SMART THERAPY

Kaushik Saha
MD, DTCD, FCCP (USA)
Consultant Pulmonologist
Assistant Professor, Burdwan Medical College
Suraksha Khardah
Zenith Super specialist Hospital

ADDITION OF FORMOTEROL TO INHALED STEROID

FEV1 (% predicted)

95

90

852 asthmatic patients

FACET study
FEV1~75% predicted
on ~800g ICS daily
Bud 800g + Form 12g
OPTIMA STUDY: similar results in mild/moderate asthma

85

Bud 200g + Form 12g

Bud 800g
80

Bud 200g

Adding formoterol better than 4x dose of ICS

No tolerance over 1 yr

75

70
-1

run-in

Time (months)

Pauwels R et al NEJM 1997 FACET Study

12

OByrne P et al AJRCCM 2001

ASTHMA CONTROL
Genes
Atopy

Environmental
factors

INFLAMMATION

COMPONENT 2
Add-on effect
LA 2-Agonists

CORTICOSTEROIDS

SYMPTOM
SYMPTOMS
SYMPTOMS
CONTROL

ADD-ON THERAPIES FOR ASTHMA

Low dose inhaled steroids
(400 g daily or less)
LABA/CS Combination
If not controlled:
Inhalers
Add LA inhaled 2-agonist
(most effective)
High dose
inhaled steroids

Add low dose theophylline

(cheapest)
Add anti-leukotriene
(less effective and expensive)

TREATMENT OF ASTHMA: CELLULAR EFFECTS

ACUTE
Virus? INFLAMMATION

LABA

Adenosine
Exercise
Fog
Mast cell

Bronchoconstriction

Antigen
Macrophage

Plasma leak

Sensory nerve
activation

Eosinophil

AIRWAY
HYPERRESPONSIVENESS
T-cell

Dendritic cell

ICS

CHRONIC
INFLAMMATION

EVOLUTION IN ASTHMA THERAPY

CONVENTIONAL

Medication Use

No adjustment in
controller

FACET
OPTIMA
GOAL

FUTURE

Single inhaler:

Maintenance & relief

Combination inhaler
replaces SABA

STAY
STEAM
STEP
SMART =
COSMOS
Single inhaler Maintenance
SMILE
And Reliever Therapy
COMPASS
AHEAD

Budesonide/formoterol
Fluticasone/salmeterol

Maintenance
+ prn SABA

Maintenance
+ prn Bud/form

STAY study (n=2750)

Bud/form (Fixed) + SABA
4 x Bud + SABA
Bud/form (SMART)
370

Morning PEF (L/min)

0.4

***

360
350

-0

***

-0.4

340

-0.8

330

-1.2

320

-1.6
40

120

200

280

OByrne P et al: AJRCCM 2005

Change in as needed
inhalations/day

360

Days Treatment

*** P<0.001

***
40

120

200

280

360

STAY STUDY: SEVERE EXACERBATIONS

Moderate asthma (n=2750)
Events/patient/year

0.4

0.35

0.40

0.3

SMART

0.2

0.19 ***

0.1

Budesonide 4x
+ terbutaline
OByrne P et al: AJRCCM 2005

Bud/form
+ terbutaline

Bud/form
+ Bud/form

SMART REDUCES SEVERE EXACERBATIONS

6 double-blind studies (n = 14,351)
Exacerbations

BUD + SABA
Bud-Form + SABA
Bud-Form + formoterol

[/100 patients/yr]

250*

40
500*

Salm-FP + SABA
Bud-Form SMART

1000*

*ICS dose of comparator

(BDP equivalents)

1000*

500*

1000*
1000*

2000*

500*

30

20

10

STEAM

Chest 2006

STEP

AHEAD

CMRO 2004 Resp Med 2004

STAY

AJRCCM 2005

COMPASS
IJCP 2007

SMILE

Lancet 2006

SMART
Bud/form as rescue therapy
as well as maintenance therapy
How does it work?
(especially in reducing exacerbations)
Why does fluticasone/salmeterol
NOT work as rescue?

