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
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
1960s
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
2000s
Anti-human IgE mAb
hr IFNhr 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;29:793-803
Steroidi inalatori per la terapia
dell’asma
DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA
FARMACO
ADULTI $
Dose bassa
Dose intermedia
Dose Alta
Beclometasone
dipropionato
200 – 500
>500 – 1000
>1000 – 2000
Beclometasone
Dipropionato HFA
100 – 200
>200 – 400
>400 – 800
Budesonide
200 – 400
>400 – 800
>800 – 1600
Flunisolide
500 – 1000
>1000 – 2000
>2000
Fluticasone
Propionato
100 – 250
>250 – 500
>500 – 1000
Ciclesonide
Mometasone
furoato
80 - 160
160 - 320
320 - 1280
200 - 400
> 400 - 800
>800 - 1200
$ confronto basato sui dati di efficacia
www.ginasma.it
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
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.
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
Binding site of omalizumab to IgE
IgE
C3
omalizumab
Clinically significant
Asthma exacerbations rate
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
1.0
0.8
0.68
0.6
0.4
0.2
0
omalizumab
placebo
0.6
P=0.002
Severe asthma
exacerbations rate
0.91
0.48
0.4
0.24
0.2
0
omalizumab
placebo
Humbert M et al; Allergy 2005; 60:309-316
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)
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
Randomized Trial of Omalizumab (Anti-IgE) for
Asthma in Inner-City Children
Busse WW et al. N Engl J Med 2011;364:1005-15
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.
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
1960s
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
2000s
Anti-human IgE mAb
hr IFNhr 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;29:793-803
Anti-TNFa therapy in asthma
Brightling C et al. JACI 2008; 121:5-10
Anti-TNFa therapy in asthma
Anti-TNFa therapy in asthma
• Small n° of patients
• Heterogeneity of response
• Safety (infections, malignancies)
A randomized, double-blind, placebo-controlled study of
tumor necrosis factor-α blockade in severe persistent
asthma
Changes from baseline in
prebronchodilator percentpredicted FEV1 through Week 24
Percent of patients free
from severe asthma
exacerbation
Wenzel SE et al. AJRCCM 2009; 179:549-58
A randomized, double-blind, placebocontrolled 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
Asthma control during the year after
bronchial thermoplasty
n= 52
n = 49
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
• FEV1
• BHR
• Rescue medication
• Symptom free days
• Symptom score
• AQLQ score
• ACQ score
p=0.003
n.s.
n.s
p=0.04
p=0.005
p=0.01
p=0.003
p=0.001
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; 356:1327-37
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.
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
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
Sal/Flu 50/100
or FP 100
Step 3
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.
Mean exacerbation rate
per patient per year
GOAL: Exacerbation rate in Phase II
0,3
0,25
0,2
0,15
0,1
0,05
0
TOTAL control
n = 592
WELL control
n = 1512
Uncontrolled
n = 1378
Bateman E et al Am J Respir Crit Care Med 2004;170:836-44.
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 + Formoterol 4.5 µg as reliever
n=1140
Enrolled: n=3829
Randomised: n=3394
Visit:
1
Month: -0.5
Formoterol/Budesonide + Formoterol/Budesonide 160/4.5 µg as
reliever (SMART) n=1113
2
0
3
1
4
4
5
8
6
12
Rabe KF et al, Lancet. 2006;368:744-53
SMILE Study: Severe Exacerbations
Total No. events
Hospitalisations/
ER treatment
p<0.001
400
377
p<0.01
p<0.001
300
296
p<0.05
140
115
194
200
100
98
70
60
100
20
Maintenance
Form/Bude + prn
Terbutal
Formoterol
Form/Bude
Rabe KF et al, Lancet. 2006;368:744-53
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
Stepwise Approach to Asthma Therapy
Controlled by low-dose
inhaled steroids
Step 2: Mild Persistent Asthma
Controller
Reliever
• Daily inhaled corticosteroid (200-500 mcg)
• Consider Leukotriene
Modifiers
• Inhaled beta2-agonist
prn
Avoid or Control Triggers
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;352:1519-1528
REGULAR CONTROLLER THERAPY VERSUS
INTERMITTENT INHALED CORTICOSTEROIDS FOR
PERSISTENT MILD ASTHMA
10-Day course of
intense combined
200 µg of budesonide
therapy
b.i.d. + placebo tablets
20 mg of zafirlukast
b.i.d. + placebo inhaler
Budesonide 800 g
bid x 10 days
10-Day course of
intense combined
therapy
Budesonide 800
g bid x 10 days
411 Enrolled
225
Randomized
to placebo tablets
+ placebo inhaler
Run-in period
Week
Visit
-4
3
-2
5
0
6
13
7
26
8
Budesonide 800
g bid x 10 days
39
11
48
12
52 54
13 14
Boushey H.A. et al, NEJM 2005;352: 1519-28
Percentage without Exacerbation
Kaplan–Meier Estimates of the Time
to a First Exacerbation of Asthma
100
80
60
40
Daily budesonide
Daily zafirlukast
20
Intermittent therapy
P=0.39
0
0
100
200
300
400
Days since Randomization
Boushey H.A. et al, NEJM 2005;352:1519-1528
RESCUE USE OF BECLOMETHASONE
AND ALBUTEROL
IN A SINGLE INHALER FOR MILD ASTHMA
In patients with mild asthma, the symptomdriven 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
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
Number of exacerbations per patients/year
EFFECT OF EXACERBATIONS
2
1,5
1
0,5
0
As needed
combination
As needed
albuterol
Regular
beclomethasone
Regular
combination
Papi A et al. N Engl J Med 2007;356:2040-52
CUMULATIVE DOSE OF BECLOMETHASONE
(BDP)
**
**
100
80
mg
60
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
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
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):973-984
March 5, 2009
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
Severe Exacerbations during the Study
Placebo
10
10 10
9
8
100
79
7
69
58
60
Mepolizumab
47
25
4
Start of 1
treatment
33
36
40
44
49
21
5
4
3
1
13
3 7
2
6
2
27
14
20
0
5557
34
40
0
3
4
Mepolizumab
31% vs 16% had no EX
8
85
80
Placebo
9
97
No. of subjects
Cumulative No. of exacerbations
120
5
6
7
Month
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9
No. of exacerbations
Haldar P. et al., N Engl J Med 2009; 360: 973-984.
