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Duration of action of inhaled formoterol First pivotal experiment in humans

Similarities and differences between Oxis ® (formoterol) and other  2 -agonists used as needed. Bronchodilating capacity (%). Duration of action of inhaled formoterol First pivotal experiment in humans. Oral route. Inhaled route. 100. 100. Salbutamol 4 mg. Formoterol 6 µg. 80.

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Duration of action of inhaled formoterol First pivotal experiment in humans

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  1. Similarities and differences between Oxis® (formoterol)and other 2-agonists used as needed

  2. Bronchodilating capacity (%) Duration of action of inhaled formoterol First pivotal experiment in humans Oral route Inhaled route 100 100 Salbutamol 4 mg Formoterol 6 µg 80 80 60 60 Salbutamol 100 µg 40 40 20 20 Formoterol 80 µg 0 0 -20 -20 420 480 420 480 60 120 180 240 300 360 0 60 120 180 240 300 360 0 Time (min) Time (min) At 8 hours terbutaline 1.25 mg was inhaled Löfdahl and Svedmyr Allergy 1989

  3. FEV (%) 1 0 1 5 2 0 2 5 Onset of action – relief of acute bronchoconstriction Comparisons 3 min after inhalation of bronchodilator Formoterol Turbuhaler 9 g ** Salbutamol Turbuhaler 50 g Salmeterol Diskhaler 50 g Placebo 0 5 N=17, adult asthmatics Methacholine-induced bronchoconstriction ** p<0.0001 for formoterol vs salmeterol and placebo; no significant difference between formoterol and salbutamol Politiek et al, Eur Respir J 1999

  4. Onset of action – bronchodilating effect 30 * Formoterol 9 µg Formoterol 4.5 µg Salbutamol 200 µg Salbutamol 100 µg Placebo 25 20 Mean FEV1(% change from baseline) 15 10 *p<0.001 for all active treatments compared with placebo 5 0 0 5 10 15 20 25 30 N = 36 adult asthmatics Double-blind, double-dummy, cross-over, randomized FEV1 measured 1, 3, 5, 7, 10, 15, 20, 25, 30 minutes after inhalation Mins after drug administration Seberová & Andersson, Respir Med 2000

  5. At 3 minutes all formoterol doses significantly better than salmeterol (p < 0.05) Onset of action –bronchodilating effect 25 Formoterol18 µg Turbuhaler Formoterol9 µg Turbuhaler Formoterol4.5 µg Turbuhaler Salmeterol 50 µg Diskhaler Placebo 20 15 FEV1 (% increase from baseline) 10 5 0 0 5 10 15 20 30 40 50 60 Minutes N = 28 Double-blind, placebo-controlled, cross-over Palmqvist et al. Eur Respir J 1997

  6. Duration of effect - bronchodilation Formoterol 18 µg Formoterol 9 µg Formoterol 4.5 µg Salmeterol 50 µg Placebo 2.8 *** 2.6 2.4 FEV1 (L) *** p<0.001 for all formoterol and salmeterol doses compared with placebo at 12 h 2.2 0 2 4 6 8 10 12 Time (h) Palmqvist et al, Eur Respir J 1997

  7. Classes of 2-agonists Speed of onset RELIEVER MEDICATION fast onset, short duration fast onset, long duration M AINTENANCE fast inhaled formoterol inhaled terbutaline inhaled salbutamol slow onset, short duration slow onset, long duration oral terbutaline oral salbutamol oral formoterol slow inhaled salmeterol oral bambuterol Duration of action short long

  8. Clinical outcome Oxis versus short acting 2-agonists

  9. Probability of remaining without a severe asthma exacerbation Formoterol 4.5 µg Terbutaline 0.5 mg 1.0 0.5 p=0.013 formoterol vs terbutaline (time to first severe exacerbation) 0.0 0 20 40 60 80 Time since randomisation (days) N = 362 asthmatics on inhaled corticosteroids Double-blind, randomized, parallel group study Tattersfield et al, Lancet 2001

  10. Mean FEV1 before and after bronchodilator FEV1 (l) 2.8 Formoterol 4.5 µg Terbutaline 0.5 mg 2.6  post bronchodilator test 2.4 before bronchodilator test  2.2 Bronchodilator = 1.5 mg terbutaline 2.0 4 8 12 N = 362 asthmatics on inhaled corticosteroids Double-blind, randomized, parallel group study Weeks after randomisation Tattersfield et al, Lancet 2001

  11. Relief medication usage Formoterol 4.5 µg Terbutaline 0.5 mg Mean number of inhalations 6 5 4 3 p=0.0005 formoterol 4.5 µg vs terbutaline 0.5 mg (total number of inhalations) 2 1 0 –10 0 10 20 30 40 50 60 70 80 90 100 Treatment days Run-in N = 362 asthmatics on inhaled corticosteroids Double-blind, randomized, parallel group study Tattersfield et al, Lancet 2001

