# US 2019/0169299 A1 · Methods for treating or preventing asthma by administering an il-4r antagonist

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- Number: US 2019/0169299 A1
- Document ID: US20190169299A1
- Status: Published application
- Kind: A1
- Application number: 16/173,848
- Filed: 2018-10-29
- Published: 2019-06-06
- Earliest claimed: 2017-10-30
- Assignees: Sanofi Biotechnology; Regeneron Pharmaceuticals, Inc.
- Applicants: Sanofi Biotechnology; Regeneron Pharmaceuticals, Inc.
- Inventors: Nikhil Amin; Neil Graham; Gianluca Pirozzi; Ariel Teper
- Web page: https://patentgrep.com/patent/US20190169299A1

## CPC

- C07K 16/2866: {against receptors for cytokines, lymphokines, interferons}
- A61B 5/445: {Evaluating skin irritation or skin trauma, e.g. rash, eczema, wound, bed sore}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 11/06: Antiasthmatics
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides methods for treating or preventing asthma and associated conditions in a patient. The methods featured in the invention comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.

## Claims

### Claim 1

A method for treating a subject having severe uncontrolled asthma comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the plurality of maintenance doses is administered during a treatment phase comprising an induction phase, an oral corticosteroid (OCS) reduction phase, and an OCS maintenance phase, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementary determining region (CDR) sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
a maintenance dose of antibody or antigen-binding fragment thereof is administered once every other week (q2w);
the loading dose is about 600 mg of the antibody or the antigen-binding fragment thereof;
each maintenance dose of antibody or antigen-binding fragment thereof is about 300 mg of the antibody or the antigen-binding fragment thereof;
a maintenance dose of antibody or antigen-binding fragment thereof is administered every fourth week (q4w);
the maintenance doses are about 500 mg of the antibody or the antigen-binding fragment thereof;
each maintenance dose of antibody or antigen-binding fragment thereof is about 750 mg of the antibody or the antigen-binding fragment thereof;
the maintenance doses of antibody or antigen-binding fragment thereof are administered for at least 24 weeks;
a first maintenance dose of antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of antibody or antigen-binding fragment thereof; or
the loading dose is eliminated.

### Claim at position 3

3-9. (canceled)

### Claim 10 (depends on 1)

The method of claim 1, wherein:
the OCS reduction phase is about 16 weeks in length; or
OCS use by the subject is reduced during the OCS reduction phase, optionally wherein the subject uses 50%, 75%, 90% or less OCS in the maintenance phase compared to the induction phase, or optionally wherein OCS use by the subject is reduced to about 5 mg/day or less in the maintenance phase, or optionally wherein administration of the OCS is reduced and/or eliminated in the maintenance phase; or
OCS use by the subject is optimized prior to treatment with the antibody or antigen-binding fragment thereof; or
the OCS is prednisone or prednisolone.

### Claim at position 5

11-16. (canceled)

### Claim 17 (depends on 1)

The method of claim 1, wherein:
the subject has a blood eosinophil count of less than about 150 cells/μl, greater than or equal to about 150 cells/μl, or greater than about 300 cells/μl; or
the subject experiences a reduction in annualized severe asthma exacerbations; or the subject experiences an improvement in lung function as measured by forced expiratory volume (FEV1) or by forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75).

### Claim at position 7

18-23. (canceled)

### Claim 24 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2.

### Claim at position 9

25-26. (canceled)

### Claim 27

A method for treating a subject having severe uncontrolled asthma comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the plurality of maintenance doses are administered during a treatment phase comprising an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively;1 or
a method for treating a subject having severe uncontrolled asthma comprising:
administering to the subject a loading dose of about 600 mg of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof, wherein each maintenance dose is about 300 mg of the antibody or antigen-binding fragment thereof,
wherein the plurality of maintenance doses is administered during a treatment phase comprising an induction phase, an oral corticosteroid (OCS) reduction phase, and a maintenance phase, and
wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences from the HCVR/ LCVR sequence pair comprising SEQ ID NOs: 1 and 2; or
a method for improving an FEVi score in a subject having moderate-to-severe uncontrolled asthma, comprising administering to the subject q2w or q4w an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R such that the subject exhibits an improvement in FEV1 score at week 4, week 12 or week 24 following administration of the antibody or antigen binding fragment, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for improving a forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75) score in a subject having moderate-to-severe uncontrolled asthma, comprising administering to the subject q2w or q4w an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R, such that the subject exhibits an improvement in FEF25-75 score at week 4 or week 24 following administration of the antibody or antigen binding fragment, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for reducing an annualized severe exacerbation rate in a subject having moderate-to-severe uncontrolled asthma, comprising administering to the subject q2w or q4w an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method of reducing or eliminating oral corticosteroid (OCS) use in a subject suffering from steroid dependent severe asthma, the method comprising
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein a reduction of at least 50% in OCS use is achieved at week 24 following administration of the loading dose, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for treating a subject having oral corticosteroid (OCS)-dependent, moderate-to-severe asthma comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for improving asthma control in a subject having oral corticosteroid-dependent asthma comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof, and
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for treating a subject having moderate-to-severe uncontrolled asthma wherein onset of asthma occurred when the subject was greater than 40 years of age comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for treating a subject having moderate-to-severe uncontrolled asthma and one or both of co-morbid chronic rhinosinusitis and nasal polyposis comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

### Claim at position 11

28-29. (canceled)

### Claim 30 (depends on 27)

The method of claim 27, wherein:
the dosage is about 200 mg q2w, about 300 mg q2w, about 500 mg q4w, or about 750 mg q4w; or
the loading dose is eliminated.

