Methods for treating atopic dermatitis by administering an il-4r antagonist 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
CA2883936 A1 2014-03-13 [CA2883936] / 2014-03-13
申请号/申请日
2013CA-2883936 / 2013-09-04
发明人
ARDELEANU MARIUS;GRAHAM NEIL;HAMILTON JENNIFER D;KIRKESSELI STEPHANE C;KUNDU SUDEEP;MING JEFFREY;RADIN ALLEN;ROCKLIN ROSS E;WEINSTEIN STEVEN P;
申请人
REGENERON PHARMACEUTICALS;SANOFI;
主分类号
IPC分类号
A61P-017/00C07K-016/28G01N-033/53
摘要
(CA2883936) 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.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2012US-61697972 2012-09-07 2012US-61738715 2012-12-18 2013FR-0056759 2013-07-10 2013US-61748588 2013-01-03 2013US-61764624 2013-02-14 2013US-61768229 2013-02-22 2013US-61770091 2013-02-27 2013US-61782420 2013-03-14 2013US-61816191 2013-04-26 2013WO-US5789
主权利要求
(CA2883936) 1. A method of treating moderate-to-severe atopic dermatitis (AD) in a patient resistant, non-responsive or inadequately responsive to treatment by either a topical corticosteroid (TCS) or a calcineurin inhibitor, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4- receptor (IL-4R) antagonist to the patient. 2. A method of treating moderate-to-severe atopic dermatitis (AD) in a patient, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4-receptor (IL-4R) antagonist to the patient, wherein the administration of the IL-4R antagonist to the patient results in an improvement in an AD- associated parameter, wherein the improvement in the AD-associated parameter is selected from the group consisting of: (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 40%; (b) a decrease from baseline in Body Surface Area Involvement of Atopic Dermatitis (BSA) score of at least 40%; (c) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 55%; (d) a decrease from baseline in SCORAD score of at least 40%; (e) a decrease from baseline in 5-D Pruritus Scale of at least 25%; and (f) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score of at least 45%. 3. A method of treating moderate-to-severe atopic dermatitis (AD) in a patient resistant, non-responsive or inadequately responsive to treatment by either a topical corticosteroid (TCS) or a calcineurin inhibitor, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4- receptor (IL-4R) antagonist to the patient, wherein the administration of the IL-4R antagonist to the patient results in an improvement in an AD-associated parameter, wherein the improvement in the AD-associated parameter is selected from the group consisting of: (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 40%; (b) a decrease from baseline in Body Surface Area Involvement of Atopic Dermatitis (BSA) score of at least 40%; (c) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 55%; (d) a decrease from baseline in SCORAD score of at least 40%; (e) a decrease from baseline in 5-D Pruritus Scale of at least 25%; and (f) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score of at least 45%. 19. A method for treating, decreasing, reducing, ameliorating or preventing pruritus in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL- 4R) antagonist. 31. A method for treating or preventing 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 IL-4R antagonist. 32. A method for treating or preventing moderate-to-severe AD in a patient resistant, non-responsive or inadequately responsive to either a TCS or a calcineurin inhibitor, 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 IL-4R antagonist. 48. A method for treating atopic dermatitis (AD) in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds interleukin-4 receptor (IL-4R), wherein administration of the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker in the subject 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 subject prior to the administration. 49. A method for treating atopic dermatitis (AD) in a subject resistant, non-responsive or inadequately responsive to either a TCS or a calcineurin inhibitor, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds interleukin-4 receptor (IL-4R), wherein administration of the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker in the subject 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 subject prior to the administration. 62. A method for improving one or more atopic dermatitis (AD)-associated parameter(s) in a subject in need thereof, or reducing the level of at least one AD-associated biomarker in the subject, the method comprising sequentially administering to a subject in need thereof a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, followed by one or more secondary doses of the pharmaceutical composition comprising the IL-4R antagonist. 73. A method for improving one or more atopic dermatitis (AD)-associated parameter(s) in a subject in need thereof, or reducing the level of at least one AD-associated biomarker in the subject, the method comprising administering to the subject a pharmaceutical composition comprising about 75 mg to about 300 mg of an antibody or antigen binding fragment thereof that specifically binds IL-4R, wherein the pharmaceutical composition is administered to the subject at a dosing frequency of once a week. 81. A method for enhancing or potentiating an immune response to an antigen in a subject, the method comprising administering a pharmaceutical composition comprising the antigen and an IL-4R antagonist. 