Nuovi trattamenti per la COPD

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1 World COPD Day Roma, Hotel Una 16 Novembre 2011 Nuovi trattamenti per la COPD Leonardo M. Fabbri Clinica di Malattie dell Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

2 NUOVI TRATTAMENTI PER LA COPD Leonardo M. Fabbri Leonardo M. Fabbri Exacerbations in COPD Current and future treatment Futuristic treatments Treatment of co-morbidities of COPD Clinica di Malattie dell Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

3 COPD EXACERBATION GOLD 2011 An exacerbation of COPD is an acute event characterized by a worsening of the patient s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication

4 OUTCOME OF COPD EXACERBATIONS In ICU patients Hospital mortality 20%-24% (1 year) In hospitalized patients Hospital mortality 2.5%-10% (5 days) In ER patients Relapse (repeat ER visit) 22%-32% (14 days) In outpatients Treatment failure rate 13%-33% (14 days) Seneff et al. JAMA. 1995; 274: ; Murata et al. Ann Emerg Med. 1991;20: ; Adams et al. Chest. 2000; 117: ; Patil et al. Arch Int Med. 2003; 163:

5 LUNG FUNCTION IMPAIRMENT, COPD HOSPITALISATIONS AND SUBSEQUENT MORTALITY COPD severity was associated with a higher rate of severe exacerbations requiring hospitalisation, although severe exacerbations at any stage were associated with a higher risk of short-term and longterm all-cause mortality Garcia-Aymeric et al, Thorax 2011;66:585e590.

6 COPD exacerbations COPD Chronic disease progressive nature lung function symptoms comorbidities Tashkin D. N Engl J Med 2010; 363: 1184 Hurst et al, N Engl J Med 2010; 363: Exacerbations typically 1-3 per year frequency proportional to COPD severity the frequent exacerbator chronic decline resulting in poorer prognosis HRQL hospitalizations mortality

7 CAUSES OF EXACERBATION OF RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS PNEUMONIA THROMBOEMBOLISM ACUTE HEART FAILURE METABOLIC ACIDOSIS ANEMIA

8 BIOCHEMICAL MARKERS OF CARDIAC DYSFUNCTION PREDICT MORTALITY IN ACUTE EXACERBATIONS OF COPD Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to hospital with acute exacerbations of COPD independently of other known prognostic indicators The pathophysiological basis for this is unknown, but indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis Chang CL et al, Thorax, available on line 9 june 2011

9 TARGETING THE LUNG ATTACKS Current management strategies for acute asthma and ECOPD within and subsequent to discharge from hospital are suboptimal We suggest that the term lung attack may resonate more with patients and the broader community FitzGerald JM, Thorax, available on line 9 june 2011

10 Breast Cancer Diseases ER % PI3Kmut 10% HER3+ All Breast Cancers HER % IGFR1+ p95+ 4% Triple negative 15% P53mut % FGFR1 Ampl 8% PTENloss 30-50% BRCAMut 8%

11 TARGETED THERAPIES IN A-NSCLC Positive Phase III Studies Erlotinib BR.21 Gefitinib IPASS/INTEREST/NEJG002 Monotherapy 2 nd /3 rd Line EGFR Mut+ EGFR Mut+ All lines A-NSCLC ComboTherapy 1 st Line Bevacizumab ECOG 4599/AVAiL Cetuximab FLEX

12 NUOVI TRATTAMENTI PER LA COPD Leonardo M. Fabbri

13 NUOVI TRATTAMENTI PER LA COPD Leonardo M. Fabbri Exacerbations in COPD Current and future treatment Futuristic treatments Treatment of co-morbidities of COPD

14 Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV 1 /FVC < 70% 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 Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add ICS OR/AND ROFLUMILAST in exacerbators Add long term oxygen if chronic respiratory failure. Consider surgical treatments Add ROFLUMILAST

15 2011 UPDATE OF THE GOLD GUIDELINES

16 Shanghai, October UPDATE OF THE GOLD GUIDELINES First choice Second choice Alternative choice A SABA or SAMA prn SABA and SAMA LABA or LAMA Theophylline B LABA or LAMA LABA and LAMA Theophylline SABA and/or SAMA C ICS/LABA or LAMA LABA and LAMA ICS and LAMA Theophylline SABA and/or SAMA Consider PDE4-inh* D ICS/LABA or LAMA ICS/LABA and LAMA ICS/LABA and PDE4-inh* LAMA and PDE4-inh Theophylline SABA and/or SAMA Carbocysteine

