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Anti-IgE in Asthma and Other Allergic Diseases Harold S. Nelson. MD Professor of Medicine National Jewish Health And University of Colorado School of Medicine.

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Presentation on theme: "Anti-IgE in Asthma and Other Allergic Diseases Harold S. Nelson. MD Professor of Medicine National Jewish Health And University of Colorado School of Medicine."— Presentation transcript:

1 Anti-IgE in Asthma and Other Allergic Diseases Harold S. Nelson. MD Professor of Medicine National Jewish Health And University of Colorado School of Medicine. Denver. Colorado, USA

2 Run-In Phase 4-6 Weeks Stable-Steroid Phase 16 Weeks Steroid-Reduction Phase 12 Weeks Double-Blind Extension Phase 24 Weeks Placebo or Omalizumab + Stable BDP Randomization Placebo or Omalizumab + BDP reduction Placebo or Omalizumab  BDP BDP Optimization Pivotal Trials: Study Design Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261. Efficacy 28 Weeks Total Safety 52 Weeks Total

3 Baseline Asthma Characteristics 008009 Baseline characteristic † OMAL n = 268 Placebo n = 257 OMAL n = 274 Placebo n = 272 Asthma, yr 21 (13) 23 (15)20 (14)19 (13) IgE, IU/mL 172 (141) 186 (142)223 (169)206 (161) BDP daily dose, µg 570 (149) 568 (148)646 (199)649 (222) Rescue  2, puffs/day 5 (3) 4 (3)5 (3) Total asthma symptom score, 0 to 9 4 (1) FEV 1, % of predicted 68 (15) 68 (14)70 (15) Hospitalized for asthma past yr, % 2 4 4 7 ER visit for asthma past yr, % 10141210 †Mean (SD) unless otherwise indicated.

4 Reduction in Asthma Exacerbations †van Elteren test; protocol-defined analysis with imputation. Stable steroid phase 16 wk Steroid-reduction phase 12 wk P =.006 † P <.001 † P =.003 † P <.001 † OmalizumabPlacebo

5 Time to First Asthma Exacerbation OMA L Placebo 0 0.25 0.50 0.75 1.0 Proportion of patients exacerbation free Time since randomization 008 0 0.25 0.50 0.75 1.0 009 0481216202428323640444852 P =.0001 † HR = 0.51 0481216202428323640444852 P =.0067 † HR = 0.63

6 Reduction in Inhaled Steroid Use Studies 008 and 009 (Combined) BDP = Beclomethasone dipropionate. †van Elteren test. P <.001 †

7 Reduction in Albuterol Use *P .05, van Elteren test. 008 009 * * * * * NS Puffs per day, n Time, wk * * * * * * * * * NS Xolair ™ Placebo

8 Reduction of Symptoms 008 009 * * * * * * NS OmalizumabPlacebo * * * * * * * * * * * * * * * * * * * * * Asthma symptom scoresNocturnal symptom scores * * * * * * * * * * * * 009 008 *P .05, van Elteren test.

9 Improvement in Pulmonary Function Time since randomization, wk * * * * * * * * * * 008 009 Mean FEV 1 % predicted *P ≤.05, ANCOVA. * * * * * * * * * Time since randomization, wk NS OmalizumabPlacebo

10 Omalizumab: Mechanisms of Action S Holgate, et al. Allergy 2009;64:1728-36 1. Omalizumab binds to the IgE molecule preventing its interaction with IgE receptors on inflammatory cells. 2. The fall in free-IgE leads to down regulation of FcεRI on basophils, mast cells and plasmacytoid dendritic cells. 3. The release of pro-inflammatory cytokines from basophils and mast cells is decreased. 4. The effect on pDCs may reduce allergen presentation to T-cells. 4. There is a decrease in levels of blood, tissue and sputum eosinophils.

11 Omalizumab in Patients with Severe Persistent Asthma J Bousquet, et al. Allergy 2005;60:302-8  Data was pooled from 7 studies, with 4,308 subjects, 93% with severe persistent asthma.  Mean baseline values: ICS 1462 mcg BDP, LABA use by 57%, FEV 1 70% predicted  Exacerbations (90% treated with OCS) - 38% Omalizumab 0.91/year Placebo 1.47/year p<.00001  Emergency Department Visits - 61% 0.026/y vs. 0.066/y p = 0.013  Hospitalizations- 50% 0.03/y vs. 0.06/yp = 0.04

12 There Are No Predictors of a Good Response to Omalizumab J Bousquet et al. Allergy 2005;60:302-8

13 Omalizumab in Children B Lanier, ex al. J Allergy Clin Immunol 2009;124:1210-6 627 children ages 6 to 11 years with asthma not fully controlled on ≥ 200 mcg FP/d plus history of ≥ 2 exacerbations or ≥ 1 hospitalization in last year. Randomized 2:1 omalizumab: placebo for 52 weeks, steroid stable first 24 weeks. Exacerbation defined as doubling dose ICS or oral CS ≥ 3 days.

14 Omalizumab in Children: Exacerbation Rate B Lanier, ex al. J Allergy Clin Immunol 2009;124:1210-6 : 24 WEEKS52 WEEKS Omalizumab0.450.78 Placebo0.641.36 % reduction / p value-31%/0.007 -43%/0.001

15 Omalizumab Safety: Anaphylaxis A joint task force of the AAAAI and ACAAI reviewed all post-marketing reports to the FDA from 1 June 2003 to December 31 2005. 35 patients experienced 41 episodes of anaphylaxis This represented 0.09% of patients receiving omalizumab.

