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Anti Immunoglobulin E Therapy

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Anti Immunoglobulin E Therapy

Presented by Suda Sibunruang, MD.

July8, 2015

Published in: Health & Medicine

Anti Immunoglobulin E Therapy

  1. 1. Anti – Immunoglobulin E Therapy Suda Sibunruang, M.D.
  2. 2. Outline Immunoglobulin E (IgE) & IgE receptors Anti – IgE monoclonal Ab (Omalizumab) • Mechanism of action • Clinical benefits • Dosing and administration • Safety • Issues in clinical use
  3. 3. Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition
  4. 4. Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition IgE levels in cord blood are low (<2 kIU/L; < 4.8 mg/L), gradually increase throughout childhood with a peak at 10 – 15 yrs of age, and then decrease throughout adulthood
  5. 5. From www.hindawi.com, access July 2015
  6. 6. Abbas AK, et al. Cellular and Molecular immunology 2014 Eighth Edition
  7. 7. Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014 • Large amount of FcεRI on cell surfaces: - mast cells, basophils • Other cell types: - antigen presenting cells IgE control level of FcεRI expression - FcεRI not occupied by IgE has a half-life on mast cell surface of 24 hrs in vitro, whereas receptors bound to IgE appear to be expressed for life of cell - Density of human basophil FcεRI expression correlates directly with serum IgE levels, where binding of IgE stabilizes receptor at cell surface
  8. 8. Picture A. from www.frontiersin.org Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19
  9. 9. Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014 - Ca-dependent lectin - Consists of a large extracellular domain with lectin head that binds IgE - Like FcεRI receptor, expression of CD23 is upregulated by IgE and IL-4 - CD23 can be shed from membrane into a soluble form, sCD23, by endogenous proteases (a disintegrin and metallopeptidase 10-ADAM10) and exogenous proteases, including dust mite major allergen Der p 1
  10. 10. Oettgen H. Middleton’s Allergy Principle and Practice. 8th edition, 2014
  11. 11. Boyman O., et al. Allergy 2015;70:727–54
  12. 12. Omalizumab • Humanized, anti-IgE monoclonal antibody • Composed of 5% murine sequences that were engrafted onto a human IgG1κ framework 5% mouse • Binds to heavy-chain constant CH3 domain of IgE molecule • Same site by which IgE binds to FcεRI Holgate ST. Q J Med 2004;97:247- 57 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90
  13. 13. Price D. Primary Care Respiratory Journal 2008;17: 62-72 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90 Omalizumab - IgE complexes Soluble, inert immune complexes that are subsequently cleared from circulation via interactions with FcγRs of hepatic sinusoidal endothelial cells of reticuloendothelial system (half-life 26 days)
  14. 14. Picture from www.what-when-how.com, access July 6, 2015 Owen CE. Pharmacology & Therapeutics 2007;113:121–33 Price D. Primary Care Respiratory Journal 2008;17: 62-72 As IgE upregulates IgE receptors on mast cells, reduction in amount of free IgE in circulation also results in a decrease in number of IgE receptors on surface of mast cells
  15. 15. Holgate ST. and Polosa R. Nature Reviews Immunology 2008;8:218-30
  16. 16. Holgate S., et. al. J Allergy Clin Immunol 2005;115:459-65
  17. 17. Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  18. 18. Owen CE. Pharmacology & Therapeutics 2007;113:121–33 Stokes JR. and Casale TB. Middleton’s Allergy 8th edition, 2014, 1480-90 - 99% reduction in free serum IgE levels has occurred within 2 hrs after omalizumab administration - Omalizumab administration reduces allergen-induced nasal challenge responses and expression of FcεRI on basophils within 7 days - Within 3 months, human basophil responsiveness (i.e., histamine releasability) was reduced by 90%
  19. 19. Stone KD., et. al. J Allergy Clin Immunol 2010;125:S73-80 Total IgE levels generally increase by up to 5-fold after omalizumab treatment because of increased stability of omalizumab-IgE complexes, whereas free IgE levels decrease by up to 95%. There is great variability in accuracy of different systems for total IgE measurements in presence of omalizumab
