Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011 Clinica di Malattie.
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Nuovi farmaci in asma e BPCONuovi farmaci in asma e BPCO
Bianca Beghè, Leonardo M Fabbri Bianca Beghè, Leonardo M Fabbri
Corso di Formazione al Personale Nycomed Corso di Formazione al Personale Nycomed Modena, 6-7/8-9 Settembre 2011Modena, 6-7/8-9 Settembre 2011
Clinica di Malattie del’Apparato RespiratorioUniversità degli Studi di Modena e Reggio Emilia
Paucity of new therapeutics for asthmaPaucity of new therapeutics for asthma
Holgate et al. Eur Respir J. 2007;29:793-803Holgate et al. Eur Respir J. 2007;29:793-803
DecadeDecade Drugs currently Drugs currently availableavailable
Drugs in developmentDrugs in development Therapeutics that Therapeutics that have failedhave failed
1960s1960s Short-acting ßShort-acting ß22-agonists-agonists Neuropeptide antagonistsNeuropeptide antagonists
1980s1980s Long-acting ßLong-acting ß22 agonists agonists Type IV PDE inhibitors (mostly Type IV PDE inhibitors (mostly targeted for COPD)targeted for COPD)
PAF antagonistsPAF antagonists
1960s1960s Inhaled and oral Inhaled and oral corticosteroidscorticosteroids
Anti-TNF-Anti-TNF-αα Thromboxane inhibitorsThromboxane inhibitors
1990s1990s Leukotriene receptor Leukotriene receptor antagonistsantagonists
Bradykinin antagonistsBradykinin antagonists
1970s1970s (Cytotoxics and (Cytotoxics and immunosuppressants)immunosuppressants)##
Anti-IL-5 mAbAnti-IL-5 mAb
1930s1930s TheophyllineTheophylline hr IL-12hr IL-12
1950s1950s Anti-cholinergicsAnti-cholinergics hr IFN- hr IFN-
2000s2000s Anti-human IgE mAbAnti-human IgE mAb hr IL-10hr IL-10
Soluble IL-4 receptorSoluble IL-4 receptor
IL-4 double muteinIL-4 double mutein
Allergen-specific ILAllergen-specific IL
VLA-4 antagonistsVLA-4 antagonists
P-selectin mAbP-selectin mAb
AntihistaminesAntihistamines
Mast cell "stabilisers"Mast cell "stabilisers"
$ confronto basato sui dati di efficacia$ confronto basato sui dati di efficacia
Fluticasone Fluticasone PropionatoPropionato
FlunisolideFlunisolide
BudesonideBudesonide
BeclometasoneBeclometasoneDipropionato Dipropionato HFAHFA
Beclometasone Beclometasone dipropionato dipropionato
>500 – 1000>500 – 1000
>2000>2000
>800 – 1600>800 – 1600
>400 – 800>400 – 800
>1000 – 2000>1000 – 2000
Dose AltaDose Alta
>250 – 500>250 – 500
>1000 – 2000>1000 – 2000
>400 – 800>400 – 800
>200 – 400>200 – 400
>500 – 1000>500 – 1000
Dose intermediaDose intermedia
100 – 250100 – 250
500 – 1000500 – 1000
200 – 400200 – 400
100 – 200100 – 200
200 – 500200 – 500
Dose bassaDose bassa
ADULTI $ADULTI $FARMACOFARMACO
DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIADOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA
CiclesonideCiclesonide 80 - 16080 - 160 160 - 320160 - 320 320 - 1280320 - 1280
www.ginasma.itwww.ginasma.it
Steroidi inalatori per la terapia Steroidi inalatori per la terapia delldell’’asmaasma
MometasoneMometasone furoatofuroato 200 - 400200 - 400 > 400 - 800> 400 - 800 >800 - 1200>800 - 1200
Original ArticleOriginal Article Tiotropium Bromide Step-Up Therapy for Adults Tiotropium Bromide Step-Up Therapy for Adults
with Uncontrolled Asthmawith Uncontrolled Asthma
Stephen P. Peters, N Engl J MedVolume 363(18):1715-1726
October 28, 2010
Peters SP, N Engl J Med 2010;363:1715-26Peters SP, N Engl J Med 2010;363:1715-26
Original ArticleOriginal Article Tiotropium Bromide Step-Up Therapy for Tiotropium Bromide Step-Up Therapy for
Adults with Uncontrolled AsthmaAdults with Uncontrolled Asthma
• When added to an inhaled glucocorticoid, When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung tiotropium improved symptoms and lung function in patients with inadequately function in patients with inadequately controlled asthma.controlled asthma.
• Its effects appeared to be equivalent to those Its effects appeared to be equivalent to those with the addition of salmeterol.with the addition of salmeterol.
L’indacaterolo, nuovo L’indacaterolo, nuovo ββ2 agonista a 2 agonista a
lunghissima durata d’azione (24 ore) è efficace lunghissima durata d’azione (24 ore) è efficace
e sicuro nei pazienti con asma persistente non e sicuro nei pazienti con asma persistente non
controllato dagli steroidi inalatori.controllato dagli steroidi inalatori.
Nuovi broncodilatatori: INDACATEROLONuovi broncodilatatori: INDACATEROLO
Sugihara N et al. Respir Me2010;104:1629-37 Sugihara N et al. Respir Me2010;104:1629-37 Beeh Km et al. Eur Respir J. 2007;29:871-8Beeh Km et al. Eur Respir J. 2007;29:871-8
omalizumabomalizumab
IgEIgE
CC33
Binding site of omalizumab to IgEBinding site of omalizumab to IgE
Benefits of omalizumab as add-on therapy in Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are patients with severe persistent asthma who are inadequately controlled despite best available inadequately controlled despite best available therapy therapy (GINA 2002 step 4 treatment): INNOVATE(GINA 2002 step 4 treatment): INNOVATE
omalizumabomalizumab
omalizumabomalizumab
placeboplacebo
placeboplacebo
Clin
ically
sig
nifi
cant
Clin
ically
sig
nifi
cant
Ast
hm
a e
xace
rbati
ons
Ast
hm
a e
xace
rbati
ons
rate
rate
Severe
ast
hm
a
Severe
ast
hm
a
exace
rbati
ons
rate
exace
rbati
ons
rate
00
00
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
0.20.2
0.40.4
0.60.6
0.680.68
0.480.48
0.910.91
0.240.24
P=0.042P=0.042
P=0.002P=0.002
Humbert M et al; Allergy 2005; 60:309-316Humbert M et al; Allergy 2005; 60:309-316
Treating to Achieve Asthma Treating to Achieve Asthma ControlControl
Step 5 – Reliever medication plus additional controller Step 5 – Reliever medication plus additional controller optionsoptions
Addition of oral glucocorticosteroids to other Addition of oral glucocorticosteroids to other controller medications may be effective controller medications may be effective ((Evidence DEvidence D) but is associated with severe ) but is associated with severe side effects (side effects (Evidence AEvidence A))
Addition of anti-IgE treatment to other Addition of anti-IgE treatment to other controller medications improves control of controller medications improves control of allergic asthma when control has not been allergic asthma when control has not been achieved on other medications (achieved on other medications (Evidence AEvidence A))
Nuove indicazioni AIFA per la Nuove indicazioni AIFA per la prescrizione di omalizumabprescrizione di omalizumab
L’omalizumab è indicato per i pazienti con:L’omalizumab è indicato per i pazienti con: - asma grave allergico (test cutaneo o in vitro positivo per - asma grave allergico (test cutaneo o in vitro positivo per allergeni perenni)allergeni perenni)
- VEMS < 80% teorico- VEMS < 80% teorico
- sintomatici o con frequenti riacutizzazioni gravi - sintomatici o con frequenti riacutizzazioni gravi nonostante nonostante l’assunzione quotidiana di alte dosi steroidi e LABA per l’assunzione quotidiana di alte dosi steroidi e LABA per via via inalatoriainalatoria
- con livelli di IgE totali fino a 1500 IU/ml- con livelli di IgE totali fino a 1500 IU/ml
Comunicato AIFAComunicato AIFAGazzetta ufficiale n 6 del 10.01.11, pag.58Gazzetta ufficiale n 6 del 10.01.11, pag.58
Randomized Trial of Omalizumab (Anti-IgE) Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Childrenfor Asthma in Inner-City Children
Busse WW et al. Busse WW et al. N Engl J Med 2011;364:1005-15N Engl J Med 2011;364:1005-15
Original ArticleOriginal Article Randomized Trial of Omalizumab (Anti-IgE) Randomized Trial of Omalizumab (Anti-IgE)
for Asthma in Inner-City Childrenfor Asthma in Inner-City Children
When added to a regimen of guidelines-When added to a regimen of guidelines-based therapy for inner-city children, based therapy for inner-city children, adolescents, and young adults, omalizumab adolescents, and young adults, omalizumab further improved asthma control, nearly further improved asthma control, nearly eliminated seasonal peaks in exacerbations, eliminated seasonal peaks in exacerbations, and reduced the need for other medications to and reduced the need for other medications to control asthma.control asthma.
