Methods for treating or preventing asthma by administering IL-4R antagonists

Abstract

This provides a method for treating moderate to severe uncontrolled asthma. [Solution] The method involves administering a combination therapy comprising i) one or more maintenance doses of inhaled corticosteroids (ICS), ii) one or more maintenance doses of long-acting β2-adrenergic agonists (LABAs), iii) a loading dose of approximately 400 to 600 mg of an interleukin-4 receptor (IL-4R) antagonist, and iv) one or more maintenance doses of approximately 200 to 300 mg of an IL-4R antagonist, wherein the ICS and LABA are administered during the period of continuous administration of the IL-4R antagonist.

Claims

1. A method for treating moderate to severe uncontrolled asthma in a person requiring it, wherein the person requires: i) One or more maintenance doses of inhaled corticosteroids (ICS), ii) long-acting β ２ One or more maintenance doses of an adrenaline stimulant (LABA), iii) A loading dose of approximately 400 to 600 mg of interleukin-4 receptor (IL-4R) antagonists, iv) A maintenance dose of 1 or more of approximately 200 to 300 mg of an IL-4R antagonist. The method comprising administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

2. The method according to claim 1, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

3. The method according to claim 2, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs. 1 / 2.

4. The method according to claim 3, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity-determining region (HCDR) sequences, each comprising sequence numbers 3, 4, and 5, and three light chain complementarity-determining (LCDR) sequences, each comprising sequence numbers 6, 7, and 8.

5. The method according to claim 4, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

6. The method according to claim 5, wherein the antibody is dupilumab.

7. The method according to claim 1, wherein one or more maintenance doses are administered every two weeks (q2w).

8. The method according to claim 1, wherein one or more maintenance doses are administered every four weeks (q4w).

9. The method according to claim 2, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

10. The method according to claim 9, wherein one or more maintenance doses are administered for at least 24 weeks.

11. The method according to claim 9, wherein the subject has a blood eosinophil count selected from the groups consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

12. The method according to claim 2, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

13. The method according to claim 12, wherein one or more maintenance doses are administered for at least 24 weeks.

14. The method according to claim 12, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

15. The method according to claim 2, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

16. The method according to claim 15, wherein one or more maintenance doses are administered for at least 24 weeks.

17. The method according to claim 15, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

18. The method according to claim 2, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

19. The method according to claim 18, wherein one or more maintenance doses are administered for at least 24 weeks.

20. The method according to claim 18, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

21. The method according to claim 2, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

22. The method according to claim 1, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

23. The method according to claim 1, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

24. The method according to claim 1, wherein LABA is selected from the group consisting of formoterol and salmeterol.

25. The method according to claim 1, wherein ICS is mometasone phlomate and LABA is formoterol.

26. The method according to claim 1, wherein ICS is budesonide and LABA is formoterol.

27. The method according to claim 1, wherein IC is fluticasone propionate and LABA is salmeterol.

28. The target group is selected from the group consisting of those aged 18 years or older, those aged 12 to under 18 years, those aged 6 to under 12 years, and those aged 2 to under 6 years, as described in claim 1. The method.

29. The subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) Forced expiratory volume (FEV1) before loading dose administration of IL-4R antagonist (40-80% predicted normal value); iii) Juniper Asthma Management Questionnaire, 5-question version (ACQ-5) score of 1.5 or higher prior to loading dose administration of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 1, wherein the patient has moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following.

30. A method for increasing FEV1 in liters of a subject requiring it, wherein the subject: i) One or more maintenance doses of IC ii) One or more maintenance doses of LABA, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

31. The method according to claim 30, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

32. The method according to claim 31, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair containing SEQ ID NO: 1 / 2.

