Omalizumab in Practice Use


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  • 5% of the humanized monoclonalanti-IgE antibody includes residues of murine origin
  • 16 wk steroid stable phase + OM vs placebo 12 wk of steroid reduction phase reduced by 25% of baseline every 2 wk 24 wk pt were maintained on RCT and lowest dose of ICS ช่วง reduction phase maintain ต่อ
  • Patient : Male and female patients aged 12 to 75 years who hadmoderate to severe, persistent, allergic asthma (asthma duration1 year) inadequately controlled with ICSs were recruited.
  • LSM, least squares mean
  • Study designThis was a randomized, open-label, parallel-group study conductedat 49 centres in five European countries (France, n =10; Germany,N = 9; Spain, n = 7; Switzerland, n =3; UK, n = 20).steps 3 and 4, i.e. daily treatment with moderate-to-high doses of inhaled corticosteroids with or without along-acting bronchodilator. Those patients in the most severe category(step 4) received daily systemic corticosteroids
  • ADRIs were Annualized number os asthma deterioration related incidence recorded in patient daily diary cards, and were defined as ‡1 of thefollowing events because of asthma: course of systemic corticosteroidsor antibiotics for > 2 days, > 2 missed school/work days (or significantlyreduced performance for nonworking adult patients, asjudged by the patient), unscheduled physician visit, or hospitalization/emergency room visit
  • Safety and tolerabilityThe percentage of omalizumab-treated patients experiencing‡1 adverse event was comparable with BSC alone[85.0% (175 of 206) and 77.4% (82 of 106), respectively;P ผ 0.116, Table 4]. The profile of adverse events(which were typically of mild-or-moderate intensity) wascomparable for the two treatment groups althoughheadache, cough and nausea were more frequent amongomalizumab recipients
  • Dose of ICS and LABA and concomittant medication were kept constant in the last 4 wk of runin period and maintain during treatment period
  • Treatmentwas discontinued in 549 patients, who were approximatelyequally divided between omalizumab (12%) andcontrol (14%) groups. Most discontinuations were due toreasons other than adverse events or inadequate efficacy
  • However, there is some suggestion of a trend of greaterrelative improvement in patients with worse lung functionas shown by baseline percentage predicted FEV1
  • Allpatients were receiving a mean ICS dose (fluticasone propionateequivalent) of 515.1 mg/d—more than double the maximumapproved dose in children
  • rate of clinically significant asthmaexacerbations (defined as worsening of asthma symptoms requiring doublingof baseline ICS dose and/or treatment with rescue systemic corticosteroids for3 days) over a period of 24 weeks (end of the fixed-steroid treatment phase).
  • Because baseline PAQLQ score in the current study was relativelyhigh, perhaps there was little room for improvement, despitehigh unmet need in terms of exacerbations and symptoms
  • A physician’sdiagnosis of asthma or documentation of symptomsof asthma for more than 1 year before studyentry was required. Patients receiving long-termtherapy for disease control were also required tohave symptoms of persistent asthma or evidenceof uncontrolled disease as indicated by hospitalizationor unscheduled urgent care in the 6 to12 months preceding study entry
  • Asthmacontrol was assessed and assigned a level in accordancewith the levels defined in report 3 ofthe NAEPP guidelines, with level 1 defined asasthma that was well controlled, levels 2 and 3 asasthma that was not well controlled, and level 4as asthma that was poorly controlledWash in period : not to be analysed to make sure for omalizumab effect
  • NAEPP guidelines, withsteps 1 and 2 applying to mild asthma, step 3 tomoderate asthma, and steps 4 through 6 to severeasthma
  • Objective To assess the efficacy and safety of omalizumab for prophylaxis of symptomsin patients with seasonal allergic rhinitis.
  • Also reduced in serum total IgE level and significant lower day miss from work or school compared with placebo
  • (≥ 400 mcg budesonideTurbuhaler) and ≥ 2 unscheduled visits for asthma during the past year or ≥ 3 during the past 2 years were enrolled
  • The score was calculated as theaverage of individual scores for nasal congestion; sneezing; itchynose, throat and palate; itchy, watery eyes; and rhinorrhea during theragweed season.