Paucity of new therapeutics for asthmaPaucity of new therapeutics for asthma
Holgate et al. Eur Respir J. 2007;29:793-803Holgate et al. Eur Respir J. 2007;29:793-803
DecadeDecade Drugs currently Drugs currently availableavailable
Drugs in developmentDrugs in development Therapeutics that Therapeutics that have failedhave failed
1960s1960s Short-acting ßShort-acting ß22-agonists-agonists Neuropeptide antagonistsNeuropeptide antagonists
1980s1980s Long-acting ßLong-acting ß22 agonists agonists Type IV PDE inhibitors (mostly Type IV PDE inhibitors (mostly targeted for COPD)targeted for COPD)
PAF antagonistsPAF antagonists
1960s1960s Inhaled and oral Inhaled and oral corticosteroidscorticosteroids
Anti-TNFAnti-TNFαα Thromboxane inhibitorsThromboxane inhibitors
1990s1990s Leukotriene receptor Leukotriene receptor antagonistsantagonists
Bradykinin antagonistsBradykinin antagonists
1970s1970s (Cytotoxics and (Cytotoxics and immunosuppressants)immunosuppressants)##
Anti-IL-5 mAbAnti-IL-5 mAb
1930s1930s TheophyllineTheophylline hr IL-12hr IL-12
1950s1950s Anti-cholinergicsAnti-cholinergics hr IFN- hr IFN-
2000s2000s Anti-human IgE mAbAnti-human IgE mAb hr IL-10hr IL-10
Soluble IL-4 receptorSoluble IL-4 receptor
IL-4 double muteinIL-4 double mutein
Allergen-specific ILAllergen-specific IL
VLA-4 antagonistsVLA-4 antagonists
P-selectin mAbP-selectin mAb
AntihistaminesAntihistamines
Mast cell "stabilisers"Mast cell "stabilisers"
Anti-TNFAnti-TNF therapy in asthma therapy in asthma
Brightling C et al. JACI 2008; 121:5-10Brightling C et al. JACI 2008; 121:5-10
Anti-TNFAnti-TNF therapy in asthma therapy in asthma
Anti-TNFa therapy in asthmaAnti-TNFa therapy in asthma
• Small n° of patientsSmall n° of patients
• Heterogeneity of responseHeterogeneity of response
• Safety (infections, Safety (infections, malignancies)malignancies)
A randomized, double-blind, placebo-controlled A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe study of tumor necrosis factor-α blockade in severe persistent asthmapersistent asthma
Wenzel SE et al. AJRCCM 2009; 179:549-58
Percent of patients Percent of patients free from severe free from severe asthma exacerbationasthma exacerbation
Changes from baseline in Changes from baseline in prebronchodilator percent-prebronchodilator percent-predicted FEV1 through Week 24predicted FEV1 through Week 24
A randomized, double-blind, placebo-A randomized, double-blind, placebo-controlled study of tumor necrosis controlled study of tumor necrosis factor-α blockade in severe persistent factor-α blockade in severe persistent asthmaasthma
Wenzel SE et al. AJRCCM 2009; 179:549-58
Overall, treatment with golimumab Overall, treatment with golimumab did did not demonstratenot demonstrate a favourable risk-benefit a favourable risk-benefit profile in this study population of patients profile in this study population of patients with severe persistent asthma.with severe persistent asthma.
n= 52 n = 49
Asthma control during the year after Asthma control during the year after bronchial thermoplastybronchial thermoplasty
Cox G et al N Engl J Med 2007; 356:1327-37Cox G et al N Engl J Med 2007; 356:1327-37
Thermoplasty Thermoplasty vsvs control, 12mo control, 12mo
• Morning PEFMorning PEF p=0.003p=0.003• FEVFEV11 n.s.n.s.• BHRBHR n.sn.s• Rescue medicationRescue medication p=0.04p=0.04• Symptom free daysSymptom free days p=0.005p=0.005• Symptom scoreSymptom score p=0.01p=0.01• AQLQ scoreAQLQ score p=0.003p=0.003• ACQ scoreACQ score p=0.001p=0.001
Asthma control during the year after Asthma control during the year after bronchial thermoplastybronchial thermoplasty
Cox G et al N Engl J Med 2007; 356:1327-37Cox G et al N Engl J Med 2007; 356:1327-37
Adverse respiratory eventsAdverse respiratory events
thermoplasty vs controlthermoplasty vs control
• up to 6 wkup to 6 wk p<0.01 p<0.01
• 6 wk-12 mo n.s6 wk-12 mo n.s
Asthma control during the year after Asthma control during the year after bronchial thermoplastybronchial thermoplasty
Cox G et al N Engl J Med 2007; 356:1327-37Cox G et al N Engl J Med 2007; 356:1327-37
Castro M et al. Am J Respir Crit Care Med 2010;181:116–24Castro M et al. Am J Respir Crit Care Med 2010;181:116–24..
This study demonstrates that BT provides clinically This study demonstrates that BT provides clinically meaningful improvements in severe exacerbations meaningful improvements in severe exacerbations requiring corticosteroids, ED visits, and time lost from requiring corticosteroids, ED visits, and time lost from work/school during the post-treatment period in patients work/school during the post-treatment period in patients with severe and inadequately controlled asthma, with severe and inadequately controlled asthma, together with improvements in quality of life. together with improvements in quality of life.
We conclude that the increased risk of adverse events We conclude that the increased risk of adverse events in the short-term after BT is outweighed by the benefit in the short-term after BT is outweighed by the benefit of BT that persists for at least 1 year. BT offers clinicians of BT that persists for at least 1 year. BT offers clinicians a novel, procedure-based, add-on therapy beyond the a novel, procedure-based, add-on therapy beyond the current use of high-dose ICS and LABA to decrease the current use of high-dose ICS and LABA to decrease the morbidity of severe asthma.morbidity of severe asthma.