33. The method according to claim 32, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

34. The method according to claim 32, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

35. The method according to claim 31, wherein the antibody is dupilumab.

36. The method according to claim 30, wherein one or more maintenance doses are administered at q2w.

37. The method according to claim 30, wherein one or more maintenance doses are administered at q4w.

38. The method according to claim 31, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

39. The method according to claim 38, wherein one or more maintenance doses are administered for at least 24 weeks.

40. The method according to claim 38, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

41. The method according to claim 31, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

42. The method according to claim 41, wherein one or more maintenance doses are administered for at least 24 weeks.

43. The method according to claim 41, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

44. The method according to claim 31, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

45. The method according to claim 44, wherein one or more maintenance doses are administered for at least 24 weeks.

46. The method according to claim 44, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

47. The method according to claim 31, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

48. The method according to claim 47, wherein one or more maintenance doses are administered for at least 24 weeks.

49. The method according to claim 47, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

50. The method according to claim 31, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

51. The method according to claim 30, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

52. The method according to claim 30, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

53. The method according to claim 30, wherein LABA is selected from the group consisting of formoterol and salmeterol.

54. The method according to claim 30, wherein ICS is mometasone phlomate and LABA is formoterol.

55. The method according to claim 30, wherein ICS is budesonide and LABA is formoterol.

56. The method according to claim 30, wherein ICS is fluticasone propionate and LABA is salmeterol.

57. The method according to claim 30, wherein the subjects are selected from the group consisting of subjects aged 18 years or older, subjects aged 12 to under 18 years, subjects aged 6 to under 12 years, and subjects aged 2 to under 6 years.

58. The subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) FEV1 40-80% predicted normal value before loading dose administration of IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations); or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 30, wherein the patient has moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following.

59. A method for improving one or more asthma-related parameters in a subject requiring such improvement, wherein the subject: i) One or more maintenance doses of IC ii) One or more maintenance doses of LABA, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) Maintenance dose of 1 or more of approximately 200 to 300 mg of IL-4R antagonist The method comprising administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

60. The method according to claim 59, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

61. The method according to claim 60, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

62. The method according to claim 61, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

63. The method according to claim 61, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

64. The method according to claim 60, wherein the antibody is dupilumab.

65. The method according to claim 59, wherein one or more maintenance doses are administered at q2w.

66. The method according to claim 59, wherein one or more maintenance doses are administered at q4w.

67. The method according to claim 60, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

68. The method according to claim 67, wherein one or more maintenance doses are administered for at least 24 weeks.

69. The method according to claim 67, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

70. The method according to claim 60, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

71. The method according to claim 70, wherein one or more maintenance doses are administered for at least 24 weeks.

72. The method according to claim 70, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

73. The method according to claim 60, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

74. The method according to claim 73, wherein one or more maintenance doses are administered for at least 24 weeks.

75. The method according to claim 73, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

76. The method according to claim 60, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

77. The method according to claim 76, wherein one or more maintenance doses are administered for at least 24 weeks.

78. The method according to claim 76, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

79. The method according to claim 60, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

80. The method according to claim 59, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

81. The method according to claim 59, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

82. The method according to claim 59, wherein LABA is selected from the group consisting of formoterol and salmeterol.

83. The method according to claim 59, wherein ICS is mometasone phlomate and LABA is formoterol.

84. The method according to claim 59, wherein ICS is budesonide and LABA is formoterol.

85. The method according to claim 59, wherein ICS is fluticasone propionate and LABA is salmeterol.

86. The method according to claim 59, wherein the subjects are selected from the group consisting of subjects aged 18 years or older, subjects aged 12 to under 18 years, subjects aged 6 to under 12 years, and subjects aged 2 to under 6 years.

87. The target is the GINA 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) FEV1 40-80% predicted normal value before loading dose administration of IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations); or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 59, wherein the patient has moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following.

88. One or more asthma-related parameters are: (1) Relative percentage change from baseline in forced expiratory volume in one second (FEV1) during week 12; (2) Annual rate of asthma management loss events during the treatment period; (3) Annual rate of severe exacerbation events during the treatment period; (4) Time to asthma management loss event during the treatment period; (5) Time to severe exacerbation event during the treatment period; (6) Time to asthma management loss event during the entire study period; (7) Time to a severe exacerbation event during the entire study period; (8) Utilization of medical resources; (9) In week 12: i) Morning and evening asthma symptom scores, ii) ACQ-5 score, iii) AQLQ score, iv) Morning and evening PEF, v) Number of inhalations per day of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief, vi) Waking up in the middle of the night Change from baseline; (10) In weeks 12 and 24: i) 22-item sinus outcome test (SNOT-22), ii) Hospital Anxiety and Depression Score (HADS), iii) EuroQual Questionnaire (EQ-5D-3L or EQ-5D-5L), iv) Numerical Rating Scale for Itch Change from baseline The method according to claim 59, selected from the group consisting of the following.