  20. 20. Clinical benefits
  21. 21. Picture from www.xolair.com, access July 2015
  22. 22. Allergic asthma
  23. 23. Effect on airway inflammation
  24. 24. Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 Djukanovic R, et. al. Am J Respir Crit Care Med 2004;170:583-93 Bronchial biopsy specimens obtained from patients with mild steroid-naive asthma and who received omalizumab show a marked decrease in inflammatory cells (eosinophils, IgE+cells, FceRI+ cells, IL-4-secreting cells, and CD3+ T lymphocytes) within epithelium and submucosa Indicate additional modulatory effects of omalizumab
  25. 25. Effect on remodelling
  26. 26. Hoshino M, et. al. Respiration 2012;83:520-8 Effects of Adding Omalizumab, an Anti-Immunoglobulin E Antibody, on Airway Wall Thickening in Asthma Obj: To assess effects on airway wall thickness using CT Methods: 30 severe persistent asthma pt were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 wks Airway dimensions were assessed at right apical segmental bronchus by CT: - airway wall area corrected for BSA (WA/BSA) - percentage wall area (WA%) - wall thickness (T)/ BSA - luminal area (Ai)/BSA % of eosinophils in induced sputum Pulmonary function Asthma Quality of Life Questionnaire (AQLQ) Results: Significantly decreased WA/BSA, WA%, T/ BSA and increased Ai/BSA, whereas conventional therapy resulted in no change -Decrease % of sputum eosinophils -Improved FEV 1 -Improved AQLQ score
  27. 27. Hoshino M, et. al. Respiration 2012;83:520-8 Effects of Adding Omalizumab, an Anti-Immunoglobulin E Antibody, on Airway Wall Thickening in Asthma Obj: To assess effects on airway wall thickness using CT Methods: 30 severe persistent asthma pt were randomized to conventional therapy with (n = 14) or without omalizumab (n = 16) for 16 wks Airway dimensions were assessed at right apical segmental bronchus by CT: - airway wall area corrected for BSA (WA/BSA) - percentage wall area (WA%) - wall thickness (T)/ BSA - luminal area (Ai)/BSA % of eosinophils in induced sputum Pulmonary function Asthma Quality of Life Questionnaire (AQLQ) Results: Significantly decreased WA/BSA, WA%, T/ BSA and increased Ai/BSA, whereas conventional therapy resulted in no change -Decrease % of sputum eosinophils -Improved FEV 1 -Improved AQLQ score Omalizumab reduced airway wall thickness and airway inflammation
  28. 28. Allergic asthma Clinical efficacy of omalizumab in patients with moderate to-severe and severe allergic asthma has been well documented in several large-scale clinical trials that involved adults, adolescents, and children Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  29. 29. Humbert M., et. al. Allergy 2005:60:309–16 Double-blind, parallel-group, multicentre study Obj: Determined effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) Participants: Patients (12-75 yrs) with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA) Method: randomized to receive omalizumab or placebo for 28 wks Omalizumab significantly improved asthma-related quality of life, morning PEF and asthma symptom scores
  30. 30. Humbert M., et. al. Allergy 2005:60:309–16 Double-blind, parallel-group, multicentre study Obj: Determined effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) Participants: Patients (12-75 yrs) with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy (high-dose ICS and LABA) Method: randomized to receive omalizumab or placebo for 28 wks Omalizumab significantly improved asthma-related quality of life, morning PEF and asthma symptom scores Omalizumab significantly reduced rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits
  31. 31. Bousquet J., et. al. Allergy 2005:60;302–8 Price D. Primary Care Respiratory Journal 2008;17: 62-72 Pooled data from 7 studies to examine effect of omalizumab on exacerbations n = 4,308 (2,511 treated with omalizumab), 93% severe persistent asthma Omalizumab was added to current asthma therapy, duration 24 – 52 wks - compared with placebo (5 double-blind studies) or - with current asthma therapy alone (2 open-label studies)