Effectiveness and Safety of Bronchial Thermoplasty in the Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Treatment of Severe Asthma: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical TrialDouble-Blind, Sham-Controlled Clinical Trial
Asthma Management and Prevention Program
Goals of Long-term Management
Achieve and maintain control of symptoms Maintain normal activity levels, including
exercise Maintain pulmonary function as close to
normal levels as possible Prevent asthma exacerbations Avoid adverse effects from asthma
medications Prevent asthma mortality
Achieve and maintain control of symptoms Maintain normal activity levels, including
exercise Maintain pulmonary function as close to
normal levels as possible Prevent asthma exacerbations Avoid adverse effects from asthma
medications Prevent asthma mortality
GOAL: design of the studyGOAL: design of the study
Sal/Flu 50/100Sal/Flu 50/100or FP 100or FP 100
8- week control assessment8- week control assessment
4- week control assessment4- week control assessment
Phase IPhase I
Phase IIPhase II
Sal/FluSal/Flu 50/250 50/250or FP 250or FP 250
Sal/FluSal/Flu e 50/500e 50/500or FP 500or FP 500
VisitVisit 11 22 33 44 55 66 77 88 99
WeekWeek -4-4 00 44 1212 2424 3636 4848 5252 5656
Step 1Step 1
Step 2Step 2
Step 3Step 3
Bateman E et al Am J Respir Crit Care Med 2004Bateman E et al Am J Respir Crit Care Med 2004;170:836-44;170:836-44..
GOAL: Exacerbation rate in Phase IIGOAL: Exacerbation rate in Phase II
0
0,05
0,1
0,15
0,2
0,25
0,3
TOTAL control WELL control Uncontrolled
Mean e
xace
rbati
on r
ate
Mean e
xace
rbati
on
rate
per
pati
ent
per
year
per
pati
ent
per
year
Bateman E et al Am J Respir Crit Care Med 2004Bateman E et al Am J Respir Crit Care Med 2004;170:836-44.;170:836-44.
n = 592 n = 1512 n = 1378n = 592 n = 1512 n = 1378
Run-inRun-in
SMILE: Study DesignSMILE: Study Design
Formoterol/BudesonideFormoterol/Budesonide + Terbutaline 0.4 + Terbutaline 0.4 mg as relievermg as reliever n=1141n=1141
Formoterol/Budesonide + FormoterolFormoterol/Budesonide + Formoterol 4.5 4.5 µg as relieverµg as reliever n=1140 n=1140
Formoterol/BudesonideFormoterol/Budesonide + Formoterol/Budesonide+ Formoterol/Budesonide 160/4.5 160/4.5 µgµg as as reliever (SMART) n=1113reliever (SMART) n=1113
Visit:Visit: 11 2 3 4 5 6 2 3 4 5 6
Month: -0.5Month: -0.5 0 1 4 8 12 0 1 4 8 12
(All patients received Form/Bude 160/4.5 (All patients received Form/Bude 160/4.5 µg bid both during run-in and following µg bid both during run-in and following Randomisation)Randomisation)
Form/Bude + Form/Bude + Terbutaline as Terbutaline as relieverreliever
RR
Enrolled: n=3829Enrolled: n=3829
Randomised: n=3394Randomised: n=3394
Rabe KF Rabe KF etet al, Lancet. 2006;368:744-53 al, Lancet. 2006;368:744-53
Total No. eventsTotal No. events Hospitalisations/Hospitalisations/
ER treatmentER treatment
Terbutal Terbutal Formoterol Formoterol Form/BudeForm/BudeMaintenance Maintenance
Form/Bude + prnForm/Bude + prn
p<0.001p<0.001
2020
6060
100100
140140
194194
296296
377377p<0.01p<0.01
p<0.001p<0.001
p<0.05p<0.05300300
200200
100100
400400
7070
9898115115
SMILE Study: Severe ExacerbationsSMILE Study: Severe Exacerbations
Rabe KF et al, Lancet. 2006;368:744-53Rabe KF et al, Lancet. 2006;368:744-53
MILD ASTHMA: an expert review on MILD ASTHMA: an expert review on epidemiologiy, clinical characteristics and epidemiologiy, clinical characteristics and treatmenttreatment
• Intermittent and mild persistent asthmaIntermittent and mild persistent asthma
• 50-75% of all asthmatic patients50-75% of all asthmatic patients
• 0.12-00.12-0..77 severe exacerbations per patient-year77 severe exacerbations per patient-year
• Associated with inflammation/remodelingAssociated with inflammation/remodeling
Dusser D et. al. Allergy 2007; 62:591-604
Permanent low-dose ICS Permanent low-dose ICS referencereference treatment treatment
Stepwise Approach to Asthma TherapyStepwise Approach to Asthma Therapy
Controlled by low-doseControlled by low-doseinhaled steroidsinhaled steroids
ControllerController
•• Daily inhaled cortico-Daily inhaled cortico- steroid (200-500 mcg)steroid (200-500 mcg)•• Consider LeukotrieneConsider Leukotriene ModifiersModifiers
RelieverReliever
•• Inhaled beta2-agonistInhaled beta2-agonist prnprn
Step 2: Mild Persistent AsthmaStep 2: Mild Persistent Asthma
Avoid or Control TriggersAvoid or Control Triggers
REGULAR CONTROLLER THERAPY VERSUS REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMAPERSISTENT MILD ASTHMA
Boushey H.A. et al, NEJM 2005;352:1519-1528Boushey H.A. et al, NEJM 2005;352:1519-1528
Mild persistent asthma may not require regular Mild persistent asthma may not require regular treatment and may be controlled with a short treatment and may be controlled with a short intermittent course of inhaled corticosteroids intermittent course of inhaled corticosteroids
(400 mcg budesonide bid x 10 days) (400 mcg budesonide bid x 10 days) taken when symptoms worsentaken when symptoms worsen
10-Day course of 10-Day course of intense intense
combined combined therapytherapy
411 Enrolled411 Enrolled
225 225 RandomizedRandomized
WeekWeekVisitVisit
-4-433
-2-255
0066
131377
262688
39391111
48481212
52521313
54541414
200 µg of budesonide200 µg of budesonideb.i.d. + placebo tabletsb.i.d. + placebo tablets
20 mg of zafirlukast20 mg of zafirlukast b.i.d. + placebo inhalerb.i.d. + placebo inhaler
to placebo tabletsto placebo tablets+ placebo inhaler+ placebo inhaler
Budesonide 800 Budesonide 800 g bid x 10 daysg bid x 10 days
Run-in periodRun-in period
10-Day course of 10-Day course of intense intense
combined combined therapytherapy
REGULAR CONTROLLER THERAPY VERSUS REGULAR CONTROLLER THERAPY VERSUS INTERMITTENT INHALED CORTICOSTEROIDS FOR INTERMITTENT INHALED CORTICOSTEROIDS FOR PERSISTENT MILD ASTHMAPERSISTENT MILD ASTHMA
Boushey H.A. et al, NEJM 2005;352: 1519-28
Budesonide 800 Budesonide 800 g bid x 10 daysg bid x 10 days
Budesonide 800 Budesonide 800 g bid x 10 daysg bid x 10 days
0
20
40
60
80
100
0 100 200 300 400
Kaplan–Meier Estimates of the Kaplan–Meier Estimates of the Time to a First Exacerbation of Time to a First Exacerbation of
AsthmaAsthma
Days since RandomizationDays since Randomization
Perc
en
tag
e w
ith
ou
t E
xace
rbati
on
Perc
en
tag
e w
ith
ou
t E
xace
rbati
on
Daily budesonideDaily budesonide
Daily zafirlukastDaily zafirlukast
Intermittent therapyIntermittent therapyP=0.39P=0.39