89. Loss of Asthma Control (LOAC) events include the following: i) Six or more additional salbutamol / albuterol or levosalmola / levalbuterol puffs over a 24-hour period for two consecutive days compared to baseline, or ii) A four-fold or greater increase in the dose of corticosteroids at the second visit, or iii) Use of systemic corticosteroids for more than 3 days, iv) Hospitalization or emergency outpatient visit due to asthma requiring systemic corticosteroids The method according to claim 88, as defined as

90. Severe exacerbation events include the following: i) Use of systemic corticosteroids for three days or more, ii) The method according to claim 88, defined as hospitalization or emergency outpatient visit due to asthma requiring systemic corticosteroids.

91. A method for reducing an asthma patient's dependence on an ICS and / or LABA for the treatment of one or more asthma exacerbations, comprising the following steps: (a) The step of selecting patients with moderate to severe asthma that is not controlled with background asthma treatment including ICS, LABA, or a combination thereof; and (b) To the patient: i) One or more maintenance doses of IC ii) One or more maintenance doses of LABA, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising the step of administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

92. IL-4R antagonists are antibodies or antigen-binding fragments that specifically bind to IL-4R. The method according to claim 91.

93. The method according to claim 92, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

94. The method according to claim 93, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

95. The method according to claim 93, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

96. The method according to claim 92, wherein the antibody is dupilumab.

97. The method according to claim 91, wherein one or more maintenance doses are administered at q2w.

98. The method according to claim 91, wherein one or more maintenance doses are administered at q4w.

99. The method according to claim 92, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

100. The method according to claim 99, wherein one or more maintenance doses are administered for at least 24 weeks.

101. The method according to claim 99, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

102. The method according to claim 92, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks.

103. The method according to claim 102, wherein one or more maintenance doses are administered for at least 24 weeks.

104. The method according to claim 102, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

105. The method according to claim 92, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

106. The method according to claim 105, wherein one or more maintenance doses are administered for at least 24 weeks.

107. The method according to claim 105, wherein the subject has a blood eosinophil count selected from the groups consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL. 。

108. The method according to claim 92, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

109. The method according to claim 108, wherein one or more maintenance doses are administered for at least 24 weeks.

110. The method according to claim 108, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

111. The method according to claim 92, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

112. The method according to claim 91, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

113. The method according to claim 91, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

114. The method according to claim 91, wherein LABA is selected from the group consisting of formoterol and salmeterol.

115. The method according to claim 91, wherein ICS is mometasone phlomate and LABA is formoterol.

116. The method according to claim 91, wherein ICS is budesonide and LABA is formoterol.

117. The method according to claim 91, wherein ICS is fluticasone propionate and LABA is salmeterol.

118. The method according to claim 91, wherein the patient is selected from the group consisting of subjects aged 18 years or older, subjects aged 12 to under 18 years, subjects aged 6 to under 12 years, and subjects aged 2 to under 6 years.

119. Patients should follow the GINA 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) Predicted normal FEV 140-80% before loading dose administration of IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations); or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 91, wherein the patient has moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following.

120. A method for treating moderate to severe uncontrolled asthma in a person requiring it, wherein the person requires: i) One or more maintenance doses of IC ii) One or more maintenance doses of LABA, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. This includes administering combination therapy, The ICS and LABA are administered during the period of continued administration of the IL-4R antagonist. The subject is a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL, and the method described above.

121. The method according to claim 120, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

122. The method according to claim 121, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

123. The method according to claim 122, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

124. The method according to claim 122, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

125. The method according to claim 121, wherein the antibody is dupilumab.

126. The method according to claim 120, wherein one or more maintenance doses are administered at q2w.

127. The method according to claim 120, wherein one or more maintenance doses are administered at q4w.

128. The method according to claim 121, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every two weeks.

129. The method according to claim 128, wherein one or more maintenance doses are administered for at least 24 weeks.

130. The method according to claim 128, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

131. The loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every two weeks, as requested. The method described in item 121.

