1. Nuovi farmaci in asma e BPCO
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. Paucity of new therapeutics for asthma
Decade
Therapeutics that have failed
Drugs currently available
Drugs in development
Paucity of new therapeutics for asthma
Decade
Drugs currently available
Drugs in development
Therapeutics that have failed
1960s
Short-acting ß2-agonists
Neuropeptide antagonists
1980s
Long-acting ß2 agonists
Type IV PDE inhibitors (mostly
targeted for COPD)
PAF antagonists
Inhaled and oral corticosteroids
Anti-TNF-α
Thromboxane inhibitors
1990s
Leukotriene receptor antagonists
Bradykinin antagonists
1970s
(Cytotoxics and immunosuppressants)#
Anti-IL-5 mAb
1930s
Theophylline
hr IL-12
1950s
Anti-cholinergics
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"
Holgate et al. Eur Respir J. 2007;29:
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
DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA
FARMACO
ADULTI $
100 – 250
500 – 1000
200 – 400
100 – 200
200 – 500
Dose bassa
>250 – 500
>1000 – 2000
>400 – 800
>200 – 400
>500 – 1000
Dose intermedia
>500 – 1000
>2000
>800 – 1600
>400 – 800
>1000 – 2000
Dose Alta
Beclometasone dipropionato
Beclometasone
Dipropionato HFA
Budesonide
Flunisolide
Fluticasone Propionato
Ciclesonide
Mometasone
furoato
>
>
$ confronto basato sui dati di efficacia 3

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

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.
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:
Beeh Km et al. Eur Respir J. 2007;29:871-8

7. Binding site of omalizumab to IgE
C3

8. (GINA 2002 step 4 treatment): INNOVATE
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
Asthma exacerbations rate
Clinically significant
0.91
1.0
0.8
0.68
0.6
0.4
0.2
omalizumab
placebo
0.6
0.48
Severe asthma exacerbations rate
P=0.002
0.4
0.24
0.2
omalizumab
placebo
Humbert M et al; Allergy 2005; 60:

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 , 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:

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.

13. Paucity of new therapeutics for asthma
Decade
Therapeutics that have failed
Drugs currently available
Drugs in development
Paucity of new therapeutics for asthma
Decade
Drugs currently available
Drugs in development
Therapeutics that have failed
1960s
Short-acting ß2-agonists
Neuropeptide antagonists
1980s
Long-acting ß2 agonists
Type IV PDE inhibitors (mostly
targeted for COPD)
PAF antagonists
Inhaled and oral corticosteroids
Anti-TNFα
Thromboxane inhibitors
1990s
Leukotriene receptor antagonists
Bradykinin antagonists
1970s
(Cytotoxics and immunosuppressants)#
Anti-IL-5 mAb
1930s
Theophylline
hr IL-12
1950s
Anti-cholinergics
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"
Holgate et al. Eur Respir J. 2007;29:
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

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

21. Cox G et al N Engl J Med 2007; 356:1327-37
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:

22. Cox G et al N Engl J Med 2007; 356:1327-37
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:

23. 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.

24. Goals of Long-term Management
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

25. GOAL: design of the study
Phase I
8- week control assessment
Phase II
4- week control assessment
Sal/Flu e 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
Week
Bateman E et al Am J Respir Crit Care Med 2004;170:

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

27. SMILE: Study Design R Run-in
(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 + Formoterol 4.5 µg as reliever
n=1140
Enrolled: n=3829
Randomised: n=3394
Formoterol/Budesonide + Formoterol/Budesonide 160/4.5 µg as reliever (SMART) n=1113
Visit:
Month:
Rabe KF et al, Lancet. 2006;368:744-53

28. SMILE Study: Severe Exacerbations
Total No. events
Hospitalisations/
ER treatment
p<0.001
p<0.01
400
377
p<0.001
296
300
p<0.05
140
194
115
200 98
100 70 60
100 20
Maintenance Form/Bude + prn
Terbutal
Formoterol
Form/Bude
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
50-75% of all asthmatic patients
severe exacerbations per patient-year
Associated with inflammation/remodeling
Permanent low-dose ICS reference treatment
Dusser D et. al. Allergy 2007; 62:

