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Anti Ig E biologics and allergic diseases

Anti Ig E biologics and allergic diseases
Presented by Pairach Supsongserm, MD.
December 18, 2020

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Anti Ig E biologics and allergic diseases

  1. 1. Anti-IgE Biologics and Allergic Diseases PAIRACH SUPSONGSERM ALLERGY AND CLINICAL IMMUNOLOGY FELLOW KING CHULALONGKORN MEMORIAL HOSPITAL 18 DECEMBER 2020
  2. 2. Outline  Introduction  Role of IgE in allergic pathophysiology  Anti-IgE biologics  Role of omalizumab in allergic diseases  Quiz
  3. 3. Introduction
  4. 4. Introduction  The discovery of IgE by Professors Kimishige and Teruko Ishizaka in 1966  Omalizumab had been first approved for in Australia (2002) followed by the United States (2003), the European Union (2005), and Japan (2009)  Used for: > Allergic asthma > Chronic urticaria > Other allergic diseases Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  5. 5. Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  6. 6. Tan HT, et al. Novel Biologicals for the Treatment of Allergic Diseases and Asthma. Curr Allergy Asthma Rep 2016.
  7. 7. Chronological Appearance of Anti-IgE Compounds Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  8. 8. Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  9. 9. Role of IgE in Allergic Pathophysiology
  10. 10. Multimorbidities Associated with Severe Allergic Asthma Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019. Mechanisms of the Development of ALLergy program (MeDALL) To identify novel mechanisms of allergy initiation during early childhood through to young adulthood 38% of allergic multimorbidities were associated with IgE sensitization
  11. 11. Structure and Receptor Interactions of IgE Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  12. 12. Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  13. 13. Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  14. 14. Anti-IgE Biologics
  15. 15. Anti-IgE Biologics  Approved monoclonal anti-IgE antibody > Omalizumab  Monoclonal anti-IgE antibody in clinical trials > Ligelizumab > Quilizumab > MEDI4212 > XmAb7195 > Omalizumab biosimilars Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.  Anti-IgE biologicals in pre-clinical evaluation > Anti-IgE designed ankyrin repeat proteins > Monoclonal anti-IgE antibody 8D6 > IgG-Fc-fusion proteins > Anti-IgE nanobodies
  16. 16. Approved Monoclonal Anti-IgE Antibody: Omalizumab  Omalizumab is a recombinant humanized immunoglobulin (IgG1) monoclonal antibody  It binds to the same C-epsilon-3 region that interacts with the IgE receptors forming complexes with free IgE  The omalizumab-IgE complexes are subsequently cleared by the hepatic reticuloendothelial system Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019. Stokes J. Anti-IgE Treatment for Disorders Other Than Asthma. Frontiers in Medicine 2017.
  17. 17. Approved Monoclonal Anti-IgE Antibody: Omalizumab  Omalizumab is specific to IgE and does not bind to IgG or IgA  It cannot bind to the IgE receptors or to IgE already attached to Fc-epsilon-RI (does not interact with cell- bound IgE or activate mast cells or basophils)  Results: > Rapid and significant decrease in free IgE levels > Decreased the expression of the high affinity FcεRI receptor on the surface of mast cells and basophils Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019. Stokes J. Anti-IgE Treatment for Disorders Other Than Asthma. Frontiers in Medicine 2017.
  18. 18. Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019.
  19. 19. Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019.
