Prof. Dr. U. Wahn

1. Prof. Dr. U. Wahn Long term use of omalizumab – Is the IgE response modified? Ulrich Wahn Department of Pediatric Pneumology and Immunology

2. Monoclonal antibody target in asthma Cately M. et al, Pharmacology & Therapeutics 132 (2011): 333-351

3. Monoclonal antibody targets in asthma Catley M. et al, Pharmacology & Therapeutics 132:333-351, 2011

4. Binding of IgE to high-affinity (FcRI) receptor Allergen binding site VL VH Ce1 CL IgE Ce2 Ce4 Ce3 a2 a1 FcRI out Cell membrane in a b g g Holgate. QJM 1998

5. Anti-IgE Rationale for anti-IgE therapy IgM APC Clinicaleffects IgG B-cell IgE T-cell B-cell Mast cellBasophil Eosinophil? Macrophage?

6. Anti IgE antibodies • Omalizumab • MaG 12

7. Action of Anti-IgE • Binding to IgE • Reduce Mast Cell survival • Attenuate tissue MC function • Reduce sputum eosinophils • Prevent production of proinflammatory mediators • Down-regulation of Fcε RI on antigen presenting cells

8. Allergic airway disease Monospecific Allergy Multiple Allergies Trees Trees + Grasses + Ragweed Grasses • Anti-IgE? • Combination of anti-IgE and SIT Ragweed Active Vaccination (SIT)

9. Early sensitisation and allergen exposure to perennial allergens * and lung function at school age * Sensitisation / exposure to mites and/or cats up to the age of 3 years MAS-90

10. Anti-IgE: Controller or disease modifier? • Label for aIgE • Mechanism of action • Possible new indications • More than a blocker? • Potential for prevention?

11. IA05: inclusion criteria • Male or female, aged 6–<12 years on entry • body weight 20–150 kg • total serum IgE ≥30 to ≤1,300 IU/mL • Diagnosis of allergic asthma ≥1year (ATS criteria) • History of moderate or severe persistent asthma (NHLBI 1997 guidelines) • Positive skin-prick test or RAST to ≥1 perennial allergen within past 2 years or at screening • Demonstrable 12% increase in FEV1 within 30 minutes of short-acting β2-agonist (SABA) within the past year

12. Inadequately controlled population despite very high asthma medication use in study IA05 LABA = long-acting β2-agonist; SD = standard deviation

13. IA05: study design – overview Double-blind treatment period Run-in Follow-up Screening Steroid adjustment Steroid stable 68 –9 –8 40 52 24 0 Evaluate steroid dose sparing every 2 weeks Reduction every 8 weeks

14. Primary efficacy objective: clinically significant asthma exacerbation rate • Definition: • worsening of asthma symptoms as judged clinically by the investigator, requiring doubling of the baseline ICS dose for ≥3 days and/or treatment with rescue systemic (oral or IV) corticosteroids • Criteria: • PEF or FEV1 <60% of personal best • PEF or FEV1 60–80% of personal best following β2-agonist administration • fall in PEF of >20% on ≥2 of any 3 consecutive days compared to personal best • >50% increase in 24-hour rescue medication use on ≥2 of any 3 consecutive days compared to normal use (≥8 puffs of salbutamol) • ≥2 night time awakenings due to asthma symptoms requiring rescue medication within previous 7 days • any other specified clinically important reason

15. Exacerbations are reduced and efficacy is maintained over time 2nd 28 weeks 1st 24 weeks – primary analysis  –54.2% p<0.001  –31% p=0.007 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Clinically significant exacerbation rate† Clinically significant exacerbation rate* Omalizumab(n=384) Control(n=192) Control(n=192) Omalizumab(n=384) †28-week treatment period *24-week treatment period

16. Study IA05: consistent reduction in asthma exacerbation rates irrespective of LABA use in IA05 LABA usersn=381 LABA non-users n=195 0 1 2 Decreased risk of exacerbations Increased risk of exacerbations Relative risk of exacerbations

17. Consistent reduction in asthma exacerbation rates across pediatric and adult studies * adjusted for an imbalance in history of asthma exacerbations 1. Bousquet J, et al Allergy 2005

