Ingen bildrubrik

1
clinical profile
Oxis
2
Oxis - key attributes

• Fast-acting b2-agonist
• can be used as needed for symptom relief
• Long-acting b2-agonist
• can be used on regular basis to reduce frequency
  and severity of asthma attacks
• Simple treatment option
• only one bronchodilator on a regular basis and as
  needed
• Turbuhaler
• dry powder inhaler system easy to use / high
  lung deposition

3
Oxis has a fast onset of action
Change from baseline FEV1()
9 µg Oxis Turbuhaler 4.5 µg Oxis Turbuhaler 20
0 µg salbutamol pMDI 100 µg salbutamol
pMDI Placebo
30
25
20
15
10
5
0
-5
30
35
-5
0
5
10
15
20
25
Minutes after drug administration
Seberová et al. AJRCCM 1999
4
Oxis has a fast onset of action
FEV1 ( increase from baseline)
18 µg Oxis Turbuhaler 9 µg Oxis
Turbuhaler 50 µg salmeterol Diskhaler 4.5 µg
Oxis Turbuhaler Placebo
25
20
15
10
5
0
60
0
5
10
15
20
30
40
50
Minutes
Palmqvist et al. ERJ 1997
5
Oxis has a fast onset of action
FEV1 ( of baseline)
110 100 90 80 70 60 50 40
Methacholine-induced bronchoconstriction
Oxis Turbuhaler 9 mg salbutamol Turbuhaler 50
mg salmeterol Diskhaler 50 mg placebo
Inhalation of study drug
-5
0
5
10
15
20
55
25
30
35
40
50
60
65
Minutes
Politiek et al. ERJ 1999
6
Oxis relieves acute airway obstruction
FEV1 ( increase from baseline)
Dosing time (total 20 inhalations)
70
methylprednisolone 40 mg i.v.
60
50
terbutaline Turbuhaler 10 mg Oxis Turbuhaler
90 µg
40
30
20
10
0
0
720
60
120
180
240
300
360
Minutes after first dose
7
Oxis has long duration of action
FEV1 (L)
2.8
18 µg Oxis Turbuhaler 50 µg salmeterol Diskhale
r 9 µg Oxis Turbuhaler 4.5 µg Oxis
Turbuhaler Placebo
2.6
2.4

2.2
0
2
4
6
8
10
12
Hours
Palmqvist et al. ERJ 1997
8
Oxis protects for 12 hours against Exercise
Induced Bronchoconstriction
Asthmatic children (8-17 years)
Percentage fall in FEV1
0
Oxis Turbuhaler 9 µg Oxis Turbuhaler 4.5
µg terbutaline Turbuhaler 0.5 mg Placebo
5
10
15
20
25
Time after Oxis dose
30
15 min
4 hrs
8 hrs
12 hrs
Time point of exercise challenge test
GrØnnerØd et al. AJRCCM 1999
9
Increased bronchoprotection by Oxis
AMP and histamine challenge
?PC20 (doubling dilutions)
plt0.05
7.5
NS
5
Oxis and salbutamol gave similar prechallenge
bronchodilator response
2.5
0
AMP Hist AMP Hist
Oxis (9?g)
Salbutamol (200?g)
Nightingale et al. AJRCCM 1999
10
Oxis reduces rate of severe exacerbations
1
Increasing Pulmicort dose p lt 0.001
Adding Oxis p 0.014
Pulmicort 800 vs. Pulmicort 200 Oxis p
0.031
0.5
Exacerbations / patient / year
0
Pulmicort 400 ?g bid?
Pulmicort 100 ?g bid?
Pulmicort 400 ?g bid Oxis 9 ?g bid
Pulmicort 100 ?g bid Oxis 9 ?g bid
Pauwels et al. NEJM 1997
11
Oxis reduces rate of severe exacerbations
Pulmicort 200 ?g Oxis
Pulmicort 200 ?g
Increase the dose of Pulmicort - 49
Pulmicort 800 ?g Oxis
Pulmicort 800 ?g
Pulmicort Oxis - 63
Add Oxis -26
Pauwels et al. NEJM 1997
12
Oxis reduces rate of mild exacerbations
40
Increasing Pulmicort dose p lt 0.001
Adding Oxis p lt 0.001
30
Pulmicort 800 vs. Pulmicort 200 Oxis p
0.76
20
Exacerbations/patient/year
10
0
Pulmicort 100 ?g bid?
Pulmicort 400 ?g bid?
Pulmicort 400 ?g bid Oxis 9 ?g bid
Pulmicort 100 ?g bid Oxis 9 ?g bid
Pauwels et al. NEJM 1997
13
Oxis reduces rate of mild exacerbations
Pulmicort 200 ?g Oxis
Pulmicort 200 ?g
Increase the dose of Pulmicort -37
Pulmicort 800 ?g Oxis
Pulmicort 800 ?g
Pulmicort Oxis - 62
Add Oxis -40
Pauwels et al. NEJM 1997
14
Why does Oxis improve asthma control?

