Omalizumab

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Omalizumab

presented by Theerapan Songnuy, MD.

October15, 2013

Published in: Health & Medicine
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Omalizumab

  1. 1. Omalizumab: The Clinical Application Theerapan Songnuy M.D.
  2. 2. Outlines • IgE & IgE receptors • Diseases specific effects of Omalizumab - Asthma - Allergic Rhinitis • Dosing • Safety • Take Home Message
  3. 3. IgE & IgE Receptors • In 1967, IgE was described by Ishizaka & colleagues
  4. 4. IgE • • • • Smaller amount than IgG, IgM, & IgA Half-life in serum only 2 days Up-regulates expression of FcE RI on effector cell Another receptor: FcERII ( CD 23) that binds with low affinity to IgE • If FcERII flow in serum, upregulate IgE production via interaction with CD 21( B cell co-receptor) • If binds to cell-surface, FcERII will inhibit IgE production Middleton 8th Edition
  5. 5. Omalizumab • • • • A humanized, monoclonal Ab Recognizes & binds to Fc portion of IgE molecule About 95% composed of human sequence Only 5% from murine sequence that engrafted onto a human IgG ( IgG 1 K) framework • Binds to heavy-chain constant ( CH 3 domain) of IgE molecule • The same site which IgE bind to FcE RI >>> soluble immune complex • Finally, get rid by RES ( i.e., mononuclear phagocyte system) Middleton 8th Edition
  6. 6. Aim: 1. To determine onset of action of omalizumab in regweed-induced change in nasal volume 2. To determine the kinetics of omalizumab-induced decreases in serum free IgE & FcERI receptors on basophils
  7. 7. Methods • Patients : - Aged 19-50 y - Ragweed SAR > 2 y - Positive SPT to mixed giant/short/Western ragweed - Positive intranasal challenge to ragweed
  8. 8. Methods • Exclusion criteria: - Asthma - Past or present immunotherapy - Omalizumab use - Severe anaphylaxis or anaphylactoid reaction - Rhinitis medicamentosa - Perennial rhinitis - Structural nasal defect - On Beta-adrenergic antagonist - Current sinusitis & URI - On AH, INS, steroid, decongestant, LTRA etc. - IgE > 700 IU/ml
  9. 9. Methods • Study design: - Randomly assigned to 2 gr. as 2:1 ratio - Omalizumab 0.016 mg/kg/IgE (IU/ml) SC or placebo on day0 & day28 - Serum total IgE at screening visit - Serum free IgE on day 3, 28, 42 - FcERI receptor expression on day 0,7,14,28 & 42 - Blood chemistry for adverse events monitoring
  10. 10. Methods • Nasal challenge: - Baseline acoustic rhinometry, spirometry - NSS spray, wait for 10 min before measure ( 3-times ) - Ragweed extract; 0.00054 AU, 0.0054 AU, 0.054 AU, 0.54 AU & 5.4 AU ( 1:20 W/V, 66.67 AU/ml ag E) then 10 min, perform rhinometry & spirometry - Stop when ; reaching a 30% decrease nasal volume, final dose, 20% decrease FEV1 - The PD30 : dose that induce a decrease 30% nasal volume • Free IgE ( solid-phase ELISA) & total IgE (Immulite) measurement • Basophil cell preparation • Ab staining & flow cytometry ; basophil expression of FcERI-alpha by mean fluorescence intensity
  11. 11. Conclusion : Clinical Improvement & Mechanism of Action • Reduced allergen-induced nasal challenge response within 2 wk ( onset) - Suggestion: need 2 doses for protection through the season • After binding to Omalizumab, free serum IgE decrease 96.1 % within 3 d • Decreased FcERI expression on basophil ( 7-14 days) - Mechanism of action of omalizumab JACI 2004; 113: 297-302
  12. 12. Additional Mechanism of Action • FcERI expressing on dendritic cell, more common in asthmatics & correlate with serum IgE level JACI 2003; 112: 1132-8
  13. 13. Middleton 8th Edition
  14. 14. Markers of Airway Inflammation • After treatment ; serum IgE, blood eosinophil, & sputum eosinophil decrease • Decreased IL-13, IL-5, & IL-8 • Nitric oxide also decreases Int Arch Allergy Immunol 2003; 131: 46-52 Pediatrics 2004; 113: 308-12
