1 / 80

Nuovi farmaci in asma e BPCO Bianca Beghè , Leonardo M Fabbri

Corso di Formazione al Personale Nycomed Modena , 6-7/8-9 Settembre 2011. Nuovi farmaci in asma e BPCO Bianca Beghè , Leonardo M Fabbri. Clinica di Malattie del’Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia. Decade. Therapeutics that have failed.

clinton-sullivan
Télécharger la présentation

Nuovi farmaci in asma e BPCO Bianca Beghè , Leonardo M Fabbri

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Decade Therapeutics that have failed Drugs currently available Drugs in development Paucity of new therapeutics for asthma Holgate et al. Eur Respir J. 2007;29:793-803 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

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

  4. Original ArticleTiotropium 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 ArticleTiotropium 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. • Its effects appeared to be equivalent to those with the addition of salmeterol.

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

  7. IgE C3 omalizumab 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 P=0.042 0.91 Clinically significant Asthma exacerbations rate 1.0 0.8 0.68 0.6 0.4 0.2 0 omalizumab placebo 0.6 0.48 Severe asthma exacerbations rate P=0.002 0.4 0.24 0.2 0 omalizumab placebo 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 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 Comunicato AIFA Gazzetta ufficiale n 6 del 10.01.11, pag.58 L’omalizumab è indicato per i pazienti con: - asma grave allergico (test cutaneo o in vitro positivo per allergeni perenni) - VEMS < 80% teorico - sintomatici o con frequenti riacutizzazioni gravi nonostante l’assunzione quotidiana di alte dosi steroidi e LABA per via inalatoria - con livelli di IgE totali fino a 1500 IU/ml

  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 ArticleRandomized 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.

  13. Decade Therapeutics that have failed Drugs currently available Drugs in development Paucity of new therapeutics for asthma Holgate et al. Eur Respir J. 2007;29:793-803 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

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

  15. Anti-TNFa therapy in asthma

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

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

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

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

  20. Asthma control during the year after bronchial thermoplasty • Thermoplasty vs control, 12mo • Morning PEF p=0.003 • FEV1 n.s. • BHR n.s • Rescue medication p=0.04 • Symptom free days p=0.005 • Symptom score p=0.01 • AQLQ score p=0.003 • ACQ score p=0.001 Cox G et al N Engl J Med 2007; 356:1327-37

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

  22. Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Trial 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. Castro M et al. Am J Respir Crit Care Med 2010;181:116–24.

  23. 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

  24. GOAL: design of the study Phase I 8- week control assessment Phase II 4- week control assessment Sal/Flue 50/500 or FP 500 Sal/Flu 50/250 or FP 250 Step 3 Sal/Flu 50/100 or FP 100 Step 2 Step 1 Visit 1 2 3 4 5 6 7 8 9 Week -4 0 4 12 24 36 48 52 56 Bateman E et al Am J Respir Crit Care Med 2004;170:836-44.

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

  26. SMILE: Study Design (All patients received Form/Bude 160/4.5 µg bid both during run-in and following Randomisation) Formoterol/Budesonide+ Terbutaline 0.4 mg as reliever n=1141 Run-in Form/Bude + Terbutaline as reliever R Formoterol/Budesonide + Formoterol4.5 µg as reliever n=1140 Enrolled: n=3829 Randomised: n=3394 Formoterol/Budesonide+ Formoterol/Budesonide160/4.5 µg as reliever (SMART) n=1113 Visit: 1 2 3 4 5 6 Month: -0.5 0 1 4 8 12 Rabe KF et al, Lancet. 2006;368:744-53

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

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

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

  30. 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 REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMA Boushey H.A. et al, NEJM 2005;352:1519-1528

