4. Omalizumab Characteristics
Murine CDRs*
Humanized mAb against IgE (< 5% of molecule)
Binds circulating IgE
regardless of specificity
Forms small, biologically inert
IgG1 kappa
Omalizumab:IgE complexes Human
framework
Does not activate complement (> 95% of molecule)
*CDR = complementarity-determining region
Adapted with permission from Boushey H. J Allergy Clin Immunol. 2001;108:S77-S83.
8. INNOVATE: INvestigatioN of Omalizumab
in seVere Asthma TrEatment
• A 28-week randomized double-blind, placebo-controlled
study to assess the efficacy and safety of add-on
omalizumab therapy in patients with severe persistent
asthma (GINA 2002)
inadequately controlled despite high doses
of ICS (> 1000 μg/day BDP) and LABA
Humbert et al., Allergy 2005
9. INNOVATE: Omalizumab reduces
clinically significant exacerbations
Exacerbations Severe exacerbations
1.0 0.5
Exacerbations [/patient-28 wks.]
0.48
- 26% 0.91 - 50%
0.4
p<0.04* p<0.002
0.68 0.3
0.5
0.2 0.24
0.1
n=209 n=210 n=209 n=210
0 0
Omalizumab Placebo Omalizumab Placebo
*Adjustment due to a pre-study imbalance in
exacerbation rate; –19.2% (p=0.156) reduction unadjusted Humbert et al., Allergy 2004
10. INNOVATE: Emergency visits
Number
Omalizumab Placebo
90 ∆ –43.9% 0.43
80 p=0.038
70
60
50
0.24
40
30
20
10
0
Total
Unscheduled Emergency Hospita-
emergency
doctor visit room visit lization
visits
Humbert et al., Allergy 2004
11. Number needed to treat with omalizumab
in addition to GINA step 4 therapy
to prevent one event above placebo per year
INNOVATE
Efficacy outcome* (n=419)
Clinically significant exacerbations 2.7
Severe exacerbations 2.0
Total emergency visits 2.8
*Note: these are not all Humbert et al., EAACI Abstract Book 2006
separate events (abstract)
12. INNOVATE: Asthma-related quality of life
Omalizumab Placebo
0.95
1,0 0.91 0.9 0.89 0.91
*
** ** ** **
0,8
Δ Score since begin of study
0,6
0,4
0,2
0
Environ- Total
Activity Emotions Symptoms
mental score
exposure
*p=0.002; **p<0.001 Humbert et al., Allergy 2004
13. Omalizumab in inadequately controlled allergic
asthma
Study Asthma Severe
Duration
patients asthma n (%) (weeks)
INNOVATE 1 inadequately controlled 419 (100) 28
ETOPA 2 inadequately controlled 312 (94.2) 52
SOLAR 3 severe asthma + rhinitis 405 (89.9) 28
Studie 4 severe 525 (99.6) 52
Studie 5 severe 546 (98.4) 52
Studie 6 severe, high-dose ICS 341 (90.9) 32
93% of patients met GINA severe
ALTO 2002 criteria for severe(88.4)
555 persistent asthma
24
1. Humbert et al., Allergy 2005 4. Busse et al., JACI 2001
2. Ayres et al., Allergy 2004 5. Soler et al., ERJ 2001
3. Vignola et al., Allergy 2004 6. Holgate et al., Clin Exp Allergy 2004
14. Consistent reduction in asthma exacerbation
rates across all seven studies
Annual exacerbation rate Percent
treatment difference reduction p-value
INNOVATE study1 0.49 26.6% 0.039
ETOPA study2 1.49 60.4% <0.001
SOLAR study3 0.29 37.5% 0.027
Busse study4 0.40 40.3% <0.001
Solèr study5 0.70 57.6% <0.001
Holgate study6 0.42 26.5% 0.165
ALTO study 0.18 15.3% 0.077
Pooled7 0.56 38.3% <0.0001
1. Humbert M, et al. Allergy 2005; 2. Ayres JG, et al. Allergy 2004; 3. Vignola AM, et al. Allergy 2004
4. Busse W, et al. J Allergy Clin Immunol 2001; 5. Solèr M, et al. Eur Respir J 2001
6. Holgate ST, et al. Clin Exp Allergy 2004; 7. Bousquet J, et al. Allergy 2005
15. Xolair general safety profile
• Large safety database of over 7,500 patients
> 5,000 treated with Xolair
majority with allergic asthma
• Frequencies of AEs were similar between Xolair
and control groups, irrespective of asthma severity
• No pattern or cluster of AEs
• Majority of AEs were mild-to-moderate
and of short duration
16. Omalizumab safety summary
All controlled studies
Most frequent adverse events (≥5% patients)
Omalizumab (%) Control (%)
Adverse event n=3,678 n=2,452
Any adverse event 74.8
75.2
Upper respiratory tract infection 15.7
15.7
Headache 15.5
15.6
Nasopharyngitis 14.4
15.9
Sinusitis 10.1
Summary of Clinical Safety
12.0
17. Asthma education
Environmental control
As needed rapid acting B2-agonist
A 級證據
力
17
20. Omalizumab 降低重度氣喘病患住院
次數 : Real-life data
Molimard, M. et al. Respiratory Medicine (2010) 104, 1381e1385
21. EFFICACY AND SAFETY OF SUBCUTANEOUS
OMALIZUMAB VERSUS PLACEBO ASADD ON
THERAPY TO CORTICOSTEROIDS FOR CHILDREN
AND ADULTS WITH ASTHMA: A SYSTEMATIC REVIEW
Gustavo
Chest 2011;139;28-35
22. 打多久才知道有沒有效 ?Persistency of response to
