Real-life Experience in      C.C.HThe Role of Anti-IgE Therapy InAsthma Management             M.D Alex Tsai
Journal of Asthma and Allergy 2011:4
N Engl J Med 2006;354:2689-95.
Omalizumab Characteristics                                                                   Murine CDRs*Humanized       ...
Airway Inflammation in       Asthma
Anti-IgE 不只是抗體…………… ..
omalizumabChang TW et al. JAllergy ClinImmunol2006;117:1203-
INNOVATE: INvestigatioN of Omalizumab          in seVere Asthma TrEatment• A 28-week randomized double-blind, placebo-cont...
INNOVATE: Omalizumab reduces                                             clinically significant exacerbations             ...
INNOVATE: Emergency visitsNumber                Omalizumab    Placebo    90                                             ∆ ...
Number needed to treat with omalizumab             in addition to GINA step 4 therapy       to prevent one event above pla...
INNOVATE: Asthma-related quality of life                                                                       Omalizumab ...
Omalizumab in inadequately controlled allergic                    asthma Study                     Asthma                 ...
Consistent reduction in asthma exacerbation          rates across all seven studies                             Annual exa...
Xolair general safety profile• Large safety database of over 7,500 patients  > 5,000 treated with Xolair  majority with ...
Omalizumab safety summary               All controlled studies    Most frequent adverse events (≥5% patients)             ...
Asthma education     Environmental controlAs needed rapid acting B2-agonist                              A 級證據            ...
Omalizumab 可降低重度氣喘患者口服類固醇之用量 : Real-life data         Molimard, M. et al. Respiratory Medicine (2010) 104, 1381e1385
Omalizumab 可降低重度氣喘患者口服類固醇之用量 : Real-life data        Molimard, M. et al. Respiratory Medicine (2010) 104, 1381e1385
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
EFFICACY AND SAFETY OF SUBCUTANEOUSOMALIZUMAB VERSUS PLACEBO ASADD ONTHERAPY TO CORTICOSTEROIDS FOR CHILDRENAND ADULTS WIT...
打多久才知道有沒有效 ?Persistency of response toomalizumabtherapy in severe allergic (IgE-mediated)asthma                           ...
Xolair Launched    in the US in July 2003 Marketing   approval in the EU in Oct. 2005 Marketing   approval in Taiwan in...
Omalizumab 可有效降低氣喘急性發作            之機會               CHEST 2011; 139(1):28–35
CHEST 2011; 139(1):28–35
Omalizumab and Difficult-to-Control            Asthma           打多久才知道有沒有效 ?                      16 週                    ...
Clin Respir J 2011 Jul 8                    28
Overview regarding data collection                 depending on the visit           ACQ   Medication   GETE   Comorbiditie...
Baselinecharacteristics of    the study   population                     30
Adverse drug reactionsPatients with at least 1 ADR                               14 (7.2% of study population)            ...
Global Evaluation of TreatmentEffectiveness (GETE) after the 16-week     約8     成有      效                                 ...
Xolair 可改善肺功能   + 11.3%               + 13.7% FEV1(L)      FEV1(%)提升 270mL     提升 10.1%                         33
Responder   + 10.4%                      + 15.6%Non-Responder   + 11.3%                      + 13.7%                      ...
Xolair 可減少惡化次數      -74.9%    p <0.0001                 35
Treatment responders showed a higher and         significant reduction of exacerbation rate                          -82.3...
Missed work/school days could   significantly be reduced            -92.1%          p <0.001                              ...
Responder   -93.1%               p <0.001Non-Responder   -78.9%               n.s.                          38
Xolair 可有效改善生活品質              -46.4% (p<0.0001)   -43.9%  p <0.0001                                  39
Responder            -55.4% (p=0.0002) -46.9%p <0.0001                                40
Non-Responder           -24.7% (n.s.) -36.1%p <0.005                           41
Xolair 可以有效減少控制藥物的          使用Numer ofpatients treated                                     -42.9%                         ...
Xolair 也可減少其他過敏疾病之            症狀減少過敏疾病症狀                   43
44
60-year-old woman                                                 Barrett esophagus  FEV     1 / FVC ratio of 57%.       ...
Thickened basement                              membraneDiffuse tissue eosinophilia C/W asthma                            ...
2005~2006 有 9                      次 AE 住院 、 其                      中 2 次插管使用                      呼吸器Xolair 300 mg every2...
4 months after treatment with           omalizumab Dramatic  improvement in symptoms Oral corticosteroids was gradually ...
重新使用 Xolair              三週後症狀改善停藥後 1 個月 AE            49FEV1 下降 25%
Take Home MessageXolairAccurate   selection and dosing of patients   Treatment response is evaluated after 16 weeks of t...
The role of anti-IgE therapy in asthma management
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The role of anti-IgE therapy in asthma management

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The role of anti-IgE therapy

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  • 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 &gt; 95% IgG1 kappa human framework and &lt; 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.
  • The role of anti-IgE therapy in asthma management