• Reduces airway oedema by decreasing plasma leak
• Influence on airway sensory nerves
• Reduces mediator release from mast cells
• Reduces airways hyperresponsiveness
• Activation of corticosteroid receptors

15
Advantages of Oxis as needed

• Reduces the number of rescue inhalations1
• Reduces severe exacerbations1
• Improves lung function1
• Improves QoL2
• Is cost-effective3

1. Tattersfield et al. AJRCCM 1999 2. Postma et
al. AJRCCM 1999 3. Berggren et al. ERJ 1999
16
Oxis as needed reduces the risk of severe
exacerbations
Proportion of patients without severe asthma
exacerbation
p0.013
1.0
Oxis Turbuhaler 4.5 mg terbutaline Turbuhaler
0.5 mg
0.5
0.0
0
10
20
30
40
100
50
60
70
80
90
Days after randomisation
Tattersfield et al. AJRCCM 1999
17
Oxis as needed improves lung function
400 390 380 370 360 350 340 330 320
Mean morning PEF (L/min)
p0.0092
Oxis Turbuhaler 4.5 mg terbutaline Turbuhaler
0.5 mg
-20
0
20
40
60
80
100
Treatment days
run-in
Tattersfield et al. AJRCCM 1999
18
Oxis as needed reduces the number of rescue
inhalations
5 4 3 2 1 0
Mean number of inhalations /day
p0.0003
terbutaline Turbuhaler 0.5 mg Oxis Turbuhaler
4.5 mg
-10
0
10
20
30
40
100
50
60
70
80
90
Treatment days
run-in
Tattersfield et al. AJRCCM 1999
19
Oxis as needed improves Quality of Life
Mean AQLQ score, overall quality of life
6.0
Oxis Turbuhaler 4.5 mg
terbutaline Turbuhaler 0.5 mg
p0.0047
5.5
5.0
4.5
0 1 2 3 4 5 6 7
8 9 10 11 12
Treatment (week)
Postma et al. AJRCCM 1999
20
Oxis as needed is cost-effective
SEK
Cost per patient for a 12 week treatment
3,386 (x Euro)
3,709 (x Euro)
cost of staying away from work duringa severe
exacerbation
health care costs for severe exacerbations
inhaled and oral steroids
study drug costs
Oxis Turbuhaler
terbutaline Turbuhaler
Berggren et al. ERJ 1999
21
Oxis - high safety margin

• Oxis Turbuhaler is well tolerated1,2,3
• Oxis Turbuhaler has a favourable therapeutic
  ratio compared with salbutamol pMDI 4
• Oxis Turbuhaler 4.5 ?g shows less systemic
  effects than terbutaline Turbuhaler 0.5 mg,
  up to 20 inhalations1
• Oxis Turbuhaler has short acting systemic
  effects
• comparable to terbutaline1, salbutamol3
• significantly shorter than salmeterol5

1. Tötterman et al. ERJ 1998 2. Malolepszy et
al. ERJ 1998 3. Lötvall et al. ERJ 1997 4. Rott
et al. ERJ 1998 5. Guhan et al. ERJ 1998
22
Oxis has short-acting systemic effects
At comparable maximal effects, similar time
profiles were observed
4.4 4.2 4.0
Serum Potassium (mmol/L)
dosing time
3.8 3.6 3.4
Oxis Turbuhaler 54 mg/day terbutaline
Turbuhaler 6 mg/day
1 2
3 4
Days
Tötterman et al. ERJ 1998
23
Oxis minimises the systemic burden
A SCHEMATIC SUMMARY OF CLINICAL RESULTS
arbitrary units
Oxis Turbuhaler Short-acting ?2-agonist
Effects in the lung after inhaled administration
0
6
12
hours
Systemically derived effects
1. Löfdahl Svedmyr, Allergy 1989 2. Palmqvist
et al. Eur Respir J 1997 3. Borgström et al.
AJRCCM 1996 4. Tötterman et al. Eur Respir J
1998 5. Lötvall et al. Eur Respir J 1997
24
Oxis - less systemic effect
Pulse rate (beats per minute)
Dosing time (total 20 inhalations)
112
methylprednisolone 40 mg i.v.
108
104
terbutaline Turbuhaler 10 mg Oxis Turbuhaler
90 µg
100
96
92
88
84
0
720
60
120
180
240
300
360
Minutes after first dose
Malolepszy et al. ERJ 1998
25
Oxis does not mask exacerbations
fall in mPEF before, during and after severe
exacerbation
Pulmicort Turbuhaler 100 mg bid Pulmicort
Turbuhaler 100 mg bid Oxis Turbuhaler 9 mg
bid Pulmicort Turbuhaler 400 mg bid Pulmicort
Turbuhaler 400 mg bid Oxis Turbuhaler 9 mg bid
10 0 -10 -20 -30
-15
-10
- 5
0
5
10
15
Days
Tattersfield et al. AJRCCM 1999
26
Oxis does not mask inflammation
Little FACET study
7.5
5.0
Sputum
Eosinophils
Pulmicort 100 ?g bid Oxis 9 ?g bid
()
2.5
Pulmicort 400 ?g bid
0.0
15
10
Sputum
EG2 cells
Pulmicort 100 ?g bid Oxis 9 ?g bid
()
5
Pulmicort 400 ?g bid
0
-1
0
1
2
3
6
9
12
Time (months)
Kips et al, Am J Respir Crit Care Med 1998
27
No tolerance with long term use of Oxis
FEV1 ( of predicted)
95
Pulmicort 100 ?g bid
Pulmicort 100 ?g bid Oxis 9 ?g bid
Pulmicort 400 ?g bid
Pulmicort 400 ?g bid Oxis 9 ?g bid
90
85
80
75
70
Months
run-in
Pauwels R et al. NEJM 1997
28
Conclusions

• Oxis displays fast onset plus long duration of
  action
• Oxis reduces exacerbation rates irrespective of
  bid or as needed treatment regimen
• Oxis improves lung function
• Oxis displays remarkably good safety profile