1. Upper Airways Research Laboratory Department of Otorhinolaryngology Advanced treatments of nasal polyposis: Anti-IL-5 and Anti-IgE Which for whom? Prof. Dr. Philippe Gevaert Department of Otorhinolaryngology Ghent University Hospital, Belgium

2. Upper Airways Research Laboratory Department of Otorhinolaryngology Advanced medical treatments in recurrent nasal polyposis Surgery = removing immunological memory

3. Upper Airways Research Laboratory Department of Otorhinolaryngology Antibiotics Anti IL-5 Anti-IL-5 Corticosteroids IL-5 ECP Eotaxin IgE Anti IL-5 Advanced medical treatments in recurrent nasal polyposis

4. Upper Airways Research Laboratory Department of Otorhinolaryngology N=354 J Allergy Clin Immunol 2005;116:1275-81

5. Upper Airways Research Laboratory Department of Otorhinolaryngology Nasal corticosteroid DROPS in nasal polyps double-blind, placebo-controlled study with nasal GCS drops After 12-weeks:  nasal blockage,  peak nasal inspiratory flow  polyp volume (CT score)  need for sinus surgery Aukema, Mulder, Fokkens; JACI 2005

6. Upper Airways Research Laboratory Department of Otorhinolaryngology Participating centers: ENT Dept: University Hospital Ghent, Belgium, University Hospital St. Rafael Leuven Belgium; University Hospital Erlangen, Germany, Adelaide University Hospital, Australia, Academic Medical Center, Amsterdam, the Netherlands T Van Zele, Gevaert P (in preparation) Oral steroids in nasal polyps: a 3-month double blind, randomized, placebo-controlled trial DBPC in 32 patient with nasal polyps, 20days methylprednisolon (Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg) Primary endpoint: endoscopic scoring with a five grade system Secoundary endpoints symptoms evaluation of local and systemical biological activity and efficacy measurement of IgE, IL-5 and ECP on nasal secretions (merocell) measurement of blood eosinophilia daily measurement of nasal peak inspiratory flow grade 01 2 34

7. Upper Airways Research Laboratory Department of Otorhinolaryngology Thibaut Van Zele, Philippe Gevaert, Gabriele Holtappels, Achim Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert Oral steroids in nasal polyps: a 3-month double blind, randomized, placebo-controlled trial DBPC in 32 patient with nasal polyps, 20days methylprednisolon (Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg)

8. Upper Airways Research Laboratory Department of Otorhinolaryngology Methylprednisolone has mild local anti-inflammatory effects Placebogroup: n=18 Methylprednisolone group: n=14 T Van Zele, Gevaert P (in preparation)

9. Upper Airways Research Laboratory Department of Otorhinolaryngology Antibiotics Anti IL-5 Anti-IL-5 Corticosteroids IL-5 ECP Eotaxin IgE Advanced medical treatments in recurrent nasal polyposis

10. Upper Airways Research Laboratory Department of Otorhinolaryngology Long term antibiotic treatment in NP DBPC study in 90 patients: 3m low-dose erythromycin, nasal douche, nasal GCS vs. sinus surgery 50% Improvement of symptoms no difference vs sinus surgery

11. Upper Airways Research Laboratory Department of Otorhinolaryngology

12. Upper Airways Research Laboratory Department of Otorhinolaryngology * Doxycycline reduces MMP9, ECP, MPO and nasal polyp size, in a double-blind, randomized, placebo controlled, multicenter trial. 20 days doxycycline (100mg/d) reduces PND Philippe Gevaert, Thibaut Van Zele, Gabriele Holtappels, Achim Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert

13. Upper Airways Research Laboratory Department of Otorhinolaryngology Placebo group: n=18 Methylprednisolone group: n=14 Oral doxycycline reduces neutrophilic and eosinophilic inflammation Gevaert P, Van Zele T (in preparation)

14. Upper Airways Research Laboratory Department of Otorhinolaryngology First double blind placebo controlled trial with antibiotics in nasal polyps that shows: a significant effect of doxycycline on nasal polyp size Doxycycline reduces local inflammation in terms of ECP and MPO effect on eosinophilic inflammation effect on neutrophilic (may be related to the effect on S. aureus) Doxycycline has a sigificant effect on remodeling (MMP-9) Doxycycline Gevaert P, Van Zele T (in preparation)

15. Upper Airways Research Laboratory Department of Otorhinolaryngology Practical management of Nasal Polyposis Nasal douche with saline Nasal corticosteroids GCS sprays: 2x/d, symptoms↓, no resolution of NP GCS drops: symptoms↓, surgery↓↓ Oral corticoids: effective but fast recurrence Antibiotics: Antibiotic ointment Long-term antibiotics: macrolides 500mg/d ged 3m doxycycline 100 mg/d ged 1m Combinations? Endoscopic sinus surgery: only chance for cure!! in NP: recurrences

