenimento nellostruzione del flusso aereo in pazienti adulti con broncopneumopatia cronica ostruttiva (BPCO). Indacaterolo, somministrato una volta al giorno alle dosi di 150 e 300 microgrammi, ha costantemente prodotto un miglioramento significativo della funzione polmonare nelle 24 ore con un rapido inizio dazione, entro 5 minuti dallinalazione. Indacaterolo, somministrato una volta al giorno alle dosi di 150 e 300 microgrammi, ha costantemente prodotto un miglioramento significativo della funzione polmonare nelle 24 ore con un rapido inizio dazione, entro 5 minuti dallinalazione. Nel 2010 approvato anche dallAgenzia Italiana del Farmaco (AIFA) ed è quindi commercializzato anche in Italia con il nome commerciali di Onbrez. Nel 2010 approvato anche dallAgenzia Italiana del Farmaco (AIFA) ed è quindi commercializzato anche in Italia con il nome commerciali di Onbrez. Barnes PJ et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther. 2010 Jan 18 Barnes PJ et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther. 2010 Jan 18

55 ONCE-DAILY BRONCHODILATORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: INDACATEROL VERSUS TIOTROPIUM Donohue JF et al,Am J Respir Crit Care Med. 2010 Donohue JF et al, Am J Respir Crit Care Med. 2010 Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD

56 Media dei minimi quadrati (MMQ). ***p<0,001 vs placebo; + p<0,05 vs tiotropio Differenza 1 = miglioramento clinicamente significativo del punteggio TDI TDI: Transitional Dyspnoea Index Il trattamento con indacaterolo ha dimostrato un progressivo miglioramento del TDI 1 punto Punteggio TDI focale Tiotropio 18 µg od Indacaterolo 300 µg od Placebo 3,0 2,0 1,0 0 ***2,38 Indacaterolo µg 150 od ***2,13***1,951,40 ***2,58 ***2,41***2,27 Settimana 12 Settimana 26 1,20 Donohue et al. AJRCCM 2010;182:155-62

57 Indacaterolo aumenta il tempo alla prima riacutizzazione rispetto al placebo (studio a 26 settimane) Pazienti senza riacutizzazioni (%) Tempo alla prima riacutizzazione (mesi) Indacaterolo 150 μg od Indacaterolo 300 μg od Tiotropio 18 μg od Placebo Indacaterolo 150 µg Indacaterolo 300 µg Tiotropio 18 µg Rapporto di rischio rispetto al placebo (IC 95%) 0,69 (0,51-0,94) 0,74 (0,55-1,05) 0,76 (0,56-1,03) 100 80 60 40 01234567 Donohue et al. AJRCCM 2010;182:155-62

58 1.38 Miglioramento del FEV 1 dopo 52 settimane *** 1.43 1.45 1.31 1.311.32 1.28 1.48 1.31 1.38 1.38 1.551.501.451.401.351.301.251.201.15 Trough FEV 1 (L) *** *** * 1.43 Giorno 2 Settimana 12 Settimana 52 Endpoint primario *** *** *** *** Dahl et al. Thorax 2010;65; 473-479 Trough = media dei valori a 23 h 10 min e 23 h 45 min post-dose. Media dei minimi quadrati (LSM). *p<0.05, ***p<0.001 vs placebo; p<0.05, p<0.001 vs formoterolo Trough = media dei valori a 23 h 10 min e 23 h 45 min post-dose. Media dei minimi quadrati (LSM). *p<0.05, ***p<0.001 vs placebo; p<0.05, p<0.001 vs formoterolo

59 Roflumilast in symptomatic chronich obstructive pulmonary disease: two randomised clinical trials Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups The Lancet 2009;374:685-94

60 M2-124 & M2-125 – Study Design Run-in 4 weeks Double-blind, randomised, parallel group Single-blind Treatment 52 weeks placebo o.d. V0RVEFU roflumilast 500µg o.d. Allowed medication: Long acting bronchodilator or short acting anticholinergics Targeting a proportion of ~ 50% of all patients on LABA Participating Countries: Australia, Austria, Canada, France, Germany, Hungary, Italy, India, New Zealand Russia, Romania, South Africa, Spain, Poland, United Kingdom, USA Follow up 2 weeks Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

61 M2-124 & M2-125 – Population (1) Diagnosis: –History of chronic obstructive pulmonary disease associated with chronic bronchitis for at least 12 months prior to baseline Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

62 M2-124 & M2-125 – Population (2) Main Criteria for Inclusion: –Age > 40 years –FEV 1 /FVC ratio (post-bronchodilator) 70% –FEV 1 (post-bronchodilator) 50% of predicted –At least one documented moderate and/or severe COPD exacerbation within one year prior to study –Not suffering from any concomitant disease that might interfere with study procedures or evaluation –Current or former smoker with a smoking history of at least 20 pack years Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

63 Pre- & Post-Bronchodilator FEV 1 M2-124 & M2-125 pooled analysis *N patients are given for pre-FEV 1 measurements 1 1.1 1.2 0820364452 Weeks Mean FEV 1 [L] placebo (pre)roflumilast 500µg (pre) placebo (post)roflumilast 500µg (post) 41228 153614731336126212101152110010611024roflumilast* 155415061419137513061241116711021072placebo* Data on file

64 COPD Exacerbations (Moderate or Severe) M2-124 & M2-125 pooled analysis Mean rate of exacerbations per patient per year = - 17% = - 17% (CI -25;-8) p = 0.0003 0 0.5 1 1.5 placebo roflumilast 500µg 1.3741.142 Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