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

31. (400 mcg budesonide bid x 10 days) taken when symptoms worsen
REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMA
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
Boushey H.A. et al, NEJM 2005;352:

32. 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
to placebo tablets
+ placebo inhaler
Budesonide 800 g bid x 10 days
Run-in period
Week
Visit -4 3 -2 5 6 13 7 26 8 39 11 48 12 52 13 54 14
Boushey H.A. et al, NEJM 2005;352:

33. 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:

34. 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:

35. Study design Papi A et al. N Engl J Med 2007;356:2040-52
Inhaled placebo b.i.d. plus
p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination
p.r.n. inhaled 100 µg salbutamol
Inhaled 250 µg beclomethasone/100 µg salbutamol combination b.i.d. plus
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. EFFECT OF EXACERBATIONS
Papi A et al. N Engl J Med 2007;356:
0,5 1
1,5 2
As needed
combination
albuterol
Regular
beclomethasone
Number of exacerbations per patients/year

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

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):
March 5, 2009

39. Original Article Mepolizumab 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):
March 5, 2009

40. 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
Figure 2. Rates of Exacerbation. Panel A shows the mean rates of total exacerbations of asthma and of minor and major exacerbations during phase 2. Error bars represent SEs. In Panel B, the cumulative number of exacerbations of asthma during phase 2 is shown; P=0.27 for the comparison between groups. Panel C shows the results of a Kaplan-Meier analysis of the time to a first exacerbation of asthma in each group during phase 2. There was no significant difference between the two groups (P=0.39). Panel D shows the frequency distribution of patients who had zero, one, and two or more exacerbations during phase 2.
Haldar P. NEJM 2009;360:973-84

41. Cumulative No. of exacerbations
Haldar P. et al., N Engl J Med 2009; 360:
Severe Exacerbations during the Study 20 40 60 80
100
120 1 2 3 4 5 6 7 8 9 10 11 12
Month
Cumulative No. of exacerbations
Start of treatment
Placebo
Mepolizumab 14 25 34 47 58 69 79 85 97
108
109 13 21 27 33 36 44 49 55 57
No. of subjects
No. of exacerbations
31% vs 16% had no EX
Figure 2. Rates of Exacerbation. Panel A shows the mean rates of total exacerbations of asthma and of minor and major exacerbations during phase 2. Error bars represent SEs. In Panel B, the cumulative number of exacerbations of asthma during phase 2 is shown; P=0.27 for the comparison between groups. Panel C shows the results of a Kaplan-Meier analysis of the time to a first exacerbation of asthma in each group during phase 2. There was no significant difference between the two groups (P=0.39). Panel D shows the frequency distribution of patients who had zero, one, and two or more exacerbations during phase 2.

42. Mepolizumab and exacerbations of refractory eosinophilic asthma
P = ns
P< 0.001
P = ns
P = 0.002
P< 0.02
P= ns
Figure 2. Rates of Exacerbation. Panel A shows the mean rates of total exacerbations of asthma and of minor and major exacerbations during phase 2. Error bars represent SEs. In Panel B, the cumulative number of exacerbations of asthma during phase 2 is shown; P=0.27 for the comparison between groups. Panel C shows the results of a Kaplan-Meier analysis of the time to a first exacerbation of asthma in each group during phase 2. There was no significant difference between the two groups (P=0.39). Panel D shows the frequency distribution of patients who had zero, one, and two or more exacerbations during phase 2.
P = ns
P = ns
Haldar P. et al. NEJM 2009;360:973-84

43. 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

44. Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia
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):
March 5, 2009

45. 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.
Figure 2. Rates of Exacerbation. Panel A shows the mean rates of total exacerbations of asthma and of minor and major exacerbations during phase 2. Error bars represent SEs. In Panel B, the cumulative number of exacerbations of asthma during phase 2 is shown; P=0.27 for the comparison between groups. Panel C shows the results of a Kaplan-Meier analysis of the time to a first exacerbation of asthma in each group during phase 2. There was no significant difference between the two groups (P=0.39). Panel D shows the frequency distribution of patients who had zero, one, and two or more exacerbations during phase 2.
Nair P. NEJM 2009;360:

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

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

48. Eosinophils in Sputum Nair P. et al., N Engl J Med 2009; 360: 985-993.10 20 30 40 50 60 70 V1 V4
W/Ex
V12 2
Sputum Eosinophils
Mepolizumab
Placebo

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

50. 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

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

52. Nuovi farmaci in asma e BPCO
Corso di Aggiornamento per Medici Internisti
Modena, Marzo 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

53. Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
FEV1/FVC < 70%
FEV1 < 30% predicted
or FEV1 < 50% predicted plus chronic respiratory failure
FEV1/FVC < 70%
30% < FEV1 < 50% predicted
FEV1/FVC < 70%
50% < FEV1 < 80%
predicted
FEV1/FVC < 70%
FEV1 > 80%
predicted
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
This provides a summary of the recommended treatment at each stage of COPD.
Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if repeated exacerbations
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 dall’Agenzia Regolatoria Europea (EMEA) nel dicembre 2009 indicato come terapia broncodilatatrice di mantenimento nell’ostruzione 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 d’azione, entro 5 minuti dall’inalazione.
Nel 2010 approvato anche dall’Agenzia 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 Jan 18 54 54

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

56. Il trattamento con indacaterolo ha dimostrato un progressivo miglioramento del TDI
Indacaterolo µg 150 od
Indacaterolo 300 µg od
Tiotropio 18 µg od
Placebo
†††
***
2,58
3,0
†††
***
2,38
***
2,41
***
2,27
***
2,13
***
1,95
2,0
1 punto
1 punto
1,40
Punteggio TDI focale
1,20
1,0
B2335S CSR Table 11–14
Reference
Mahler DA, Palange P, Iqbal A, Owen R, Higgins M, Kramer B. Indacaterol once-daily improves dyspnoea in COPD patients: a 26-week placebo-controlled study with open-label tiotropium comparison. Abstract to be presented at ERS 2009.
N° pazienti 2059
Obiettivo efficacia e sicurezza vs. placebo e tiotropio
Disegno randomizzato in doppio cieco verso placebo a gruppi paralleli
Durata 6 mesi
Farmaci indacaterolo 150 µg e 300 µg od, tiotropio 18 µg od, placebo
Settimana 12
Settimana 26
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
Donohue et al. AJRCCM 2010;182:155-62 56

57. Indacaterolo aumenta il tempo alla prima riacutizzazione rispetto al placebo (studio a 26 settimane)
Indacaterolo 150 μg od
Indacaterolo 300 μg od
Tiotropio 18 μg od
Placebo
100 80
Pazienti senza riacutizzazioni (%) 60 40 1 2 3 4 5 6 7
ancora dati sulle riacutizzazioni.
Studio verso placebo Indacaterolo risulta sovrapponibile a Tiotropio.
N° pazienti 2059
Obiettivo efficacia e sicurezza vs. placebo e tiotropio
Disegno randomizzato in doppio cieco verso placebo a gruppi paralleli
Durata 6 mesi
Farmaci indacaterolo 150 µg e 300 µg od, tiotropio 18 µg od, placebo
Tempo alla prima riacutizzazione (mesi)
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)
Donohue et al. AJRCCM 2010;182:155-62 57

