Biologic agents in allergic diseases Presented by Amornrat Prasertcharoensuk, MD. February1, 2019

1. Biologics (Monoclonal Antibodies)
in Allergic Diseases
Amornrat Prasertcharoensuk, MD.
Division of Allergy and Clinical Immunology
Faculty Medicine, King Chulalongkorn Memorial Hospital

2. Monoclonal Antibodies

3. Outline
Asthma
Chronic urticaria
Rhinitis with nasal polyp
Atopic dermatitis
Phenotype and endotype >> approach to specific biologic agent for a specific patient

4. Asthma

5. Zhu et al. Potential new targets for drug development in severe asthma World Allergy Organization Journal 2018
Activation type 2-high and type 2-low inflammatory pathways

6. Zhu et al. Potential new targets for drug development in severe asthma World Allergy Organization Journal 2018
Activation type 2-high and type 2-low inflammatory pathways

7. Asthma
Curr Opin Allergy Clin Immunol 2018, 18:509–518

8. MURARO ET AL, Precision medicine in patients with allergic diseases, J Allergy Clin Immunol 2016;137:1347-58

9. • Humanized monoclonal antibody, binds to the Fc portion (CH3
domain) of the immunoglobulin E (IgE) molecule
• Omalizumab’s mechanisms of action include decreased levels of
circulating free IgE, expression of the IgE receptor FcεRI on critical
effector cells, inflammation, and allergen-induced mediator release
Omalizumab
Jeffry R. Stokes and Thomas B. Casel Anti-Immunoglobulin E Therapy. Middleton 8th edition

10. Omalizumab
Jeffry R. Stokes and Thomas B. Casel Anti-Immunoglobulin E Therapy. Middleton 8th edition

11. Jeffry R. Stokes and Thomas B. Casel Anti-Immunoglobulin E Therapy. Middleton 8th edition
Omalizumab

12. Hanania NA, Wenzel S, Rosen K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187:804–811
Asthma exacerbation rate

13. Jeffry R. Stokes and Thomas B. Casel Anti-Immunoglobulin E Therapy. Middleton 8th edition
Omalizumab

14. Jeffry R. Stokes and Thomas B. Casel Anti-Immunoglobulin E Therapy. Middleton 8th edition

15. Anti-IgE in allergic disease
B. Balbino et al. / Pharmacology & Therapeutics 191 (2018) 50–64
Qulizumab(anti M1prime),Ligelizumab,
Lumiliximab(anti CD23) : No longer in
clinical development
J Allergy Clin Immunol 2017;139:1411-21
IgE-blocking strategies. There have been 4 mAb
strategies that target IgE (anti-M1 prime, anti-CD23,
anti–IL-4/IL-13, and anti-IgE)

16. Zhu et al. Potential new targets for drug development in severe asthma World Allergy Organization Journal 2018
Anti– IL-5

17. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21
Anti– IL-5 strategies
Mepolizumab
(Nucala®)
Anti-IL-5 Humanized IgG1
Reslizumab
(Cinqair®)
Anti-IL-5 Humanized IgG4
Benralizumab Anti-IL-5Rα with
ADCC
Humanized IgG1

18. T.V. Saco et al. / Ann Allergy Asthma Immunol 120 (2018) 357–366

19. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014
Mepolizumab
MENSA

20. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014

21. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014

22. Lancet 2012; 380: 651–59

23. Aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations
Eosinophilic phenotype, by eosinophil count >300 cells per µL in 12 months before screening,
or > 150 cells per µL at screening (blood)
Lancet Respir Med 2017; 5: 390–400
MUSCA

24. Lancet Respir Med 2017; 5: 390–400

25. Mepolizumab
• Higher blood eosinophil more likely benefit
• Reduced asthma exacerbation
• Improved FEV1
• Corticosteroid sparing effects
• Not approved for any other eosinophilic conditions
Mepolizumab
J Allergy Clin Immunol 2017;139:1411-21

26. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21
Anti– IL-5 strategies
Mepolizumab
(Nucala®)
Anti-IL-5 Humanized IgG1
Reslizumab
(Cinqair®)
Anti-IL-5 Humanized IgG4
Benralizumab Anti-IL-5Rα with
ADCC
Humanized IgG1