    1. 1. Real-life Experience in C.C.HThe Role of Anti-IgE Therapy InAsthma Management M.D Alex Tsai
    2. 2. Journal of Asthma and Allergy 2011:4
    3. 3. N Engl J Med 2006;354:2689-95.
    4. 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.
    5. 5. Airway Inflammation in Asthma
    6. 6. Anti-IgE 不只是抗體…………… ..
    7. 7. omalizumabChang TW et al. JAllergy ClinImmunol2006;117:1203-
    8. 8. INNOVATE: INvestigatioN of Omalizumab in seVere Asthma TrEatment• A 28-week randomized double-blind, placebo-controlledstudy to assess the efficacy and safety of add-onomalizumab therapy in patients with severe persistentasthma (GINA 2002)  inadequately controlled despite high doses of ICS (> 1000 μg/day BDP) and LABA Humbert et al., Allergy 2005
    9. 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. 10. INNOVATE: Emergency visitsNumber 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. 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. 12. INNOVATE: Asthma-related quality of life Omalizumab Placebo 0.95 1,0 0.91 0.9 0.89 0.91 * ** ** ** ** 0,8Δ 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. 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) 3293% of patients met GINA severe ALTO 2002 criteria for severe(88.4) 555 persistent asthma 241. Humbert et al., Allergy 2005 4. Busse et al., JACI 20012. Ayres et al., Allergy 2004 5. Soler et al., ERJ 20013. Vignola et al., Allergy 2004 6. Holgate et al., Clin Exp Allergy 2004
    14. 14. Consistent reduction in asthma exacerbation rates across all seven studies Annual exacerbation rate Percent treatment difference reduction p-valueINNOVATE study1 0.49 26.6% 0.039ETOPA study2 1.49 60.4% <0.001SOLAR study3 0.29 37.5% 0.027Busse study4 0.40 40.3% <0.001Solèr study5 0.70 57.6% <0.001Holgate study6 0.42 26.5% 0.165ALTO study 0.18 15.3% 0.077Pooled7 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. 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. 16. Omalizumab safety summary All controlled studies Most frequent adverse events (≥5% patients) Omalizumab (%) Control (%)Adverse event n=3,678 n=2,452Any adverse event 74.8 75.2Upper respiratory tract infection 15.7 15.7Headache 15.5 15.6Nasopharyngitis 14.4 15.9Sinusitis 10.1 Summary of Clinical Safety 12.0
    17. 17. Asthma education Environmental controlAs needed rapid acting B2-agonist A 級證據 力 17
    18. 18. Omalizumab 可降低重度氣喘患者口服類固醇之用量 : Real-life data Molimard, M. et al. Respiratory Medicine (2010) 104, 1381e1385
    19. 19. Omalizumab 可降低重度氣喘患者口服類固醇之用量 : Real-life data Molimard, M. et al. Respiratory Medicine (2010) 104, 1381e1385
    20. 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. 21. EFFICACY AND SAFETY OF SUBCUTANEOUSOMALIZUMAB VERSUS PLACEBO ASADD ONTHERAPY TO CORTICOSTEROIDS FOR CHILDRENAND ADULTS WITH ASTHMA: A SYSTEMATIC REVIEWGustavo Chest 2011;139;28-35
    22. 22. 打多久才知道有沒有效 ?Persistency of response toomalizumabtherapy in severe allergic (IgE-mediated)asthma Bousquet, J. et al. Allergy.2011 May;66(5):671-8
    23. 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
    24. 24. Omalizumab 可有效降低氣喘急性發作 之機會 CHEST 2011; 139(1):28–35
    25. 25. CHEST 2011; 139(1):28–35
    26. 26. Omalizumab and Difficult-to-Control Asthma 打多久才知道有沒有效 ? 16 週 27 Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90
    27. 27. Clin Respir J 2011 Jul 8 28
    28. 28. Overview regarding data collection depending on the visit ACQ Medication GETE Comorbidities FEV1 Exacerbation Days of absenceBaseline X X X X X X16Weeks X X X X X X6Months X X X 29
    29. 29. Baselinecharacteristics of the study population 30
    30. 30. Adverse drug reactionsPatients with at least 1 ADR 14 (7.2% of study population) n %Patients with serious ADR 0 0Total 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
    31. 31. Global Evaluation of TreatmentEffectiveness (GETE) after the 16-week 約8 成有 效 32
    32. 32. Xolair 可改善肺功能 + 11.3% + 13.7% FEV1(L) FEV1(%)提升 270mL 提升 10.1% 33
    33. 33. Responder + 10.4% + 15.6%Non-Responder + 11.3% + 13.7% 34
    34. 34. Xolair 可減少惡化次數 -74.9% p <0.0001 35
    35. 35. Treatment responders showed a higher and significant reduction of exacerbation rate -82.3%Responder p <0.0001Non- -21.8%Responder n.s. 36
    36. 36. Missed work/school days could significantly be reduced -92.1% p <0.001 37
    37. 37. Responder -93.1% p <0.001Non-Responder -78.9% n.s. 38
    38. 38. Xolair 可有效改善生活品質 -46.4% (p<0.0001) -43.9% p <0.0001 39
    39. 39. Responder -55.4% (p=0.0002) -46.9%p <0.0001 40
    40. 40. Non-Responder -24.7% (n.s.) -36.1%p <0.005 41
    41. 41. Xolair 可以有效減少控制藥物的 使用Numer ofpatients treated -42.9% -23.6% -18.3% 42
    42. 42. Xolair 也可減少其他過敏疾病之 症狀減少過敏疾病症狀 43
    43. 43. 44
    44. 44. 60-year-old woman Barrett esophagus  FEV 1 / FVC ratio of 57%. Esophagus resection Gastric interposition FEV 1 / FVC: 57% FEV 1 : 1.16 L (49% predicted) Total IgE: 491 IU/L Specific IgE: Neg Skin prick test:Neg 45CT : No interstitial lung disease or emphysema
    45. 45. Thickened basement membraneDiffuse tissue eosinophilia C/W asthma 46
    46. 46. 2005~2006 有 9 次 AE 住院 、 其 中 2 次插管使用 呼吸器Xolair 300 mg every2 weeks 47
    47. 47. 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
    48. 48. 重新使用 Xolair 三週後症狀改善停藥後 1 個月 AE 49FEV1 下降 25%
    49. 49. Take Home MessageXolair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

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