  20. 20. Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  21. 21. Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  22. 22.  19 patients with allergic asthma were treated 3 months of omalizumab  A marker of eosinophil apoptosis (annexin V) was increased in those patients treated with omalizamab and annexin-positive eosinophils were increased compared to baseline  Cellular production of GM-CSF, used for eosinophil growth and survival, was decreased
  23. 23. Monoclonal Anti-IgE Antibody in Clinical Trials: Ligelizumab  Ligelizumab is a humanized monoclonal IgG1 antibody that binds IgE with an affinity of ∼1.4 χ 10−10 M but does not interact with FcεRIα-bound IgE  It does not accelerate dissociation of pre-formed FcεRIα:IgE complexes  Ligelizumab recognizes a distinct IgE epitope, only partially overlapping with that of omalizumab  Ligelizumab binds to both Cε3 domains across the IgE-Fc dimer and favors the recognition of IgE in an open Fc conformation  It shares significantly more overlap with the binding epitope of FcεRI on IgE than omalizumab and is superior in inhibiting this interaction  Ligelizumab shows almost no overlap with the CD23-binding site and is therefore less efficient than omalizumab in blocking IgE:CD23 interactions Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  24. 24. Monoclonal Anti-IgE Antibody in Clinical Trials: Ligelizumab  Ligelizumab is predicted to have a therapeutic advantage over omalizumab in FcεRI-driven allergic disorders  Ligelizumab showed significantly better symptom control in comparison with omalizumab in a phase IIb dose-finding trial for CSU  It was also superior to omalizumab in the inhibition of primary human basophil activation and a passive systemic anaphylaxis mouse model  It might be less suitable for the treatment of allergic disorders that heavily rely on CD23-dependent processes including antigen presentation or trans-epithelial transport (eg, eosinophilic lung inflammation)  The distinct receptor inhibition profile provides a plausible explanation as to why ligelizumab lacked superior efficacy over omalizumab treatment in a phase II clinical trial with allergic asthma patients Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  25. 25. Binding Characteristics and Modes-of-Action of Ligelizumab Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  26. 26. Binding Characteristics and Modes-of-Action of Quilizumab/MEDI4212/XmAb7195 Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  27. 27. Omalizumab Biosimilars Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  28. 28. Anti-IgE Biologicals in Pre-Clinical Evaluation Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.
  29. 29. Role of Omalizumab in Allergic Diseases
  30. 30. Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019.
  31. 31. Role of Omalizumab in Allergic Diseases  Severe allergic adult asthma  Severe childhood allergic asthma  Chronic urticaria  Allergic rhinitis  Chronic rhinosinusitis  Atopic dermatitis  Food allergies Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020. Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  32. 32. Efficacy of Omalizumab in Severe Allergic Adult Asthma  Omalizumab is the first biologic that was globally approved for the treatment of severe or moderate to severe allergic asthma  Effects: > Improvement in QOL and pulmonary function > Reduction in >> Asthma symptoms (77%) >> Asthma exacerbations (43%) >> Doses of ICS/OCS Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019. Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  33. 33. Efficacy of Omalizumab in Severe Allergic Adult Asthma  A decline in serum free IgE levels from baseline to 16 or 32 weeks after treatment was associated with reduced exacerbation frequency 2 years after omalizumab treatment  Omalizumab discontinuation after 28 weeks of treatment showed that suppressed free IgE levels returned to baseline within 18- 20 weeks, which was accompanied with re- emergent of asthma symptoms Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  34. 34. GINA Guideline 2020.