17 FIGURE 2. PROPORTION OF PARTICIPANTS FREE FROM ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) FOR 1 YEAR, ACCORDING TO STUDY GROUP Albert RK Et Al, NEJM,August 25, 2011 vol. 365 no. 8

18 CHRONIC AZITHROMYCIN DECREASES THE FREQUENCY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS When added to usual treatment, azithromycin, 250 mg taken daily for one year decreases COPD exacerbations and improves quality of life but also causes hearing decrements in a small fraction of subjects Alpert RK et al, New Engl J Med 2011; 365:

19 THE EFFECT OF TELITHROMYCIN IN ACUTE EXACERBATIONS OF ASTHMA This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear Johnston SL et al, NEJM 2006;354(15):

20 TC DEL POLMONE DI PAZIENTE CON ENFISEMA PREVALENTE AI LOBI INFERIORI Lobi inferiori Corbetta L et al, 2011

21 TC DEL POLMONE DI PAZIENTE CON ENFISEMA PREVALENTE AI LOBI SUPERIORI Lobi superiori Corbetta L et al, 2011

22 VALVOLE UNIDIREZIONALI ZEPHYR A BECCO D'ANATRA: PORZIONE ENDOBRONCHIALE CHE ADERISCE ALLA PARETE BRONCHIALE Corbetta L et al, 2011

23 VALVOLA SPIRATION AD OMBRELLINO Corbetta L et al, 2011

24 A RANDOMIZED STUDY OF ENDOBRONCHIAL VALVES FOR ADVANCED EMPHYSEMA Endobronchial-valve treatment for advanced heterogeneous emphysema induced modest improvements in lung function, exercise tolerance, and symptoms at the cost of more frequent exacerbations, pneumonia, and hemoptysis after implantation Sciurba et al, N Engl J Med 2010; 363;13

25 TRACHEOBRONCHOPLASTY FOR SEVERE TRACHEOBRONCHOMALACIA* A PROSPECTIVE OUTCOME ANALYSIS In experienced hands, surgical central airway stabilization with posterior tracheobronchial splinting using a polypropylene mesh improves respiratory symptoms, health-related quality of life, and functional status in highly selected patients with severe symptomatic TBM. Majid A et al, Chest 2008; 134:

26 DYNAMIC AIRWAY CT Majid A et al, Chest 2008; 134:

27 SILICONE STENT Majid A et al, Chest 2008; 134:

28 SKETCH SHOWING THE PLICATION OF THE POSTERIOR MEMBRANOUS WALL OF THE TRACHEA AND MAINSTEM BRONCHUS USING A MARLEX MESH Majid A et al, Chest 2008; 134:

29 TRACHEOBRONCHOPLASTY FOR SEVERE TRACHEOBRONCHOMALACIA* A PROSPECTIVE OUTCOME ANALYSIS In experienced hands, surgical central airway stabilization with posterior tracheobronchial splinting using a polypropylene mesh improves respiratory symptoms, health-related quality of life, and functional status in highly selected patients with severe symptomatic TBM. Majid A et al, Chest 2008; 134:

30 TIOTROPIUM IMPROVES LUNG FUNCTION IN PATIENTS WITH SEVERE ASTHMA: a randomised controlled trial The addition of once-daily tiotropium to asthma treatment including high dose ICS plus LABA, provides significant improvements in lungfunction over 24 hours in patients with inadequately controlled, severe, persistent asthma Long-term studies are needed to assess patient reported outcomes and exacerbation rates. Kerstjens HAM et al, JACI, August 2011

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32 EFFECTIVENESS AND SAFETY OF BRONCHIAL THERMOPLASTY IN THE TREATMENT OF SEVERE ASTHMA 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:

33 BRONCHIAL THERMOPLASTY FOR SEVERE ASTHMA No < airway hyperresponsiveness or > FEV1 > quality of life < severe exacerbations < emergency department visits < days lost from school or work bronchospasm occasionally hospitalization Momen M. Wahidi, MD, MBA and Monica Kraft, MD, AJRCCM, in press.

