Methods for treating atopic dermatitis by administering an il-4r antagonist

Abstract

The present invention provides methods for treating atopic dermatitis (AD). Also provided are methods for improving one or more AD-associated parameter(s), and methods for decreasing the level of at least one AD-associated biomarker in a subject in need thereof. The methods of the present invention comprise administering to a subject in need thereof a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist such as an anti-IL-4R antibody.

1 - 149 . (canceled) 
     
     
         150 . A method of treating moderate-to-severe atopic dermatitis (AD) in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds interleukin-4-receptor (IL-4R). 
     
     
         151 . The method of  claim 150 , wherein the antibody or antigen-binding fragment thereof that binds IL-4R comprises complementarity determining regions (CDRs) in a heavy chain variable region (HCVR)/light chain variable region (LCVR) sequence pair of SEQ ID NOs: 162/164. 
     
     
         152 . The method of  claim 150 , wherein the antibody or antigen-binding fragment that binds IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively. 
     
     
         153 . The method of  claim 152 , wherein the antibody or antigen-binding fragment that binds IL-4R comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO: 164. 
     
     
         154 . The method of  claim 150 , wherein the patient is resistant, non-responsive or inadequately responsive to treatment by either a topical corticosteroid (TCS) or a calcineurin inhibitor. 
     
     
         155 . The method of  claim 150 , wherein the patient, following administration of the pharmaceutical composition, exhibits an improvement in one or more AD-associated parameters. 
     
     
         156 . The method of  claim 155 , wherein the improvement in the one or more AD-associated parameters is selected from the group consisting of:
 (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 25%;   (b) a decrease from baseline in Body Surface Area Involvement of Atopic Dermatitis (BSA) score of at least 35%;   (c) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 45%;   (d) a decrease from baseline in SCORAD score of at least 30%;   (e) a decrease from baseline in 5-D Pruritus Scale of at least 15%; and   (f) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score of at least 25%.   
     
     
         157 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in IGA of at least 25% on day 22 through at least day 85 after administration of the pharmaceutical composition. 
     
     
         158 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in BSA score of at least 40% on day 29 through at least day 85 after administration of the pharmaceutical composition. 
     
     
         159 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in EASI score of at least 50% on day 29 through at least day 85 after administration of the pharmaceutical composition. 
     
     
         160 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in SCORAD score of at least 30% on day 29 through at least day 85 after administration of the pharmaceutical composition. 
     
     
         161 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in 5-D Pruritus Scale of at least 15% on day 15 through at least day 85 after administration of the pharmaceutical composition. 
     
     
         162 . The method of  claim 156 , wherein the improvement in an AD-associated parameter is a decrease from baseline in NRS score of at least 25% at the end of week 2 through at least the end of week 10 after administration of the pharmaceutical composition. 
     
     
         163 . The method of  claim 150 , wherein the pharmaceutical composition comprises about 50 mg to about 600 mg of the antibody or antigen-binding fragment thereof. 
     
     
         164 . The method of  claim 163 , wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of the antibody or antigen-binding fragment thereof. 
     
     
         165 . The method of  claim 150 , wherein the pharmaceutical composition is administered to the patient subcutaneously or intravenously. 
     
     
         166 . The method of  claim 150 , wherein a second therapeutic agent is administered to the patient before, after or concurrent with the pharmaceutical composition. 
     
     
         167 . The method of  claim 166 , wherein the second therapeutic agent is selected from the group consisting of a TCS and calcineurin inhibitor. 
     
     
         168 . A method for treating moderate-to-severe AD in a patient, the method comprising: (a) selecting a patient who exhibits an elevated level of at least one AD-associated biomarker prior to, or at the time of treatment; and (b) administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds IL-4R. 
     
     
         169 . The method of  claim 168 , wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs in a HCVR/LCVR sequence pair of SEQ ID NOs: 162/164. 
     
     
         170 . The method of  claim 168 , wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively. 
     
     
         171 . The method of  claim 170 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO: 164. 
     
     
         172 . The method of  claim 168 , wherein the AD-associated biomarker is IgE. 
     
     
         173 . The method of  claim 172 , wherein the patient is selected on the basis of exhibiting an IgE level of greater than 1500 kU/L prior to or at the time of treatment (“baseline”). 
     
     
         174 . The method of  claim 168 , wherein the AD-associated biomarker is Thymus and Activation Regulated Chemokine (TARC). 
     
     
         175 . The method of  claim 174 , wherein the patient is selected on the basis of exhibiting a TARC level of greater than 1000 pg/mL prior to or at the time of treatment (“baseline”). 
     
     
         176 . The method of  claim 173 , wherein the patient exhibits between about 5% and 20% decrease in IgE level from baseline at day 36 or later following the administration of the pharmaceutical composition. 
     
     
         177 . The method of  claim 175 , wherein the patient exhibits between about 25% and 70% decrease in TARC level from baseline at day 4 or later following the administration of the pharmaceutical composition. 
     
     
         178 . The method of  claim 168 , wherein administration of the pharmaceutical composition to the patient results in a decrease in at least one AD-associated biomarker in the patient by day 4, 8, 15, 22, 25, 29 or 36 following administration of the pharmaceutical composition as compared to the level of the biomarker in the patient prior to the administration. 
     
     
         179 . The method of  claim 168 , wherein the patient is resistant, non-responsive or inadequately responsive to either a TCS or a calcineurin inhibitor. 
     
     
         180 . The method of  claim 168 , wherein the pharmaceutical composition comprises about 50 mg to about 600 mg of the antibody or antigen-binding fragment that specifically binds IL-4R. 
     
     
         181 . The method of  claim 180 , wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of the antibody or antigen-binding fragment that specifically binds IL-4R. 
     