  32. 32. Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  33. 33. Hanania NA, et. al. Ann Intern Med 2011;154:573-82 (EXTRA) Prospective, multicenter, randomized, double-blind, placebo-controlled trial 193 sites in USA and 4 sites in Canada Obj: To evaluate efficacy and safety of omalizumab in (850) patients (12-75 yrs) with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy Duration: 48 wks Primary end point: Rate of protocol defined exacerbations Results: Rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (25% reduction), increase time to first asthma exacerbation, improved mean AQLQ(S) scores, reduced mean daily albuterol puffs, decreased mean asthma symptom score. Incidence of adverse events were similar. Protocol-defined asthma exacerbation was worsening asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term OCS, an exacerbation was a 20-mg or more increase in average daily dose of oral prednisone
  34. 34. Hanania NA, et. al. Ann Intern Med 2011;154:573-82 (EXTRA) Prospective, multicenter, randomized, double-blind, placebo-controlled trial 193 sites in USA and 4 sites in Canada Obj: To evaluate efficacy and safety of omalizumab in (850) patients (12-75 yrs) with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy Duration: 48 wks Primary end point: Rate of protocol defined exacerbations Results: Rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (25% reduction), increase time to first asthma exacerbation, improved mean AQLQ(S) scores, reduced mean daily albuterol puffs, decreased mean asthma symptom score. Incidence of adverse events were similar. Protocol-defined asthma exacerbation was worsening asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term OCS, an exacerbation was a 20-mg or more increase in average daily dose of oral prednisone Omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy
  35. 35. Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8 Randomized, double-blind, placebo-controlled trial Obj: Evaluated ability of omalizumab to improve disease control sufficiently to enable ICS reduction in patients with severe allergic asthma Omalizumab improved asthma symptoms and asthma related QoL , and reduced rescue medication requirements compared to placebo
  36. 36. Holgate ST, et. al. Clin Exp Allergy 2004;34:632-8 Randomized, double-blind, placebo-controlled trial Obj: Evaluated ability of omalizumab to improve disease control sufficiently to enable ICS reduction in patients with severe allergic asthma Omalizumab improved asthma symptoms and asthma related QoL , and reduced rescue medication requirements compared to placebo Omalizumab improves asthma control in severe allergic asthma, reducing ICS requirements without worsening of symptom control or increase in rescue medication use
  37. 37. Vignola AM, et. al. Allergy 2004;59:709-17 Multicentre, randomized, double-blind, placebo controlled trial Obj: To evaluate efficacy and safety in patients with concomitant moderate-to-severe asthma and persistent allergic rhinitis Method: 405 pts (12–74 yrs) with a stable treatment (400 µg budesonide Turbuhaler) and  2 unscheduled medical visits for asthma during past year or  3 during past 2 years were enrolled to receive omalizumab or placebo for 28 wks Fewer patients experienced asthma exacerbations (20.6%) than placebo-treated patients (30.1%) Clinically significant ( 1.0 point) improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire occurred in 57.7% of omalizumab compared with 40.6% of placebo Serious adverse events were observed in 1.4% of Omalizumab and 1.5% of placebo
  38. 38. Tsabouri S. et. al. J Allergy Clin Immunol Pract 2014;2:332-40 Obj: To assess efficacy and safety in poorly controlled AR 11 studies (1997-2010) of 2870 patients were finally included Result: Significant reduction in daily nasal symptom severity score, daily nasal rescue medication score and improvement QoL Efficacy of omalizumab in reducing DNSSS
  39. 39. Braunstahl GJ, et. al. Respir Med 2013;107:1141-51 The eXpeRience registry: The ‘real-world’ effectiveness of omalizumab in allergic asthma 2-year, single-arm, open-label, observational 943 pts with uncontrolled persistent allergic asthma Evaluate effectiveness variables (physician’s Global Evaluation of Treatment Effectiveness [GETE], change from baseline in exacerbation rate, symptoms, rescue medication use, and oral corticosteroid [OCS] use 69.9% responded after 16 (±1) wks Proportion of patients with no clinically significant exacerbations increased Symptoms and rescue medication use at Month 24 were reduced by >50% from baseline. Maintenance OCS use was lower at Month 24 (14.2%) compared with Month 12 (16.1%) and baseline (28.6%) Acceptable safety profile GETE: overall clinical evaluation of asthma control at 16 weeks, based on all available information: patient interview and physical examination, and review of patient notes and diary