  12. Oxis® as needed improves quality of life Mean AQLQ score, overall quality of life 6.0 p=0.0047 5.5 Formoterol Turbuhaler4.5 g Terbutaline Turbuhaler 0.5 mg 5.0 4.5 0 1 2 3 4 5 6 7 8 9 10 11 12 N = 362 asthmatics on inhaled corticosteroids Double-blind, randomized, parallel group study Treatment (weeks) Postma et al. AJRCCM 1999

  13. Reduction of daytime bronchodilator usage 3.5 3 Formoterol 9 µg as needed Terbutaline 0.5 mg as needed 2.5 2 Average ß2-agonist use (time/day) 1.5 1 0.5 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Days N = 236 asthmatics on inhaled budesonide and formoterol (Oxis) 9 µg bid. Open, randomized, parallel-group and crossover O’Connor et al. AJRCCM 2000

  14. Oxis relieves acute airway obstruction

  15. –5 0 5 10 15 20 25 30 35 40 45 50 55 60 Oxis relieves acute airway obstruction 100 90 80 FEV1 (% of baseline) 70 FormoterolTurbuhaler9 g Salmeterol Diskhaler 50 g 60 Salbutamol 50 g 50 Placebo Inhalation 40 Time (min) N=17, adult asthmatics, methacholine-induced bronchoconstriction Politiek et al, Eur Respir J 1999

  16. Relieves acute airway obstruction 1.8 Formoterol 90 µg total dose Terbutaline 10 mg total dose 1.7 1.6 1.5 1.4 1.3 Administration of formoterol/terbutaline Mean FEV1 1.2 1.1 Administration of methylprednisolone 1.0 0.9 0.8 0 60 120 180 240 300 360 720 N = 36 adults Randomized, parallel, double-blind Emergency room treatment of acute bronchoconstriction Mins after first dose Malolepszy et al. Eur Respir J 2001

  17. Oxis protects against AMP and histamine challenge

  18. Increased bronchoprotection by Oxis AMP and histamine challenge p<0.05 Mast cell 7.5 stabilising effect NS 5 (doubling dilutions) Formoterol and salbutamol gave similar prechallenge bronchodilator response 2.5 20 PC  0 AMP Hist AMP Hist Formoterol 9g Salbutamol 200 g N=16, mild atopic asthma Nightingale et al. AJRCCM 1999

  19. Formoterol protects against late phase reaction to allergen challenge

  20. 20 15 10 5 FEV1 (% change) 0 -5 -10 -15 -20 -25 -30 0 10 20 30 45 60 2 3 4 5 6 7 (hours) (min) Time after inhalation Formoterol protects against late phase reaction to allergen Formoterol/Control challenge Formoterol/Allergen challenge Placebo Beclomethasone/Control challenge Placebo/Allergen challenge 24 Wong et al. Am Rev Respir Dis 1992

  21. Oxis protects against cold dry air

  22. Protection againstcold dry air 100 * ** *** Formoterol 9g † 75 ‡ Salbutamol 200 g Percent protection *p=0.02, **p=0.0002, ***p=0.0006 compared with placebo 50 †p=0.002, ‡ p=0.0005 compared with salbutamol 25 15 min 4 h 8 h N=12 asthmatic children (2-5 years). Administered by mechanically actuated dry-powder inhaler and spacer Time since dosing Nielsen & Bisgaard, AJRCCM 2001

  23. Oxis protects against exercise induced bronchoconstriction

  24. Oxis protects against exercise-induced bronchoconstriction at -18 C during regular treatment 0 Maximum fall in FEV1 (%) 5 Formoterol 9 µg Terbutaline 0.5 mg Placebo 10 * * 15 * * 20 25 30 Time after dose 15 min 4 h 8 h 12 h Time point of exercise challenge test *p<0.05 vs terbutaline Vilsvik et al, Respir Med 2001

  25. Formoterol 9 µg Formoterol 4.5 µg Terbutaline Placebo Oxis protects against exercise-induced bronchoconstriction Asthmatic children (6-17 years) 0 * –5 * * * * * –10 FEV1 change from baseline (%) –15 –20 Time after dose –25 4 h 8 h 12 h 15 min Time point of exercise challenge test *p<0.05 vs terbutaline Grönneröd et al, Respir Med 2000

  26. Oxis – high safety margin

  27. Oxis – less systemic effectPulse rate 112 Formoterol 90 µg total dose Terbutaline 10 mg total dose 108 Administration of formoterol/terbutaline 104 100 Administration of methylprednisolone bpm 96 92 88 84 N = 36 adults Randomized, parallel, double-blind Emergency room treatment of acute bronchoconstriction 0 60 120 180 240 300 360 720 Mins after first dose Malolepszy et al. Eur Respir J 2001