27. Asthma was
inadequately controlled by medium-to-high doses of
inhaled corticosteroid based therapy and who had blood
eosinophils of 400 cells per μL or higher and one or more
exacerbations in the previous year
Lancet Respir Med 2015; 3: 355–66

28. CHEST 2016; 150(4):799-810

29. Reslizumab
J Allergy Clin Immunol 2017;139:1411-21
Approved for severe asthma with an eosinophilic phenotype
Formulation is IV on a monthly weight based schedule (3 mg/kg)

30. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21
Anti– IL-5 strategies
Mepolizumab
(Nucala®)
Anti-IL-5 Humanized IgG1
Reslizumab
(Cinqair®)
Anti-IL-5 Humanized IgG4
Benralizumab Anti-IL-5Rα with
ADCC
Humanized IgG1
Pharmacology & Therapeutics 169 (2017) 57–77

31. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage
inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;
Benralizumab

32. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage
inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;

33. BUSSE ET AL, J ALLERGY CLIN IMMUNOL
VOLUME 143, NUMBER 1 JANUARY 2019

34. Baseline characteristic
BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

35. Rate of clinically significant exacerbations
BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

36. Rate of exacerbations requiring ED visits/hospitalization
BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

37. Change from baseline in ACQ
BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

38. BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

39. BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

40. Results
BUSSE ET AL, J ALLERGY CLIN IMMUNOL VOLUME 143, NUMBER 1 JANUARY 2019

41. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21
Dupilumab
Fully human IgG4,
Anti-IL-4Rα
Pharmacology & Therapeutics 169 (2017) 57–77

42. BOGUNIEWICZ, J Allergy Clin Immunol Pract 2017;5:1477-87

43. T.V. Saco et al. / Ann Allergy Asthma Immunol 120 (2018) 357–366
Dupilumab

44. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018; 378:2486–2496.

45. IL-13 blocking strategies
• IL-13 stimulates bronchial epithelial cells to produce
periostin and DPP-4
• Tralokinumab and lebrikizumab are mAbs againts IL-13
• Lebrikizumab’s effect on FEV1 were greater in patients
with higher periostin value (8.2% vs 1.6%) respectively1
• But the development of lebrikizumab of asthma has
been stopped
• Tralokinumab has also had variable results in clinical
trials
1Corren J, et al.N Engl J Med 2011;365:1088-1098
Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21

46. Doran et al. IL-13 in Asthma and Other Eosinophilic Disorders, Front. Med. 4:139, September 2017

47. Doran et al. IL-13 in Asthma and Other Eosinophilic Disorders, Front. Med. 4:139, September 2017

48. N Engl J Med 2011

49. Doran et al. IL-13 in Asthma and Other Eosinophilic Disorders, Front. Med. 4:139, September 2017

50. Strategies against epithelial cell alarmins
 Airway epithelium-derived cytokines,
such as IL23, IL33 and thymic stromal
lymphopoietin(TSLP)
 Treatment with AMG 157( an mAb to
TSLP) has been reported to reduce
allergen-induced early and late
asthmatic response, blood and
sputum eosinophil counts, and Feno
values
Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21

51. Strategies against epithelial cell alarmins
Varricchi et al, Front. Immunol. 9:1595, 2018

52. PGD2
www.thelancet.com/respiratory Vol 4 September 2016

53. Expert Opinion on Pharmacotherapy 2018

54. Zhu et al. World Allergy Organization Journal (2018) 11:30
Clinical trials/Novel Targets

55. FDA approved therapies in Severe Asthma
Zhu et al. Potential new targets for drug development in severe asthma World Allergy Organization Journal

56. American Journal of Rhinology & Allergy, 2018

57. MURARO ET AL, Precision medicine in patients with allergic diseases, J Allergy Clin Immunol 2016;137:1347-58

58. T.V. Saco et al. / Ann Allergy Asthma Immunol 120 (2018) 357–366

59. Zhu et al. Potential new targets for drug development in severe asthma World Allergy Organization Journal 2018
Activation type 2-high and type 2-low inflammatory pathways