65 Median Time to First COPD Exacerbation (Moderate or Severe) M2-124 & M2-125 pooled analysis Hazard ratio = 0.89 (CI 0.80;0.98) p = 0.0185 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 Probability of not experiencing and exacerbation Weeks 082036445241228 placebo roflumilast 500µg Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94

66 Incidence of AEs ( 2.0%) Independent of Investigator Causality Assessments (1/2) M2-124 & M2-125 pooled analysis (n=3092) roflumilast 500µg o.d. (n=1547) placebo (n=1545) COPD10%13% Weight Loss 10%3% Diarrhoea8%3% Nasopharyngitis6%6% Nausea4%2% Bronchitis4%4% Headache3%7% Data on file

67 Conclusions RoflumilastRoflumilast –Improves pre and post bronchodilator FEV1 Effect independent of concomitant LABA therapy, previous ICS therapy, or baseline disease severityEffect independent of concomitant LABA therapy, previous ICS therapy, or baseline disease severity –Decreases exacerbation rate Mild, moderate or severeMild, moderate or severe Prolongs time to eventProlongs time to event - Safety profile over 1 year is consistent with previous - Safety profile over 1 year is consistent with previous studies studies –Generally mild to moderate –Generally seen early in trial –Gastrointestinal events most frequent –Limited resulting dropouts –Weight loss was modest

68 Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials The Lancet 2009;374:685-94 Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups

69 Run-in 4 weeks Treatment 24 weeks M2-127: Salmeterol 50µg b.d. as maintenence for all patients M2-128: Tiotropium 18µg o.d. as maintenence for all patients V0RVEFU Roflumilast 500µg o.d. Follow up 2 weeks Placebo o.d. Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Roflumilast as Add-On Therapy in COPD

70 M2-127 & M2-128 – Study Population Diagnosis: –History of chronic obstructive pulmonary disease for at least 12 months prior to baseline –In study M2-128 also associated with chronic bronchitis, not a pre-requisite in study M2- 127 Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

71 Main Criteria for Inclusion Age 40 yearsAge 40 years FEV 1 /FVC ratio (post-bd) 70%FEV 1 /FVC ratio (post-bd) 70% FEV 1 (post-bd) between 40% and 70 % predFEV 1 (post-bd) between 40% and 70 % pred FEV 1 increase of 12% or 200 ml after 400 mcg salbutamolFEV 1 increase of 12% or 200 ml after 400 mcg salbutamol Current or former smoker with a smoking history of at least 10 pack yearsCurrent or former smoker with a smoking history of at least 10 pack years M2-128 only: maintenance treatment with tiotropium for at least 3 months prior to baselineM2-128 only: maintenance treatment with tiotropium for at least 3 months prior to baseline Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

72 RoflumilastPlacebo 1.3 1.4 1.5 1.6 466467455463410437389419374403359384 082441218 Weeks Salmeterol + Placebo Salmeterol+ Roflumilast Pre bd FEV 1 [L] Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1 Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

73 1.4 1.5 1.6 1.7 371372364363343352325350318347310333 082441218 Weeks RoflumilastPlacebo Pre bd FEV 1 [L] Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Tiotropium + Placebo Tiotropium+ Roflumilast Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV 1

74 Roflumilast as Add-On Therapy in COPD Post-bronchodilator FEV 1 Mean change in post bd FEV 1 [ml] D= 81 ml p < 0.0001 = 60 ml = 60 ml p < 0.0001 -20 0 20 40 60 80 100 74 -7 688 Salmeterol Tiotropium n=460 n=452 n=363 n=364 Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

75 Median Time to First Moderate or Severe COPD Exacerbation HR = 0.6 p = 0.0067 0.80 0.85 0.90 0.95 1.00 048122418 Weeks Probability of not experiencing an exacerbation Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Salmeterol + Placebo Salmeterol+ Roflumilast

76 Median Time to First COPD Moderate or Severe Exacerbation HR = 0.8 p = 0.1959 0.80 0.85 0.90 0.95 1.00 0481224 Weeks 18 Probability of not experiencing an exacerbation Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Tiotropium + Placebo Tiotropium+ Roflumilast

77 Roflumilast as Add-On Therapy in COPD SOBQ (Shortness of Breath Questionnaire) Mean change in SOBQ Score Mean change in SOBQ Score p= 0.0051 = - 2.6 -5 -4 -3 -2 0 1 048 12 1824 Weeks Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 Tiotropium + Placebo Tiotropium+ Roflumilast

78 Incidence of Adverse Events Sal + Roflumilast (n = 466) Sal + Placebo (n = 467) Tio + Roflumilast (n = 374) Tio + Placebo (n = 369) COPD16%24%16%18% Weight decrease 9%1%6%1% Diarrhoea8%3%9%<1% Nasopharyngitis7%7%6%5% Nausea5%<1%3%1% Headache3%1%2%0% Back pain 3%2%2%1% Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

79 Change in Body Weight [kg] = - 2.1 kg = - 2.1 kg p < 0.0001 = - 2.1 kg = - 2.1 kg p < 0.0001 -4 -2 0 2 4 048121824 048121824 Salmeterol Trial Tiotropium Trial -4 -2 0 2 4 Weeks Roflumilast as Add-On Therapy in COPD Adverse Events - Body Weight Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703

80 Conclusions: –Roflumilast improves lung function in patients with moderate to severe COPD who are already treated with long acting bronchodilators –Roflumilast treatment is accompanied by class – specific side effects (but no cardiovascular AEs or pneumonias) –Roflumilast might qualify as a recommended oral therapy on top of bronchodilators such as Salmeterol and Tiotropium (Role of ICS..?) Roflumilast as Add-On Therapy in COPD Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703


Download ppt "Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011 Clinica di Malattie."

Similar presentations


Ads by Google