Boushey H.A. et al, NEJM 2005;352:1519-1528
Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52
In patients with mild asthma, the symptom-In patients with mild asthma, the symptom-driven use of inhaled driven use of inhaled beclomethasone/albuterol combination in a beclomethasone/albuterol combination in a single inhaler is as effective as regular use single inhaler is as effective as regular use of inhaled beclomethasone and is of inhaled beclomethasone and is associated with a lower 6-month cumulative associated with a lower 6-month cumulative dose of the inhaled corticosteroiddose of the inhaled corticosteroid
RESCUE USE OF BECLOMETHASONE AND ALBUTEROL IN A SINGLE INHALER FOR MILD ASTHMA
Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52
Study designStudy design
Inhaled placebo b.i.d. plus Inhaled placebo b.i.d. plus
p.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combinationp.r.n. inhaled 250µg beclomethasone/100 µg salbutamol combination
Inhaled placebo b.i.d. plusInhaled placebo b.i.d. plus
p.r.n. inhaled 100 µg salbutamolp.r.n. inhaled 100 µg salbutamol
Inhaled 250 µg beclomethasone/100 µg salbutamol combination b.i.d. plusInhaled 250 µg beclomethasone/100 µg salbutamol combination b.i.d. plus
p.r.n. inhaled 100 µg salbutamolp.r.n. inhaled 100 µg salbutamol
Inhaled 250 µg beclomethasone b.i.d. plusInhaled 250 µg beclomethasone b.i.d. plus
p.r.n. 100 µg salbutamolp.r.n. 100 µg salbutamol
BeclomethasoneBeclomethasone(500µg/day)(500µg/day)
Visit 1Visit 1(screening)(screening)
Visit 2Visit 2(randomization)(randomization)
Visit 3Visit 3 Visit 4Visit 4 Visit 5Visit 5 Visit 6Visit 6 Visit 7Visit 7 Visit 8Visit 8(end of (end of
treatment)treatment)
6-month Treatment Period6-month Treatment Period
4-Week Run-in Period4-Week Run-in Period
Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52
00
0,50,5
11
1,51,5
22
As neededAs neededcombinationcombination
As neededAs neededalbuterolalbuterol
RegularRegularbeclomethasonebeclomethasone
RegularRegularcombinationcombination
Num
ber
of
exace
rbati
ons
per
Num
ber
of
exace
rbati
ons
per
pati
ents
/year
pati
ents
/year
Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52
EFFECT OF EXACERBATIONSEFFECT OF EXACERBATIONS
Papi A et al. N Engl J Med 2007;356:2040-52Papi A et al. N Engl J Med 2007;356:2040-52
00
2020
4040
6060
8080
100100
prn BDP/Sprn BDP/S prn Sprn S regular BDPregular BDP regularregularBDP/SBDP/S
********
mg
mg
CUMULATIVE DOSE OF BECLOMETHASONE CUMULATIVE DOSE OF BECLOMETHASONE (BDP)(BDP)
Original ArticleOriginal Article Mepolizumab and Exacerbations of Mepolizumab and Exacerbations of
Refractory Eosinophilic AsthmaRefractory Eosinophilic Asthma
Pranabashis Haldar, M.R.C.P., Christopher E. Brightling, Ph.D., 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 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., 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., 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, F.R.C.P., Andrew J. Wardlaw, Ph.D., F.R.C.P., and Ian D. Pavord, D.M., F.R.C.P.D.M., F.R.C.P.
N Engl J MedN Engl J MedVolume 360(10):973-984Volume 360(10):973-984
March 5, 2009March 5, 2009
Original ArticleOriginal Article Mepolizumab and Exacerbations of Mepolizumab and Exacerbations of
Refractory Eosinophilic AsthmaRefractory Eosinophilic Asthma
N Engl J MedN Engl J MedVolume 360(10):973-984Volume 360(10):973-984
March 5, 2009March 5, 2009
BackgroundBackground
Exacerbations of asthma are associated Exacerbations of asthma are associated with substantial morbidity and mortality and with with substantial morbidity and mortality and with considerable use of health care resources. considerable use of health care resources. Preventing exacerbations remains an important Preventing exacerbations remains an important goal of therapy. There is evidence that goal of therapy. There is evidence that eosinophilic inflammation of the airway is eosinophilic inflammation of the airway is associated with the risk of exacerbationsassociated with the risk of exacerbations
Mepolizumab and exacerbations of Mepolizumab and exacerbations of refractory eosinophilic asthmarefractory eosinophilic asthma
Haldar P. NEJM 2009;360:973-84Haldar P. NEJM 2009;360:973-84
Study DesignStudy Design
Randomized, double – blind, placebo-Randomized, double – blind, placebo-controlled, parallel-group study of 61 subjects controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a who had refractory eosinophilic asthma and a history of recurrent severe exacerbationshistory of recurrent severe exacerbations
Mepolizumab (anti-IL-5 monoclonal AB) for 50 Mepolizumab (anti-IL-5 monoclonal AB) for 50 weeksweeks
Primary outcome: n° of severe exacerbationsPrimary outcome: n° of severe exacerbations
Secondary outcomes: QoL, FEVSecondary outcomes: QoL, FEV11, use of SABA, , use of SABA, PCPC2020
Haldar P. et al., N Engl J Med 2009; 360: 973-984.Haldar P. et al., N Engl J Med 2009; 360: 973-984.
Severe Exacerbations during the StudySevere Exacerbations during the Study
00
2020
4040
6060
8080
100100
120120
11 22 33 44 55 66 77 88 99 1010 1111 1212
MonthMonth
Cu
mu
lati
ve N
o.
of
exacerb
ati
on
sC
um
ula
tive N
o.
of
exacerb
ati
on
s
Start of Start of treatmenttreatment
PlaceboPlacebo
MepolizumaMepolizumabb
44
1144
2255
3344
4477
5588
6699
7799
8855
9977
101088
101099
33 77
1133
2211
2277
3333
3366
4400
4444
4499
5555
5577
No.
of
su
bje
cts
No.
of
su
bje
cts
00
11
22
33
44
55
66
77
88
99
1010
00 11 22 33 44 55 66 77 88 99
No. of exacerbationsNo. of exacerbations
MepolizumMepolizumabab
PlaceboPlacebo
31% vs 16% had no EX31% vs 16% had no EX
Mepolizumab and exacerbations of Mepolizumab and exacerbations of refractory eosinophilic asthma refractory eosinophilic asthma
Haldar P. et al. NEJM 2009;360:973-84
P< 0.001P< 0.001
P = nsP = ns
P = 0.002P = 0.002
P< 0.02P< 0.02
P = nsP = ns
P = nsP = ns
P= ns P= ns
P = nsP = ns
Mepolizumab therapy reduces exacerbations Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with and improves AQLQ scores in patients with refractory eosinophilic asthmarefractory eosinophilic asthma
The results of our study suggest that The results of our study suggest that eosinophils have a role as important effector eosinophils have a role as important effector cells in the pathogenesis of severe cells in the pathogenesis of severe exacerbations of asthma in this patient exacerbations of asthma in this patient population.population.
