1 / 32

Targeted Therapies in Difficult-to-Control Asthma

Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale. Targeted Therapies in Difficult-to-Control Asthma. Paul M O’Byrne

gerik
Download Presentation

Targeted Therapies in Difficult-to-Control Asthma

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

  2. Targeted Therapies in Difficult-to-Control Asthma Paul M O’Byrne EJ Moran Campbell Professor of Medicine Firestone Institute for Respiratory Health, St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada

  3. GINA Guidelines 2011 Phenotyping Empiric Treatment

  4. Omalizumab and Difficult-to-Control Asthma

  5. Omalizumab and Difficult-to-Control Asthma Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

  6. Omalizumab and Difficult-to-Control Asthma Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

  7. Bronchial Thermoplasty Catheter has an expandable wire array at the tip • Radiofrequency energy that is converted to heat in the airway wall • Monopolar radiofrequency (RF) energy • Temperature controlled: 65 °C • 10 seconds • Signal for successful activation • Multiple safety algorithms to ensure controlled energy delivery 7

  8. Bronchial Thermoplasty Miller J D et al. Chest 2005;127:1999-2006

  9. Bronchial Thermoplasty Cox PG, et al. Am J Respir crit Care Med 2006; 173:965-9

  10. Bronchial Thermoplasty

  11. GINA Guidelines 2011 Phenotyping Empiric Treatment

  12. Induced Sputum O’Byrne PM, Nair P. Lancet 2006; 368:794-308

  13. 120 BTS management group 100 80 Severe Exacerbations (number) 60 Sputum management group 40 20 0 0 2 4 6 8 10 12 Time (months) GREEN R, et al . LANCET 2002; 360: 1715-21

  14. LOMA study Jayaram L, et al. Eur Respir J 2006; 27:483-94

  15. Effect of SCH55700, a Humanized Anti-Human Interleukin-5 Antibody, in Severe Persistent Asthma 26 severe asthmatics. FEV1 49-61% predicted. All on high dose ICS or oral corticosteroids. FEV1 Blood Eosinophils Kips J, et al. Am J Respir Crit Care Med 2003; 167:1655-9

  16. Mepolizumab in asthma • Subjects: • moderate/severe asthma • inhaled corticosteroids up to 1000 mcg/day • symptoms mean 5 on 12 point scale • FEV1 68% predicted • Treatment: • SB 240563 250 mg or 750 mg or placebo Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

  17. Mepolizumab in asthma Asthma Exacerbations (% patients) p=0.06 Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

  18. Subject characteristics Mepolizumab Placebo 9 10 n 57.9 (4M) 59.3 (7M) Age, y (gender, M) 11.8 9.2 Years of symptoms FEV1 % predicted 65.5 68.2 Δ FEV1, exacerbation % 43.7 45.0 Δ FEV1, SABA % 17.1 27.4 Prednisone, mg (years ) 10 (9.7) 10 (8.0) ICS, mg 1000 1000 LABA, n 8 9 NAIR P, et al. N Engl J Med 2009; 360:985-93

  19. Sputum and Blood Eosinophils NAIR P, et al. N Engl J Med 2009; 360:985-93

  20. Prednisone Reduction n=9 n=10 100 80 prednisone reduction as % of maximum possible reduction 60 40 20 0 mepolizumab placebo p<0.05 NAIR P, et al. N Engl J Med 2009; 360:985-93 .

  21. Asthma Exacerbations NAIR P, et al. N Engl J Med 2009; 360:985-93.

  22. Mepolizumab and Difficult-to-Control Asthma

  23. Mepolizumab in Difficult-to-Control Asthma Haldar P et al. N Engl J Med 2009; 360:973-984

  24. New Drugs for Asthma • Modifications of existing drugs: • Untra-longacting inhaled β2-agonists • Modified inhaled corticosteroids • Glucocorticosteroid receptor agonists • New ICS/LABA combinations • New approaches • Anti-sense against IL-3, IL-3, GM-CSF and CCR • Anti-sense IL-4R • Anti-IL-9 • Anti-IL-13 • Anti-C5a • Anti-Ox 40L • CXCR2 antagonist • CRTH2 antagonists

  25. Oligonucleotide Therapeutic Approaches 3. ISS/ CpG motif (ssDNA) 5. Aptamer (DNA or RNA) 4. Decoy (dsDNA) Competition for TF “Blocks” transcription! Nucleus Transcription factor TLR9 DNA (GENE) Immuno- stimulation Promoter RNAseH Transcription “Blocks” receptor function! RNA Translation PROTEIN RNAseH RISC 2. siRNA (dsRNA) 1. Antisense (ssDNA) mRNA degradation Paolo Renzi MD.

  26. Rationale: • By down-regulating the expression of the eotaxin receptor (CCR3) and the common beta chain for IL-3, IL-5, and GM-CSF, • an inhaled anti-sense, ASM8 will inhibit the migration and survival of eosinophils, basophils, mast cells. • and thereby inhibit allergen-induced airway responses.

  27. Effect of ASM8 on βc and CCR-3 mRNA in sputum cells % change from pre-allergen levels % change from pre-allergen levels Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

  28. Sputum Cell Counts Pre-dose vs Post Allergen Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

  29. Allergen-Induced Sputum Eosinophilia p=0.005 p=0.043

  30. Allergen-induced Fall in FEV1

  31. Summary • Phenotyping is important to identify the best choice of treatment in difficult-to-control asthma. • Bronchial thermoplasty is the only novel treatment recently approved for severe asthma. • Anti-IL-5 mAbs appear very promising for asthma with a persisting airway eosinophilia • Many other therapeutic approaches are being studied for the management of difficult-to-control asthma.

More Related