COMBINATION INHALERS DIFFER

budesonide/formoterol

Similar to
fluticasone

fluticasone/salmeterol

Similar to
budesonide

Formoterol
Salmeterol
>12h bronchodilator
>12h bronchodilator
FLEXIBLE
FLEXIBLE
DOSING
Rapid onsetDOSING NO
Slower
onset
RESCUE
NEVER
ASeffects
RESCUE
Short side THERAPY
effects
Longer
side
Steep dose-response Flat dose-response
(full agonist)
(partial agonist)

Patients with severe exacerbations (%)

COMPASS: SMART VS FIXED DOSE COMBINATION

Time to first severe exacerbation

15

NS
10

FP/salm (50/250 bd)

Bud/from fixed dose
(400/12 bd)

p=0.023

Bud/form SMART
(200/6 bd + as needed)
5

20

40

60

80

100

120

Days since randomisation

Kuna P et al.: Int J Clin Pract. 2007

140

160

SMILE STUDY: COMPARISON OF RELIEVER THERAPY

Patients with severe exacerbations (%)

Bud/form mainenance b.d. + reliever:

25

Time to first exacerbation

Terbutaline
P<0.01

20

Formoterol

P<0.005

15

Bud/form

10
5
0

60

120

180

240

Days since randomisation

Rabe K et al: Lancet 2006

300

360

LABA TIME COURSE

Methacholine

FEV1 (% of baseline)

100
90

FP/salm 25/250 g

***

Placebo

80
70
60

Baseline

Bud/form 200/6 g

10

15

20

Time (min)
van der Woude HJ et al: Pulm Pharm Ther 2004

25

30

CELLS IN ASTHMA EXACERBATIONS

Viruses

Pollutants

Allergens

Formoterol

Epithelial
cells

Y Y

Mast cell
Histamine
Cys-LTs
PGD2 etc
Plasma leakage

Bronchoconstriction

EXACERBATION

EFFECT OF FORMOTEROL ON SPUTUM NEUTROPHILS

Formoterol 24g b.d. x 4 weeks

2500

Sputum IL-8

Sputum neutrophils
P=0.005
2.5

P=0.01
2000

NS

1500
1000
500
0

Formoterol Placebo Budesonide

0
4
0
4 wks
0
4

Treatment

Maneechotesuwan K et al: Chest 2005

[IL-8 (ng/mL)]

Neutrophilsn(x103/mm3)

Mild asthma patients

P = 0.002
P<0.0001

NS

2.0
1.5
1.0
0.5
0

Formoterol Placebo
0
4
0
4

Budesonide
0
4

Treatment

NEUTROPHILIC PRECEDES LOSS OF CONTROL OF ASTHMA

Asthmatic patients: inhaled steroid withdrawal vs ICS continuation (control)

Sputum IL-8

Sputum neutrophils
p=0.0009

p=0.001

60

40

20

3000

2000

1000

Control

p<0.0001

4000

80

Sputum IL-8 (ng/mL)

Sputum neutrophils (%)

p=0.02

-2 wk Control Exacerbn

Maneechotesuwan K et al: Chest 2007

Control -2 wk Control Exacerbn

 NEUTROPHILS IN VIRAL EXACERBATIONS

Formoterol
Rhinovirus

Asthmatic children (n=28)

4

Sputum neutrophils

Epithelial cells

IL-8

p<0.001
Acute

Recovery

Norzila MZ etNeutrophils
al: AJRCCM 2000

Sputum IL-8

20

IL-8 (ng/mL)

Neutrophils (x106/mL)