18. IA05: secondary and other endpoints • Secondary end points (at 24 weeks): • nocturnal symptoms • β2rescue medication use • quality of life • clinically significant asthma exacerbation rate (52 weeks) • Other end points included: • hospital admissions, ER visits and unscheduled doctor’s office visits • global patient and physician evaluations • lung function • school and caregiver absenteeism • analysis of primary for the subgroup ‘inadequately controlled, on high-dose ICS and a LABA’

19. Physician’s overall assessment shows consistently greater proportion of omalizumab patients achieving marked improvement Marked improvement or completecontrol†(% patients) Omalizumab Control 100 80 60 40 20 0 84.8 *** 79.1 *** 68.5 ** 66.2 *** 60.5 *** 60.2 *** 59.2 53.1 *** 55.7 44.2 42.8 42.0 34.7 33.3 IA05 Study 10 INNOVATE1 SOLAR2 Busse3 Solèr4 Holgate5 1. Humbert M, et al. Allergy 2005; 2. Vignola AM, et al. Allergy 20043. Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ 20015. Holgate ST, et al. Clin Exp Allergy 2004 **p<0.01; ***p<0.001†as assessed by physician’s global evaluation of treatment effectiveness

20. FEV1 (mL): most effect achieved after12–16 weeks in study IA05 Change from baseline, LSM Omalizumab Placebo * Weeks *p<0.05

21. Seasonal variation in days with symptoms and frequency of exabation Busse W. et al, N Engl J Med 364;11, 2011

22. Anti-IgE in polysensitized allergic childrenDemography and baseline characteristics * = median ** = spec. IgE values > 100 have been set to 125; <0.35 set to 0

23. P<0.001* 1 P=0.032* 0.89 P=0.001* 0.8 0.61 0.6 0.49 Symptom load (median) 0.4 0.26 0.2 0 n=54 n=59 n=55 n=53 SIT birch + Placebo SIT birch +Omalizumab SIT grass +Omalizumab SIT grass + Placebo * = Wilcoxon test (2-sided) SYMPTOM LOAD(grasspollen season)

24. RESCUE MEDICATION SCORE(entire pollen season) P<0.001* P=0.001*  78% 0,3  81% 0.27 0,2 Rescue medication score (median) 0.16 0,1 0.06 0.03 0 n=54 n=55 n=53 n=59 SITgrass + Placebo SITgrass +Omalizumab SIT birch +Omalizumab SIT birch +Placebo *=Wilcoxon test (2-sided)

25. In vitro release of leukotrienes during and after treatment with anti-IgE

26. Nasal tryptase secretion during anti-IgE treatment Bez C, Clin Exp Allergy 2004; 34 (7):1079-85

27. Reduction in serum free IgE following s.c. administration of omalizumab Median free IgE (ng/mL) 300 • 300mg administered once monthly for 48 weeks topatients with moderate-to-severe asthma 200 Day 1 post-dose 100 0 0 1 3 7 14 112 168 252 336 Days (not to scale) Day 0 = screening (n=93)

28. Ongoing studies including pediatric evaluations • ICATA: Inner-city anti-IgE therapy for asthma (Phase IV) • multi-center, randomized, double-blind, placebo-controlled, parallel group study: omalizumab vs placebo • children and adolescents (6–20 years) with moderate-to-severe allergic asthma (n=500) • ICATA will evaluate: unmet need, burden of illness, efficacy safety, mechanism of action • US26 (Phase IV) • descriptive non-interventional study • children with moderate-to-severe allergic asthma (n=500) • US26 will describe: unmet need, burden of illness

29. Histamin CD63 aktiviert Basophil Activation Histamin naiv CD203c CD203c+ CD63- CD203c+ CD63+

30. Long term use of Anti IgE • Reduction of basophil sensitivity persists for years Disease Modification?

31. Effects of anti-IgE therapy on food allergen specific T cell responses in eosinophil associated gastrointestinal disordersBarbara Foster, Shabnam Foroughi, Yuzhi Yin and Calman Prussin Clinical and Molecular Allergy 2011, 9:7 „… this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo.“

32. Anti-IgE strategies currently under investigation Rabe K.F., et al, Allergy 66:1142-1151, 2011

33. Conclusion • Anti IgE reduces symptoms and exacerbation in children and adults with IgE mediated disease induced by food or aeroallergens • Few studies suggest that anti IgE might have the potential to modify the course of asthma • Larger studies are needed to assess the disease modifying effects of anti IgE-treatment