Mepolizumab and exacerbations of Mepolizumab and exacerbations of refractory eosinophilic asthma refractory eosinophilic asthma
Haldar P. et al NEJM 2009;360:973-84Haldar P. et al NEJM 2009;360:973-84
Original ArticleOriginal Article
Mepolizumab for Prednisone-Mepolizumab for Prednisone-Dependent Asthma with Sputum Dependent Asthma with Sputum
EosinophiliaEosinophiliaParameswaran Nair, M.D., Ph.D., Marcia M.M. Pizzichini, M.D., Ph.D., 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 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. Efthimiadis, M.L.T., Emilio Pizzichini, M.D., Ph.D., Frederick E.
Hargreave, M.D., and Paul M. O'Byrne, M.B.Hargreave, M.D., and Paul M. O'Byrne, M.B.
N Engl J MedN Engl J MedVolume 360(10):985-993Volume 360(10):985-993
March 5, 2009March 5, 2009
Mepolizumab and exacerbations of Mepolizumab and exacerbations of refractory eosinophilic asthmarefractory eosinophilic asthma
Nair P. NEJM 2009;360: Nair P. NEJM 2009;360: 985-93985-93
Study DesignStudy DesignRandomized, double – blind, placebo-controlled, Randomized, double – blind, placebo-controlled, parallel-group study of 20 subjects with persistent parallel-group study of 20 subjects with persistent sputum eosinophilia and symptoms despite sputum eosinophilia and symptoms despite prednisone treatmentprednisone treatment
Mepolizumab (anti-IL-5 monoclonal AB) for up to 26 Mepolizumab (anti-IL-5 monoclonal AB) for up to 26 weeksweeks
Primary outcomes: n° of exacerbations and steroid Primary outcomes: n° of exacerbations and steroid reductionreduction
Secondary outcomes: QoL, FEVSecondary outcomes: QoL, FEV11, use of SABA, PC, use of SABA, PC2020, , sputum and blood eos.sputum and blood eos.
Nair P. et al., N Engl J Med 2009; 360: 985-993.Nair P. et al., N Engl J Med 2009; 360: 985-993.
Prednisone dose reductionPrednisone dose reduction
RandomizationRandomization
Mepolizumab (750 mgMepolizumab (750 mg))
PlaceboPlacebo
00
WashoutWashout8 wk8 wk
00
22
22
44
66
66
1010
88
1414
1010
1818
1212
2222
1414
2626
VisitVisit
WeekWeek
Starting doses of PrednisoneStarting doses of Prednisone
25.025.020.020.017.517.515.015.012.512.510.010.0
7.57.55.05.0
20.020.015.015.012.512.510.010.0
7.57.57.57.55.05.02.52.5
15.015.010.010.0
7.57.57.57.55.05.05.05.02.52.50.00.0
10.010.07.57.55.05.05.05.02.52.52.52.50.00.00.00.0
7.57.55.05.05.05.05.05.02.52.52.52.50.00.00.00.0
5.05.05.05.05.05.05.05.02.52.52.52.50.00.00.00.0
Run inRun in6 wk6 wk
Protocol for reduction in the dose of prednisoneProtocol for reduction in the dose of prednisone
Analysis of the Proportion of Patients without Analysis of the Proportion of Patients without an Asthma Exacerbation during the Studyan Asthma Exacerbation during the Study..
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626WeeksWeeks
Pati
ents
wit
hout
exace
rbati
on (
%)
Pati
ents
wit
hout
exace
rbati
on (
%)
RandomizationRandomization
PlaceboPlacebo
MepolizumabMepolizumab
No. At riskNo. At riskMepolizumMepolizumababPlaceboPlacebo
991100
9999
8877
7777
7755
7744
7733
7722
Nair P. et al NEJM 2009;360:985-93Nair P. et al NEJM 2009;360:985-93
Nair P. et al., N Engl J Med 2009; 360: 985-993Nair P. et al., N Engl J Med 2009; 360: 985-993..
Eosinophils in SputumEosinophils in Sputum
0
10
20
30
40
50
60
70
V1 V4 W/Ex V12
2
Sp
utu
m E
os
ino
ph
ils
0
10
20
30
40
50
60
70
V1 V4 W/Ex V12
2
Mepolizumab Placebo
Nair P. et al., N Engl J Med 2009; 360: 985-993.Nair P. et al., N Engl J Med 2009; 360: 985-993.
Eosinophils in BloodEosinophils in BloodB
lood
Eosin
op
hils (
per
mm
3)
Mepolizumab
0
300400
600
900
1200
1500
1800
V1 V4 W/Ex V12
Placebo
0
300400
600
900
1200
1500
1800
V1 V4 W/Ex V12
Mepolizumab for prednisone-dependent Mepolizumab for prednisone-dependent asthma with sputum eosinophilia asthma with sputum eosinophilia
Nair P. et al NEJM 2009;360:985-93Nair P. et al NEJM 2009;360:985-93
Mepolizumab reduced the number of Mepolizumab reduced the number of
blood and sputum eosinophils and allowed blood and sputum eosinophils and allowed
prednisone sparing in patients who had prednisone sparing in patients who had
asthma with sputum eosinophilia despite asthma with sputum eosinophilia despite
prednisone treatmentprednisone treatment
ConclusionsConclusions
• new therapies (severe/refractory asthma):new therapies (severe/refractory asthma): – anti-IgE anti-IgE – anti-TNF-anti-TNF-αα– thermoplastythermoplasty– anti- IL5anti- IL5
• new strategiesnew strategies– GOAL vs SMARTGOAL vs SMART– Adding tiotropium bromideAdding tiotropium bromide– BESTBEST– eNO or EOS guidedeNO or EOS guided
NEW TREATMENTS FOR ASTHMANEW TREATMENTS FOR ASTHMA
Nuovi farmaci in asma e BPCONuovi farmaci in asma e BPCO
Bianca Beghè, Leonardo M Fabbri, Bianca Beghè, Leonardo M Fabbri,
Corso di Aggiornamento per Medici InternistiCorso di Aggiornamento per Medici InternistiModena, 29-30 Marzo 2011Modena, 29-30 Marzo 2011
Clinica di Malattie del’Apparato RespiratorioUniversità degli Studi di Modena e Reggio Emilia
AddAdd inhaled glucocorticosteroidsinhaled glucocorticosteroids if if repeated exacerbationsrepeated exacerbations
IV: Very SevereIV: Very Severe III: SevereIII: Severe II: ModerateII: Moderate I: MildI: Mild
Therapy at Each Stage of COPDTherapy at Each Stage of COPD
• FEV1/FVC < 70%
• FEV1 > 80% predicted
• FEV1/FVC < 70%
• 50% < FEV1 < 80% predicted
• FEV1/FVC < 70%
• 30% < FEV1 < 50% predicted
• FEV1/FVC < 70%
• FEV1 < 30% predicted
or FEV1 < 50% predicted plus chronic respiratory failure
AddAdd regular treatment with one or more regular treatment with one or more long-acting long-acting bronchodilatorsbronchodilators (when needed); (when needed); AddAdd rehabilitation rehabilitation
Active reduction of risk factor(s); influenza vaccinationActive reduction of risk factor(s); influenza vaccination
AddAdd short-acting bronchodilator (when needed) short-acting bronchodilator (when needed)
AddAdd long term long term oxygenoxygen if chronic if chronic respiratory respiratory failure. Consider failure. Consider surgical surgical treatmentstreatments
Nuovi trattamenti per la BPCONuovi trattamenti per la BPCOIndacateroloIndacaterolo
• Indacaterolo è il primo Ultra-LABA approvato dall’Agenzia Indacaterolo è il primo Ultra-LABA approvato dall’Agenzia Regolatoria Europea (EMEA) nel dicembre 2009 indicato come terapia Regolatoria Europea (EMEA) nel dicembre 2009 indicato come terapia broncodilatatrice di mantenimento nell’ostruzione del flusso aereo in broncodilatatrice di mantenimento nell’ostruzione del flusso aereo in pazienti adulti con broncopneumopatia cronica ostruttiva (BPCO). pazienti adulti con broncopneumopatia cronica ostruttiva (BPCO). • Indacaterolo, somministrato una volta al giorno alle dosi di 150 e 300 Indacaterolo, somministrato una volta al giorno alle dosi di 150 e 300 microgrammi, ha costantemente prodotto un miglioramento microgrammi, ha costantemente prodotto un miglioramento significativo della funzione polmonare nelle 24 ore con un rapido inizio significativo della funzione polmonare nelle 24 ore con un rapido inizio d’azione, entro 5 minuti dall’inalazione. d’azione, entro 5 minuti dall’inalazione.