2-receptors

15

10

p<0.01

L
Acute

Recovery

INHALED CORTICOSTEROID REDUCTION

** Symptoms

2.5

Inhaled steroid from

1600-800 200g daily

Rescue
2-agonist

** ExNO

20

0.0

Median change

Median change

5.0

*
*
Inflammation precedes symptoms
15

*
Inflammation with
loss
of
control
10

-2.5

Median change

10

Time (weeks)

Sputum
eosinophils

-10

-20

PEF

-30

FEV1

*
0

Time (weeks)

Time (weeks)

Jatakanon A et al: AJRCCM 2000

EFFECT OF A SINGLE DOSE OF INHALED STEROID

Single dose of budesonide (2400g) within 6h

50
40
30
20
10
0

Eosinophils
Placebo
Budesonide
p<0.05

100

PC20 hypertonic NaCl (mL)

Sputum eosinophils (%)

60

Reactivity
Budesonide
p<0.05

10

0.1

Gibson P et al: Am J Respir Crit Care Med 2001

Placebo

RAPID ONSET OF STEROID EFFECT ON AHR

Adenosine monophosphate challenge

PC20 AMP [mg/ml]

40

Placebo

Ciclesonide (400g daily)

p<0.001

35

p<0.001

p<0.001

30
25

Effect on airway
mast cells

20
15
10
5
0

day 0

Erin E et al: Chest 2008

3 hours

day 3

day 7

EFFECT OF STEROIDS ON AIRWAY MAST CELLS

Adenosine
Allergen
Cold air

INHALED STEROIDS

Epithelial
cells
SCF

Bronchoconstriction

Mast cells

RAPID EFFECT OF ICS ON SPUTUM CYTOKINES

Induced sputum: 3 hours after inhaled steroid
150

30

MIP-1

100

p<0.001
50

MIP-1 (pg/mL)

IL-6 (pg/ml)

IL-6
20

10

p<0.001
0

Plbo

400g

1600g

Ciclesonide

Erin E et al: Chest 2008

Plbo

400g 1600g

Ciclesonide

Th2 LYMPHOCYTES IN ASTHMA

Antigen-presenting cell (dendritic cell)
CD3
CD28
T cell receptor
GATA-3

Y Y
Mast cell

IL-13

IL-4

Co-stimulation

Th2 lymphocyte

IL-5

IgE
Eosinophil

GATA-3 REGULATION
CD3

CD28

Th2 cell
p38MAPK
Cytoplasm

Nucleus

GATA3

Importin-

Th2 cytokine gene

IL-4, IL-5, IL-13

Maneechotesuwan K et al: J Immunol 2006

Allergic
inflammation

GATA-3 REGULATION
CD3

CD28

Th2 cell

Corticosteroid
p38MAPK
GR

Cytoplasm

MKP-1
Importin-

Nucleus

GATA3

Th2 cytokine gene

Corticosteroids GATA-3
(Th2 cytokine expression)
gene
GR GR MKP-1
Rapid
onset
Potent effect Allergic
Prolonged effect
IL-4, IL-5, IL-13

inflammation

EFFECT OF CORTICOSTEROIDS ON IL-5

IL-5 (pg/ml)

15

Nasal lavage: hay fever subjects

**

10

Gr Pollen

**

Similar results with

IL-4, IL-13

Topical corticosteroids inhibit Th2 cells rapidly

Budesonide
(200 g at -30min)

0
0

10 12 14 16 18 20 22 24

Time (h)
Erin E et al: Allergy 2005

CELLULAR EFFECTS OF RESCUE Formoterol/Budesonide

Budesonide/formoterol
EXPLAINS WHY BUD/FORM
Budesonide
Formoterol
IS THE MOST EFFECTIVE RELIEVER

Neutrophils

Mast cells

Eosinophils
Eotaxins

Th2 cells
IL-5

BRONCHIAL BLOOD FLOW IN ASTHMA

Bronchovideomicroscopy
75
Salbutamol
Normal

**

60

60

Qaw (l/min/ml)

Qaw (l/min/ml)