  • Pairwise comparisons of adverseevents in each group illustrate that immunotherapy alonewas associated with a greater than 5-fold significantincrease in risk of adverse events compared with placebo(OR, 5.41; P5.001)
  • Patients (n5275) age 18 to 55 years
  • Statไม่significant แต่ ตัวเลขมันต่าง
  • UAS : urticarial activity score
  • In approximately half of the patients with CIU, no cause for thecondition has been identified2,5however, approximately 30% to50% of patients with CIU reportedly produce IgGautoantibodiesagainst either IgE or its high-affinity receptor (FceRI).5 Crosslinkingautoantibodies directed against the a-subunit of FceRIlead to histamine release through degranulation of cutaneousmast cells and blood basophil
  • Total IgE 30- 700
  • Analyses of pooleddata from published clinical trials have indicatedthat
  • Total serum IgE levels will generally increaseduring treatment, because of the presence of circulatingIgE–anti-IgE complexes
  • Omalizumab in Practice Use

    1. 1. Omalizumab in practical use Sadudee Boonmee, MD
    2. 2. Topic outline• Introduction of anti IgE• Clinical application for - Asthma - Allergic rhinitis - Immunotherapy - Chronic urticaria• Dosage• Safety
    3. 3. • Omalizumab is a humanized monoclonal anti- IgE antibody (IgG1), molecular weight 150 kD• binds to Fc portion of IgE molecule at Cε3 same site where IgE binds to FcεRI
    4. 4. Mechanism o action• primary mechanism of action of omalizumab is the binding of free IgE in the circulation• secondary mechanism of action  down regulation of FcεRI expression (on Mast cell, Basophil, DC, monocyte) and Low affinity FcεRII (CD23) (B cell ) Journal of Asthma and Allergy 2011:4
    5. 5. • Form trimer of two omalizumab molecule per IgE antibody or form other complexbiologically inert complex do not activate complementand are cleared by the reticular endothelial systemHalf life = 26 day Anti-IgE therapyImmunol Allergy Clin N Am ( ) –
    6. 6. • omalizumab does not bind to receptor-bound IgE  does not trigger degranulation by cross- linking IgE located on FceRI receptors of mast cells or basophils
    7. 7. Omalizumab and asthma
    8. 8. Expert Panel Report 3: Guidelines for the Diagnosis and and management of asthmaOmalizumab may be considered at this step for patients who have sensitivity torelevant perennial allergens (e.g., dust mites, cockroach, cat, or dog) (Evidence B)
    9. 9. GINA Guideline 2011
    10. 10. Effectiveness of omalizumab in reducingcorticosteroid burden in patients with moderateto severe persistent allergic asthma • pooled analysis (N 1,071) of 2 similarly designed, randomized, double-blind, placebo- controlled omalizumab trials and their extension phases • Pt. aged 12 to 75 years with moderate to severe, persistent, allergic asthma and inadequately controlled with ICSs
    11. 11. J ALLERGY CLIN IMMUNOL AUGUST 2001 Eur Respir J 2001; 18: 254–261
    12. 12. Ann Allergy Asthma Immunol. 2003;91:154–159. Eur Respir J 2002; 20: 73–78
    13. 13. • Inclusion criteria 1. positive skin prick test result in response to at least 1 perennial allergen (including Dermatophagoides farinae, Dermatophagoides pteronyssinus, cockroach, dog, or cat) 2. total serum IgE level of 30 IU/mL through 700 IU/mL 3. body weight of 150 kg or less 4. 12% or greater increase in forced expiratory volume in 1 second (FEV1) over baseline value within 30 minutes of taking 1 to 2 puffs of albuterol (90 g per puff) 5. baseline FEV1 of 40% through 80% of the predicted normal value for the patient 6. mean daily total symptom score of 3.0 or higher (range, 0- 9) during the 14 days before randomization 7. ICS doses equivalent to beclomethasone dipropionate of 420 through 840 g/d (study 1 ) and 500 through 1,200 g/d
    14. 14. Outcome Measures• Corticosteroid burden Median change in ICS from baseline to the end of steroid – reduction phase and steroid extension phase P < 0.001 for each phase Phase Dose of BDP Dose of BDP equivalent in equivalent in Omalizumab group Placebo group Steroid stable 669.7 680 Steroid reduction 210.5 338 Extension 263 394
    15. 15. Outcome• Number of OCS bursts significantly lower for the omalizumab group
    16. 16. Outcome• Clinical outcome (28 wk core study and 24 wk extension phase)
    17. 17. Adverse events
