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

1. A method for reducing the incidence of one or more asthma exacerbations in a subject suffering from severely persistent asthma comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R),

wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and

wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

2. The method of claim 1 , wherein the asthma exacerbation is selected from the group consisting of:

(a) a 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on two consecutive days;

(b) six or more additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on two consecutive days; and

(c) a deterioration of asthma requiring:

systemic (oral and/or parenteral) steroid treatment, or

(ii) an increase in inhaled corticosteroids to at least 4 times the last dose received prior to discontinuation, or

(iii) hospitalization.

3. The method of claim 1 , wherein the pharmaceutical composition comprises 75 mg to 600 mg of the antibody or antigen-binding fragment thereof.

4. The method of claim 1 , wherein the pharmaceutical composition is administered to the subject at a dosing frequency of once every two weeks.

5. A method for improving one or more asthma-associated parameter(s) in a subject suffering from severely persistent asthma comprising administering to the subject a pharmaceutical composition comprising an a therapeutically effective amount of antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy, wherein the improvement in an asthma-associated parameter is selected from the group consisting of:

(a) an increase from baseline of forced expiratory volume in 1 second (FEV1) of at least 0.10 L;

(b) an increase from baseline of morning peak expiratory flow rate (AM PEF) of at least 10.0 L/min;

(c) an increase from baseline of evening peak expiratory flow rate (PM PEF) of at least 1.0 L/min;

(d) a decrease from baseline of daily albuterol or levalbuterol use of at least 1 inhalation/day;

(e) a decrease from baseline of five-item Asthma Control Questionnaire (ACQ5) score of at least 0.5 points;

(f) a decrease from baseline of nighttime awakenings (no. of times per night) measured daily of at least 0.2 times per night; and

(g) a decrease from baseline of 22-item Sino-Nasal Outcome Test (SNOT-22) score of at least 5 points, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

6. The method of claim 5 , wherein the pharmaceutical composition comprises 75 mg to 600 mg of the antibody or antigen-binding fragment thereof.

7. The method of claim 1 , wherein the background therapy is selected from the group consisting of: a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, a leukotriene inhibitor, a corticosteroid, a methylxanthine, an NSAID, nedocromil sodium, cromolyn sodium, a long-acting beta2 agonist and an anti-fungal agent or any combinations thereof.

8. A method for treating or reducing the incidence of asthma exacerbations or improving one or more asthma-associated parameter(s) in a subject suffering from severely persistent asthma comprising administering to the subject a single initial dose of a pharmaceutical composition comprising a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R) followed by one or more secondary doses of the pharmaceutical composition,

wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and

wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

9. The method of claim 8 , wherein each of the initial dose and the secondary doses of the pharmaceutical composition comprises 75 mg to 600 mg of the antibody or antigen-binding fragment.

10. The method of claim 9 , wherein each of the secondary doses is administered 1 to 8 weeks after the immediately preceding dose.

11. A method of treating severely persistent asthma in a subject comprising:

(a) selecting a subject that has severely persistent asthma and exhibits one or both of a blood eosinophil level of at least 300 cells per microliter and a sputum eosinophil level of at least 3%; and

(b) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4-receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy.

12. A method of reducing or eliminating a severely persistent asthma patient's dependence on a background therapy comprising inhaled corticosteroids (ICS) and/or long-acting beta-agonists (LABA) for the treatment of one or more asthma exacerbations comprising:

(a) selecting a patient who has severely persistent asthma that is partially controlled or uncontrolled with a background asthma therapy comprising an ICS, a LABA, or a combination thereof;

(b) administering to the patient a defined dose of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4-receptor (IL-4R) at a defined frequency for an initial treatment period while maintaining the patient's background asthma therapy for the initial treatment period, wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160; and

(c) gradually reducing or eliminating the dosage of ICS and/or LABA administered to the patient over the course of a subsequent treatment period while continuing to administer the antibody or antigen-binding fragment thereof to the patient at the defined frequency and dose used during the initial treatment period, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

13. The method of claim 12 , wherein the ICS is fluticasone, budesonide, or mometasone.

14. A method of treating severely persistent asthma in a patient comprising:

(a) selecting a patient with an elevated level of a biomarker selected from the group consisting of thymus and activation-regulated chemokine (TARC), IgE, eotaxin-3, periostin, carcinoembryonic antigen (CEA), YKL-40, and fractional exhaled nitric oxide (FeNO); and

(b) administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

15. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR)/light chain variable region (LCVR) sequence pair of SEQ ID NOs: 162/164.