  15. 15. Markers of Airway Inflammation • Decreased tissue & sputum eosinophil • Decreased cell positive for FcERI • Reduced CD3, CD4, CD8 & B lymphocyte Am J Respir Crit Care Med 2004; 170: 583-93
  16. 16. Aim: To assess FENO, peripheral blood eosiniphil count, & serum periostin as biomarkers of Th2 inflammation & predictors of treatment effects of omalizumab
  17. 17. Methods • Patients : - Age 12-75 y - Severe persistent allergic asthma for > 1 y - Inadequate controlled despite on ICS & LABA - Night-time awakening >1 / wk - Daytime symptom & need > 2 rescue / wk - Documented as exacerbation > 1 /y - Documented as allergy to perennial allergens - Baseline pre-bronchodilator FEV1 40-80% of predicted value - Serum IgE 30-700 IU/ml - BW 30-150 kg
  18. 18. Methods • Exclusion criteria: - Exacerbation with ETT in prior 12 mon - Exacerbation with systemic steroid in prior 1 mon - Active lung diseases - Treated with omalizumab in prior 12 mon - Smoking > 10 pack-years - R/O diseases with high serum IgE
  19. 19. Conclusion • Omalizumab yields benefit in all high-level biomarker subgroup especially the “first time to exacerbation” • No consistent trend of secondary endpoint of change at 48 wk as compared to baseline • Omalizumab is well tolerated, no serious adverse events • Limitation: - Overall sample size not sufficient - Biomarkers not available in all enrolled patients • Need further study for explore characteristic & prognostic effects of these biomarkers
  20. 20. Evidence that significant over-lap exists on immunopathogenesis of the atopic & nonatopic variants of asthma Aim: To investigate biological & clinical effects of omalizumab in refractory non-atopic asthma CHEST 2013; 144(2): 411-419
  21. 21. Methods • Patients: - Aged 18-70 y - Severe, persistent, non-atopic asthma - Uncontrolled despite high-dose ICS ( > 1,000 ug beclometasone dipropionate or equivalent/d ) plus LABA with/with out OCS - At least 2 exacerbations need systemic steroid - At least 1 admission or ED visit or both - Total serum IgE 30-700 IU/ml - Negative for multi-allergic testing (Aspergillusspecific) - IgE –radioallergosorbent blood test CHEST 2013; 144(2): 411-419
  22. 22. Methods • Exclusion criteria : - Current or former smokers with a > 10 packyear history - Smokers who had quit within prior 3 y - Asthma exacerbation prior 4 wk - Previous use of omalizumab - Pregnancy or breastfeeding - Uncontrolled other chronic diseases CHEST 2013; 144(2): 411-419
  23. 23. Methods • Study design: - RPCDB, phase3B - Ten French centers - The screening visit ( 2-wk), add-on treatment phase ( 16-wk) - During Sep 2009-Feb 2011 - Remain previous dose of asthma drugs - Omalizumab dose depend on the wk0 data ( total IgE level & BW ) - F/U at wk 4,8,12, & 16 CHEST 2013; 144(2): 411-419
  24. 24. Methods • Primary end point : -The change of FcERI expression on basophil & pDC2s at wk 16 compared to wk0 • Secondary end point: - PFT - Asthma control questionnaire score - physician & patient global evaluation of treatment effectiveness ( GETE)* - Exacerbation rate - FENO CHEST 2013; 144(2): 411-419 * Allergy 2005; 60(3): 309-316
  25. 25. Message from this study • Decreased FcERI expression on basophils & pDC2 with Omalizumab treatment in uncontrolled non-atopic asthma • Increased in postbronchodilator FEV1 • Trend toward improvement in asthma-exacerbation rate after 16 wk of treatment *** The first RCT in non-atopic asthma with omalizumab But : 1. Why did non-atopic asthma has similar response to oamalizumab as atopic group? 2. Need more study
  26. 26. JACI 2013; 131: 110-6