132. The method according to claim 131, wherein one or more maintenance doses are administered for at least 24 weeks.

133. The method according to claim 131, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

134. The method according to claim 121, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered every four weeks.

135. The method according to claim 134, wherein one or more maintenance doses are administered for at least 24 weeks.

136. The method according to claim 134, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

137. The method according to claim 121, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered every four weeks.

138. The method according to claim 137, wherein one or more maintenance doses are administered for at least 24 weeks.

139. The method according to claim 137, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

140. The method according to claim 121, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

141. The method according to claim 120, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

142. The method according to claim 120, wherein LABA is selected from the group consisting of formoterol and salmeterol.

143. The method according to claim 120, wherein ICS is mometasone phlomate and LABA is formoterol.

144. The method according to claim 120, wherein ICS is budesonide and LABA is formoterol.

145. The method according to claim 120, wherein ICS is fluticasone propionate and LABA is salmeterol.

146. The target age groups are: those aged 18 and over, those aged 12 to under 18, and those aged 6 to under 12. The method according to claim 120, selected from the group consisting of subjects under 18 years of age and subjects between 2 and under 6 years of age.

147. The target is the GINA 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) FEV1 40-80% predicted normal value before loading dose administration of IL-4R antagonist; iii) ACQ-5 score of 1.5 or higher before administration of a loading dose of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after salbutamol / albuterol 200 μg to 400 μg (2 to 4 inhalations); or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 120, wherein the patient has moderate to severe uncontrolled asthma for 12 months or more based on one or more of the following.

148. An IL-4R antagonist for use in the treatment and / or prevention of asthma and related conditions.

149. A pharmaceutical composition comprising an anti-IL4R antibody or its antigen-binding fragment for use in the treatment and / or prevention of asthma and related conditions.

150. A method for treating moderate to severe uncontrolled asthma in a subject having low or moderate blood eosinophil levels, wherein the method is applied to the subject: i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and ii) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a treatment containing the following.

151. The method according to claim 150, relating to a patient having a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL.

152. The method according to claim 150, which applies to a patient having a blood eosinophil count of less than approximately 200 cells / μL.

153. The method according to claim 150, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

154. The method according to claim 153, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

155. The method according to claim 154, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

156. Claim 15: The antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO:

2. The method described in 5.

157. The method according to claim 156, wherein the antibody is dupilumab.

158. The method according to claim 153, wherein one or more maintenance doses are administered at q2w.

159. The method according to claim 153, wherein one or more maintenance doses are administered at q4w.

160. The method according to claim 158 or 159, wherein one or more maintenance doses are administered for at least 24 weeks.

161. The method according to claim 153, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q4w.

162. The method according to claim 161, wherein one or more maintenance doses are administered for at least 24 weeks.

163. The method according to claim 153, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q2w.

164. The method according to claim 163, wherein one or more maintenance doses are administered for at least 24 weeks.

165. The method according to claim 153, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q4w.

166. The method according to claim 165, wherein one or more maintenance doses are administered for at least 24 weeks.

167. The method according to claim 153, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q2w.

168. The method according to claim 167, wherein one or more maintenance doses are administered for at least 24 weeks.

169. The method according to claim 150, wherein the subject has an elevated level of one or more biomarkers selected from the group consisting of the following biomarkers: periostin, thymic and activating regulatory chemokines (TARC), dipeptidyl peptidase 4 (DPP4), eosinophil cationic protein (ECP), eotaxin-3, total IgE, antigen-specific IgE, and exhaled nitric oxide concentration (FeNO).

170. A method for treating moderate to severe uncontrolled asthma in subjects requiring it, wherein the subjects are between approximately 12 and 75 years of age, and the method is applied to the subjects: i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and ii) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a treatment containing the following.

171. The method according to claim 170, relating to a patient having a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL.

172. The method according to claim 170 applies to a patient having a blood eosinophil count of less than approximately 200 cells / μL.