    18. 18. • Summary• Pt. persistent asthma symptoms at baseline who received adjunctive omalizumab - able to reduce systemic corticosteroid burden - Maintaining or improving asthma control and lung function - improved clinical outcomes (reduced asthma impairment and a decreased risk of exacerbations) - Omalizumab  effective option for treating moderate to severe persistent allergic asthma, which can minimize the burden of systemic corticosteroids
    19. 19. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorlycontrolled (moderate-to-severe) allergic asthma: ETOPA• randomized, open-label, multicentre, parallel-group Study• 312 pt ( 12 – 75 yr) with poorly control (moderate to severe ) allergic asthma , treat step 3 and 4 of the NHLBI receiving ≥ 400 mcg/day (adolescent) or ≥ 800 mcg/day (adult) inhaled BDP or equivalent were included• patients were randomized (2 : 1) to receive BSC (best starndard care ) with or without subcutaneous omalizumab for 12 months Allergy 2004: 59: 701–708
    20. 20. • dose of omalizumab at least 0.016 mg/kg for every IU/ml of total IgE every 4 weeks according to patient body weight and serum total IgE at screening Allergy 2004: 59: 701–708
    21. 21. • primary efficacy variable : annualized number of asthma deterioration-related incidents (ADRIs) - those treated with omalizumab experienced 4.84 fewer ADRIs per patient-year compared with BSC alone, a reduction of 49.6% [95%CI : 27.8–64.8%] - omalizumab-treated patients remained ADRI-free during the study compared with BSC alone [36.1% vs 20.2% - prolongation of the time to first ADRI with omalizumab vs. BSC (median time to first ADRI of 126 vs 75 days ) Allergy 2004: 59: 701–708
    22. 22. • Secondary efficacy variables annualized mean number of exacerbations - lower with omalizumab than BSC (1.12 and 2.86 per patient- year ; P < 0.001) = a reduction of 60.8% (95% CI: 46.9–71.0%) - omalizumab remained exacerbation-free during the study compared with BSC alone ( 49.5% and 26.4%; P = 0.001)• median rescue bronchodilator use 0.60 puffs / day for omalizumab vs 3 puffs per/day for BSC (P < 0.001)• Patients treated with omalizumab showed a significant improvement in morning FEV1 , difference in absolute FEV1 of 0.2 L (2.48 and 2.28 L ; P = 0.02 ) Allergy 2004: 59: 701–708
    23. 23. • In conclusion : therapy with omalizumab, combined with BSC, is well tolerated and offers the potential to improve disease control and symptoms in patients with poorly controlled (moderate-to-severe) allergic asthma Allergy 2004: 59: 701–708
    24. 24. Benefits of omalizumab as add-on therapy in patientswith severe persistent asthma who are inadequatelycontrolled despite best available therapy(GINA 2002 step 4 treatment): INNOVATE • 28 weeks in a double-blind, parallel-group, multicentre study • 419 pt (12–75 yr ) inadequately controlled with high-dose ICS and LABA with reduced lung function were randomized to receive either omalizumab ( 209 pt) vs placebo ( 210 pt ) • Omalizumab dose of at least 0.016 mg/kg per IU/ml of IgE subcutaneously (based on the patient’s bodyweight and total serum IgE level ) was administered every 2 or 4 weeks Allergy 2005: 60: 309–316
    25. 25. - In omalizumab treated group ,clinically significant asthmaexacerbation (adjustment for baseline exacerbation rate )was reduced by 26% as compared with placebo (0.68 vs 0.91,P = 0.042)- Severe exacerbation rate (PEF or FEV1 <60% of personalbest, requiring treatment with systemic corticosteroids) washalved in the omalizumab group (0.24 vs 0.48, P = 0.002 ) Allergy 2005: 60: 309–316
    26. 26. • Total emergency visits in the treated-group were reduced by 44% ( 0.24 vs 0.43, P = 0.038 )• Clinically meaningful improvement asthma quality of life questionnaire (AQLQ) ( > 0.5-point from baseline) was observed in the treated-group as compared to placebo (60.8% vs 47.8%, p =0.008)• Mean morning PEF sinificant greater for omalizumab than placebo ( P= 0.042)• FEV1 (% predicted) difference = 2.8% ( P=0.0043 ) Allergy 2005: 60: 309–316
    27. 27. Safety and tolerability : similar in Omalizumab andPlacebo Allergy 2005: 60: 309–316
    28. 28. • conclusion, omalizumab significantly - decreased asthma exacerbation rates in these difficult-to- treat pt with severe persistent asthma who were inadequately controlled despite high-dose ICS and concomitant LABA therapy as recommended according to GINA step 4. - Omalizumab also significantly reduced the severe asthma exacerbation rate and the need for emergency medical interventions - Patients QoL was improved, Allergy 2005: 60: 309–316