  40. 40. Poachanukoon O.,et. al. J Allergy Clin Immunol 2014;AB2 abstract METHODS: Multi-center, observational study in severe allergic asthma patients RESULTS: 61 patients were reviewed - ACT score increased from 13.8 baseline to 16.4 at Wk 16 (p=0.201) and increased to 20.6 at Wk 52 (p=0.005) - Proportion of patients with controlled asthma (ACT score >20) increased from 17% baseline to 52.8% and 72.2% at Wk 16 and 52 - Mean annualized rate of asthma exacerbations was reduced - Mean hospitalization rate was reduced - Reduction in ER visits - Mean daily dose of ICS equivalent to fluticasone was reduced slightly - 78.7% patients continued omalizumab for at least 1 year - Of the 9 patients who discontinued omalizumab, 55.5% had relapse within 3 months and needed to restart treatment
  41. 41. Remark • Limited data are available on efficacy of omalizumab for active smokers and for exsmokers with substantial pack-year histories because these patients often are excluded from clinical trials • But it is suggested that efficacy is likely to be similar to that in nonsmokers Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  42. 42. Global Initiative for Asthma (GINA), 2015 update
  43. 43. Indication in the United States • Approved in 2003 for treatment of patients  12 yrs with moderate-to severe persistent allergic asthma despite treatment with ICS Price D. Primary Care Respiratory Journal 2008;17: 62-72
  44. 44. Indication in the European Union Approved in 2005 as add-on therapy in patients >12 years with severe persistent allergic asthma: • Positive skin test or serum IgE to a perennial aeroallergen • Reduced lung function (FEV1 <80%) • Frequent daytime symptoms or night-time awakenings • Multiple documented severe asthma exacerbations (PEF/FEV1 <60% of patients’ maximum recorded) despite receiving daily high-dose ICS plus a LABA Price D. Primary Care Respiratory Journal 2008;17: 62-72 ‘Multiple severe asthma exacerbations’ is defined as either two or more severe exacerbations of asthma requiring hospital admission within the previous year, or three or more severe exacerbations of asthma within the previous year, at least one of which required admission to hospital
  45. 45. Holgate S., et. al. Respiratory Medicine 2009;103:1098-113
  46. 46. แนวทางการให้ยา Omalizumab (asthma) ผู้ป่วยต้องมีเกณฑ์ทุกข้อดังนี้ • ต้องอยู่ในการดูแลของแพทย์ผู้เชี่ยวชาญด้านโรคปอดและภูมิแพ้ • ผู้ป่วยต้องใช้ยาตามแพทย์สั่งได้ถูกต้องสม่าเสมอ • ต้องมีการสืบค้นว่าผู้ป่วยไม่มีภาวะ/โรคอย่างอื่นที่เป็นสาเหตุทาให้ ควบคุม โรคหืดไม่ได้ และหลีกเลี่ยงสิ่งกระตุ้น • มีระดับ Total lgE 75-1,300 IU/mL • มีการตรวจสารก่อภูมิแพ้ด้วยการตรวจสอบ skin prick test หรือ specific IgE ต่อ สารก่อภูมิแพ้ในอากาศ (aero-allergen) ให้ผล บวก • ได้รับการรักษาโรคหืดตาม ระดับที่ 4 มาเป็นเวลาอย่างน้อย 6 เดือนแล้ว ยังคุมอาการ (Uncontrolled ตาม GINA) ร่วมกับประเมิน PEF variability > 20% • มีอาการกาเริบของ (Exacerbation) อย่างรุนแรงโดยต้องได้systemic corticosteroids มากกว่าหรือเท่ากับ 2 ครั้งในช่วง 1 ปีที่ ผ่านมา หรือมีประวัติการ ใช้สเตียรอยด์ชนิดรับประทาน (Prednisolone) มากกว่าหรือเท่ากับ 10 มิลลิกรัมต่อวัน ติดต่อกันนานเกินกว่า 30 วัน แนวทางการวินิจฉัยและรักษาโรคหืด ในประเทศไทย V.5 สาหรับผู้ใหญ่และเด็ก พ.ศ. 2555/ สมาคมสภาองค์กรโรคหืดแห่งประเทศไทย
  47. 47. การประเมินผู้ป่ วยหลังได้รับยา Omalizamab หลังได้รับยา Omalizamab เป็นเวลา 16 อาทิตย์แล้วประเมินผู้ป่วย อยู่ในระดับ controlled ตาม GINA ยกเว้น ผลการตรวจสมรรถภาพ ปอด (ในตารางที่ 3) ร่วมกับมีค่า PEF variability < 15% ให้ยาต่อ จนครบ 6 เดือน แล้วให้หยุดยา แต่ถ้าประเมินผู้ป่วยหลังได้เป็นเวลา 16 อาทิตย์ ไม่อยู่ในระดับ controlled ให้หยุดยาไม่ให้ยาต่อ ในกรณีที่ หยุดยา หลังที่ ให้ยาครบ 6 เดือนแล้วผู้ป่วยมีอาการกาเริบ พิจารณาให้ยา ใหม่ตามข้อ บ่งชี้ข้างต้น แนวทางการวินิจฉัยและรักษาโรคหืด ในประเทศไทย V.5 สาหรับผู้ใหญ่และเด็ก พ.ศ. 2555/ สมาคมสภาองค์กรโรคหืดแห่งประเทศไทย