35 Barnes PJ. Chest 2008; 134: EMERGING PHARMACOTHERAPIES FOR COPD

36 Expression of CXCR2 on Neutrophils Pharmacol Rev 56: , 2004 Barnes JACI 2007

37 CXCR2 Biology Airway Epithelium Ciliated Epithelial Cells Goblet Cell (discharging) Alveolus Type I Type II Goblet cell hyperplasia Mucus secretion Smooth Muscle Macrophage Contraction Migration CXCR2 Neutrophil Angiogenesis Chemotaxis Eosinophil Fibroblast myofibroblast Blood Vessel T-cell Microvascular leakage VCAM-1 expression Mast Cell Capillary collagen Blood Vessel fibroblast neutrophil

38 Effect of 50 mg of SCH on Ozone-Induced Airway Neutrophilia in Healthy Subjects Screening P < P = Sputum neutrophils Cells X 10 6 /ml P < Pre ozone Post ozone Placebo SCH Prednisolone Holz et al Eur Respir J. 2010:

39 TESRA (Treatment of Emphysema with a Selective Retinoid Agonist) study results Paul Jones on behalf of TESRA Steering Committee Members and Investigators

40 Study design Screening Period Up to 6 weeks Start optimized COPD therapy * 2-year Double-blind Treatment Period Safety Follow-Up Period N = 492 N = 329 Palovarotene (5 mg qd) p.o + optimized COPD therapy 4 Weeks N = 160 Placebo p.o. + optimized COPD therapy * Optimized COPD therapy = SABA prn + Tiotropium + ICS+LABA (either Advair or Symbicort at highest registered dose)

41 Outcomes (measured every 6 months) Post-bronchodilator FEV 1 (primary outcome) Diffusing capacity CT densitometry (15% percentile) measured yearly 6-MWD SGRQ TDI

42 TESRA Patient Disposition 492 randomized patients 2 patients not treated (0.4%) 490 patients 1 patient (no efficacy FUP) ITT pop Placebo 160 patients Palovarotene 329 patients 1 patient received palovarotene for 28 days Safety pop Placebo 159 patients Palovarotene 5 mg 329 patients 29 % withdrawals 15 % due to safety 14 % non-safety Dose reduction 3 (2 %) permanent dose reduction Dose reduction 28 (9%) permanent dose reduction 32 % withdrawals 22 % due to safety 10 % non-safety Completers Placebo 114 patients (71 %) Palovarotene 225 patients (68 %)

43 Summary Palvoratene appears to have low toxicity In placebo treated patients, 2 regions of interest in the lower lung (lower half and lowest quartile) showed faster disease progression across most measures ITT analysis in whole lung Palvarotene efficacy did not differ from placebo Post hoc analysis in the lower lung Palvarotene was associated with less worsening over time in most outcomes These observations require confirmation using more detailed analysis of emphysema progression in different parts of the lung If confirmed, the observations from this hypothesis-generating study require testing in patients with lower lung emphysema

44 COPD Exacerbations* Incidence of COPD exacerbations (% of patients) % of COPD exacerbations leading to: * Defined as worsening of COPD symptoms requiring either orals steroids and/or antibiotics Reported as Adverse Events by Investigator 44

45 Clustering by expression levels of periostin, CLCA1 and serpinb2 in epithelial brushings identifies two groups of subjects with asthma Woodruff et al. AJRCCM 2009

46 LEBRIKIZUMAB TREATMENT IN ADULTS WITH ASTHMA Jonathan Corren, Robert F. Lemanske, Jr., Nicola A. Hanania, Phillip E. Korenblat, Merdad V. Parsey, Joseph R. Arron, Jeffrey M. Harris, Heleen Scheerens, Lawren C. Wu, Zheng Su, Sofia Mosesova, Mark D. Eisner, Sean P. Bohen, and John G. Matthews. August 3, 2011