16 Omalizumab Safety: Anaphylaxis Timing1-3 rd Dose≥ 4 th DoseTotal < 30 min11516 30-60 min617 1-2 hours505 2-12 hours415 > 12 hours303 Unknown325 Total32941 L. Cox, ex al. J Allergy Clin Immunol 2007120:1373- 7

17 Omalizumab Safety: Recommendations for Administration L. Cox, ex al. J Allergy Clin Immunol 2007120:1373-7 Patient should sign informed consent. Patient should be instructed in administration of auto-injected epinephrine and carry for 24 hours after each dose of omalizumab Patients should remain under observation for 2 hours after the first 3 administrations, then 30 minutes after each subsequent administration.

18 Omalizumab: Unapproved and Unproven Uses Seasonal & perennial allergic rhinitis Chronic urticaria: - Autoimmune (JACI 2008;122:569-73) - Non-autoimmune (JACI 2010;126:664-5) - Delayed pressure, dermagraphism, cholinergic Food allergy (Allergy Asthma Proc 2010;31:76-83) Chronic sinusitis (JACI 2008;121:257-8) Atopic dermatitis (Allergy Asthma Proc 2008;29:530-7) Allergic bronchopulmonary Aspergillosis (Ped Pulmonol 2009;44:516)

19 Omalizumab: Unapproved and Unproven Uses Idiopathic anaphylaxis Ann Allergy Asthma Immunol 2009;102:257-8) Fire ant anaphylaxis (immunotherapy failure) (JACI 2010;126:664-5) Occupational latex sensitivity (JACI 2004;113:360-1) Systemic mastocytosis (JACI 2010;126:415-6) Systemic mastocytosis plus anaphylaxis to bee sting (Allergy 2009;64:1384-5) Adjunct to hymenoptera immunotherapy (Allergy 2007;62:963-4). Insulin allergy (N Engl J Med 2009;360:1045-7)

20 Omalizumab as an Adjunct in Allergen Immunotherapy

21 Omalizumab Pretreatment Decreases Acute Reactions after Rush Immunotherapy for ragweed-induced Seasonal Allergic Rhinitis  123 adults with ragweed allergic rhinitis  Pretreated with 9 weeks of omalizumab or placebo  1 day rush immunotherapy to top dose of 1.2 mcg Amb a 1  Followed by 12 weeks of combined omalizumab or placeb and weekly immunotherapy with increase in dose to 12 mcg Amb a 1. TB Casale, et al J Allergy Clin Immunol 2006;117:134-40

22 Reduction of IgE by Pre-Treatment with Omalizumab: Results  Anaphylaxis risk vs. placebo during RIT: IT alone OR 12.1 Om plus IT OR 2.1  Anaphylaxis risk vs. placebo during weekly buildup: IT alone 9.7% Om plus IT0% TB Casale, et al. J. Allergy Clin Imm 20061117:134-40

23 Effect of Pretreatment with Omalizumab on the Tolerability of Specific Immunotherapy in Patients with Persistent Symptomatic Asthma Inadequately Controlled with Inhaled Corticosteroids Massanari M, Nelson H, Casale T, Busse W, Kianifard F, Geba G, Zeldin R

24 Omalizumab as an Adjunct to Immunotherapy: Study Design  Subjects with at least moderate persistent allergic asthma. - Symptomatic on inhaled corticosteroids - FEV1 ≥ 75% predicted - Positive prick skin test to cat, dog or house dust mite standardized extract.  Excluded for severe asthma, oral corticosteroid-requiring exacerbation within 3 months, ED visit or hospitalization within 6 months.

25 OmalizumabCluster IT Placebo Maintenance IT Cluster IT Screening Period 1 Period 2 Period 3 Period 4 3 wk overlap Xolair and Immunotherapy: Study Design 275 Patients, Randomized 1:1 Visit 0 Visit 1 Visit 5 Visit 11 Visit 14 Visit 19 - 2wks 0 13wks 16 wks 17 wks 24 wks

26 Change in Average Total Asthma Symptom Score Before Initiating Immunotherapy N=124N=119 Omalizumab Placebo Baseline Mean Score (Day -14 to Day -1) 1.151.17 Change From Baseline to Visit 5 in Total Average Asthma Symptom Score (Average total symptom score Day 91 to Day 97)

27 Proportion of Patients Who Experienced a Systemic Allergic Reaction N=126 N=122 P= 0.017 N = 32 N = 17

28 SARs in Patients According to Average Total Asthma Symptom Scores* Pre Immunotherapy > *Average total symptom score Day 91 to Day 97

29 Severity of First Systemic Allergic Reaction N=17 N=32

30 Proportion of Patients Who Experienced a Systemic Allergic Reaction According to Allergen Sensitivity N=209N=188 N=168 N=29N=11N=14N=25N=15N=16 15  g Fel d 1, 15  g Can d 1, 7  g Der p 1

31 Percent of Patients who Achieved Target Maintenance IT Dose p=0.004

32 Conclusions  Pretreatment with omalizumab significantly reduced systemic allergic reactions from IT  Pretreatment with omalizumab resulted in a clinically meaningful shift in severity of systemic allergic reactions from IT  A significantly higher proportion of omalizumab patients were able to reach target maintenance dose of IT  Omalizumab was well tolerated

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