  31. REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMA 10-Day course of intense combined therapy 10-Day course of intense combined therapy 200 µg of budesonide b.i.d. + placebo tablets Budesonide 800 g bid x 10 days 20 mg of zafirlukast b.i.d. + placebo inhaler Budesonide 800 g bid x 10 days 411 Enrolled 225 Randomized Budesonide 800 g bid x 10 days to placebo tablets + placebo inhaler Run-in period Week Visit -4 3 -2 5 0 6 13 7 26 8 39 11 48 12 52 13 54 14 Boushey H.A. et al, NEJM 2005;352: 1519-28

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

  33. RESCUE USE OF BECLOMETHASONE AND ALBUTEROL IN A SINGLE INHALER FOR MILD ASTHMA 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 Papi A et al. N Engl J Med 2007;356:2040-52

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

  35. 2 1,5 Number of exacerbations per patients/year 1 0,5 0 As needed As needed Regular Regular combination albuterol beclomethasone combination Papi A et al. N Engl J Med 2007;356:2040-52 Papi A et al. N Engl J Med 2007;356:2040-52 EFFECT OF EXACERBATIONS

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

  37. Original ArticleMepolizumab 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

  38. Original ArticleMepolizumab and Exacerbations of Refractory Eosinophilic Asthma 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 N Engl J Med Volume 360(10):973-984 March 5, 2009

  39. Mepolizumab and exacerbations of refractory eosinophilic asthma 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, FEV1, use of SABA, PC20 Haldar P. NEJM 2009;360:973-84

  40. Severe Exacerbations during the Study Placebo Mepolizumab 10 120 109 Placebo 108 9 97 100 8 85 79 7 80 69 6 58 Mepolizumab Cumulative No. of exacerbations No. of subjects 5 60 47 57 55 4 49 34 44 40 40 3 36 25 33 27 2 14 20 21 4 1 13 7 3 0 0 Start of treatment 0 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 11 12 Month No. of exacerbations Haldar P. et al., N Engl J Med 2009; 360: 973-984. 31% vs 16% had no EX

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

  42. Mepolizumab and exacerbations of 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. Haldar P. et al NEJM 2009;360:973-84

  43. 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

  44. Mepolizumab and exacerbations of refractory eosinophilic asthma 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, FEV1, use of SABA, PC20, sputum and blood eos. Nair P. NEJM 2009;360: 985-93

  45. Washout 8 wk Prednisone dose reduction Mepolizumab (750 mg) Placebo Randomization 0 2 4 6 8 10 12 14 Visit Week 0 2 6 10 14 18 22 26 Starting doses of Prednisone 25.0 20.0 17.5 15.0 12.5 10.0 7.5 5.0 20.0 15.0 12.5 10.0 7.5 7.5 5.0 2.5 15.0 10.0 7.5 7.5 5.0 5.0 2.5 0.0 10.0 7.5 5.0 5.0 2.5 2.5 0.0 0.0 7.5 5.0 5.0 5.0 2.5 2.5 0.0 0.0 5.0 5.0 5.0 5.02.52.50.00.0 Nair P. et al., N Engl J Med 2009; 360: 985-993. Protocol for reduction in the dose of prednisone Run in 6 wk

  46. Analysis of the Proportion of Patients without an Asthma Exacerbation during the Study. 100 90 Mepolizumab 80 70 60 Patients without exacerbation (%) 50 40 30 Randomization 20 Placebo 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks No. At risk Mepolizumab Placebo 9 10 9 9 8 7 7 7 7 5 7 4 7 3 7 2 Nair P. et al NEJM 2009;360:985-93

  47. Eosinophils in Sputum 70 70 60 60 50 50 40 40 Sputum Eosinophils 30 30 20 20 10 10 2 2 0 0 V4 V4 V1 W/Ex V12 V1 W/Ex V12 Mepolizumab Placebo Nair P. et al., N Engl J Med 2009; 360: 985-993.

  48. Eosinophils in Blood 1800 1800 1500 1500 1200 1200 Blood Eosinophils (per mm3) 900 900 600 600 400 400 300 300 0 0 V4 V4 V1 V1 W/Ex W/Ex V12 V12 Mepolizumab Placebo Nair P. et al., N Engl J Med 2009; 360: 985-993.

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

More Related