Mepolizumab and exacerbations of refractory
eosinophilic asthma
P< 0.001
P = 0.002
P = ns
P = ns
P< 0.02
P= ns
P = ns
P = ns
Haldar P. et al. NEJM 2009;360:973-84
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
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
Mepolizumab and exacerbations of refractory
eosinophilic asthma
Study Design
Randomized, double – blind, placebo-controlled, parallelgroup 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
Protocol for reduction in the dose of prednisone
Run in
6 wk
Washout
8 wk
Prednisone dose reduction
Mepolizumab (750 mg)
Placebo
Randomization
Visit
0
2
4
6
8
10
12
14
Week
0
2
6
10
14
18
22
26
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
5.0
2.5
2.5
0.0
0.0
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
Nair P. et al., N Engl J Med 2009; 360: 985-993.
Patients without exacerbation (%)
Analysis of the Proportion of Patients without
an Asthma Exacerbation during the Study.
100
No. At risk
Mepolizumab
Placebo
90
Mepolizumab
80
70
60
50
40
30
20 Randomization
Placebo
10
0
0
2
9
1
0
4
6
8
10 12 14 16 18 20 22 24 26
9
9
8
7
Weeks
7
7
7
5
7
4
7
3
7
2
Nair P. et al NEJM 2009;360:985
Sputum Eosinophils
Eosinophils in Sputum
70
70
60
60
50
50
40
40
30
30
20
20
10
10
2
0
2
0
V1
V4
W/Ex V12
Mepolizumab
V1
V4
W/Ex V12
Placebo
Nair P. et al., N Engl J Med 2009; 360: 985-993.
Blood Eosinophils (per mm3)
Eosinophils in Blood
1800
1800
1500
1500
1200
1200
900
900
600
600
400
300
400
300
0
0
V1
V4
W/Ex V12
Mepolizumab
V1
V4
W/Ex V12
Placebo
Nair P. et al., N Engl J Med 2009; 360: 985-993.
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
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
Corso di Aggiornamento per Medici Internisti
Modena, 29-30 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
Therapy at Each Stage of COPD
I: Mild
II: Moderate
III: Severe
IV: Very Severe
• FEV1/FVC < 70%
• FEV1/FVC < 70%
• FEV1 > 80%
predicted
• FEV1/FVC < 70%
• FEV1/FVC < 70%
• 50% < FEV1 < 80%
predicted
• 30% < FEV1 < 50%
predicted
• FEV1 < 30% predicted
or FEV1 < 50%
predicted plus chronic
respiratory failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
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
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.
2010 Jan 18
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
Il trattamento con indacaterolo ha dimostrato un progressivo
miglioramento del TDI
Indacaterolo µg 150 od
†††
***
1,95
***
2,13
1,20
***
2,38
***
2,27
1 punto
1 punto
Punteggio TDI focale
Tiotropio 18 µg od
Placebo
†††
3,0
2,0
Indacaterolo 300 µg od
***
2,41
***
2,58
1,40
1,0
0
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
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
Pazienti senza
riacutizzazioni (%)
100
80
60
40
0
1
2
3
4
5
6
7
Tempo alla prima riacutizzazione (mesi)
Indacaterolo Indacaterolo Tiotropio
150 µg
300 µg
18 µg
Rapporto di rischio
rispetto
al placebo
(IC 95%)
0,69
0,74
0,76
(0,51-0,94) (0,55-1,05) (0,56-1,03)
Donohue et al. AJRCCM 2010;182:155-62
Miglioramento del FEV1 dopo 52 settimane
1.55
1.45
***
1.43
1.40
1.35
††
†
††
†
1.31
1.30
***
1.45
Placebo
***
Formoterolo 12 µg b.i.d.