omalizumabtherapy in severe allergic (IgE-mediated)
asthma
Bousquet, J. et al. Allergy.2011 May;66(5):671-8
23. Xolair
Launched in the US in July 2003
Marketing approval in the EU in Oct. 2005
Marketing approval in Taiwan in Apr. 2007
Got reimbursement in Taiwan in Jun. 2008
29. Overview regarding data collection
depending on the visit
ACQ Medication GETE Comorbidities FEV1 Exacerbation Days of
absence
Baseline X X X X X X
16Weeks X X X X X X
6Months X X X
29
31. Adverse drug reactions
Patients with at least 1 ADR 14 (7.2% of study population)
n %
Patients with serious ADR 0 0
Total number of ADRs (on single event basis) 21 100
Respiratory, thoracic and mediastinal disorders 2 9.5
Infections and infestations 3 14.3
General disorders and administration site conditions 6 28.6
Nervous system disorders 4 19.0
Eye disorders 1 4.8
Surgical and medical procedures 0 0
Gastrointestinal disorders 3 14.3
Musculoskeletal and connective tissue disorders 0 0
Immune system disorders 0 0
Cardiac disorders 0 0
Injury, poisoning and procedural complications 0 0
Investigations 0 0
Skin and subcutaneous tissue disorders 1 4.8
31
Vascular disorders 1 4.8
32. Global Evaluation of Treatment
Effectiveness (GETE) after the 16-week
約8
成有
效
32
48. 4 months after treatment with
omalizumab
Dramatic improvement in symptoms
Oral corticosteroids was gradually tapered and
discontinued completely
FEV 1 improved from 1.16 L (47% predicted) to
2.23 L (93% predicted)
FEV 1 /FVC ratio improved from 57% to 69%
Without a single asthma exacerbation during the
ensuing 2.5 years of treatment with omalizumab.
48
50. Take Home Message
Xolair
Accurate selection and dosing of patients
Treatment response is evaluated after 16 weeks of therapy
Treatment should only be continued in responders
Anaphylactic-like reactions are rare
50
Editor's Notes
Figure 1 Mechanism of action of omalizumab. Omalizumab binds to ige, thus forming immune complexes that reduce levels of circulating free ige and prevent their interactions with high-affinity IgE receptors (FcεRi) expressed by dendritic cells, mast cells, basophils, and eosinophils. As a consequence, ige-dependent antigen presentation, mast cell/basophil degranulation, and eosinophil infiltration are inhibited. Anti-ige therapy with omalizumab also results in decreased FcεRi expression. All these effects are responsible for a reduction of allergic airway inflammation, as well as of related asthma symptoms and exacerbations.
Figure 1. Pathophysiology of Asthma. Aeroallergens initially interact with the immune system when they are taken up by dendritic cells (Panel A). This process occurs by phagocytosis and may be enhanced after initial sensitization by the binding of allergen-specific IgE to high-affinity receptors (FcεRIs) on the surface of dendritic cells. Dendritic cells process the allergen and present it, bound to major-histocompatibility-complex (MHC) molecules, to T cells. T cells are stimulated by the interaction of MHC-bound antigen with surface T-cell receptors, causing T-cell proliferation and the subsequent release of cytokines. These cytokines stimulate B cells to become plasma cells that produce IgE. B cells express low-affinity Fcε receptors (FcεRIIs); interaction of IgE with these receptors may influence B-cell differentiation and regulation of IgE synthesis. IgE produced by plasma cells binds to the surface of mast cells and basophils and, when cross-linked by allergen, induces degranulation and the release of inflammatory mediators. This process results clinically in an acute asthma attack. Omalizumab is a monoclonal anti-IgE antibody that binds to the Fc region of the IgE molecule (Panel B). In so doing, omalizumab prevents IgE from binding to cell-surface receptors. Omalizumab is unable to bind to IgE molecules that are already bound to FcεRIs; as a result, it cannot induce anaphylaxis. Reduced binding of IgE to FcεRIs on mast cells and basophils inhibits degranulation and the release of inflammatory mediators. There is also marked down-regulation of FcεRIs . Reduced IgE binding to FcεRI on dendritic cells may reduce the ability of these cells to process antigen efficiently. Reduced IgE binding to FcεRII on B cells is thought to alter B-cell differentiation and the regulation of IgE synthesis. All these effects may contribute to the prevention of acute exacerbations of asthma.