• Nel 2010 approvato anche dall’Agenzia Italiana del Farmaco (AIFA) Nel 2010 approvato anche dall’Agenzia Italiana del Farmaco (AIFA) ed è quindi commercializzato anche in Italia con il nome commerciali ed è quindi commercializzato anche in Italia con il nome commerciali di Onbrez.di Onbrez.
Barnes PJ eBarnes PJ et al. Integrating indacaterol dose selection in a clinical t al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol study in COPD using an adaptive seamless design. Pulm Pharmacol Ther. 2010 Jan 18Ther. 2010 Jan 18
ONCE-DAILY BRONCHODILATORS FOR CHRONIC ONCE-DAILY BRONCHODILATORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: INDACATEROL OBSTRUCTIVE PULMONARY DISEASE: INDACATEROL
VERSUS TIOTROPIUMVERSUS TIOTROPIUM
Donohue JF et al,Donohue JF et al, Am J Respir Crit Care Med. 2010Am J Respir Crit Care Med. 2010
Indacaterol was an effective once-daily Indacaterol was an effective once-daily bronchodilator and was at least as effective as bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for tiotropium in improving clinical outcomes for patients with COPDpatients with COPD
Media dei minimi quadrati (MMQ). ***p<0,001 vs placebo; Media dei minimi quadrati (MMQ). ***p<0,001 vs placebo; ++p<0,05 vs tiotropiop<0,05 vs tiotropioDifferenza ≥1 = miglioramento clinicamente significativo del punteggio TDIDifferenza ≥1 = miglioramento clinicamente significativo del punteggio TDITDI: Transitional Dyspnoea IndexTDI: Transitional Dyspnoea Index
Il trattamento con indacaterolo ha dimostrato un Il trattamento con indacaterolo ha dimostrato un progressivo miglioramento del TDIprogressivo miglioramento del TDI
1 p
un
to1 p
un
to
1 p
un
to1 p
un
to
Pu
nte
gg
io T
DI
focale
Pu
nte
gg
io T
DI
focale
Tiotropio 18 µg odTiotropio 18 µg odIndacaterolo 300 µg odIndacaterolo 300 µg od PlaceboPlacebo
3,03,0
2,02,0
1,01,0
00
††††††
******2,32,388
Indacaterolo µg 150 odIndacaterolo µg 150 od
******2,12,133
******1,91,955
1,41,400
††††††
******2,52,588
******2,42,411
******2,22,277
Settimana 12Settimana 12 Settimana 26Settimana 26
1,21,200
Donohue et al. AJRCCM 2010;182:155-62Donohue et al. AJRCCM 2010;182:155-62
Indacaterolo aumenta il tempo alla prima Indacaterolo aumenta il tempo alla prima riacutizzazione rispetto al placebo (studio a 26 riacutizzazione rispetto al placebo (studio a 26
settimane)settimane)P
azi
en
ti s
en
za
Pazi
en
ti s
en
za
riacu
tizzazio
ni (%
)ri
acu
tizzazio
ni (%
)
Tempo alla prima riacutizzazione (mesi)Tempo alla prima riacutizzazione (mesi)
Indacaterolo 150 μg Indacaterolo 150 μg odod
Indacaterolo 300 μg Indacaterolo 300 μg odod
Tiotropio 18 μg odTiotropio 18 μg od PlaceboPlacebo
101000
8080
6060
404000 11 22 33 44 55 66 77
Donohue et al. AJRCCM 2010;182:155-62Donohue et al. AJRCCM 2010;182:155-62
1.381.38
Miglioramento del FEVMiglioramento del FEV11 dopo 52 dopo 52 settimanesettimane
Placebo Formoterolo 12 µg b.i.d. Indacaterolo 300 µg o.d.******1.431.43 1.451.45
1.311.31 1.321.321.281.28
1.481.48
1.311.31
1.381.38
1.551.55
1.501.50
1.451.45
1.401.40
1.351.35
1.301.30
1.251.25
1.201.20
1.151.15
Tro
ugh F
EV
Tro
ugh F
EV
11 (
L) (
L)
******
*** ***
**1.431.43
Giorno 2Giorno 2 Settimana 12Settimana 12 Settimana 52Settimana 52Endpoint primarioEndpoint primario
*** ***
†††††† *** ***
††††††
††
Dahl et al. Thorax 2010;65; 473-479Dahl et al. Thorax 2010;65; 473-479
•Trough = media dei valori a 23 h 10 min e 23 h 45 min post-dose. Media dei minimi quadrati Trough = media dei valori a 23 h 10 min e 23 h 45 min post-dose. Media dei minimi quadrati (LSM) . (LSM) . *p<0.05, ***p<0.001 vs placebo; *p<0.05, ***p<0.001 vs placebo; ††p<0.05, p<0.05, ††††††p<0.001 vs formoterolop<0.001 vs formoterolo
Roflumilast in symptomatic chronich Roflumilast in symptomatic chronich obstructive pulmonary disease: two obstructive pulmonary disease: two randomised clinical trialsrandomised clinical trials
Calverley PM, Rabe KF, Goehring UM, Kristiansen Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups study groups
The Lancet 2009;374:685-94The Lancet 2009;374:685-94
M2-124 & M2-125 – Study DesignM2-124 & M2-125 – Study Design
Run-inRun-in4 weeks4 weeks
Double-blind, randomised, parallel group Double-blind, randomised, parallel group Single-blindSingle-blind
TreatmentTreatment52 weeks52 weeks
placebo o.d.placebo o.d.
V0 R VE FU
roflumilast 500µg o.d.roflumilast 500µg o.d.
