Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale...

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

http://www.avvocati.it/formazione/convegni/logo_unimore.png


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



placeboplacebo

placeboplacebo

Clin

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Clin

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sig

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Ast

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Ast

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rate

Severe

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Severe

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rate

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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



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



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

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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 corticosteroid (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



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

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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


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


00

0,50,5

11

1,51,5

22

As neededAs neededcombinationcombination

As neededAs neededalbuterolalbuterol

RegularRegularbeclomethasonebeclomethasone

RegularRegularcombinationcombination

Num

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Num

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EFFECT OF EXACERBATIONSEFFECT OF EXACERBATIONS


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


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

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ati

on

sC

um

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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.


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


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]


Tiotropium + PlaceboTiotropium + Placebo

Tiotropium+ RoflumilastTiotropium+ Roflumilast


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


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


Tiotropium + Placebo


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


Tiotropium + PlaceboTiotropium + Placebo


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%


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


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..?)



Nuovi farmaci in asma e BPCO Bianca Beghè, Leonardo M Fabbri Corso di Formazione al Personale...

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