***
Trough FEV1 (L)
1.50
Indacaterolo 300 µg o.d.
1.48
1.38 1.38
†
*
1.31
1.28
1.43
***
1.32
1.25
1.20
1.15
Giorno 2
Settimana 12
Endpoint primario
Settimana 52
•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; 473-479
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
M2-124 & M2-125 – Study Design
Double-blind, randomised, parallel group
Single-blind
roflumilast 500µg o.d.
Run-in
4 weeks
V0
R
Treatment
52 weeks
Follow up
2 weeks
VE
FU
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
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
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
Calverley PMA, Rabe, KF,et al. Lancet 2009;374:685–94
Pre- & Post-Bronchodilator FEV1
M2-124 & M2-125 pooled analysis
Mean FEV1 [L]
1.2
1.1
1
1536 1473 1336 1262
1210
1152
1100
1061
1024 roflumilast*
1554 1506 1419 1375
1306
1241
1167
1102
1072
20
28
Weeks
36
44
52
0
4
8
12
placebo (pre)
placebo (post)
*N patients are given for pre-FEV1 measurements
Data on file
roflumilast 500µg (pre)
roflumilast 500µg (post)
placebo*
COPD Exacerbations (Moderate or Severe)
M2-124 & M2-125 pooled analysis
 = - 17%
(CI -25;-8)
p = 0.0003
1.5
1
0.5
1.374
1.142
0
placebo
roflumilast 500µg
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94
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 = 0.0185
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0
4
8
12
20
28
36
44
52
Weeks
placebo
roflumilast 500µg
Calverley PMA, Rabe, KF ,et al. Lancet 2009;374:685–94
Incidence of AEs ( 2.0%)
Independent of Investigator Causality
Assessments (1/2)
M2-124 & M2-125 pooled analysis
(n=3092)
Data on file
roflumilast 500µg
o.d.
(n=1547)
placebo
(n=1545)
COPD
10%
13%
Weight Loss
10%
3%
Diarrhoea
8%
3%
Nasopharyngitis
6%
6%
Nausea
4%
2%
Bronchitis
4%
4%
Headache
3%
7%
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
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
Roflumilast as Add-On Therapy in COPD
Roflumilast 500µg o.d.
Run-in
4 weeks
V0
R
Treatment
24 weeks
Follow up
2 weeks
VE
FU
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
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 M2127
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
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
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD
Pre-bronchodilator FEV1
1.6
Salmeterol+ Roflumilast
1.5
1.4
1.3
Salmeterol + Placebo
466
467
455
463
410
437
0
4
8
389
419
12
Weeks
374
403
359
384
18
24
Roflumilast
Placebo
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD
Pre-bronchodilator FEV1
1.7
Tiotropium+ Roflumilast
1.6
1.5
Tiotropium + Placebo
1.4
371
372
364
363
343
352
0
4
8
325
350
12
Weeks
318
347
310
333
18
24
Roflumilast
Placebo
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD
Post-bronchodilator FEV1
Tiotropium
Salmeterol
100
80
 = 60 ml
p < 0.0001
= 81 ml
p < 0.0001
n=452
n=364
60
40
20
n=460
0
8
68
n=363
-7
74
-20
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Probability of not experiencing an
exacerbation
Median Time to First Moderate or Severe
COPD Exacerbation
1.00
Salmeterol+ Roflumilast
0.95
0.90
HR = 0.6
0.85
p = 0.0067
Salmeterol + Placebo
0.80
0
4
8
12
Weeks
18
24
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Probability of not experiencing an
exacerbation
Median Time to First COPD Moderate or
Severe Exacerbation
1.00
Tiotropium+ Roflumilast
0.95
0.90
HR = 0.8
p = 0.1959
0.85
0.80
Tiotropium + Placebo
0
4
8
12
18
24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD SOBQ
(Shortness of Breath Questionnaire)
1
0
Tiotropium + Placebo
-1
-2
p= 0.0051
-3
Tiotropium+ Roflumilast
-4
-5
0
4
8
12
Weeks
18
24
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Incidence of Adverse Events
Sal +
Roflumilast
(n = 466)
Sal +
Placebo
(n = 467)
Tio +
Roflumilast
(n = 374)
Tio +
Placebo
(n = 369)
COPD
16%
24%
16%
18%
Weight
decrease
9%
1%
6%
1%
Diarrhoea
8%
3%
9%
<1%
Nasopharyngitis
7%
7%
6%
5%
Nausea
5%
<1%
3%
1%
Headache
3%
1%
2%
0%
Back pain
3%
2%
2%
1%
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Roflumilast as Add-On Therapy in COPD
Adverse Events - Body Weight
4
Salmeterol Trial
2
0
 = - 2.1
kg
-2
-4
p < 0.0001
0
4
8
12
18
24
4
Tiotropium Trial
2
0
 = - 2.1
kg
-2
-4
p < 0.0001
0
4
8
12
18
24
Weeks
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
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..?)
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703