Bronchial blood flow measured

by inhaled acetylene uptake
75 Budesonide
Asthma

45

Asthma

**

**

45

Budesonide: rapid 30bronchial

blood flow
Normal
**
Salbutamol:
no effect

30

Normal

15

15

Asthma

0
0

15

30

45

Time (minutes)

Paredi P et al: Resp Res 2005

60

75

0
20
30
Tanaka
H et10
al: AJRCCM
2003

Time (minutes)

40

INTERACTIONS BETWEEN
CORTICOSTEROIDS AND 2-AGONISTS
Corticosteroid

2-Agonist

2-Adrenoceptor
Glucocorticoid
receptor

Anti-inflammatory effect

Bronchodilatation

Effect of corticosteroids on -agonist effects

Effect of -agonists on corticosteroid effects
2

LABA/ICS ON EPITHELIAL RANTES (CCL5)

CCL5 release (% control)

BEAS2B epithelial cells infected with rhinovirus (RV16)

LABA/ICS
Epithelial RANTES (CCL-5) Rhinovirus
in asthma exacerbation
120

2-receptors

100
80

Epithelial cells

60

p<0.001

RANTES

40
20
0

Control
Edwards MR et al: AJRCMB 2006

Salmeterol Fluticasone

Salm/Flut

(1nM)
Eosinophils (0.1nM)
T-lymphocytes

POST-ALLERGEN AIRWAY HYPERRESPONSIVENESS

PC20 (doubling doses)

Methacholine PC20 24h Post-Allergen

2.0

1.5

Single dose during early response

NS

1.0

NS
p<0.005

0.5

0.0

Placebo

Budesonide

Duong ML et al: J Allergy Clin Immunol 2007

Formoterol

Budesonide
+ Formoterol

CONCLUSIONS
Corticosteroids and 2-agonists affect different and
complementary
aspects
of asthma pathophysiology
Formoterol during
exacerbations:

Reverses bronchoconstriction

Inhibits mast cell mediator release

Inhibits neutrophils
Budesonide has rapid action on inflammation

- eNO, eos, mast cell numbers (adenosine), Th2 lymphocytes

Rescue Bud/form may have enhanced effects

- Molecular interaction between ICS and LABA
- Enhanced anti-inflammatory effects

THERE IS A STRONG SCIENTIFIC RATIONALE

FOR BUD/FORM SMART THERAPY IN ASTHMA

Maintenance therapy:
Highly effective

Rescue therapy:
Highly effective

SINGLE INHALER THERAPY

Barnes PJ. Scientific rationale for using a single inhaler for
asthma control. Eur Resp J 2007;25:587-596

Chapter 4. Asthma Management

and Prevention Program
Component 3: Assess, Treat, and
Monitor Asthma Treatments
Treating to achieve control: Step 3: Reliever
medication plus one or two controllers
If a combination inhaler containing formoterol and
budesonide is selected, it may be used for both rescue
and maintenance. This approach has been shown to
result in reductions in exacerbations and improvements
in asthma control in adults and adolescents at relatively
low doses of treatment (Evidence A)
GINA 2006: page 60

EVOLUTION OF ASTHMA TREATMENT

Fluticasone + salmeterol

Oral
Oral
steroid
steroid

Budesonide + formoterol

SMART
SMART

LIKELY TO BE THE MOST

LABA
New treatments
EFFECTIVE
THERAPY
FOR
ASTHMA
severe asthma
BDP/formoterol FOR >15 YEARS for
(1-5% of patients)
Fluticasone/formoterol

needed
LABA/ICS
ICS
High dose
Mometasone/formoterol
ICS
Anti-IgE
Low dose
Ciclesonide/formoterol
Anti-TNF
Short-acting -agonist as neededOther?
Mometasone/indacaterol
Step 1 Step 2 ??
Step 3
Step 4
Step 5
2

Mild
Episodic

Mild
Moderate
Persistent Persistent

Severe
Persistent

THANK YOU