Omalizumab works by forming complexes with circulating IgE which inhibits the binding of IgE to the high-affinity IgE receptor (Fc RI) on the surface of mast cells and basophils . Binding of Omalizumab to IgE forms small, biologically inert complexes. To avoid the clinical problems associated with murine antibodies, humanization of the murine anti-IgE was performed. Humanized anti-IgE was developed by grafting the variable sequence of a mouse antibody (binds to the Fc3 binding domain of IgE) onto the constant IgG1 kappa human framework. Omalizumab consists of > 95% IgG1 kappa human framework and < 5% mouse sequence, which is hidden from the immune system when Omalizumab binds to IgE. (Refer to full prescribing information for questions about the immunogenicity of Omalizumab.)
Figure 2. Pooled relative risk for the number of patients with at least one asthma exacerbation (with 95% CI) of eligible studies comparing omalizumab with placebo at the end of the stable-steroid phase. M-H 5 Mantel-Haenszel.
ACQ, Asthma Control Questionnaire; FEV1, Forced expiratory volume in 1 second; IgE, Immunoglobulin E
Figure 1 Global Evaluation of Treatment Effectiveness (GETE) by investigators recorded after the 16-week treatment period with OMA. Patients with excellent or good GETE were classified as responders to treatment, whereas patients with moderate and poor or worse GETE were classified as non-responders.
Figure 2 (A) Effect of OMA treatment on forced expiratory volume in 1s (FEV1) as absolute values in l and as % predicted during the 16-week treatment period; mean ± standard deviation, relative changes to baseline. (B) Effect of OMA treatment in patients who respond and (C) not respond to treatment (GETE = excellent or good) on forced expiratory volume in 1s (FEV1) as absolute values in l and as % predicted during the 16-week treatment period; mean ± standard deviation, relative changes to baseline.
Figure 3 (A) Effect of OMA treatment on the rate of asthma exacerbations during the 16-week treatment period; mean ± standard deviation, relative changes to baseline. (B) Effect of OMA treatment on the rate of asthma exacerbations in responders and (C) nonresponders to treatment (GETE = excellent or good) during the 16-week treatment period; mean ± standard deviation, relative changes to baseline.
Figure 3 (A) Effect of OMA treatment on the rate of asthma exacerbations during the 16-week treatment period; mean ± standard deviation, relative changes to baseline. (B) Effect of OMA treatment on the rate of asthma exacerbations in responders and (C) nonresponders to treatment (GETE = excellent or good) during the 16-week treatment period; mean ± standard deviation, relative changes to baseline.
Figure 4 (A) Effect of OMA treatment on days of school/work absence due to asthma during the 16-week treatment period; mean ± standard deviation, relative changes to baseline. (B) Effect of OMA treatment on the days of absence in responders and (C) non-responders to treatment (GETE = excellent or good) during the 16-week treatment period; mean ± standard deviation, relative changes to baseline.
Figure 4 (A) Effect of OMA treatment on days of school/work absence due to asthma during the 16-week treatment period; mean ± standard deviation, relative changes to baseline. (B) Effect of OMA treatment on the days of absence in responders and (C) non-responders to treatment (GETE = excellent or good) during the 16-week treatment period; mean ± standard deviation, relative changes to baseline.
Figure 5 Effect of OMA treatment on asthma symptoms, assessed by the modified Asthma Control Questionnaire (ACQ), during the 16-week and 6-month treatment period; mean ± standard deviation, relative changes to baseline. Graph (A) represents all patients; graph (B) represents responders; graph (C) represents non-responders.
Figure 5 Effect of OMA treatment on asthma symptoms, assessed by the modified Asthma Control Questionnaire (ACQ), during the 16-week and 6-month treatment period; mean ± standard deviation, relative changes to baseline. Graph (A) represents all patients; graph (B) represents responders; graph (C) represents non-responders.
Figure 5 Effect of OMA treatment on asthma symptoms, assessed by the modified Asthma Control Questionnaire (ACQ), during the 16-week and 6-month treatment period; mean ± standard deviation, relative changes to baseline. Graph (A) represents all patients; graph (B) represents responders; graph (C) represents non-responders.
Figure 6 OMA enables reduction of additional controller medication. The absolute number of patients receiving theophylline, leukotriene antagonists and oral corticosteroids at baseline and control visit is given and their relative changes under treatment.
Figure 7 Effect of OMA on symptoms of concomitant allergic disorders. The improvements, illustrated as relative reduction of symptoms between baseline and control visit is given.
Figure 1. Chest radiograph at time of first exacerbation.
Figure 2. A bronchial biopsy specimen showing a thickened basement membrane and diffuse tissue eosinophilia (arrows) compatible with asthma.
Figure 3. All FEV 1 measurements carried out between 2000 and 2009. The FEV 1 improved and remained stable after the start of omalizumab in December 2006. After withdrawal of omalizumab, FEV 1 deteriorated. Finally, FEV 1 improved again when omalizumab was restarted.
Figure 3. All FEV 1 measurements carried out between 2000 and 2009. The FEV 1 improved and remained stable after the start of omalizumab in December 2006. After withdrawal of omalizumab, FEV 1 deteriorated. Finally, FEV 1 improved again when omalizumab was restarted.