173. The method according to claim 170, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

174. The method according to claim 173, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

175. The method according to claim 174, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

176. The method according to claim 175, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

177. The method according to claim 176, wherein the antibody is dupilumab.

178. The method according to claim 170, wherein one or more maintenance doses are administered at q2w.

179. The method according to claim 170, wherein one or more maintenance doses are administered at q4w.

180. The method according to claim 178 or 179, wherein one or more maintenance doses are administered for at least 24 weeks.

181. The method according to claim 173, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q4w.

182. The method according to claim 181, wherein one or more maintenance doses are administered for at least 24 weeks.

183. The method according to claim 173, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q2w.

184. The method according to claim 183, wherein one or more maintenance doses are administered for at least 24 weeks.

185. The method according to claim 173, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q4w.

186. A maintenance dose of one or more is administered for at least 24 weeks, as described in claim 185. The method.

187. The method according to claim 173, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q2w.

188. The method according to claim 187, wherein one or more maintenance doses are administered for at least 24 weeks.

189. The method according to claim 170, wherein the subject has an elevated level of one or more biomarkers selected from the group consisting of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

190. A method for treating moderate to severe uncontrolled asthma in a person requiring it, wherein the person requires: i) One or more oral doses of prednisone, ii) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iii) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more. The method comprising administering a combination therapy including the following.

191. The method according to claim 190, wherein each person is administered one or more oral doses of approximately 10 mg or less of prednisone.

192. The method according to claim 190, wherein each person is administered one or more oral doses of 5 mg or less of prednisone.

193. The method according to claim 190, relating to having a blood eosinophil count between approximately 200 and approximately 299 cells / μL.

194. The method according to claim 190, relating to a patient having a blood eosinophil count of less than approximately 200 cells / μL.

195. The method according to claim 190, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

196. The method according to claim 195, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

197. The method according to claim 196, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

198. The method according to claim 197, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

199. The method according to claim 198, wherein the antibody is dupilumab.

200. The method according to claim 190, wherein one or more maintenance doses are administered at q2w.

201. The method according to claim 190, wherein one or more maintenance doses are administered at q4w.

202. The method according to claim 200 or 201, wherein one or more maintenance doses are administered for at least 24 weeks.

203. The method according to claim 195, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q4w.

204. The method according to claim 203, wherein one or more maintenance doses are administered for at least 24 weeks.

205. The method according to claim 195, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q2w.

206. The method according to claim 205, wherein one or more maintenance doses are administered for at least 24 weeks.

207. The method according to claim 195, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q4w.

208. The method according to claim 207, wherein one or more maintenance doses are administered for at least 24 weeks.

209. The method according to claim 195, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q2w.

210. The method according to claim 209, wherein one or more maintenance doses are administered for at least 24 weeks.

211. The method according to claim 190, wherein the subject has an elevated level of one or more biomarkers selected from the group consisting of the following biomarkers: Eos, periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

212. A method for reducing the incidence of asthma exacerbations in one or more subjects requiring it, wherein the subject: i) One or more maintenance doses of IC ii) One or more maintenance doses of a second long-term control agent, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a combination therapy including the ICS and the second long-term asthma control agent, wherein the ICS and the second long-term asthma control agent are administered during the period of continued administration of the IL-4R antagonist.

213. Asthma exacerbations are, (a) A reduction of 30% or more from baseline in maximum morning expiratory flow rate (PEF) for two consecutive days; (b) Six or more additional seizure medication puffs of albuterol or levalbuterol in a 24-hour period for two consecutive days (compared to baseline); and (c) Asthma exacerbation requiring the following: (i) Systemic (oral and / or parenteral) steroid treatment, (ii) An increase in inhaled corticosteroids to at least four times the last dose received before discontinuation, or (iii) Hospitalization The method according to claim 212, selected from the group consisting of the following.

214. The method according to claim 212 or 213, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

215. The method according to claim 214, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

216. The method according to claim 215, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

217. The method according to claim 216, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

218. The method according to claim 217, wherein the antibody is dupilumab.

219. A method for improving the forced expiratory volume in one second (FEV1) of a subject that requires it: (i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and (ii) A pharmaceutical composition comprising a maintenance dose of 1 or more of approximately 200 to 300 mg of the IL-4R antagonist. The method comprising administering a therapeutically effective amount of a pharmaceutical composition containing the above to a subject.