  27. 27. Methods • Patients : - Aged > 18 y with chronic rhino-sinusitis with nasal polyp and asthma - Diagnosed by respiratory physician > 2 y - Total serum IgE 30-700 Ku/ml - SPT
  28. 28. Methods • Study design : - RCT,DBPC, 2-centers - 2007-2008 - Omalizumab used as SC 2 wk/8 injections or montly/ 4 injections - Dose based on BW and total serum IgE level - F/U q 2 wk for 10 visits
  29. 29. Methods • Primary end point : - Reduction of total nasal endoscopic polyp scores ( TPSs) at wk16 - Sum of both sides of scores were used • Secondary end point : - Change in Lund Mackay CT score - Nasal & asthma symptoms - Spiro-metry - QOL questionnaire score
  30. 30. Message from this study • Omalizumab is effective in both allergic & non-allergic asthma with CRSwNP • Local IgE level play a role in pathophysiology of CRSwNP & asthma
  31. 31. Aim: To identify the clinical & economic circumstances whether omalizumab is cost-effectiveness by using a mathematic model JACI 2007; 120: 1146-52
  32. 32. Methods • • • • Asthma policy model Target population Effect of ICS therapy Effect of Omalizumab therapy
  33. 33. • JACI 2007; 120: 1146-52 JACI 2007; 120: 1146-52
  34. 34. JACI 2007; 120: 1146-52
  35. 35. Omalizumab: Economic Perspective • Not cost-effectiveness for treating severe asthma • Compared to the “ dialysis threshold” need $ 93,500 per QALY in 2002 • Limitations: - A model-based - FEV1 % predicted not represent prognosis
  36. 36. Dosing • FDA approved only Xolair • Lyophilized powder in doses of 75mg & 150 mg • Mixed with sterile water for subcutaneous injection • Liquid formation is forth coming • Recommended dose = 0.016 mg/kg per 1.0 IU of IgE q 4 wk , in mod-severe allergic asthma • Age greater than 12 y
  37. 37. Dosing • Absorbed slowly • Reaching a peak serum concentration at 7 d • Average absolute bioavailability 62% • Serum elimination half-life 26 d • Clearance average 2.4+- 1.1 ml/kg/d • After first dose, rising serum IgE ( bound & unbound) due to a formation of omalizumab-IgE complex ( slower elimination rate) • At 3 mon after start treatment, total IgE level rising to 8 folds, where as free IgE decrease
  38. 38. Dosing • After discontinuation, need a year to reverse total IgE to be at level of pre-treatment • About 40 % of patients not effective • Free IgE level in non-responder & responder were similar • May be due to: - Inexert relationship between free IgE & FcERI expression - Ratio of sIgE/total IgE inordinately high for clinically important - Differences in intrinsic cullular sensitivity ( mast cell, basophil) JACI 2009; 123: 107-13
  39. 39. Safety • Well-tolerated both adult & children • Few adverse reactions: - Most common is local reaction; pruritus, burning, pain, swelling, redness, warmth, hives & bruising - Cancer not proved as increased risk http:// www.gene.com/download/pdf/xolair_prescribing.pdf ( accessed Dec 30, 2012) Ann Allergy Asthma Immunol 2003; 91: 182-8
  40. 40. Safety • Due to decreased serum IgE level, higher incidence & severity of helminthic infection • Post marketing reports: - Severe thrombocytopenia - Alopecia - Anaphylaxis ( 2 cases)
  41. 41. Take Home Messages • A selective anti-IgE humanized Mab • A novel therapy option for patients with severe allergic asthma & other allergic diseases • Omalizumab inhibits activation of mast cell, basophil & decreases effect of eosinophil • Efficacy; reduce exacerbation in mod-severe allergic asthma • For other allergic conditions need further studies • Safety & well tolerated both adult & children • On daily practice, physicians have to carefully make a decision on case by case
  42. 42. THANK YOU VERY MUCH

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