Allowed medicationAllowed medication: Long acting bronchodilator or short acting : Long acting bronchodilator or short acting anticholinergicsanticholinergics
Targeting a proportion of ~ 50% of all patients on LABATargeting a proportion of ~ 50% of all patients on LABA
Participating Countries: Australia, Austria, Canada, France, Germany, Hungary, Italy, India, Participating Countries: Australia, Austria, Canada, France, Germany, Hungary, Italy, India, New Zealand Russia, Romania, South Africa, Spain, Poland, United New Zealand Russia, Romania, South Africa, Spain, Poland, United Kingdom, USAKingdom, USA
Follow upFollow up2 weeks2 weeks
Calverley PMA, Rabe, KF ,Calverley PMA, Rabe, KF ,et alet al. . LancetLancet 2009;374:685– 2009;374:685–9494
M2-124 & M2-125 – Population (1)M2-124 & M2-125 – Population (1)
Diagnosis:Diagnosis:
– History of chronic obstructive History of chronic obstructive
pulmonary disease pulmonary disease associated with associated with
chronic bronchitischronic bronchitis for at least 12 for at least 12
months prior to baselinemonths prior to baseline
Calverley PMA, Rabe, KF ,Calverley PMA, Rabe, KF ,et alet al. . LancetLancet 2009;374:685–942009;374:685–94
M2-124 & M2-125 – Population (2)M2-124 & M2-125 – Population (2)
Main Criteria for InclusionMain Criteria for Inclusion::
– Age > 40 yearsAge > 40 years
– FEVFEV11/FVC ratio (post-bronchodilator) /FVC ratio (post-bronchodilator) 70% 70%
– FEVFEV11 (post-bronchodilator) (post-bronchodilator) 50% of predicted 50% of predicted
– At leastAt least one documented moderate and/or severe one documented moderate and/or severe COPD exacerbationCOPD exacerbation within one year prior to study within one year prior to study
– Not suffering from any concomitant disease that Not suffering from any concomitant disease that might interfere with study procedures or evaluationmight interfere with study procedures or evaluation
– Current or former smoker with a smoking history of Current or former smoker with a smoking history of at least 20 pack yearsat least 20 pack years
Calverley PMA, Rabe, KF,Calverley PMA, Rabe, KF,et alet al. . LancetLancet 2009;374:685– 2009;374:685–9494
Pre- & Post-Bronchodilator Pre- & Post-Bronchodilator FEVFEV11
M2-124 & M2-125 pooled analysisM2-124 & M2-125 pooled analysis
*N patients are given for pre-FEV1 measurements
11
1.11.1
1.21.2
00 88 2020 3636 4444 5252Weeks
Mean F
EV
Mean F
EV
11 [
L] [
L]
placebo (pre) roflumilast 500µg (pre)placebo (post) roflumilast 500µg (post)
44 1212 2828
15361536 14731473 13361336 12621262 12101210 11521152 11001100 10611061 10241024 roflumilast*roflumilast*
15541554 15061506 14191419 13751375 13061306 12411241 11671167 11021102 10721072 placebo*placebo*
Data on file
COPD Exacerbations (Moderate or COPD Exacerbations (Moderate or Severe)Severe)
M2-124 & M2-125 pooled analysisM2-124 & M2-125 pooled analysis
Mean r
ate
of
exace
rbati
ons
per
Mean r
ate
of
exac e
rbati
ons
per
pati
ent
per
year
pat i
ent
per
year
= - 17%= - 17%(CI -25;-8)(CI -25;-8)p = 0.0003p = 0.0003
00
0.50.5
11
1.51.5
placeboplacebo roflumilast 500µgroflumilast 500µg
1.3741.374 1.1421.142
Calverley PMA, Rabe, KF ,Calverley PMA, Rabe, KF ,et alet al. . LancetLancet 2009;374:685–942009;374:685–94
Median Time to First Median Time to First COPD Exacerbation COPD Exacerbation (Moderate or Severe)(Moderate or Severe) M2-124 & M2-125 M2-124 & M2-125
pooled analysispooled analysis
Hazard ratio = 0.89Hazard ratio = 0.89(CI 0.80;0.98)(CI 0.80;0.98)
p = 0.0185p = 0.0185
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
11
Pr o
bab
il it y
of
not
Pro
bab
i lit y
of
not
exp
eri
en
c in
g a
nd
exp
er i
en
c in
g a
nd
exac e
r bat i
on
exac e
rbati
on
WeeksWeeks0 8 20 36 44 524 12 28
placeboplacebo roflumilast 500µg roflumilast 500µg Calverley PMA, Rabe, KF ,Calverley PMA, Rabe, KF ,et alet al. . LancetLancet 2009;374:685–942009;374:685–94
Incidence of AEs (Incidence of AEs ( 2.0%) 2.0%)Independent of Investigator Causality Independent of Investigator Causality
Assessments (1/2)Assessments (1/2)
M2-124 & M2-125 M2-124 & M2-125 pooled analysispooled analysis
(n=3092)(n=3092)
roflumilast roflumilast 500µg o.d.500µg o.d.
(n=1547)(n=1547)
placeboplacebo(n=1545)(n=1545)
COPDCOPD 10%10% 13%13%
Weight LossWeight Loss 10%10% 3%3%
DiarrhoeaDiarrhoea 8%8% 3%3%
NasopharyngitisNasopharyngitis 6%6% 6%6%
NauseaNausea 4%4% 2%2%
BronchitisBronchitis 4%4% 4%4%
HeadacheHeadache 3%3% 7%7%
Data on file
ConclusionsConclusions• RoflumilastRoflumilast
– Improves pre and post bronchodilator FEV1Improves pre and post bronchodilator FEV1• Effect independent of concomitant LABA therapy, previous ICS Effect independent of concomitant LABA therapy, previous ICS
therapy, or baseline disease severitytherapy, or baseline disease severity– Decreases exacerbation rateDecreases exacerbation rate
• Mild, moderate or severeMild, moderate or severe• Prolongs time to eventProlongs time to event
- Safety profile over 1 year is consistent with previous - Safety profile over 1 year is consistent with previous
studiesstudies– Generally mild to moderateGenerally mild to moderate– Generally seen early in trialGenerally seen early in trial– Gastrointestinal events most frequentGastrointestinal events most frequent– Limited resulting dropoutsLimited resulting dropouts– Weight loss was modestWeight loss was modest
Roflumilast in symptomatic chronic obstructive Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical pulmonary disease: two randomised clinical trialstrials
The Lancet 2009;374:685-94The Lancet 2009;374:685-94
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups M2-127 and M2-128 study groups
Run-inRun-in4 weeks4 weeks
TreatmentTreatment24 weeks24 weeks
M2-127: Salmeterol 50µg b.d. as maintenence for all M2-127: Salmeterol 50µg b.d. as maintenence for all patientspatientsM2-128: Tiotropium 18µg o.d. as maintenence for all M2-128: Tiotropium 18µg o.d. as maintenence for all patients patients
V0V0 RR VEVE FUFU
Roflumilast 500µg o.d.Roflumilast 500µg o.d.
Follow upFollow up2 weeks2 weeks
Placebo o.d.Placebo o.d.