58. Miglioramento del FEV1 dopo 52 settimane
1.55
1.50
1.45
1.40
1.35
1.30
1.25
1.20
1.15
†††
†††
***
***
1.45
1.43
***
1.38
1.43
***
1.48
*** *
1.38 †
1.31
Trough FEV1 (L)
1.31
1.32
1.28
The primary efficacy analysis in the INVOLVE study (B2334) showed that treatment with indacaterol 300 or 600 µg once daily resulted in trough FEV1 values at week 12 that were significantly higher (1.48 L, p<0.001 in both groups) than in the placebo group (1.31 L). Secondary analyses also showed that trough FEV1 values were significantly higher in indacaterol recipients than in patients receiving formoterol and that the benefits were apparent as early as Day 2 and were sustained through 52 weeks.
Reference
Magnussen H, Paggiaro P, Jack D, Owen R, Higgins M, Kramer B. Bronchodilator treatment with indacaterol once-daily vs formoterol twice-daily in COPD: a 52-week study. Am J Respir Crit Care Med 2009;179:A6184 (+ Poster [Paggiaro et al])
Dahl R, Kolman P, Jack D, Owen R, Kramer B, Higgins M. Indacaterol once-daily provides sustained 24-hour bronchodilation over 52 weeks of treatment in COPD. Am J Respir Crit Care Med 2009;179:A4545.
[CSR Table 11–5, Table 11–12]
Giorno 2
Settimana 12
Settimana 52
Endpoint primario
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
Dahl et al. Thorax 2010;65; 58 58

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. Double-blind, randomised, parallel group
M2-124 & M2-125 – Study Design
Single-blind
Double-blind, randomised, parallel group
roflumilast 500µg o.d.
Run-in
4 weeks
Follow up
2 weeks
Treatment
52 weeks V0 R VE FU
Key Message
Both studies were 12 month, multi-country, multi-centre, placebo-controlled, double-blind, randomised, parallel group design.
Maintenance treatment with long acting beta-2 agonists (LABA) or short acting anticholinergics (SAMA) where allowed during the studies.
The studies involved a 4 week run-in period, a 52 week treatment phase and a 2 week follow-up phase.
Patients were randomised to one of the following two treatment groups – Roflumilast 500µg o.d or Placebo o.d
Patients were allowed concomitant medication by way of short acting anticholinergic at regular dosing and LABA in order to reflect common clinical practice. The studies were stratiified for LABA use and approximately 50% of patients used a LABA concomtant to study medication. Approximately 40% of patients in both treatment arms used a SAMA
1523 patients were included at baseline for M2-124
1568 patients were included at baseline for M2-125
placebo 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
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94 60 60

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
Key Message:
COPD patients had to have a history of chronic bronchitis (daily cough and sputum production according to ATS criteria*) and be symptomatic for the 12 months prior to inclusion in the study
* History of COPD for at least 12 months as defined in the ATS/ERS consensus statement (Standards for the Diagnosis and Management of patients with COPD, 2004) and chronic productive cough for 3 months in each of the 2 years prior to baseline visit V0 (if other causes of productive cough have been excluded)
The reason for the patient population selection was based on observations from previous clinical trials (eg M2-111 and M2-112) where this population was identified as having more frequent exacerbations and responding to roflumilast treatment on this outcome.
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94 61 61

62. M2-124 & M2-125 – Population (2) Main Criteria for Inclusion:
Age > 40 years
FEV1/FVC ratio (post-bronchodilator)  70%
FEV1 (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
Key Message
Patients included in the study were symptomatic
Main criteria for inclusion were FEV1 post bronchodilator of  50% of predicted in addition to a history of at least one moderate or severe COPD exacerbation within one year prior to the study. Finally patients were also required to have a total cough and sputum score of  14 during the last week directly preceding the randomization visit
Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94 62 62

63. Pre- & Post-Bronchodilator FEV1 M2-124 & M2-125 pooled analysis
1.2
1.1
Mean FEV1 [L]
Key Message
Treatment with Roflumilast provides statistically significant sustained improvements in lung function (pre-bronchodilator and post-bronchodilator FEV1) over 12 months compared to placebo
The improvement in lung function observed with roflumilast was seen within the first 4-8 weeks of treatment and was sustained throughout the one year treatment period 1
1536
1473
1336
1262
1210
1152
1100
1061
1024
roflumilast*
1554
1506
1419
1375
1306
1241
1167
1102
1072
placebo* 4 8 12 20 28 36 44 52
Weeks
placebo (pre)
roflumilast 500µg (pre)
placebo (post)
roflumilast 500µg (post)
*N patients are given for pre-FEV1 measurements
Data on file 63