16. Upper Airways Research Laboratory Department of Otorhinolaryngology Treatment of nasal polyposis following EP³OS

17. Upper Airways Research Laboratory Department of Otorhinolaryngology Antibiotics Anti IL-5 Anti-IL-5 Corticosteroids Advanced medical treatments in recurrent nasal polyposis

18. Upper Airways Research Laboratory Department of Otorhinolaryngology IL-5 and eosinophils in nasal polyposis  ECP   IL-5  IL-5        Migration Homing Survival Activation Maturation Differentiation Recruitement IL5 + Eotaxin

19. Upper Airways Research Laboratory Department of Otorhinolaryngology  ECP   IL-5  IL-5        Migration Homing Survival Activation Maturation Differentiation Recruitement IL5 + Eotaxin Anti-interleukin 5 in nasal polyposis Anti IL-5 x x x

20. Upper Airways Research Laboratory Department of Otorhinolaryngology Objective and study design To asses the therapeutic potential of two injections of 750 mg IV mepolizumab (28days) endoscopic score symptom scores CT scan Two-arm, randomized, double blind, placebo controlled, trial 30 Subjects Severe nasal polyps 20 Subjects 10 Subjects Weeks 0 1 4 128 * MEPO 750mg IV Placebo Dosing Follow up * Primary endpoint 24 3648

21. Upper Airways Research Laboratory Department of Otorhinolaryngology Endpoints Primary endpoint Endoscopic Nasal polyp score 8 weeks post 1 st dosing Secondary endpoints CT scan assessment (blinded) Difference 50% Symptom score Peak nasal inspiratory flow nasal (merocel) and systemic Inflammatory mediators 0 1 2 3 4Score 0 1 4 3 2

22. Upper Airways Research Laboratory Department of Otorhinolaryngology Endoscopic Nasal polyp score and improvement * *  intranasal steroids permitted 10/20 12/20 13/20

23. Upper Airways Research Laboratory Department of Otorhinolaryngology Need for surgery - Number of exclusions (= sytemic steroids or AB or surgery) p=0.03 **

24. Upper Airways Research Laboratory Department of Otorhinolaryngology CT scores improvement from baseline at week 8

25. Upper Airways Research Laboratory Department of Otorhinolaryngology 8 weeks post 1 st Mepo dose Baseline CT SCAN

26. Upper Airways Research Laboratory Department of Otorhinolaryngology Symptoms  intranasal steroids permitted

27. Upper Airways Research Laboratory Department of Otorhinolaryngology Peak nasal inspiratory flow (change from baseline)

28. Upper Airways Research Laboratory Department of Otorhinolaryngology Anti IgE in nasal polyposis 24 patients:16 got anti-IgE 8 got placebo 4 (evt 8) Injections over 3 months  IgE ? Local Anti-IgE Concentration? Anti IgE x  IgE x

29. Improvement in total nasal polyp score Omalizumab (n=15) versus placebo (n=8)

30. Improvement in symptoms Omalizumab (n=15) versus placebo (n=8)

31. UPSIT smell test

32. Upper Airways Research Laboratory Department of Otorhinolaryngology CT-scans before and after Anti-IgE

33. Upper Airways Research Laboratory Department of Otorhinolaryngology CT-scans before and after Anti-IgE

34. Upper Airways Research Laboratory Department of Otorhinolaryngology CT-scans before and after Anti-IgE -10 -5 0 5 15 20 25 30 better obsAbetter obsB mean percentage improvement placebo omalizumab

35. Upper Airways Research Laboratory Department of Otorhinolaryngology Allergic versus non allergic patients

36. Upper Airways Research Laboratory Department of Otorhinolaryngology Anti IgE Anti-IgE Antibiotics Vaccination IL-5 ECP Eotaxin IgE Anti IL-5 Anti-IL-5 Corticosteroids First DBPC finished in 24 NP patients In Ghent New multicenter trial started with 120 NP patients Future therapeutic options in nasal polyposis

37. Upper Airways Research Laboratory Department of Otorhinolaryngology Practical management of Nasal Polyposis Nasal douche with saline Nasal corticosteroids GCS sprays: 2x/d, symptoms↓, no resolution of NP GCS drops: symptoms↓, surgery↓↓ Oral corticoids: effective but fast recurrence Antibiotics: Antibiotic ointment Long-term antibiotics: macrolides 500mg/d ged 3m doxycycline 100 mg/d ged 1m Future: Omalizumab (antiIgE) allergic 85% vs non allergic NP 55% Mepolizumab (anti-IL5): 2 injections in 65% better

38. Upper Airways Research Laboratory Department of Otorhinolaryngology Upper Airways Research Laboratory 2009