  48. 48. แนวทางการวินิจฉัยและรักษาโรคหืด ในประเทศไทย V.5 สาหรับผู้ใหญ่และเด็ก พ.ศ. 2555/ สมาคมสภาองค์กรโรคหืดแห่งประเทศไทย
  49. 49. Garcia G., et. al. Chest 2013;144:411–9
  50. 50. Urticaria
  51. 51. Chang T.et al. J Allergy Clin Immunol 2014
  52. 52. Casale TB., et. al. J Allergy Clin Immunol Pract 2015 article in press
  53. 53. Maurer M. et. al., J Eur Acad Dermatol Venereol 2015;29:s16-32
  54. 54. Zuberbier T. et al. Allergy 2014; 69: 868–87
  55. 55. แนวทางการให้ยา Omalizumab (urticaria) • ผู้ป่วยต้องอยู่ในการดูแลของแพทย์ผู้เชี่ยวชาญด้านโรคผิวหนัง และ/หรือ โรคภูมิแพ้ • มีอายุ 12 ปี ขึ้นไป • ได้รับการตรวจวินิจฉัยเพิ่มเติมว่าไม่มีสาเหตุหรือปัจจัยกระตุ้นอื่นที่ทาให้เกิดโรคลมพิษ - การตรวจทางห้องปฏิบัติการที่จาเป็น คือ CBC, UA, ANA • ได้รับการวินิจฉัยจากแพทย์ผู้เชี่ยวชาญว่าเป็น chronic spontaneous urticaria และไม่ตอบสนองต่อการรักษาพื้นฐาน มีความรุนแรงของโรคระดับปานกลางถึงรุนแรง • ผู้ป่วยมีอาการของโรคมาอย่างน้อย 3 เดือน แต่ยังไม่ตอบสนองต่อการรักษา ถึงแม้จะได้รับการรักษาตามขั้นตอนการรักษามาตรฐาน (อ้างอิงแนวทางการรักษาโรคลมพิษ แห่งประเทศไทย 2557 ) จึงจะมีการพิจารณาให้ยา omalizumab Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  56. 56. Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  57. 57. Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  58. 58. Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  59. 59. Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  60. 60. Omalizumab beyond asthma/urticaria
  61. 61. Boyman O., et al. Allergy 2015;70:727–54 A number of trials are underway…
  62. 62. • Rhinitis • Atopic dermatitis • Hymenoptera allergy • Mastocytosis • Idiopathic anaphylaxis • Ocular allergy • Eosinophilic gastrointestinal diseases • Food allergy • Latex allergy • Mieniere’s disease • Churg-Strauss Syndrome • Hyper IgE syndrome • Bronchopulmonary aspergillosis Omalizumab beyond asthma/urticaria Sanchez J. et. al. Allergol Immunopathol (Madr) 2012;40:306-15
  63. 63. Dosing and administration
  64. 64. 75 mg 150 mg Lyophilized product takes 15 to 20 min to dissolve From www.xolair.com, access July 2015
  65. 65. Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19 Subcutaneous injection every 2 or 4 weeks, with dose being based on pretreatment serum total IgE levels and body weight
  66. 66. Vichyanond P. Asian Pac J Allergy Immunol 2011;29:209-19 Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 Patients whose baseline IgE levels or BW are outside limits of dosing table should not receive omalizumab
  67. 67. Dosage & body weight • Doses should be adjusted for significant changes in body weight • Calculate from total body weight, not ideal body weight เอกสารกากับยา Ledford DK, et. al. Expert Opin Biol Ther 2009;9:933-43
  68. 68. Dosage & IgE level • Total IgE levels are elevated during treatment and remain elevated for up to 1 yr after discontinuation • Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination • Interruptions lasting < 1 yr: Dose based on serum IgE levels obtained at the initial dose determination • Interruptions lasting ≥ 1 yr : Re-test total serum IgE levels for dose determination เอกสารกากับยา
  69. 69. Use solution for sc administration within 8 hrs following reconstitution when stored in the vial at 2 - 8°C, or within 4 hrs of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from direct sunlight From www.xolair.com, access July 2015
  70. 70. Other concerns (1) Xolair has not been studied or inadequately studied: • Patients < 6 yrs or > 65 yrs • Patients with autoimmune diseases • Patients with pre-existing renal or hepatic impairment เอกสารกากับยา
  71. 71. Other concerns (2) • One 150 mg Xolair powder vial and solvent for solution dose contains 108 mg of sucrose • Not indicated for relief of acute bronchospasm or status asthmaticus • No formal drug interaction studies have been performed with Xolair เอกสารกากับยา
  72. 72. Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ/ สมาคมแพทย์ผิวหนังแห่งประเทศไทย สมาคมโรคภูมิแพ้ โรคหืด และวิทยาภูมิคุ้มกันแห่งประเทศไทย ชมรมแพทย์ผิวหนังเด็กแห่งประเทศไทย
  73. 73. Other concerns (3) • Maximum tolerated dose of Xolair has not been determined. • Single IV doses of up to 4,000 mg have been administered to patients without evidence of dose limiting toxicities • Highest cumulative dose administered to patients was 44,000 mg/20 wk period เอกสารกากับยา