    29. 29. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergencymedical visits in patients with severe persistent asthma• pooled data from 7 studies ,omalizumab was added to current asthma therapy and compared with placebo (in five double-blind studies) or with current asthma therapy alone (in two open-label studies)• included 4308 patients (2511 treated with omalizumab and 1797 were control ), 93% severe persistent asthma Allergy 2005: 60: 302–308
    30. 30. Study 1 : INNOVATEStudy 2 : ETOPAStudy 3 : SOLARStudy 4,5 : 2Study 6 :Study 7 : ALTO unpublished Allergy 2005: 60: 302–308
    31. 31. • Asthma exacerbations ← ← ← ← ← Reduced asthma ← exacerbation 38% in omalizumab group Allergy 2005: 60: 302–308
    32. 32. • Emergency visits Reduced ER visit 47 % in omalizumab group Allergy 2005: 60: 302–308
    33. 33. Improvement with omalizumab was seenregardless of age, sex, baseline FEV1, baselineserum IgE, dosind schedule Allergy 2005: 60: 302–308
    34. 34. • Conclusion : Omalizumab should be considered as add-on treatment for patients with severe persistent asthma who continue to suffer with inadequately controlled asthma despite best available therapy. Allergy 2005: 60: 302–308
    35. 35. Omalizumab for the treatment of exacerbationsin children with inadequately controlled allergic(IgE-mediated) asthma • International, multicenter randomized, double-blind, placebo-controlled trial• Children age 6 to <12 years with moderate to severe allergic asthma• BW 20 -150 kg , SPT + at least 1 perrennial allergen, serum total Ig E 30 -1300 IU/ml Bob Lanier (J Allergy Clin Immunol -
    36. 36. • 1 week of screening phase• 8 week of run-in phase ( adjust ICS dose to optimized asthma control for first 4 wk )• Pt. were randomized to receive omalizumab or placebo• In study group Omalizumab 75 -300 mg 1-2 time q month ( every 2-4 wk )• Double-blind treatment period - 24-week fixed-steroid phase (constant ICS dose unless adjustment was required for an exacerbation) - 28-week adjustable-steroid phase Bob Lanier (J Allergy Clin Immunol -
    37. 37. Bob Lanier (J Allergy Clin Immunol -
    38. 38. Primary efficacy end point : rate of clinically significant asthma exacerbation over 24 wk period Secondary efficacy end point : rate of clinically significant asthma exacerbation over 52 wk periodBob Lanier (J Allergy Clin Immunol -
    39. 39. • Rate of clinically severe exacerbations reduced 44% over a period of 24 weeks (0.10 vs 0.18; RR [95% CI], 0.55 [0.32- 0.95]; P=0.031)• Sustained over a period of 52 weeks (rate, 0.12 vs 0.24)  50% reduction (RR [95% CI], 0.49 [0.30-0.80]; P 0.004)• Investigator and patient global evaluation of treatment effectiveness (GETE) at 52 weeks favored omalizumab with rate of excellent or good by 79 % and 80% ( physicial and patient respectively ) by 56% and 72% respectively in placebo group ( both P < 0.001 ) Bob Lanier (J Allergy Clin Immunol -
    40. 40. • Other secondary end point - nocturnal asthma symptom Numerically greater change in omalizumab - daily puff of rescue medication group but no statistically - QoL significantClinical implications: Many children with moderate-to-severeallergic (IgE-mediated) asthma remain inadequately controlled • Safetydespite treatment with ICSs. Add-on omalizumab reducesexacerbations in this population and may provide an additionaltherapeutic option At least 1 AE; mild or moderate in severity. no statistically significant of AEs in the omalizumab group compared with placebo
    41. 41. Randomized Trial of Omalizumab (Anti-IgE)for Asthma in Inner-City Children • randomized, double-blind, placebo- controlled, parallel-group trial at multiple centers • 419 inner-city children, adolescents, and young adults (6 to 20 years of age) with persistent allergic asthma • at least 1 + SPT to perennial allergen, BW 20 – 150 kg, tatol serum IgE 30-1300 IU/mL William W. Busse, N ENGL J MED 364;11
    42. 42. 4 wk run - in Wk 0 Wk 36 Wk 60 Randomized Wk 12 wash -in Omalizumab vs placebo sc injection Omalizumab 75-375 mg every 2-4 wk Additional visit for evalute and management of care every 3 mo - Adjusted Rx based on symptom that occured during previous 2 wk -adherence to the study regimen - other asthma treatments - FEV1 William W. Busse, N ENGL J MED 364;11