     
         182 . The method of  claim 168 , wherein the pharmaceutical composition is administered subcutaneously or intravenously to the patient. 
     
     
         183 . The method of  claim 168 , wherein a second therapeutic agent is administered to the subject before, after or concurrent with the pharmaceutical composition. 
     
     
         184 . The method of  claim 183 , wherein the second therapeutic agent is selected from the group consisting of a TCS and a calcineurin inhibitor. 
     
     
         185 . A method for improving one or more atopic dermatitis (AD)-associated parameter(s) in a patient in need thereof, or reducing the level of at least one AD-associated biomarker in the patient, the method comprising sequentially administering to a patient in need thereof a single initial dose of a pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds IL-4R, followed by one or more secondary doses of the pharmaceutical composition comprising the antibody or fragment thereof. 
     
     
         186 . The method of  claim 185 , wherein the antibody or fragment thereof comprises heavy and light chain CDR sequences in a HCVR/LCVR sequence pair of SEQ ID NOs: 162/164. 
     
     
         187 . The method of  claim 185 , wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively. 
     
     
         188 . The method of  claim 187 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO: 164. 
     
     
         189 . The method of  claim 185 , wherein each secondary dose is administered 1 to 8 weeks after the immediately preceding dose. 
     
     
         190 . The method of  claim 189 , wherein the one or more secondary doses of the pharmaceutical composition are administered weekly. 
     
     
         191 . The method of  claim 185 , wherein at least 4 secondary doses of the anti-IL-4R antibody are administered to the patient, and wherein each secondary dose is administered 1 week after the immediately preceding dose. 
     
     
         192 . The method of  claim 185 , wherein the initial dose and the one or more secondary doses each comprise 50 mg to 600 mg of the anti-IL-4R antibody. 
     
     
         193 . The method of  claim 192 , wherein the initial dose and the one or more secondary doses each comprise 75 mg to 300 mg of the anti-IL-4R antibody. 
     
     
         194 . The method of  claim 185 , wherein the initial dose comprises a first amount of the antibody or antigen-binding fragment thereof and the one or more secondary doses each comprise a second amount of antibody or fragment thereof. 
     
     
         195 . The method of  claim 194 , wherein the first amount of antibody or antigen-binding fragment thereof is 1.5×, 2×, 2.5× or 3× the second amount of the antibody or antigen-binding fragment thereof. 
     
     
         196 . The method of  claim 185 , wherein the pharmaceutical composition is administered to the patient subcutaneously or intravenously. 
     
     
         197 . The method of  claim 185 , wherein a second therapeutic agent is administered to the patient before, after or concurrent with one or more doses of the pharmaceutical composition. 
     
     
         198 . The method of  claim 197 , wherein the second therapeutic agent is selected from the group consisting of a TCS and a calcineurin inhibitor. 
     
     
         199 . A method of improving one or more atopic dermatitis (AD)-associated parameters in a patient in need thereof, the method comprising:
 administering a therapeutically effective amount of an anti-IL-4R antibody or antigen-binding fragment thereof concomitantly with a topical corticosteroid (TCS) to the patient, wherein the improvement in the one or more AD-associated parameters is selected from the group consisting of:
 (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 45%; 
 (b) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score of at least 60%; 
 (c) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 65%; and 
 (d) a decrease from baseline in SCORAD score of at least 50%. 
   
     
     
         200 . The method of  claim 199 , wherein the anti-IL-4R antibody or fragment thereof comprises heavy and light chain CDR sequences from the HCVR/LCVR sequence pair of SEQ ID NOs: 162/164. 
     
     
         201 . The method of  claim 199 , wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively. 
     
     
         202 . The method of  claim 199 , wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO: 164. 
     
     
         203 . The method of  claim 199 , wherein the patient has moderate-to-severe AD. 
     
     
         204 . The method of  claim 199 , wherein the TCS is selected from the group consisting of a group I TCS, group II TCS and group III TCS. 
     
     
         205 . The method of  claim 199 , wherein the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 
     
     
         206 . The method of  claim 199 , wherein the improvement in the one or more AD-associated parameters is a decrease from baseline in IGA of at least 50% on day 29 after administration of the antibody or antigen-binding fragment thereof. 
     
     
         207 . The method of  claim 199 , wherein the improvement in the one or more AD-associated parameters is a decrease from baseline in NRS of at least 65% on day 29 after administration of the antibody or antigen-binding fragment thereof. 
     
     
         208 . The method of  claim 199 , wherein the improvement in the one or more AD-associated parameters is a decrease from baseline in EASI of at least 70% on day 29 after administration of the antibody or antigen-binding fragment thereof. 
     
     
         209 . The method of  claim 199 , wherein the improvement in the one or more AD-associated parameters is a decrease from baseline in SCORAD of at least 60% on day 29 after administration of the antibody or antigen-binding fragment thereof. 
     
     
         210 . A method to reduce dependence on a topical corticosteroid (TCS) for controlling at least one symptom in a patient with moderate-to-severe AD, the method comprising:
 selecting a patient with moderate-to-severe AD;   administering a therapeutically effective amount of an anti-IL-4R antibody or antigen-binding fragment thereof concomitantly with a TCS to the patient; and   gradually reducing the amount of the TCS, while maintaining the dose of the anti-IL-4R antibody or antigen-binding fragment thereof.   
     
     
         211 . The method of  claim 210 , wherein the antibody or fragment thereof comprises heavy and light chain CDR sequences from the HCVR/LCVR sequence pair of SEQ ID NOs: 162/164. 
     
     
         212 . The method of  claim 210 , wherein the dosage of TCS is reduced by about 20% to about 50% over 4 weeks in a patient treated with the anti-IL-4R antibody as compared to a patient not treated with anti-IL-4R antibody. 
     
     
         213 . The method of  claim 210 , wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 50-600 mg.