220. The method according to claim 219, wherein the improvement in asthma-related parameters is an increase of at least 0.10 L of FEV1 from baseline.

221. The method according to claim 219 or 220, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

222. The method according to claim 221, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

223. The method according to claim 222, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences comprising SEQ ID NOs. 3, 4, and 5, and three LCDR sequences comprising SEQ ID NOs. 6, 7, and 8, respectively.

224. Claim 22: The antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO:

2. The method described in 3.

225. The method according to claim 224, wherein the antibody is dupilumab.

226. A method for reducing the incidence of asthma exacerbations in one or more subjects requiring it, wherein the subjects have low or moderate blood eosinophil levels and / or are between approximately 12 and approximately 75 years of age, and the method applies to the subjects: i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and ii) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a treatment containing the following.

227. Asthma exacerbations are, (a) A reduction of 30% or more from baseline in maximum morning expiratory flow rate (PEF) for two consecutive days; (b) Six or more additional seizure medication puffs of albuterol or levalbuterol in a 24-hour period for two consecutive days (compared to baseline); and (c) Asthma exacerbation requiring the following: (i) Systemic (oral and / or parenteral) steroid treatment, (ii) An increase in inhaled corticosteroids to at least four times the last dose received before discontinuation, or (iii) Hospitalization The method according to claim 226, selected from the group consisting of the following.

228. The method according to claim 226 or 227, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

229. The method according to claim 228, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

230. The method according to claim 229, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

231. The method according to claim 230, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

232. The method according to claim 231, wherein the antibody is dupilumab.

233. A method for improving FEV1 in a subject who has low or moderate blood eosinophil levels and / or is between 12 and 75 years of age, the method is (i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, (ii) A pharmaceutical composition comprising a maintenance dose of 1 or more of approximately 200 to 300 mg of the IL-4R antagonist. The method comprising administering a therapeutically effective amount of a pharmaceutical composition containing the above to a subject.

234. The method according to claim 233, wherein the improvement in asthma-related parameters is an increase of at least 0.10 L of FEV1 from baseline.

235. The method according to claim 233 or 234, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

236. The method according to claim 235, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

237. The method according to claim 236, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

238. The method according to claim 237, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

239. The method according to claim 238, wherein the antibody is dupilumab.

240. A method for treating moderate to severe uncontrolled asthma in a subject requiring such treatment, wherein the subject has low or moderate blood eosinophil levels and / or is between 12 and 75 years of age, and the method is applied to the subject: i) One or more maintenance doses of IC ii) One or more maintenance doses of a second long-term control agent, iii) Loading dose of approximately 400 to 600 mg of IL-4R antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a combination therapy including the ICS and the second long-term asthma control agent, wherein the ICS and the second long-term asthma control agent are administered during the period of continued administration of the IL-4R antagonist.

241. The method according to claim 240, wherein one or more maintenance doses of ICS are medium to high doses.

242. The method according to claim 240, wherein the subject has a blood eosinophil count between approximately 200 and approximately 299 cells / μL.

243. The method according to claim 240, which is applicable to a patient having a blood eosinophil count of less than approximately 200 cells / μL.

244. The method according to claim 1, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

245. The method according to claim 244, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

246. The method according to claim 245, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

247. Claim 24: The antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO:

2. The method described in 6.

248. The method according to claim 247, wherein the antibody is dupilumab.

249. A method for treating moderate to severe uncontrolled asthma in a person requiring it, wherein the person requires: i) One or more oral doses of prednisone, ii) One or more maintenance doses of ICS, iii) One or more maintenance doses of a second inhaled asthma long-term control agent, iv) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and v) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a combination therapy including the ICS and a second inhaled asthma long-term control agent, wherein the ICS and the second inhaled asthma long-term control agent are administered during the period of continued administration of the IL-4R antagonist.

250. The method according to claim 249, wherein one or more maintenance doses of ICS are medium to high doses.

251. The method according to claim 249, wherein each person is administered an oral dose of 1 or more of approximately 10 mg or less of prednisone.

252. The method according to claim 249, wherein each person is administered one or more oral doses of 5 mg or less of prednisone.