    43. 43. • Allergen skin testing of a panel of 14 extracts: mouse and rat epithelia, dog epithelium, dust mites (Der f and Der p), cat hair, an American–German cockroach mix, German cockroach, molds (Penicillium notatum, aspergillus species, Alternaria tenuis, and Cladosporium herbarum),timothy grass, and a ragweed mix (Greer Laboratories)• Total serum levels of IgE and allergen-specific IgE levels for dust mites, German cockroach, and A. tenuis were measured• Dust from the participant’s bed and bedroom floor was collected with validated self-collection procedure and assayed for dust mite (Der p 1 and Der f 1), German cockroach (Bla g 1), cat (Fel d 1), dog (Can f 1), and mouse (Mus m 1) William W. Busse, N ENGL J MED 364;11
    44. 44. • Nasal-secretion samples collected at 4/8 research sites at week 48 and within 7 days after the onset of an asthma exacerbation. Total RNA was extracted and analyzed (PCR) William W. Busse, N ENGL J MED 364;11
    45. 45. William W. Busse, N ENGL JMED 364;11
    46. 46. Primary outcome : days with symptom (No./2wk ) Reduced 24.5% William W. Busse, N ENGL J MED 364;11
    47. 47. Primary outcome : Exacerbation (%)
    48. 48. Primary outcome : Lower dose of ICS William W. Busse, N ENGL J MED 364;11
    49. 49. Other outcome ← ← ← ← ←
    50. 50. Subgroup analysis• omalizumab’s benefit was greatest in participants who were both sensitized and exposed to cockroach allergen and in those sensitized to dust mites, two major relevant indoor allergens - reduced day of symptom per 2 week interval 48.5% - reduced dose of ICS 32.9% - reduced asthma exacerbation 38.4% , OR 3.7 William W. Busse, N ENGL J MED 364;11
    51. 51. post hoc analysis of Omalizumab on Seasonal Exacerbationsnearly doubled in the placebo group seasonal spike exacerbations was notduring the fall and spring as compared observed in the omalizumab groupwith summer (4.3% in fall and 4.2% in spring vs. 3.3% in(9.0% and 8.1%, respectively, vs. 4.6%; summer), and the difference between theP<0.001). placebo and omalizumab groups was significant (P<0.001 ) William W. Busse, N ENGL J MED 364;11
    52. 52. post hoc analysis of Omalizumab on SeasonalExacerbations daily dose of ICS varied little during the year in the omalizumab group whereas in the placebo group, dose adjustments were required to achieve asthma control William W. Busse, N ENGL J MED 364;11
    53. 53. One or more adverse events were reported in 47.4% of Safety participants in the placebo group and 39.4% of those in the omalizumab group (P = 0.06)- Omalizumab group had significantly more GI disorders but significantly fewer hematologicdisorders compared with placebo gr. - Seven participants had anaphylaxis: 6 in placebo gr. and 1 in omalizumab gr. William W. Busse, N ENGL J MED 364;11
    54. 54. Randomized Trial of Omalizumab (Anti-IgE)for Asthma in Inner-City Children• In summary omalizumab reduces symptoms and exacerbations in children, adolescents, and young adults with persistent allergic asthma, providing protection beyond that conferred with guidelines-directed care. Our findings may also help identify those patients most likely to have a response to omalizumab and provide insight into novel mechanisms of asthma exacerbations that could lead to improved treatment William W. Busse, N ENGL J MED 364;11
    55. 55. Omalizumab and AR
    56. 56. Effect of Omalizumab on Symptomsof Seasonal Allergic RhinitisA Randomized Controlled Trial• Randomized, double-blind, dose-ranging, placebo- controlled trial ,25 OPD center in USA• 536 patients (12 to 75 years) with at least a 2-year Hx of moderate to severe ragweed-induced seasonal allergic rhinitis and a baseline IgE level between 30 and 700 IU/mL.• randomly assigned to receive omalizumab, 50 m, 150 mg, 300 mg or placebo sc 2 wk prior to ragweed season and repeated during the pollen season every 3-4 wk JAMA, December 19, 2001—Vol 286, No. 23
    57. 57. JAMA, December 19, 2001—Vol 286, No. 23
    58. 58. Rhinitis-specific quality oflife scores were consistentlybetter in pt. who received300 mg of omalizumabthan in those who receivedlower dosages or placeboand did not decline duringpeak season