  28. Oxis – less systemic effectMean serum potassium 4.4 Formoterol 90 µg total dose Terbutaline 10 mg total dose 4.2 4.0 Administration of formoterol/terbutaline mmol/l 3.8 Administration of methylprednisolone 3.6 3.4 3.2 N = 36 adults Randomized, parallel, double-blind Emergency room treatment of acute bronchoconstriction 0 60 120 180 240 300 360 720 Mins after first dose Malolepszy et al. Eur Respir J 2001

  29. Oxis – less systemic effect Cardiac frequency Daily doses 84 Formoterol 54 µg 80 Formoterol 90 µg Terbutaline 6 mg 76 Cardiac frequency (beats/min) Terbutaline 10 mg 72 68 Dosing times 64 60 Day 1 Day 2 Day 3 Day 4 Tötterman et al, Eur Respir J 1998

  30. Oxis – less systemic effect Mean serum potassium 4.1 3.9 Serum potassium (mmol/l) Formoterol 90 µg/day 3.7 Terbutaline 10 mg/day 3.5 Dosing times 3.3 Day 1 Day 2 Day 3 Day 4 Tötterman et al, Eur Respir J 1998

  31. 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, Eur Respir J 1998

  32. Oxis minimises systemic burden A schematic summary of clinical results arbitrary units Oxis Therapeutic effects short-acting ß2-agonists 0 6 12 short-acting ß2-agonists Time after dose (hrs) Oxis Systemic effects Derived from: 1. Ringdal N et al. Respir Med 19982. Palmqvist M et al. ERJ 1997 3. Borgström L et al. AJRCCM 1996 4. Tötterman KJ et al. ERJ 19985. Rosenborg J et al. Eur J Clin Pharmacol 2000 6. Malolepszy J et al. ERJ 2001

  33. Oxis is cost effective

  34. 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 Oxis as needed is cost-effective 3,709 3,386 cost of staying away from work duringa severe exacerbation health care costs for severe exacerbations Cost per patient for a 12 week treatment (SEK) inhaled and oral steroids study drug costs N = 362 asthmatics formoterol 4.5 g and terbutaline 0.5 mg used as needed Oxis Turbuhaler Terbutaline Turbuhaler Berggren et al. Respir Med 2001

  35. Turbuhaler® is effective in acute asthma

  36. Turbuhaler in acuteasthma - FEV1 salbutamol Turbuhaler 2000 g total dose 2.0 salbutamol pMDI plus spacer 4000 g total dose Dosing time 1.5 FEV1 (litres) 1.0 0 0 20 40 60 80 100 120 140 160 Time (minutes) N = 86 asthmatic adults Emergency room treatment Nana et al, Respir Med 1998

  37. Turbuhaler in acute asthma -symptoms 100 salbutamol Turbuhaler 2000 g total dose 90 80 salbutamol pMDI plus spacer 4000 g total dose 70 60 Symptom score Dosing time 50 40 30 20 10 0 0 20 40 60 80 100 120 140 160 180 Time (minutes) N = 86 asthmatic adults Emergency room treatment Nana et al, Respir Med 1998

  38. Turbuhaler vs pMDI plus spacerin acute asthma Turbuhaler pMDI +Nebuhaler Increase in FEV1 (L) 0.6 0.4 0.2 p = 0.0004 *** 0 10 25 (baseline) min inhalation 2.5 mg terbutaline inhalation 2.5 mg terbutaline Tønnesen et al. Chest 1994

  39. Advantages of Oxis as neededvs salbutamol or terbutaline • Provides both fast and long acting effect1, 2 • Reduces severe exacerbations3 • Improves lung function3 • Reduces the number of reliever inhalations3, 5 • Improves Quality of Life4 • Is more cost-effective6 1. Seberová et al. Respir Med 2000 2. Palmqvist et al. Eur Respir J 1997 3. Tattersfield et al. Lancet 2001 4. Postma et al. AJRCCM 1999 5. O’Connor et al. AJRCCM 2000 6. Berggren et al. Respir Med2001

  40. Advantages of Oxis as neededvs salbutamol or terbutaline • Increased protection against AMP indicating mast cell stabilising effects1 • Protects against late phase allergic reaction (formoterol pMDI)2 • Provides longer protection against cold dry air3 and exercise induced bronchoconstriction4, 5 • Minimises the systemic burden6, 7 1. Nightingale et al. AJRCCM 1999 2. Wong et al. Am Rev Respir Dis 1992 3. Nielsen & Bisgaard. AJRCCM 2001 4. Vilsvik et al, Respir Med 2001 5. Grönneröd et al, Respir Med 2000 6. Malolepszy et al. Eur Respir Med 2001 7. Tötterman et al, Eur Respir J 1998 .

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