253. The method according to claim 249, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

254. The method according to claim 253, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

255. The method according to claim 254, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

256. The method according to claim 255, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

257. The method according to claim 256, wherein the antibody is dupilumab.

258. A method for treating moderate to severe uncontrolled asthma in subjects requiring it, wherein the subjects are between approximately 12 and 17 years of age, and the method is applied to the subjects: i) A loading dose of approximately 400 to 600 mg of IL-4R antagonist, and ii) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a treatment containing the following.

259. The method according to claim 258, wherein the subject has a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL.

260. The subject is the person described in claim 258, who has a blood eosinophil count of less than approximately 200 cells / μL. Law.

261. The method according to claim 258, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

262. The method according to claim 261, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

263. The method according to claim 262, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

264. The method according to claim 263, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

265. The method according to claim 264, wherein the antibody is dupilumab.

266. The method according to claim 258, wherein one or more maintenance doses are administered at q2w.

267. The method according to claim 258, wherein one or more maintenance doses are administered at q4w.

268. The method according to claim 266 or 267, wherein one or more maintenance doses are administered for at least 24 weeks.

269. The method according to claim 261, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q4w.

270. The method according to claim 269, wherein one or more maintenance doses are administered for at least 24 weeks.

271. The method according to claim 261, wherein the loading dose comprises 600 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 300 mg of the antibody or its antigen-binding fragment administered at q2w.

272. The method according to claim 271, wherein one or more maintenance doses are administered for at least 24 weeks.

273. The method according to claim 261, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q4w.

274. The method according to claim 273, wherein one or more maintenance doses are administered for at least 24 weeks.

275. The method according to claim 261, wherein the loading dose comprises 400 mg of the antibody or its antigen-binding fragment, and one or more maintenance doses comprise 200 mg of the antibody or its antigen-binding fragment administered at q2w.

276. The method according to claim 275, wherein one or more maintenance doses are administered for at least 24 weeks.

277. The method according to claim 258, wherein the subject has an elevated level of one or more biomarkers selected from the group consisting of the following biomarkers: eosinophils (Eos), periostin, TARC, DPP4, ECP, eotaxin-3, total IgE, antigen-specific IgE, and FeNO.

278. The method according to claim 191 or 192, wherein one or more oral doses of prednisone are administered as a daily dose.

279. The method according to claim 251 or 252, wherein one or more oral doses of prednisone are administered as a daily dose.

280. A method for treating moderate to severe uncontrolled asthma in a person requiring it, wherein the person requires: i) One or more maintenance doses of inhaled corticosteroids (ICS), ii) long-acting β ２ One or more maintenance doses of an adrenaline stimulant (LABA), iii) Interleukin-4 receptor (IL-4R) antagonist loading dose of approximately 4 mg / kg, iv) A maintenance dose of approximately 2 mg / kg of IL-4R antagonist, or 1 or more. The method comprising administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

281. The method according to claim 280, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

282. The method according to claim 281, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs. 1 / 2.

283. The method according to claim 282, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity-determining region (HCDR) sequences, each comprising sequence numbers 3, 4, and 5, and three light chain complementarity-determining region (LCDR) sequences, each comprising sequence numbers 6, 7, and 8.

284. The method according to claim 283, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

285. The method according to claim 284, wherein the antibody is dupilumab.

286. The method according to claim 280, wherein one or more maintenance doses are administered every two weeks (q2w).

287. The method according to claim 280, wherein one or more maintenance doses are administered every four weeks (q4w).

288. A method for treating moderate to severe uncontrolled asthma in a subject having low or moderate blood eosinophil levels, wherein the method is applied to the subject: i) A loading dose of approximately 4 mg / kg of IL-4R antagonist, and ii) A maintenance dose of approximately 2 mg / kg of the IL-4R antagonist, or 1 or more. The method comprising administering a treatment containing the following.

289. The method according to claim 288, relating to a patient having a blood eosinophil count between approximately 200 cells / μL and approximately 299 cells / μL.

290. The method according to claim 288, relating to a patient having a blood eosinophil count of less than approximately 200 cells / μL.

291. The method according to claim 288, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

292. The method according to claim 291, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from an HCVR / LCVR sequence pair comprising SEQ ID NO: 1 / 2.