    59. 59. Efficacy and tolerability of anti-immunoglobulin Etherapy with omalizumab in patients withconcomitant allergic asthma and persistent allergicrhinitis: SOLAR• aim : to evaluate the efficacy and safety of omalizumab in patients with moderate-to-severe asthma and persistent AR• multicentre, randomized, double-blind, parallel- group, placebo controlled trial• 405 patients (12–74 years) with a stable asthma treatment• Omalizumab (≥ 0.016 mg/kg/IgE [IU/ml] per 4 weeks) or placebo for 28 weeks Allergy 2004: 59: 709–717
    60. 60. • patients treated with omalizumab fewer experienced asthma exacerbations (20.6% vs 30.1%, P = 0.02 )• Clinically significant (≥ 1.0 point) improvement in AQLQ and RQLQ occurred in 57.7% of omalizumab pt vs 40.6% placebo pt . (P < 0.001) Allergy 2004: 59: 709–717
    61. 61. P < 0.05 In conclusion, thisasthma symptom score Change from baseline in total study of patients with concomitant asthma and P< 0.001 PAR found that omalizumab is significantly more efficacious than placebo in preventing asthma exacerbations and in improving disease-related QoL when added to standard asthma and rhinitis therapies. P< 0.001 Change from baseline in total combined symptom scoreChange from baseline in total rhinitis symptom score Allergy 2004: 59: 709–717
    62. 62. Omalizumab and IT
    63. 63. Omalizumab pretreatment decreases acutereactions after rush immunotherapy forragweed-induced seasonal allergic rhinitis• randomized, double-blind, placebo-controlled study• 159 pt. were randomized to the 4 treatment arms• Pretreatment with omalizumab vs placebo• One-day RIT completed at least 3 weeks before the start of ragweed season• After RIT, pt. had 12 weekly visits to receive IT and omalizumab injections (weeks 0-12) , 3 additional follow-up visits (weeks 13, 19, and 31) (J Allergy Clin Immunol 2006;117:134-40.)
    64. 64. (J Allergy Clin Immunol 2006;117:134-40.)
    65. 65. (J Allergy Clin Immunol 2006;117:134-40.)
    66. 66. • primary efficacy endpoint : comparison of the average daily allergy severity scores between Pt. receiving omalizumab + IT vs IT alone statistically significant improvement in severity scores for patients treated with omalizumab and IT vs IT alone (P = 0.02) intent-to-treat basis, the benefit of omalizumab + IT was significant Improve in severity scores 0.69 vs 0.86 (P < 0 .044). Casale et al JACI 2006;117:134-40
    67. 67. • secondary endpoint : comparison of the incidence of AE (examine of omalizumab on the safety of IT) Casale et al JACI 2006;117:134-40
    68. 68. Omalizumab + immunotherapy vs immunotherapy only demonstratedthat the addition of omalizumabresulted in a significant, 5-fold decrease in risk ofanaphylaxis caused by RIT (OR, 0.17; P = 0.026 ) Casale et al JACI 2006;117:134-40
    69. 69. • Summary : - Omalizumab pretreatment enhances the safety of RIT for ragweed allergic rhinitis - combined therapy (omalizumab + IT) : effective strategy to permit more rapid and higher doses of allergen IT : given more safely and greater efficacy to patients with allergic diseases Casale et al JACI 2006;117:134-40
    70. 70. • Randomized, double-blind, parallel-group, 26 wk study• 275 adult pt. with at least moderate persistent allergic asthma inadequately controlled with ICS• SPT positive to at least 1 of 3 perennial aeroallergens• Specific immunotherapy (SIT) began after 12 wk of omalizumab or placebo• Antihistamine could also be administered prior to each SIT dose• Systemic allegic reaction were evaluated J Allergy Clin Immunol -
    71. 71. 3 wk overlap omalizumab/placebo +SIT SIT to HDM and cat 4 wk, 18 injection cluster regimen followed by 7 wk of weekly maintenance therapyRandomized Efficacy populationN=275 n=248 J Allergy Clin Immunol -
    72. 72. • primary efficacy variable was a SAR within 1 hr after injection of SIT• SAR within 1st hr occurred in 49 pt. (19.8%)• 32 (26.2%) in placebo gr. vs 17 (13.5%) in omalizumab gr , the difference was significant (P < 0.006) J Allergy Clin Immunol -
    73. 73. Day 98 Placebo = 13 pt Omalizumab =3 ptless proportion of pt. who had their 1stSAR after injection in omalizumabgroup than placebo J Allergy Clin Immunol -
    74. 74. Secondary efficacy variables1. Severity of the first SAR to SITP = 0.192 J Allergy Clin Immunol -
    75. 75. Secondary efficacy variables2. Decreased in propotion of pt. receiving recue medication during SITTreatment with omalizumab decreased the proportion ofpatients receiving at least 1 rescue medication during SIT(10.3% for omalizumab vs 24.6% for placebo). J Allergy Clin Immunol -