16. A method for the treatment of severely persistent asthma in a subject whose asthma is inadequately controlled with moderate-to-high dose inhaled corticosteroid (ICS) and a second controller medication, comprising sequentially administering to the subject a single initial dose of a pharmaceutical composition comprising a therapeutically effective amount of an antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof specifically binds an interleukin-4 receptor (IL-4R), and wherein administration of the single initial dose is followed by one or more secondary doses of the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof,

wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs:148, 150 and 152, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs:156, 158 and 160, and

wherein the pharmaceutical composition is an add-on maintenance treatment to the moderate-to-high dose inhaled corticosteroid (ICS) and a second controller medication, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

17. The method of claim 16 , wherein a systemic corticosteroid is administered to the subject before, after, or concurrent with the pharmaceutical composition.

18. The method of claim 16 , wherein the initial dose and the secondary doses of the pharmaceutical composition each comprise the same amount of the antibody or antigen-binding fragment.

19. The method of claim 16 , wherein the initial dose and the secondary doses of the pharmaceutical composition are administered every two weeks.

20. The method of claim 16 , wherein the initial dose and the secondary doses of the pharmaceutical composition are administered every four weeks.

21. The method of claim 1 , wherein the pharmaceutical composition administered to the subject systemically, subcutaneously, intravenously or intranasally.

22. The method of claim 5 , wherein the pharmaceutical composition is administered to the subject systemically, subcutaneously, intravenously, or intranasally.

23. The method of claim 8 , wherein the pharmaceutical composition is administered to the subject systemically, subcutaneously, intravenously, or intranasally.

24. The method of claim 8 , wherein the background therapy is selected from the group consisting of: a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, a leukotriene inhibitor, a corticosteroid, a methylxanthine, an NSAID, nedocromil sodium, cromolyn sodium, a long-acting beta2 agonist and an anti-fungal agent, or any combinations thereof.

25. The method of claim 8 , wherein at least 8 secondary doses of the antibody or antigen-binding fragment thereof are administered to the subject, wherein each of the secondary doses is administered 2 weeks after the immediately preceding dose.

26. The method of claim 12 , wherein the LABA is salmeterol or formoterol.

27. The method of claim 12 , wherein the ICS/LABA combination is fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol.

28. The method of claim 12 , wherein a patient whose background therapy comprises LABA and ICS or LABA only eliminates the dosage of LABA at the end of the subsequent treatment period.

29. The method of claim 12 , wherein the dosage of LABA and/or ICS is gradually reduced or eliminated over the course of 2 to 8 weeks.

30. A method for reducing the incidence of one or more asthma exacerbations in a subject suffering from severely persistent asthma comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an antibody that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody comprises a heavy chain variable region (HCVR)/light chain variable region (LCVR) sequence pair of SEQ ID NOs: 162/164, and wherein the pharmaceutical composition is an add-on maintenance treatment administered in combination with a background therapy, and

wherein the subject has an eosinophilic phenotype comprising a blood eosinophil level of at least 300 cells per microliter, and/or a sputum eosinophil level of at least 3%.

31. The method of claim 21 , wherein the pharmaceutical composition is administered subcutaneously with a needle and syringe, a pen delivery device, or an autoinjector.

32. The method of claim 22 , wherein the pharmaceutical composition is administered subcutaneously with a needle and syringe, a pen delivery device, or an autoinjector.

33. The method of claim 23 , wherein the pharmaceutical composition is administered subcutaneously with a needle and syringe, a pen delivery device, or an autoinjector.