60. Asthma
Type 2 – low asthma
CXCR2 antagonist (SCH527123) : given 4 weeks
 Reduced sputum neutrophil but not improved in lung functions or
symptom score
CXCR2 antagonist( AZD5069) :
 Not reduce the frequency of severe exacerbation in patients with
uncontrolled severe asthma
Nair P et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum
neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2012;42:1097-103
O’Byrne PM, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled
persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016

61. Asthma
Type 2 – low asthma
IL 17 induce production of IL 8
IL 17 levels reported increased in the sputum with severe asthma
IL- 17 blocker( Brodalumab) : not show benefits in asthma
: show significant mental health issues
(risk for suicide)
J Allergy Clin Immunol 2017;139:1411-21

62. L.A. Manka and M.E. Wechsler / Ann Allergy Asthma Immunol 121 (2018) 406-413
Biologic Medications Approved for use or studied in Severe Asthma

63. L.A. Manka and M.E. Wechsler / Ann Allergy Asthma Immunol 121 (2018) 406413

64. Chronic Urticaria
JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017

65. JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017

66. Omalizumab
JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017
Responder with in 12 weeks
Duration of therapy cessation resulted in an increase in weekly symptoms and returning to placebo levels within 16 weeks

67. JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017
Omalizumab

68. Adeeb Bulkhi et al, Immunol Allergy Clin N Am 37 (2017) 95–112
Omalizumab

69. Anti-IgE mAbs (under inverstigation)
JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017
Ligelizumab (humanized IgG1 mAb) 6-fold to 9-fold increase in potency in vivo
for ligelizumab compared with omalizumab with a similar safety profile
Quilizumab, a humanized IgG1
Quilizumab or placebo for a 20-week
30% decrease in serum IgE was found in the quilizumab group a
no statistical difference was observed

70. Other biologic for CU
JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017

71. Hirono and Ichida, Pediat Therapeut 2015, 5:3
Other biologic for CU

72. Adeeb Bulkhi et al, Immunol Allergy Clin N Am 37 (2017) 95–112

73. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21

74. Federici et al. Anti-IL-1 treatment in autoinflammatory diseases, October 2013
IL-1 blockade

75. JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017

76. JOSHI AND KHAN, J ALLERGY CLIN IMMUNOL PRACT NOVEMBER/DECEMBER 2017

77. Rhinitis with nasal polyps

78. MURARO ET AL, Precision medicine in patients with allergic diseases, J Allergy Clin Immunol 2016;137:1347-58

79. Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21
T.V. Saco et al. / Ann Allergy Asthma Immunol 120 (2018) 357–366
Nasal polyposis
- Mucosal eosinophilia correlates with increased
chance of nasal polyps recurrence after surgery
- Predominant T2 cytokine profiles

80. American Journal of Rhinology & Allergy, 2018

81. MURARO ET AL, Precision medicine in patients with allergic diseases, J Allergy Clin Immunol 2016;137:1347-58
Pathogenesis of Atopic dermatitis

82. MURARO ET AL, Precision medicine in patients with allergic diseases, J Allergy Clin Immunol 2016;137:1347-58

83. BOGUNIEWICZ, J Allergy Clin Immunol Pract 2017;5:1477-87

84. KENNEDY, HEIMALL, AND SPERGEL, J Allergy Clin Immunol 2018;142:1740-7
Biologic with Atopic dermatitis

85. KENNEDY, HEIMALL, AND SPERGEL, J Allergy Clin Immunol 2018;142:1740-7
T.V. Saco et al. / Ann Allergy Asthma Immunol 120 (2018) 357–366
Atopic dermatitis
Dupilumab approved for treatment of moderate to severe atopic
dermatitis in adults, with a fixed dose of 300 mg SC every 2 weeks

86. Omalizumab Anti IL 5 Dupilumab
Asthma
Chronic urticaria
Nasal polyps
Atopic dermatitis
Conclusion
Thomas B. Casale, MD, J Allergy Clin Immunol 2017;139:1411-21