    76. 76. Secondary efficacy variables3. More pt. achieved target maintenance SIT dose in the omalizumab treatment group 87.3% 72.1%, Placebo Omalizumab J Allergy Clin Immunol -
    77. 77. Post hoc : subgroup analysis was conducted to determinewhether antihistamine pretreatment to SIT affected the rate of SARs 27.1% Antihistamine pre Rx Nonantihistamine preRx24.3% 14.5% 12% Loacal reaction Omalizumab = 53.2% Placebo :49.2% P = 0.52 J Allergy Clin Immunol -
    78. 78. Total Asthma Symptom Daily puffs of rescue 0.72 Score (mean) beta agonist(mean) 0.69 0.45 0.46 Asthma No. of puff of symptom rescue beta score agonistPlacebo Omalizumab placebo Omalizumab Post hoc : Lower total asthma symptom scores and lower daily puffs of rescue beta agonist – 1 week prior to cluster SIT J Allergy Clin Immunol -
    79. 79. Total asthma Daily puffs of rescue β agonist symptom score (mean ) (mean) 23% 23.9% % of Pt. developed grade 3 SAR% of Pt. developed grade 3 SAR 9% 12.5% 6% 7.4% 3.5% 2% No. of No. puff > of puff Score > Score = placebo Omalizumab Post hoc: Level of asthma control on the rate of respiratory (grade 3) SAR J Allergy Clin Immunol -
    80. 80. • In summary : omalizumab pre treatment + SIT - Improved asthma symptom - Reduced recue use of β- agonist - Significant reducing the proportion of pt. who experienced SAR to SIT - Enable more pt. to achieve the target maintenance dose of immunotherapy. J Allergy Clin Immunol -
    81. 81. Omalizumab and urticaria
    82. 82. • evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite H1-antihistamine therapy• phase II, prospective, double-blind, placebo controlled, dose- ranging study investigated omalizumab in - pt. 12 to 75 years in USA - pt. 18 to 75 years in Germany 90 patients(UAS over 7 days (UAS7) of 12 or greater despite antihistamine Rx)• randomized to receive a single SC dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H1-antihistamine (J Allergy Clin Immunol 2011;128:567-73.)
    83. 83. • 300 mg omalizumab group (-19.9 vs- 6.9, P < .001) 600-mg omalizumab group (- 14.6 vs - 6.9, P < 0.047) greater improvement versus the placebo in UAS• Summary : fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H1-antihistamines (J Allergy Clin Immunol 2011;128:567-73.)
    84. 84. Indication for omalizumab in asthma• FDA approved omalizumab (Xolair ) - adults and adolescents ( ≥ 12 years ) - moderate to severe persistent asthma - test positive for reactivity to a perennial aero allergen - whose symptoms are inadequately controlled with inhaled corticosteroids
    85. 85. The 2007 NHLBI Guidelines state that signs oflack of control• >2 exacerbations per year requiring oral corticosteroid bursts• Symptoms >2 days per week• Reliever medication required >2 days per week• Nighttime awakenings 1 to 3 times per week• FEV1 or peak flow at 60% to 80% predicted/personal best• Limited participation in normal activities• Needing urgent medical care, including hospitalization
    86. 86. Recommendation by TAC• Omalizumzb (Anti-IgE)•••• Total lgE - IU/mL• skin prick test specific IgE aero- allergen)• Uncontrolled
    87. 87. Recommendation by TAC• Exacerbation) systemic corticosteroids Prednisolone)
    88. 88. GINA ( ≥ 5 years) and TAC - Pt. age > 6 yr. with moderate to severe asthma with uncontrolled by GINA step 4 - Sensitization to aeroallergen - High Ig E level
    89. 89. Recommended dose• Dosing base on body weight and total serum IgE level• Recommended dose 0.016 mg/kg//IU of IgE /4 wk, administered SC every 2-4 wk interval (150 to 375 mg)• 150 mg lyophilized powder+sterile water = 5 ml/vial
    90. 90. After recommended dose serum free IgE declines rapidly andreach < 50 ng/ml Slowly absorb peak level 7-8 days Half-life 26 days Omalizumab 150 mg >> 18100 Asian Pac J Allergy Immunol 2011;29:209-19
    91. 91. Predicting response to omalizumab• patients who had a response to omalizumab - ratio of observed to expected forced expiratory volume in one second (FEV1) < 65 % - taking doses of inhaled corticosteroids equivalent to more than 800 μg of beclomethasone dipropionate per day - at least one visit to the emergency department in the past year• Patients requiring daily oral corticosteroids to control their asthma less likely to have a response to omalizumab Chest 2004;125;1378-1386
    92. 92. • Omalizamab Omalizamab controlled GINA PEF variability < 15% controlled