  74. 74. Safety
  75. 75. Corren J, et. al. Clin Exp Allergy 2009;39:788-97 Safety and tolerability of omalizumab Analyzed safety using data from clinical studies involving > 7,500 patients as well as post-marketing data in 2003 – 2006 (57,300 patients) Overall incidence of adverse events with omalizumab similar to that in placebo or control groups
  76. 76. Most common systemic adverse events Adults • Nasopharyngitis • Headache • Upper respiratory tract infection • Sinusitis Children • Nasopharyngitis • Upper respiratory tract infection • Headache • Sinusitis Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  77. 77. Cox L, et. al. J Allergy Clin Immunol 2007;120:1373-7 Summary of recommendations • Informed consent • Anaphylaxis education • Epinephrine autoinjector - 24 hrs after administration • Preinjection health assessment - V/S, lung functions • Wait period after injection - 2 hrs for first 3 injections and 30 min for subsequent injections (captured 75% of anaphylactic reactions) Obj: reviewing data on anaphylaxis and anaphylactoid reactions Duration: 2003 – 2005 Results: 35 patients had 41 episodes from 39,510 patients ( 0.09%)
  78. 78. Cox L, et. al. J Allergy Clin Immunol 2011;128:210-12 Duration: 2006 – 2008
  79. 79. Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5 Omalizumab Omalizumab antibody Excipients: - Sucrose - L-histidine - Polysorbate 20 Obj: to examine whether omalizumab skin testing is safe and to establish an appropriate nonirritating concentration for prick and intradermal testing Participants: no prior exposure to omalizumab or other biologic therapies Positive reaction: 3-mm wheal or larger and/or 10-mm or larger erythema over negative control Antiomalizumab IgG was analyzed 10 weeks after skin testing
  80. 80. Lieberman P, et. al. Ann Allergy Asthma Immunol 2010;105:493-5 Intradermal Test in Healthy Volunteers (First Cohort, n=30) and Allergic Asthma Patients (Second Cohort, n=30) 1:10,000 contains 12.5 g/mL of protein SPT with all concentrations diluted with NSS did not elicit any nonspecific reactions No detectable IgG ab to omalizumab
  81. 81. Shankara T. and Petrov A. Curr Opin Allergy Clin Immunol 2013;13:19–24
  82. 82. Malignancy Analysis of pooled data from omalizumab phase I to III clinical studies showed a numerical imbalance in incidence of malignancy between placebo (0.18%) and omalizumab (0.5%) Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36
  83. 83. Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9 Obj: Examine incidence of malignancy using pooled data from clinical trials No cluster of histologies was identified
  84. 84. Busse W., et. al. J Allergy Clin Immunol 2012;129:983-9 A causal relationship between omalizumab therapy and malignancy is unlikely
  85. 85. Long A. et. al. J Allergy Clin Immunol 2014;134:560-7 Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) - Request of FDA - 5-year observational cohort study conducted in patients  12 yrs with moderate-to-severe asthma (approximately 5,000 pts treated with omalizumab and 2800 control) - Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy Time to first study-emergent primary malignancy - Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC - Overall frequency and frequency of individual cancer are consistent with expectations for general population
  86. 86. Long A. et. al. J Allergy Clin Immunol 2014;134:560-7 Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) - Pooled clinical trial data in 2003 showed malignancies in 0.5% of omalizumab- treated patients compared with 0.2% of control - 5-year observational cohort study conducted in patients  12 yrs with moderate-to-severe asthma - Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy Time to first study-emergent primary malignancy - Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to first confirmed study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC
  87. 87. Long A. et. al. J Allergy Clin Immunol 2014;134:560-7 Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) - Pooled clinical trial data in 2003 showed malignancies in 0.5% of omalizumab- treated patients compared with 0.2% of control - 5-year observational cohort study conducted in patients  12 yrs with moderate-to-severe asthma - Obj: Evaluate long-term safety of omalizumab, primarily risk of malignancy Time to first study-emergent primary malignancy - Crude malignancy rates were similar (16 & 19/1000 patient-years) - Time to first confirmed study-emergent primary malignancy were similar - Hazard ratio (omalizumab vs nonomalizumab) of 1.09 for all malignancies and 1.15 for all malignancies excluding NMSC Omalizumab is not associated with an increased risk of malignancy
  88. 88. Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12 Prospective, observational study of pregnant women exposed to ≥1 dose of omalizumab within 8 wks prior to conception or at any time during pregnancy
  89. 89. Namazy J., et. al. J Allergy Clin Immunol 2015;135:407-12 Do not increase risk of preterm birth or SGA infants and prevalence of major congenital defects in general population with asthma Omalizumab is classified as a Pregnancy Category B medication
  90. 90. Nursing mother • In monkeys, milk levels of omalizumab were measured at 0.15% of the maternal serum concentration • It is not known whether Xolair is present in human breast milk; however, IgG is present in human milk in small amounts • Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xolair and any potential adverse effects on breastfed child from Xolair or from underlying maternal condition • Exercise caution when administering Xolair to a nursing woman เอกสารกากับยา
  91. 91. Parasitic (Helminth) Infection • Monitor patients at high risk of geohelminth infection while on Xolair therapy • Insufficient data are available to determine length of monitoring required for geohelminth infections after stopping Xolair treatment • 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo, odds ratio for infection was 1.96 • Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different เอกสารกากับยา
  92. 92. Other adverse events Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 • None of omalizumab recipients developed measurable antiomalizumab antibodies • Although thrombocytopenia was noted in preclinical studies, a decrease in platelet counts of 100 x 10⁹/L was seen in only 3.4% of omalizumab and 2.3% of controls
  93. 93. Issues in clinical use
  94. 94. Predictors of response Not all patients respond to omalizumab !
  95. 95. Predictors of response Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 • It was difficult to reliably predict by using pretreatment characteristics • Physician’s GETE at 16 wks was the most meaningful measurement of treatment response and the best discriminator of treatment outcomes
  96. 96. Price D. Primary Care Respiratory Journal 2008;17: 62-72 1. Overall physician assessment
  97. 97. Price D. Primary Care Respiratory Journal 2008;17: 62-72
  98. 98. Price D. Primary Care Respiratory Journal 2008;17: 62-72 1. Overall physician assessment 2. Composite measure of asthma control AQLQ: Asthma related quality of life
  99. 99. UK responder algorithm Holgate S., et. al. Respiratory Medicine 2009;103:1098-113
  100. 100. Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 Baseline levels of fraction of exhaled nitric oxide (FeNO), peripheral blood eosinophils, and serum periostin Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was significantly greater in patients with high versus low baseline levels of all 3 biomarkers
  101. 101. Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 Baseline levels of fraction of exhaled nitric oxide (FeNO), peripheral blood eosinophils, and serum periostin Reduction in asthma exacerbations over 48 wks with omalizumab versus placebo was significantly greater in patients with high versus low baseline levels of all 3 biomarkers Stratified approach to treatment, and to determine value of these biomarkers for guiding decisions on initiation of omalizumab which may potentially enhance cost- effectiveness
  102. 102. Duration of therapy Optimal duration has yet to be determined