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695– 2009;374:695–703703
Roflumilast as Add-On Therapy in Roflumilast as Add-On Therapy in COPDCOPD
M2-127 & M2-128 – Study PopulationM2-127 & M2-128 – Study Population
Diagnosis:Diagnosis:
– History of chronic obstructive pulmonary History of chronic obstructive pulmonary
disease for at least 12 months prior to disease for at least 12 months prior to
baselinebaseline
– In study M2-128 also associated with In study M2-128 also associated with
chronic bronchitis, not a pre-requisite in chronic bronchitis, not a pre-requisite in
study M2-127study M2-127
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–7032009;374:695–703
Main Criteria for InclusionMain Criteria for Inclusion
• Age Age 40 years 40 years
• FEVFEV11/FVC ratio (post-bd) /FVC ratio (post-bd) 70% 70%
• FEVFEV11 (post-bd) between (post-bd) between 40% and 40% and 70 % pred 70 % pred
• FEVFEV11 increase of increase of 12% or 12% or 200 ml after 400 mcg 200 ml after 400 mcg salbutamolsalbutamol
• Current or former smoker with a smoking history of Current or former smoker with a smoking history of at least 10 pack yearsat least 10 pack years
• M2-128 only: maintenance treatment with M2-128 only: maintenance treatment with tiotropium for at least 3 months prior to tiotropium for at least 3 months prior to baselinebaseline
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
RoflumilastRoflumilastPlaceboPlacebo
1.31.3
1.41.4
1.51.5
1.61.6
466466467467
455455463463
410410437437
389389419419
374374403403
359359384384
00 88 242444 1212 1818WeeksWeeks
Salmeterol + PlaceboSalmeterol + Placebo
Salmeterol+ RoflumilastSalmeterol+ Roflumilast
Pr e
bd
FE
VPre
bd
FE
V11 [
L] [
L ]Roflumilast as Add-On Therapy in Roflumilast as Add-On Therapy in
COPDCOPDPre-bronchodilator FEVPre-bronchodilator FEV11
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
1.41.4
1.51.5
1.61.6
1.71.7
371371372372
364364363363
343343352352
325325350350
318318347347
310310333333
00 88 242444 1212 1818
WeeksWeeks
RoflumilastRoflumilastPlaceboPlacebo
Pr e
bd
FEV
Pre
bd
FEV
11 [
L]
[L]
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
Tiotropium + PlaceboTiotropium + Placebo
Tiotropium+ RoflumilastTiotropium+ Roflumilast
Roflumilast as Add-On Therapy in Roflumilast as Add-On Therapy in COPDCOPD
Pre-bronchodilator FEVPre-bronchodilator FEV11
Roflumilast as Add-On Therapy in COPDRoflumilast as Add-On Therapy in COPDPost-bronchodilator Post-bronchodilator FEVFEV11
Mean c
hange in p
os t
bd F
EV
Mean c
hange in p
os t
bd F
EV
11
[ml]
[ml ]
= 81 ml= 81 mlp < 0.0001p < 0.0001
= 60 ml= 60 mlp < 0.0001p < 0.0001
-20-20
00
2020
4040
6060
8080
100100
7474-7-7
686888
SalmeterolSalmeterol TiotropiumTiotropium
n=46n=4600
n=45n=4522
n=36n=3633
n=36n=3644
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Median Time to First Median Time to First Moderate or SevereModerate or Severe COPD ExacerbationCOPD Exacerbation
HR = 0.6HR = 0.6p = 0.0067p = 0.0067
0.800.80
0.850.85
0.900.90
0.950.95
1.001.00
00 44 88 1212 24241818
WeeksWeeks
Pro
babili
ty o
f not
experi
enci
ng a
n
Pro
babili
ty o
f not
experi
enci
ng a
n
exace
rbati
on
exace
rbati
on
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
Salmeterol + PlaceboSalmeterol + Placebo
Salmeterol+ Roflumilast
Median Time to First COPD Moderate or Median Time to First COPD Moderate or Severe ExacerbationSevere Exacerbation
HR = 0.8HR = 0.8p = 0.1959p = 0.1959
0.800.80
0.850.85
0.900.90
0.950.95
1.001.00
00 44 88 1212 2424
WeeksWeeks
1818
Pro
babili
ty o
f not
experi
enci
ng a
n
Pro
babili
ty o
f not
experi
enci
ng a
n
exace
rbati
on
exace
rbati
on
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Tiotropium + Placebo
Tiotropium+ RoflumilastTiotropium+ Roflumilast
Roflumilast as Add-On Therapy in COPDRoflumilast as Add-On Therapy in COPD SOBQ (Shortness of Breath Questionnaire)SOBQ (Shortness of Breath Questionnaire)
Mean c
hang
e in S
OB
Q S
core
Mean c
hang
e in S
OB
Q S
c ore
p= 0.0051
= - 2.6
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
00 44 88 1212 1818 2424
WeeksWeeks
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
Tiotropium + PlaceboTiotropium + Placebo
Tiotropium+ RoflumilastTiotropium+ Roflumilast
Incidence of Adverse Events Incidence of Adverse Events
Sal +Sal +Roflumilast Roflumilast (n = 466) (n = 466)
Sal +Sal +PlaceboPlacebo
(n = 467)(n = 467)
Tio +Tio +Roflumilast Roflumilast (n = 374)(n = 374)
Tio +Tio +PlaceboPlacebo
(n = 369)(n = 369)
COPDCOPD 16%16% 24% 24% 16%16% 18%18%
Weight Weight decreasedecrease 9% 9% 1%1% 6% 6% 1%1%
DiarrhoeaDiarrhoea 8%8% 3% 3% 9%9% <1%<1%
NasopharyngitiNasopharyngitiss
7%7% 7%7% 6%6% 5%5%
NauseaNausea 5% 5% <1% <1% 3% 3% 1%1%
HeadacheHeadache 3% 3% 1%1% 2%2% 0%0%
Back painBack pain 3%3% 2%2% 2%2% 1%1%
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
Change in B
ody W
eig
ht
[kg]
Change in B
ody W
eig
ht
[ kg]
= - 2.1 = - 2.1 kgkg
p < 0.0001p < 0.0001
= - 2.1 = - 2.1 kgkg
p < 0.0001p < 0.0001
-4-4
-2-2
00
22
44
00 44 88 1212 1818 2424
00 44 88 1212 1818 2424
Salmeterol TrialSalmeterol Trial
Tiotropium TrialTiotropium Trial
-4-4
-2-2
00
22
44
WeeksWeeks
Roflumilast as Add-On Therapy in Roflumilast as Add-On Therapy in COPDCOPD Adverse Events - Adverse Events - Body WeightBody Weight
Fabbri LM, Calverley PMA Fabbri LM, Calverley PMA et alet al. . LancetLancet 2009;374:695–703 2009;374:695–703
ConclusionsConclusions::
– Roflumilast improves lung function in patients with moderate Roflumilast improves lung function in patients with moderate
to severe COPD who are already treated with long acting to severe COPD who are already treated with long acting
bronchodilatorsbronchodilators
– Roflumilast treatment is accompanied by class – specific side Roflumilast treatment is accompanied by class – specific side
effects (but no cardiovascular AE’s or pneumonias)effects (but no cardiovascular AE’s or pneumonias)
– Roflumilast might qualify as a recommended oral therapy on Roflumilast might qualify as a recommended oral therapy on
top of bronchodilators such as Salmeterol and Tiotropium top of bronchodilators such as Salmeterol and Tiotropium
(Role of ICS..?) (Role of ICS..?)
Roflumilast as Add-On Therapy in Roflumilast as Add-On Therapy in COPDCOPD
Fabbri LM, Calverley PMA et al. Lancet 2009;374:695–703
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