47 Results: change in FEV1 Corren J et al, N Engl J Med 2011

48 Conclusions Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. Corren J et al, N Engl J Med 2011; August 3, 2011

49 GATA-3 IS THE MASTER TRANSCRIPTION FACTOR IN TH2-DRIVEN INFLAMMATORY DISEASES Barnes P, JCI 118 (2008):

50 THE TRANSCRIPTION FACTORS GATA-3 AND TBET PLAY A CRUCIAL ROLE IN INFLAMMATION Ansel KM, et al. Annu. Rev. Immunol. 24 (2006):

51 SB010: MECHANISM OF ACTION

52 INTERLEUKIN-13 AND -4 EXPRESSION IN THE CENTRAL AIRWAYS OF SMOKERS WITH CHRONIC BRONCHITIS T-helper-2 and -1 protein expression is present in the central airways of smokers and interleukin-4 and -13 could contribute to mucus hypersecretion in chronic bronchitis. Miotto D, Boschetto P, Mapp C et al Eur Respir J 2003; 22:

54 SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Barnes PJ et al., Eur Respir J 2009;33:

55 Clinical Case Report

56 Man 60 years old Smoker (90 p/y) Occupation trader of fruit No familiarity for lung disease No occupational/environmental exposures

57 Symptoms and signs reported: increasing dyspnea (even at rest) fatigue ankle edema Chest: reduced murmur SaO2 (supine, air) 94%; ABP 130/80

58 Previous clinical history COPD (1990) with severe emphysema GOLD III Major depression (2000) Hypertension (1990) Diabetes mellitus type II (2006) Chronic pulmonary heart failure(2010) Congestive heart failure (2010) Obstructive sleep apnea syndrome (2011) Obesity (BMI 36)

59 Home Therapy - Bisoprolol 2,5 mg/day - Valsaltan 80 mg/day - Furosemide 250 mg/day - Canrenoato potassium 100 mg/day - Venlafaxine 150 mg/day - Pregabalin 300 mg/day - Triptych 150 mg/day - Metformin 1000 mg/day - Salmeterol/Fluticasone 50/500 1 inhalation/bid - Tiotropium 18 mcg 1 in./day - O2 therapy 1 L/min. at night

60 Diagnostic tests performed Blood examination normal [in particolar normal ESR (10 mm), PCR (0.58 mg/dl) and D-dimer (370 ng/ml)] but with mild increase in glycemia (138 mg/dl) Arterial blood gas analysis hypoxemia (ph 7.43, po2 63 mmhg, pco2 49 mmhg, so2 92%) Respiratory function tests severe obstructive ventilatory failure [FEV1 48% (1.71 L), FVC 71% (3.32 L), TLC 108%, RV/TLC 136%; TLCO(Va) 68%] Polysomnography A+H 7,8 / h; mean oxygen saturation 86,8% Echocardiogram (August 2011) nothing significant to report, except for a slight increase in PAPs; EF 45%.

61 Pulmonary emphysema on CT-scan

62 micronodule of 4 mm

63 REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ACE INHIBITORS, AND ARBS IN PATIENTS WITH COPD These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials. Mancini JB et al. J Am Coll Cardiol 2006;47(12):

64 Β-BLOCKERS MAY REDUCE MORTALITY AND RISK OF EXACERBATIONS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE Treatment with beta-blockers may reduce the risk of exacerbations and improve survival in patients with COPD, possibly as a result of dual cardiopulmonary protective properties Rutten FH et al, Arch Intern Med May 24;170(10):880-7

66 World COPD Day Roma, Hotel Una 16 Novembre 2011 Nuovi trattamenti per la COPD Leonardo M. Fabbri Clinica di Malattie dell Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

67 ACUTE EFFECTS OF INDACATEROL ON LUNG HYPERINFLATION IN MODERATE COPD: A COMPARISON WITH TIOTROPIUM Diagnosis of moderate (as classified by the Global Initiative for Chronic Obstructive Lung Disease [GOLD] Guidelines, 2007) chronic obstructive pulmonary disease (COPD) and: Smoking history of at least 10 pack-years Forced expiratory volume in 1 second (FEV1 < 80% and 50% of the predicted normal value Post-bronchodilator FEV1/Forced Vital capacity (FVC) < 0.7 Rossi A, Centanni B, Cerveri I, Gulotta C, Foresi A, Cazzola M, BrusascoV. Respiratory Medicine (2011) xx, 1e7