  103. 103. Nopp A, et. al. Allergy 2010;65:56-60 Obj: Report clinical and immunological state of patients 3 yrs after a 6-year period of Xolair treatment for severe allergic asthma Participants: 18 cat allergen sensitivity pt with asthma Results: 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment -Most patients were in stable clinical condition -16/18 had not increased nightly asthma attacks -14/18 little or no increase in medication -CD-sens to cat was still significantly lower than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels -Considerable, downregulation of basophil allergen sensitivity
  104. 104. Nopp A, et. al. Allergy 2010;65:56-60 Obj: Report clinical and immunological state of patients 3 yrs after a 6-year period of Xolair treatment for severe allergic asthma Participants: 18 cat allergen sensitivity pt with asthma Results: 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment -Most patients were in stable clinical condition -16/18 had not increased nightly asthma attacks -14/18 little or no increase in medication -CD-sens to cat was still significantly lower than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels -Considerable, downregulation of basophil allergen sensitivity Most patients had good asthma control for up to 3 yrs after omalizumab withdrawal
  105. 105. Nopp A, et. al. Allergy 2010;65:56-60 Obj: Report clinical and immunological state of patients 3 yrs after a 6-year period of Xolair treatment for severe allergic asthma Participants: 18 cat allergen sensitivity pt with asthma Results: 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment -Most patients were in stable clinical condition -16/18 had not increased nightly asthma attacks -14/18 little or no increase in medication -CD-sens to cat was still significantly lower than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels -Considerable, downregulation of basophil allergen sensitivity Pro: Most patients had good asthma control for up to 3 yrs after omalizumab withdrawal Con: Slavin et. al. found that reducing dose of omalizumab at 6 months led to a recurrence of asthma symptoms in patients assessed as responders by physician evaluation at 16 wks
  106. 106. Pharmacokinetic-pharmacodynamic modelling Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 • IgE production decreases with duration of treatment by approximately 54%/yr, reaching a new equilibrium after 5 years of treatment • After withdrawal, IgE production is predicted to increase slowly, potentially taking 15 years to return to baseline, which suggests that patients may not need to continue omalizumab indefinitely • Further research into appropriate duration of treatment is required
  107. 107. Access from www.clinicaltrials.gov/ct2/show/NCT01125748, July 9, 2015 -Study of patients who received omalizumab continuously for up to 5 or more years and who were randomized to either continue or discontinue omalizumab, with follow up for a further year -Results will help to clarify effects of omalizumab withdrawal after successful long term therapy
  108. 108. Monitoring requirements
  109. 109. Monitoring requirements Humbert M. et. al. J Allergy Clin Immunol Pract 2014;2:525-36 • Anaphylactic reactions sometimes occurs for the first time after multiple administrations • Assessment of responses at 16 wks by using GETE
  110. 110. Cost: a major obstacle
  111. 111. ธนะวัฒน์ วงศ์พัน/การศึกษาความคุ้มค่าทางเศรษฐศาสตร์และข้อเสนอเพื่ อปรับราคายา Omalizumab ที่เหมาะสมสาหรับผู้ป่วยหอบหืดในประเทศไทย/2556
  112. 112. ธนะวัฒน์ วงศ์พัน/การศึกษาความคุ้มค่าทางเศรษฐศาสตร์และข้อเสนอเพื่ อปรับราคายา Omalizumab ที่เหมาะสมสาหรับผู้ป่วยหอบหืดในประเทศไทย/2556
  113. 113. ธนะวัฒน์ วงศ์พัน/การศึกษาความคุ้มค่าทางเศรษฐศาสตร์และข้อเสนอเพื่ อปรับราคายา Omalizumab ที่เหมาะสมสาหรับผู้ป่วยหอบหืดในประเทศไทย/2556
  114. 114. ธนะวัฒน์ วงศ์พัน/การศึกษาความคุ้มค่าทางเศรษฐศาสตร์และข้อเสนอเพื่ อปรับราคายา Omalizumab ที่เหมาะสมสาหรับผู้ป่วยหอบหืดในประเทศไทย/2556
  115. 115. Take home messages • Omalizumab is humanized anti-IgE mAb • Important treatment option for patients with moderate-to-severe or severe allergic asthma who remain uncontrolled despite current standard therapies • A number of trials are underway that are investigating efficacy, safety and roles in conditions other than asthma and urticaria
  116. 116. Thank you for your attention

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