293. The method according to claim 292, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three HCDR sequences, each comprising sequence numbers 3, 4, and 5, and three LCDR sequences, each comprising sequence numbers 6, 7, and 8.

294. The method according to claim 293, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

295. The method according to claim 294, wherein the antibody is dupilumab.

296. The method according to claim 288, wherein one or more maintenance doses are administered at q2w.

297. The method according to claim 288, wherein one or more maintenance doses are administered at q4w.

298. A method for treating persistent asthma in a subject requiring it, wherein the subject: i) One or more maintenance doses of inhaled corticosteroids (ICS) ii) long-acting β ２ One or more maintenance doses of an adrenaline stimulant (LABA), iii) A loading dose of approximately 400 to 600 mg of interleukin-4 receptor (IL-4R) antagonist, and iv) A maintenance dose of approximately 200 to 300 mg of the IL-4R antagonist, one or more doses. The method comprising administering a combination therapy including the ICS and LABA, wherein the ICS and LABA are administered during the period of continued administration of the IL-4R antagonist.

299. The method according to claim 298, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

300. The method according to claim 299, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy chain and light chain CDR sequences from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair comprising SEQ ID NOs. 1 / 2.

301. The method according to claim 300, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity-determining region (HCDR) sequences, each comprising sequence numbers 3, 4, and 5, and three light chain complementarity-determining region (LCDR) sequences, each comprising sequence numbers 6, 7, and 8.

302. The method according to claim 301, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 1 and an LCVR having the amino acid sequence of SEQ ID NO:

2.

303. The method according to claim 302, wherein the antibody is dupilumab.

304. The method according to claim 298, wherein one or more maintenance doses are administered every two weeks (q2w).

305. The method according to claim 298, wherein one or more maintenance doses are administered every four weeks (q4w).

306. The method according to claim 299, wherein the antibody or its antigen-binding fragment is administered to a subject systemically, intradermally, intravenously, or intranasally.

307. The method according to claim 298, wherein the subject has a blood eosinophil count selected from the group consisting of 300 cells / μL or more, 200 to 299 cells / μL, and less than 200 cells / μL.

308. The method according to claim 298, wherein the ICS is selected from the group consisting of mometasone furoate, budesonide, and fluticasone propionate.

309. The method according to claim 298, wherein LABA is selected from the group consisting of formoterol and salmeterol.

310. The method according to claim 298, wherein ICS is mometasone phlomate and LABA is formoterol.

311. The method according to claim 298, wherein ICS is budesonide and LABA is formoterol.

312. The method according to claim 298, wherein ICS is fluticasone propionate and LABA is salmeterol.

313. The method according to claim 298, wherein the subjects are selected from the group consisting of subjects aged approximately 18 years or older, subjects aged approximately 12 to approximately 75 years, subjects aged approximately 12 to approximately 18 years, subjects aged approximately 6 to approximately 11 years, and subjects aged approximately 2 to approximately 5 years.

314. The subjects are the International Guidelines for Asthma Management (GINA) 2009 guidelines and the following criteria: i) Existing treatments using a stable ICS / LABA dose for at least one month prior to the loading dose administration of an IL-4R antagonist (250 μg fluticasone 2x propionate twice daily, or the daily dose of an equivalent ICS); ii) Forced expiratory volume (FEV1) before loading dose administration of IL-4R antagonist (40-80% predicted normal value); iii) Juniper Asthma Management Questionnaire, 5-question version (ACQ-5) score of 1.5 or higher prior to loading dose administration of an IL-4R antagonist; iv) Reversibility of at least 12% and 200 mL of FEV1 before administration of a loading dose of an IL-4R antagonist and after 200 μg to 400 μg (2 to 4 inhalations) of salbutamol / albuterol; or v) The following events occurred within one year prior to the administration of a loading dose of an IL-4R antagonist: a) Treatment with one or more systemic (oral or parenteral) steroid bursts for asthma exacerbation, b) Hospitalization or emergency medical visit due to worsening asthma Have you ever experienced any of the following? The method according to claim 298, wherein the person has persistent asthma for 12 months or more based on one or more of the following.

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