82. A method for enhancing or potentiating an immune response to an antigen in a subject, the method comprising (a) administering a vaccine composition comprising the antigen to the subject; and (b) administering an IL-4R antagonist prior to, concurrent with, and/or subsequent to administration of the vaccine composition to the subject. 84. A pharmaceutical composition to enhance or potentiate an immune response against an antigen in a subject, the composition comprising: (a) the antigen; and (b) an IL-4R antagonist. 86. A method of treating moderate-to-severe atopic dermatitis (AD) in a patient, the method comprising administering a therapeutically effective amount of an interleukin-4-receptor (IL-4R) antagonist concomitantly with a topical corticosteroid (TCS) to the patient, wherein the administration results in an improvement in an AD-associated parameter, wherein the improvement in the AD-associated parameter is selected from the group consisting of: (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 50%; (b) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score of at least 65%; (c) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 70%; and (d) a decrease from baseline in SCORAD score of at least 60%. 93. A method of monitoring whether a therapeutic dose of an interleukin-4 receptor (IL- 4R) antagonist administered to a human subject is safe, said method comprising: acquiring information regarding the safety of the antagonist following administration to a human, wherein the information includes the occurrence of one or more events selected from the group consisting of an anaphylactic reaction or acute allergic reaction requiring immediate treatment, severe injection site reaction lasting longer than 24 hours, severe infection, any parasitic infection, alanine aminotransferase (ALT) increase >= 2 Upper Limit Normal Range (ULN), QTc >=500 ms, pregnancy, overdose, and herpes simplex type II viral infection; determining that the one or more said events has occurred, determining that said therapeutic dose is not safe, and, optionally advising that the therapeutic dose be discontinued or lowered. 98. A method of monitoring whether a therapeutic dose of an interleukin-4 receptor (IL- 4R) antagonist administered to a human subject is safe, said method comprising: acquiring information regarding the safety of the antagonist following administration to a human, wherein the information includes the occurrence of one or more events selected from the group consisting of anaphylactic reaction or acute allergic reaction requiring immediate treatment, severe injection site reaction lasting longer than 24 hours, severe infection, any parasitic infection, alanine aminotransferase (ALT) increase >= 2 Upper Limit Normal Range (ULN), QTc >=500 ms, pregnancy, overdose, and herpes simplex type II viral infection; determining that the one or more of said events has not occurred; and determining that said therapeutic dose is safe. 103. A method of quantifying or monitoring an amount of anti-drug antibodies in blood serum of a human subject following administration of drug wherein the drug is an interleukin-4 receptor (IL-4R) antagonist, said method comprising: (a) obtaining a sample of said blood serum from a human subject who was administered a dose of said IL-4R antagonist; and (b) determining the amount of anti-drug antibodies in said serum sample. 110. A therapeutic dosage form of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, wherein administration of the dose form to a human provides one or more of: (a) an area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to real time (AUC Iast) from about 4 mg=h/ml to about 20 mg=h/ml; (b) a maximum plasma concentration observed (C max) from about 15 ug/ml to about 42 ug/ml; (c) a first time to reach a maximum plasma concentration (tmax) from about 40 hr to about 280 hr; (d) an area under the plasma concentration versus time curve extrapolated to infinity (AUC) from about 5,000,000ng/h*mL to about 25,000,000 ng/h*mL and (e) a time to reach terminal half-life of (t1/2z) from about 50 h to about 200 h. 117. A method of comparing an interleukin-4 receptor (IL-4R) antagonist manufactured by a first process and proposed equivalent second process, said method comprising acquiring information regarding the safety of the antagonist following administration of the antagonist manufactured by the first process to a first human, and following administration of the antagonist manufactured by the second process to a second human, wherein the information includes: one or more events selected from the group consisting of an anaphylactic reaction or acute allergic reaction requiring immediate treatment, severe injection site reaction lasting longer than 24 hours, severe infection, any parasitic infection, alanine aminotransferase (ALT) increase >= 2 Upper Limit Normal Range (ULN), QTc >=500 ms, pregnancy, overdose, and herpes simplex type II viral infection; and wherein if the information is not significantly different for the antagonist manufactured by the first process and the antagonist manufactured by the second process, then the two processes are determined to be acceptable for manufacturing equivalent antagonists; and wherein if the information is determined to be significantly different for the antagonist manufactured by the first process and the antagonist manufactured by the second process, then the two processes are determined to be unacceptable for manufacturing equivalent antagonists. 