  35. 35. Efficacy of Omalizumab in Severe Allergic Adult Asthma  Administered subcutaneously every two or four weeks  Dose determined according to the patient's body weight and serum total IgE levels (30- 1500 IU/mL), ranging from 75 to 600 mg Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  36. 36. Responses to Omalizumab Treatment in Atopic Eosinophilic and Atopic Non-Eosinophilic Patients  The efficacy of omalizumab may be greater in more enriched population with high type 2 biomarkers: > FeNO > Blood eosinophils > Serum periostin Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  37. 37. Role of Omalizumab in Severe Asthma Comorbidities: Aspirin-Exacerbated Respiratory Disease  Omalizumab treatment: > Reduced daily oral corticosteroid doses and frequency of asthma exacerbations > Reduction in urinary concentrations of leukotriene E4 and prostaglandin D2 metabolite > Improved asthma control > Aspirin tolerance Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  38. 38. Role of Omalizumab in Severe Asthma Comorbidities: Allergic Bronchopulmonary Aspergillosis  A systematic review of 102 cases from 30 published literature summarized beneficial effects of omalizumab treatment against ABPA: > Significant improvement in symptoms > Reduction in frequency of exacerbations > Reduction of steroid requirement Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  39. 39. Role of Omalizumab in Severe Asthma Comorbidities: Asthma-COPD Overlap  Omalizumab treatment: > Improvements in asthma outcomes similar to those in patients without ACO Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  40. 40. Reports of Omalizumab Treatment in Childhood Asthma  Omalizumab treatment in children >12 years old: > Improvement of symptoms/acute exacerbations > Reduction of ER visits  Likely to be effective in patients with Th2-type immune response  Effects of omalizumab: > Improvement in QOL of asthmatic children and adolescents > Improvement in QOL of caregivers > Reduction in ICS use > No improvement of FEV1 Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  41. 41. Reports of Omalizumab Treatment in Childhood Asthma: Viral-Infection Induced Asthma  Omalizumab treatment: > Reduced the frequency of acute exacerbation of asthma due to viral infection > Decreased the duration of rhinovirus (RV) infection/viral shedding/the risk of RV illness Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  42. 42. Reports of Omalizumab Treatment in Childhood Asthma: Laboratory Tests Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  43. 43. Reports of Omalizumab Treatment in Childhood Asthma: Laboratory Tests Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  44. 44. GINA Guideline 2020.
  45. 45. GINA Guideline 2020.
  46. 46. Omalizumab Dose Adjustment in Pediatric Patients Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  47. 47. Role of Omalizumab in Chronic Urticaria  Urticaria is characterized by repeating emergence of transient and local edema of the skin or mucosa, mostly with itch  Up to 40% of CSU may be associated with autoantibodies against IgE or FcεRI  Non-sedating 2nd generation antihistamine is the mainstay treatment  Omalizumab was approved for treatment of CSU by EMA (EU) and FDA (USA) in 2014, and PMDA (Japan) in 2017  The fixed dose of 300 mg of omalizumab every 4 weeks is optimal for CSU Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  48. 48. Mechanisms of Actions of Omalizumab in The Pathogenesis of Urticaria  Omalizumab rapidly decreases level of circulating free IgE, followed by a decrease of IgE and FcεRI on basophils and mast cells in the skin  It may explain the effect of omalizumab on the mediators release in response to IgG autoantibodies against IgE or FcεRI (type IIb autoimmunity) Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  49. 49. Treatment of Chronic Urticaria Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  50. 50. Prognosis and Parameters to Predict Efficacies of Omalizumab  The analysis of 50 studies involving 921 patients: > 89.5% complete or partial response > 10.5% no response or being refractory  Clinically apparent improvement of the symptoms is observed within a week after the first injection  Urticaria may relapse in 4-8 weeks after the last injection Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  51. 51. Effects of Omalizumab Against Allergic Rhinitis in The US and Europe  Clinical trials of omalizumab treatment against allergic rhinitis have been conducted for several years by subcutaneous injection  Different from doses used in asthma, the trials for hay fever have been conducted at single doses of 150 mg or 300 mg of omalizumab Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019. Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  52. 52. Effects on Japanese Cedar Pollinosis in Japan  Placebo-controlled comparative study (2002) and a comparative study (2003) with an anti- allergy drug were conducted on JC  The amount of omalizumab was determined according to body weight and IgE level immediately before administration in December as 0.0016 mg/kg/IgE (IU/mL) and revised every 4 weeks  IgE was uniformly reduced to the detection limit (50 ng/mL) in the administration group Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  53. 53. Effects on Japanese Cedar Pollinosis in Japan Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  54. 54. Effects on Japanese Cedar Pollinosis in Japan Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.
  55. 55. ARIA Guideline 2019.
  56. 56. Omalizumab in Chronic Rhinosinusitis Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  57. 57. Omalizumab in Atopic Dermatitis Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  58. 58. Omalizumab in Food Allergies Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  59. 59. Omalizumab in Food Allergies Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
  60. 60. Stokes J. Anti-IgE Treatment for Disorders Other Than Asthma. Frontiers in Medicine 2017.
  61. 61. Quiz
  62. 62. Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019.
  63. 63. Finish…

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