64. Mean rate of exacerbations per patient per year
COPD Exacerbations (Moderate or Severe) M2-124 & M2-125 pooled analysis
 = - 17%
(CI -25;-8)
p =
1.5
Mean rate of exacerbations per patient per year 1
The 2nd co-primary endpoint was the mean reduction in rate of moderate and
severe exacerbations over the 52 weeks.
Key Message
Treatment with roflumilast significantly reduced the rate of
moderate and severe exacerbations over 12 months compared to
placebo
In both pivotal studies, roflumilast significantly reduced the rate of moderate and
severe exacerbations by 17% versus placebo in this population of COPD patients.
The results on this slide combined with the lung function data meet the regulatory
requirements for demonstrating efficacy of roflumilast
0.5
1.374
1.142
placebo
roflumilast 500µg
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94 64

65. Probability of not experiencing and exacerbation
Median Time to First COPD Exacerbation (Moderate or Severe) M2-124 & M2-125 pooled analysis 1
0.9
Hazard ratio = 0.89
(CI 0.80;0.98)
p =
0.8
0.7
Probability of not experiencing and exacerbation
0.6
0.5
Key Message
Treatment with roflumilast demonstrated a significantly longer time to
first exacerbation when compared to placebo
0.4
0.3
0.2 4 8 12 20 28 36 44 52
Weeks
placebo
roflumilast 500µg
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94 65

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)
COPD
10%
13%
Weight Loss 3%
Diarrhoea 8%
Nasopharyngitis 6%
Nausea 4% 2%
Bronchitis
Headache 7%
Key message
The AE profile is consistent with the profile we have seen for roflumilast in previous studies.
This slide describes the reported AEs independent of causality assessment by investigator. Weight decrease was reported as an AE, in addition to regular weight measurement at clinic visits. A weight decreaseof on average 2kg was seen in the roflumilast enhanced COPD study program. In a three month follow-up after treatment discontinuation, the majority of patients regained weight. Weight change was one of the Topics Of Special Interest (TOSI) documented at each clinic visit for regulatory purposes. More detailed information on this topic is found later in the slideset.
AE’s such as diarrhoea, headache and nausea that were more frequent in the roflumilast treatment arm occurred at the beginning of treatment, resolved with continued treatment and did not lead to sequelae.
Data on file 66 66

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

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

69. Roflumilast as Add-On Therapy in COPD
Roflumilast 500µg o.d.
Run-in
4 weeks
Follow up
2 weeks
Treatment
24 weeks V0 R VE FU
Key Message
M2-127 and M2-128 were 6 month, multi-country, multi-centre, double-blind, randomised, parallel group studies.
The studies involved a 4 week run-in period, a 24 week treatment phase and a 2 week follow-up phase.
Patients in Study M2-127 were on salmeterol maintenance treatment at baseline and randomised to either placebo or roflumilast 500 µg o.d.
Patients in Study M2-128 were on tiotropium maintenance treatment for at least three months at baseline and randomised to either placebo or roflumilast 500 µg o.d.
1221 patients were included at baseline in M2-127 with 933 patients randomised
910 patients were included at baseline in M2-128 with 743 patients randomised
M2-127 study was conducted in 135 centres in ten countries
M2-128 study involved 85 centres in seven countries
Placebo o.d.
M2-127: Salmeterol 50µg b.d. as maintenence for all patients
M2-128: Tiotropium 18µg o.d. as maintenence for all patients
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 69 69

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
The next three slides list the key inclusion criteria for the studies.
Key Message
COPD patients had to have the COPD diagnosis 12 months prior to study start.
M2-128 patients had to have a COPD diagnosis for at least 12months, and symptoms of chronic bronchitis according to ATS criteria.
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 70 70

71. Main Criteria for Inclusion
Age  40 years
FEV1/FVC ratio (post-bd)  70%
FEV1 (post-bd) between  40% and  70 % pred
FEV1 increase of  12% or  200 ml after 400 mcg salbutamol
Current 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 baseline
Key Message
The main inclusion criteria were patients needed to be aged over 40 years, current or ex-smokers (at least 1 year of smoking cessation) with a smoking history of at least 10 pack-years. Patients were also moderate or severe COPD patients as measured by FEV1
In addition patients in study M2-128 had to have a maintenance treatment with tiotropium for at least 3 months prior to baseline
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 71 71

72. Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV1
1.6
Salmeterol+ Roflumilast
1.5
Pre bd FEV1 [L]
1.4
Salmeterol + Placebo
Key Message
The additional significant improvements in lung function (pre-bronchodilator FEV1) were sustained over 6 months of treatment when roflumilast was used concomitantly with salmeterol, compared with salmeterol plus placebo
M2-127
This graph illustrates that the improvement in pre-bronchodilator FEV1 was seen at 4 weeks and sustained throughout treatment. By week 24, pre-bronchodilator FEV1 in the Roflumilast + Salmeterol arm remained significantly greater when compared to the salmeterol + placebo arm
Study medication was to be withheld in the morning of study visit days, as was salmeterol for 10 hours and reliever medication for at least 4 hours prior to pulmonary function tests. The pre-bronchodilator measurement thus represents the ‘worst-case’ in terms of lung function improvement, as it is the smallest degree of improvement that would be observed over the dose interval.
The fact that the onset of effect of roflumilast on FEV1 is not immediate shows that the effect is not due to bronchodilation by smooth muscle relaxation, and can likely be explained by the anti-inflammatory effects of roflumilast.
466
467
455
463
410
437
389
419
374
403
359
384
Roflumilast
Placebo
1.3 4 8 12 18 24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 72 72

73. Roflumilast as Add-On Therapy in COPD Pre-bronchodilator FEV1
1.7
Tiotropium+ Roflumilast
1.6
Pre bd FEV1 [L]
1.5
Key Message
The improvements in lung function (pre bronchodilator FEV1) were sustained over 6 months of treatment when roflumilast was used concomitantly with tiotropium compared with tiotropium plus placebo
M2-128
This graph illustrates that the improvement in pre-bronchodilator FEV1 was seen at 4 weeks and sustained throughout treatment. By week 24, pre-bronchodilator FEV1 in the roflumilast + tiotropium arm remained significantly greater when compared to the tiotropium + placebo arm
Study medication was to be withheld in the morning of study visit days, as was tiotropium for 20 hours and reliever medication for at least 4 hours prior to pulmonary function tests. The pre-bronchodilator measurement thus represents the ‘worst-case’ in terms of lung function improvement, as it is the smallest degree of improvement that would be observed over the dose interval.
Tiotropium + Placebo
371
372
364
363
343
352
325
350
318
347
310
333
Roflumilast
Placebo
1.4 4 8 12 18 24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 73 73

74. Roflumilast as Add-On Therapy in COPD Post-bronchodilator FEV1
Salmeterol
Tiotropium
100
 = 60 ml
p <
= 81 ml
p < 80
n=452
n=364 60 40
Mean change in post bd FEV1 [ml] 20
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.
n=460 8 68
n=363 74 -7
-20
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 74 74

75. Median Time to First Moderate or Severe COPD Exacerbation
1.00
Salmeterol+ Roflumilast
0.95
Probability of not experiencing an
exacerbation
0.90
HR = 0.6 p =
0.85
Note: Data not in paper
Key Message
Roflumilast given concomitantly with salmeterol as underlying maintenance medication significantly increased the time to first exacerbation (moderate and severe exacerbations, ie intervention with systemic corticosteroids and hospitalisation/or death respectively) compared with salmeterol plus placebo. Although the study was only of 6 month duration and thus not designed to evaluate exacerbations over a full year, it showed substantial benefit of roflumilast in reducing the risk of these pivotal events in a population of moderate to severe COPD patients in this post-hoc analysis. These findings are consistent with the one year pivotal trials showing that the benefit of roflumilast in reducing exacerbations is independent of underlying treatment with long-acting bronchodilators
Salmeterol + Placebo
0.80 4 8 12 18 24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 75 75