    93. 93. Side effect of omalizumab• most common adverse • adverse events needed clinical reactions (>1% more frequent intervention in XOLAIR-treated patients) - injection site reaction (45%) - arthralgia (8%) - viral infections (23%) - pain (general) (7%) - URI (20%) - leg pain (4%) - sinusitis (16%) - fatigue (3%) - headache (15%) - dizziness (3%) - pharyngitis (11%) - fracture (2%) - arm pain (2%) (Omalizumab = control) - pruritus (2%) - dermatitis (2%) - earache (2%)
    94. 94. Omalizumab safety• In 2007 Omalizumab Joint Task Force (OJTF) report anaphlaxis rate 0.1% of 39,510 pt. (incidence approximately 0.2% )• five-step recommendations 1.obtaining informed consent of anaphylaxis education 3.availability epinephrine autoinjector 4. pre-injection health assessment 5. waiting period of 30 minutes after each injection (with an extended waiting period after the first 3 injections to 2 hours) J Allergy Clin Immunol -
    95. 95. Anaphylaxis to omalizumab• It lacks complement fixing activity• the molecule is so extensively humanized that antibodies to the remaining mouse epitopes are unlikely but merit further study• Polysorbate, an additive used to promote the rapid solubilization of pharmaceuticals in aqueous solutions, has been reported to cause hypersensitivity reactions J Allergy Clin Immunol -
    96. 96. • Possible mechanisms - antiallotypic or anti-idiotypic antibodies (IgE or IgG) against this reagent that were either pre-existing before drug administration or had developed after initial exposures or a response to the aggregated preparations of omalizumab• Another possible mechanism is that an unrelated event happened to occur near the time of omalizumab administration (eg, accidental food allergen ingestion J Allergy Clin Immunol -
    97. 97. • Previous pooled data (2003) malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%) warranting further investigation• This pooled analysis primary assessed the incidence of primary malignancy in 32 randomized, doubleblind, placebo-controlled (RDBPC) trials• 11,459 unique patients in all clinical trials• The primary analysis identified malignancies in 25 patients (RDBPC trials): - 14 in 4,254 omalizumab-treated patients - 11 in 3,178 placebo-treated patients J Allergy Clin Immunol 2012;129:983-9.)
    98. 98. • Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 and 4.45, respectively• no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials• The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely J Allergy Clin Immunol 2012;129:983-9.)
    99. 99. Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to SevereAsthma (EXCELS)• observational study• 5000 Xolair treated patients and 2500 non-Xolair treated patients(control group)• primary objective - to assess the long-term safety profile of Xolair in patients followed for 5 years• Interim data may suggest a risk of cardiovascular and cerebrovascular adverse event• EXCELS study is ongoing and final results are not expected until 2013 Early Communication about an Ongoing Safety Review of Omalizumab ,FDA , 7/16/2009
    100. 100. IgE level mornitoring• Monitoring of total serum IgE levels during the course of therapy with omalizumab is not indicated, (these levels will be elevated as a result of the presence of circulating IgE–anti-IgE complexes) Nat Biotechnol 2000; -
    101. 101. Omalizumab mechanism of action• Decreased free serum IgE• Decreased expression of FcεRI (on mast cell, basophil, dendritic cell, and monocyte)• Decreased FeNO• Decreased eosinophil (serum, sputum, bronchial biopsy)• Decreased circulating IL 13• Decreased B lymphocyte• Decreased Ag-induced mediator release from basophil and mast cells• Decreased airway inflamation
    102. 102. Omalizumab effects on asthma• Decreased exacerbation• Decreased ICS dose• Decreased asthma symptoms• Decreased recue medication use• Increased quality of life• Deceased ER visit• Decreased hospitalization• Improved pulmonary function (small effect)
    103. 103. Omalizumab on AR• Decreased daily symptom• Decreased recue medication usage• Improved quality of life• Decreased nasal allergen challenge response• Decreased missed school and work days
    104. 104. Thank you
    105. 105. Pharmacoeconomis• Cost-effectiveness• QALY = Quality Adjusted Life Year• Best day in your life = 100• What is your score today?• If your score today = 80• And this condition continues for 5 years• So you lost 1 QALY
    106. 106. From Xolair website