122. A method of comparing an interleukin-4 receptor (IL-4R) antagonist manufactured by a first process and proposed equivalent second process, said method comprising: acquiring information regarding a therapeutic dose of the antagonist following administration of the dose of the antagonist manufactured by the first process to a first human, and following administration of the dose of the antagonist manufactured by the second process to a second human, wherein the information includes one or more of: (a) area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to real time (AUC Iast) from about 4 mg - h/ml to about 20 mg - h/ml; (b) maximum plasma concentration observed (C max) from about 15 ug/ml to about ug/ml; (c) first time to reach a maximum plasma concentration (tmax) from about 40 hr to about 280 hr; (d) area under the plasma concentration versus time curve extrapolated to infinity (AUC) from about 5,000,000ng/h*mL to about 25,000,000 ng/h*mL and (e) time to reach terminal half-life of (t1/2z) from about 50 h to about 200 h, wherein if the information is not significantly different for the antagonist manufactured by the first process and the antagonist manufactured by the second process, then the two processes are determined to be acceptable for manufacturing equivalent antagonists; and wherein if the information is determined to be significantly different for the antagonist manufactured by the first process and the antagonist manufactured by the second process, then the two processes are determined to be unacceptable for manufacturing equivalent antagonists. 123. A method for monitoring the effectiveness of treatment of moderate-tosevere AD in a subject comprising: (a) determining the expression level of one or both of TARC and serum IgE in a biological sample acquired from the subject before treatment with an IL-4R antagonist; (b) determining the expression level of one or both of TARC and serum IgE in a biological sample acquired from the subject aftertreatment with the IL-4R antagonist; (c) comparing the level determined in step (a) with the level in step (b); and (d) concluding that the treatment is effective when the level determined in step (b) is lower than the level determined in step (a), or concluding that the treatment is not effective when the level determined in step (b) is the same or higher than the level determined in step (a). 125. A method for monitoring a subject's response to treatment with an IL-4R antagonist, wherein the subject has moderate-to-severe AD, the method comprising: (a) acquiring information regarding the expression level of one or both of TARC and IgE in a biological sample from the subject following administration of the IL-4R antagonist to the subject; and (b) providing an indication that the treatment should be continued if the expression level of TARC or IgE has decreased as compared to the level before treatment with the IL-4R antagonist. 126. An IL-4R antagonist for use in treatment and/or prevention of atopic dermatitis. 127. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen binding fragment thereof for use in the treatment and/or prevention of atopic dermatitis. 139. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen binding fragment thereof for use in treatment of AD in a subject, wherein the treatment results in an improvement in an AD-associated parameter. 142. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen binding fragment thereof for use in treatment of AD in a subject having an elevated level of an AD-associated biomarker prior to, or at the time of treatment, wherein the AD- associated biomarker is selected from one or both of TARC or serum IgE. 143. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen binding fragment thereof for use in treatment of AD in a subject, wherein the treatment results in a decrease in an AD-associated biomarker in the subject by day 4, 8, 15, 22, 25, 29 or 36 following treatment as compared to the level of the biomarker in the subject prior to treatment, wherein the AD-associated biomarker is selected from one or both of TARC or serum IgE. 144. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen binding fragment thereof for use in improving an AD-associated parameter, or for reducing the level of an AD-associated biomarker in a subject, wherein the pharmaceutical composition is sequentially administered to the subject as a single initial dose followed by one or more secondary doses.
法律状态
(CA2883936) LEGAL DETAILS FOR CA2883936  Actual or expected expiration date=2033-09-04    Legal state=ALIVE    Status=PENDING     Event publication date=2013-09-04  Event code=CA/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=CA CA2883936  Application date=2013-09-04  Standardized application number=2013CA-2883936     Event publication date=2014-03-13  Event code=CA/A1  Event type=Examination events  Application laid open  Publication country=CA  Publication number=CA2883936  Publication stage Code=A1  Publication date=2014-03-13  Standardized publication number=CA2883936
专利类型码
A1
国别省市代码
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