### Claim at position 13

31-38. (canceled)

### Claim 39 (depends on 27)

The method of claim 27, wherein:
the subject has a blood eosinophil count of less than about 150 cells/μl;
the subject has a blood eosinophil count of greater than or equal to about 150 cells/μl;
the subject has a blood eosinophil count of greater than about 300 cells/μl;
the subject has an FeNO level of greater than or equal to 25 ppb;
the subject has an FeNO level of between greater than or equal to about 25 ppb and about 50 ppb;
the subject has an FeNO level of greater than or equal to 50 ppb; or
the subject exhibits at least a 10% or 25% reduction in a biomarker selected from the group consisting of FeNO, eotaxin-3, total IgE, periostin and thymus and activation regulated chemokine (TARC) at week 4, week 12 or week 24 following administration of the IL-4R antibody or fragment thereof.

### Claim at position 15

40-55. (canceled)

### Claim 56 (depends on 27)

The method of claim 27, wherein:
the OCS use is reduced to less than 5 mg per day at week 24 following administration of the loading dose;
the dependency on OCS use is substantially eliminated after a period of time following administration of the loading dose, optionally wherein the period of time is after 40 weeks, 45 weeks, 50 weeks, 52 weeks or greater;
the OCS is prednisone or prednisolone;
a reduction of at least 75% in OCS use is achieved;
a reduction of at least 90% in OCS use is achieved; or
the OCS-dependent asthma is oral corticosteroid-dependent severe asthma.

### Claim at position 17

57-59. (canceled)

### Claim 60 (depends on 27)

The method of claim 27, wherein:
the loading dose is about 600 mg of the antibody or the antigen-binding fragment thereof;
the maintenance doses are about 300 mg of the antibody or the antigen-binding fragment thereof;
the maintenance doses are administered for at least 24 weeks;
a first maintenance dose of antibody or antigen-binding fragment thereof is administered two weeks after the loading dose of antibody or antigen-binding fragment thereof;
a maintenance dose of antibody or antigen-binding fragment thereof is administered once every other week (q2w);
a maintenance dose of antibody or antigen-binding fragment thereof is administered every fourth week (q4w);
the maintenance doses are about 500 mg of the antibody or the antigen-binding fragment thereof;
the maintenance doses are about 750 mg of the antibody or the antigen-binding fragment thereof.

### Claim at position 19

61-66. (canceled)

### Claim 67 (depends on 27)

The method of claim 27, wherein the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

### Claim at position 21

68-79. (canceled)

### Claim 80 (depends on 88)

The method of claim 88, wherein the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

### Claim at position 23

81-84. (canceled)

### Claim 85

A method for treating a subject having oral corticosteroid-dependent asthma or moderate-to-severe asthma and co-morbid moderate-to-severe atopic dermatitis comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

### Claim at position 25

86-87. (canceled)

### Claim 88

A method for treating a subject having moderate-to-severe uncontrolled asthma and co-morbid allergic rhinitis comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or
a method for improving allergic rhinitis-related quality of life of a subject having moderate-to-severe uncontrolled asthma and co-morbid allergic rhinitis comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; or p1 a method for improving allergic rhinitis-related quality of life in a subject having oral corticosteroid-dependent asthma comprising:
administering to the subject a loading dose of an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-,4R); and
administering to the subject a plurality of maintenance doses of the antibody or the antigen-binding fragment thereof,
wherein the loading dose and the plurality of maintenance doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively.

### Claim at position 27

89-90. (canceled)

### Claim 91 (depends on 88)

The method of claim 88, wherein morning and evening daily asthma symptoms are improved.

### Claim 92

(canceled)

### Claim 93 (depends on 27)

The method of claim 27, wherein health related quality of life is improved.

### Claim 94

(canceled)

### Claim 95 (depends on 85)

The method of claim 85, wherein:
the loading dose is 400 mg and the maintenance doses are 200 mg, and the maintenance doses are administered every other week;
the loading dose is 600 mg and the maintenance doses are 300 mg, and the maintenance doses are administered every other week; or
the antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

### Claim 96 (depends on 85)

The method of claim 85, wherein the subject is an adult, the subject is an adolescent, or the subject is 12 years of age or older.

### Claim 97 (depends on 1)

The method of claim 1, wherein the subject is an adult, the subject is an adolescent, or the subject is 12 years of age or older.

### Claim 98 (depends on 27)

The method of claim 27, wherein the subject is an adult, the subject is an adolescent, or the subject is 12 years of age or older.