76. Median Time to First COPD Moderate or Severe Exacerbation
1.00
0.95
Tiotropium+ Roflumilast
Probability of not experiencing an
exacerbation
0.90
HR = 0.8
p =
0.85
Note: Data not in paper
Key Message
There was a trend for roflumilast, given concomitantly with tiotropium as underlying maintenance medication, to increase the time to first moderate or severe exacerbation over 6 months compared to tiotropium plus placebo with a hazard ratio of 0.8, but it did not reach statistical significance (p=0.196). This was a pre-specified analysis in the statistical analysis plan, although the study was of only 6 month duration and thus not designed to evaluate exacerbations over a full year, the findings are consistent with the one year pivotal studies that the effect of roflumilast in reducing exacerbations is independent of underlying treatment with long-acting bronchodilators. Furthermore the secondary analysis also including mild exacerbations in the analysis showed a significantly reduced hazard ratio
As compared to the salmeterol study (m2-127) this study was also somewhat smaller which can explain a loss of power.
Tiotropium + Placebo
0.80 4 8 12 18 24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 76 76

77. Mean change in SOBQ Score
Roflumilast as Add-On Therapy in COPD SOBQ (Shortness of Breath Questionnaire) 1
Tiotropium + Placebo -1
 = - 2.6
Mean change in SOBQ Score -2 p= -3
Note: Data not in paper
Key Message
Roflumilast given concomitantly with tiotropium significantly improved breathlessness as measured by SOBQ compared with tiotropium plus placebo, although it did not reach the clinically important difference
Tiotropium+ Roflumilast -4 -5 4 8 18 24 12
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 77 77

78. Incidence of Adverse Events
Sal + Roflumilast (n = 466)
Sal + Placebo (n = 467)
Tio + Roflumilast (n = 374)
Tio + Placebo (n = 369)
COPD
16%
24%
18%
Weight decrease 9% 1% 6%
Diarrhoea 8% 3%
<1%
Nasopharyngitis 7% 5%
Nausea
Headache 2% 0%
Back pain
Key message
The AE profile is consistent with the profile we have seen for roflumilast in previous studies.
This slide describes the reported AEs independent of causality assessment by investigator. Weight decrease was reported as an AE. Weight changes were also recorded at clinic visits. A weight decrease of on average 2.1 kg was seen in the M2-127 and M2-128 studies. Weight decrease was reversible as in a three month follow-up after treatment discontinuation, the majority of patients regained weight. Weight change was one of the Topics Of Special Interest (TOSI) documented at each clinic visit for regulatory purposes in the 6-month trials. AEs such as diarrhoea, headache and nausea that were more frequent in the roflumilast treatment arm occurred at the beginning of treatment, resolved with continued treatment and did not lead to sequelae.
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 78 78

79. Roflumilast as Add-On Therapy in COPD Adverse Events - Body Weight4
Salmeterol Trial 2
 = kg
p < -2 -4 4 8 12 18 24
Change in Body Weight [kg] 4
Tiotropium Trial 2
Key Message
The average weight loss was 2.1 kg with the main change during the first part of the 6 months of roflumilast treatment. There was little change in the placebo group. Weight decrease was similar in the two trials. This weight decrease is the same level as seen in studies M2-124 and M2-125 over 12 months.
Weight decrease was generally somewhat larger in roflumilast treated patients reporting gastrointestinal events and/or headache than inpatients not reporting these symptoms , but weight decrease can not fully be attributed to these symptoms. Weight decrease was present in all BMI categories, numerically less in underweight and normal BMI and numerically larger in overweight and obese patients, although these differences were not statistically significant. Data on file shows that the weight loss was reversible upon treatment discontinuation
The mechanisms behind the weight decrease cannot fully be explained by PDE4 inhibitor related side effects, but remains to be explored.
 = kg
p < -2 -4 4 8 12 18 24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 79 79

80. Roflumilast as Add-On Therapy in COPD
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 AE’s or pneumonias)
Roflumilast might qualify as a recommended oral therapy on top of bronchodilators such as Salmeterol and Tiotropium (Role of ICS..?)
Key Message
The primary variable in both studies was mean change from baseline in pre-bronchodilator FEV1 during the treatment period.
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703 80 80