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. Cell membrane CLCLCLCL C1C1C1C1 C2C2C2C2 2222 11  IgE Allergen binding site Holgate. QJM 1998 C3C3 C4C4C4C4 VHVHVHVH VLVLVLVL Fc  RI out in Binding of IgE to high-affinity (Fc  RI) receptor

5. Rationale for anti-IgE therapy B-cell T-cell IgM IgG Clinical effects IgE APC Anti-IgE Mast cell Basophil 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 Fc ε RI on antigen presenting cells

8. Allergic airway disease Monospecific AllergyMultiple Allergies Trees + Grasses + Ragweed Anti-IgE? Combination of anti-IgE and SIT Trees Grasses 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 FEV 1 within 30 minutes of short-acting β 2 -agonist (SABA) within the past year

12. Inadequately controlled population despite very high asthma medication use in study IA05 Overall IA05 Mod ITT (n=576 ) High-dose ICS + LABA Mod ITT (n=235) Age (years), mean (SD) 8.6 (1.7)9.0 (1.7) Sex % female 32.334.5 Duration of asthma, mean (SD) 5.7 (2.6)6.1(2.8) IgE (IU/mL), mean (SD) 469.7 (338.0)440.0 (321.0) FEV 1 [% predicted], mean (SD) 86.4 (18.0)82.1 (18.1) FEV 1 [% reversibility], mean (SD) 25.1 (16.5)28.0 (18.5) ICS daily dose, mean (SD) (fluticasone equivalent) 515.1 (285.4)744.0 (262.7) LABA use, % 67.4100 Daily OCS use, % 1.32.6 Anti-leukotriene, % 36.657.4 LABA = long-acting β 2 -agonist; SD = standard deviation

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

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 FEV 1 <60% of personal best –PEF or FEV 1 60–80% of personal best following β 2 -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. Omalizumab (n=384) Control (n=192) Clinically significant exacerbation rate † 1.0 0.8 0.6 0.4 0.2 0 2 nd 28 weeks  –54.2% p<0.001 Exacerbations are reduced and efficacy is maintained over time 1 st 24 weeks – primary analysis Omalizumab (n=384) Control (n=192) Clinically significant exacerbation rate* 1.0 0.8 0.6 0.4 0.2 0  –31% p=0.007 *24-week treatment period † 28-week treatment period

16. Study IA05: consistent reduction in asthma exacerbation rates irrespective of LABA use in IA05 LABA users n=381 012 Decreased risk of exacerbations Relative risk of exacerbations LABA non-users n=195 Increased risk of exacerbations

17. Consistent reduction in asthma exacerbation rates across pediatric and adult studies Percent reductionp value IA0531%0.007 IA05: patients on high ICS + LABA34%0.047 Study 10 46%<0.001 Adult studies INNOVATE study26%*0.156 ETOPA study 60% <0.001 SOLAR study38%0.027 Busse study40%<0.001 Solèr study58%<0.001 Holgate study27%0.165 ALTO study15%0.077 Pooled adult studies 1 38%<0.001 1. Bousquet J, et al Allergy 2005 * adjusted for an imbalance in history of asthma exacerbations

18. IA05: secondary and other endpoints Secondary end points (at 24 weeks): –nocturnal symptoms –β 2 rescue 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. **p<0.01; ***p<0.001 † as assessed by physician’s global evaluation of treatment effectiveness Physician’s overall assessment shows consistently greater proportion of omalizumab patients achieving marked improvement Marked improvement or complete control † (% patients) Omalizumab Control IA05 Study 10 INNOVATE 1 SOLAR 2 Busse 3 Solèr 4 Holgate 5 100 80 60 40 20 0 60.5 *** 42.8 60.2 *** 42.0 53.1 *** 33.3 66.2 *** 34.7 68.5 ** 44.2 1. Humbert M, et al. Allergy 2005; 2. Vignola AM, et al. Allergy 2004 3. Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ 2001 5. Holgate ST, et al. Clin Exp Allergy 2004 55.7 79.1 *** 84.8 *** 59.2

20. FEV 1 (mL): most effect achieved after 12–16 weeks in study IA05 Change from baseline, LSM * *p<0.05 Omalizumab Placebo Weeks

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

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

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

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

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. 300mg administered once monthly for 48 weeks to patients with moderate-to-severe asthma Day 0 = screening (n=93) Days (not to scale) Reduction in serum free IgE following s.c. administration of omalizumab Day 1 post-dose 0 300 200 100 013714112168252336 Median free IgE (ng/mL)

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

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 disorders Effects of anti-IgE therapy on food allergen specific T cell responses in eosinophil associated gastrointestinal disorders Barbara 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