TWI790457B - Methods for treating atopic dermatitis by administering an il-4r antagonist - Google Patents

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.

Description

Methods of treating atopic dermatitis by administering IL-4R antagonists

Pursuant to 35 U.S.C. § 119(e), this application claims the benefit of the following U.S. Provisional Patent Applications: 61/697,972 filed September 7, 2012; 61/738,715; 61/748,588 filed January 3, 2013; 61/764,624 filed February 14, 2013; 61/768,229 filed February 22, 2013; 61/770,091, filed March 27; 61/782,420, filed March 14, 2013; 61/816,191, filed April 26, 2013, and 35 U.S.C. § 119(b) French application 1356759, set to be filed on 10 July 2013; the foregoing disclosures are hereby incorporated by reference in their entirety.

The present invention relates to the treatment and/or prevention of atopic dermatitis and related conditions. More specifically, the invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists to treat or prevent atopic dermatitis to a patient in need thereof.

Atopic dermatitis (AD) is a chronic/relapsing inflammatory skin disease characterized by extreme itching (eg, severe pruritus) and scaly and dry eczema-like lesions. AD is often accompanied by other atopic diseases such as allergic rhinitis and asthma. Severe illness can significantly impair physical function due to severe psychological problems, significant insomnia, and impaired quality of life, leading to result in high socioeconomic costs.

The pathophysiology of AD is influenced by complex interactions between immunoglobulin E (IgE)-mediated sensitization, the immune system, and environmental factors. Primary skin defects may be an immune disorder causing IgE-mediated sensitization with epithelial barrier dysfunction as a consequence of genetic mutations and local inflammation. AD usually begins in childhood before age 5 and may persist into adulthood.

Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams, or injections. However, most treatment options provide only temporary, incomplete relief of symptoms. Furthermore, many patients with moderate to severe AD develop resistance to treatment with topical corticosteroids or calcineurin inhibitors. Therefore, there is a need in the art for new targeted therapies for the treatment and/or prevention of AD.

According to certain aspects of the present invention, there are provided methods of treating, preventing, and/or reducing the severity of symptoms of atopic dermatitis (AD), including moderate-to-severe AD. Certain embodiments of the invention relate to methods of treating, ameliorating or preventing moderate to severe AD in patients resistant to topical corticosteroid or calcineurin inhibitor therapy. In certain embodiments, the present invention discloses methods of treatment for patients with moderate to severe AD uncontrolled with topical corticosteroids or calcineurin inhibitors. The methods of the invention comprise administering to a subject or patient in need of treatment a pharmaceutical composition comprising a therapeutic amount of an interleukin-4 receptor (IL-4R) antagonist. According to certain embodiments of the invention, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4R. Exemplary anti-IL-4R antibodies useful in the context of the methods of the invention are described elsewhere herein, including in Working Example 1. In certain embodiments, the IL-4R antagonist is an anti-IL-4R antibody having the binding properties of a control antibody referred to herein as "mAb1" (e.g., an antibody comprising the complementarity determining region of mAb1 or antigen-binding fragments thereof). In one embodiment, the above-mentioned antibody or antigen-binding fragment thereof that binds to IL-4R comprises several complementarity determining regions (CDRs) in the heavy chain variable region (HCVR)/light chain variable region (LCVR) sequence pair, the The serial number of the sequence pair is: 162/164.

Certain embodiments of the present invention relate to certain methods of treating, alleviating, ameliorating or preventing pruritus in a patient comprising administering a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist. In one embodiment, the patient has moderate to severe AD. In certain embodiments, the AD patient is resistant to treatment with topical corticosteroids or calcineurin inhibitors.

In certain embodiments, the present invention includes certain methods of treating patients with moderate to severe AD comprising administering a pharmaceutical composition comprising a therapeutic amount of Antibodies or antigen-binding fragments thereof that bind IL-4R. Such improvements can be determined, measured or quantified by methods well known in the art. AD related parameters and their improvement are discussed elsewhere in this paper, including for example Working Example 7.

50%(EASI50)的有響應者百分比。 According to certain exemplary embodiments, the present invention provides methods of improving one or more AD-related parameters in a subject in need thereof. Improvements in AD-related parameters include, for example, a decrease in the "Study Director's Global Assessment" (IGA) score; a decrease in the "Atopic Dermatitis Involved Body Surface Area" (BSA) score; a decrease in the "Eczema Area and Severity Index" (EASI ) score; SCORAD score; 5-D Pruritus Index; and/or Pruritus Numeric Rating Scale (NRS) score. In some exemplary embodiments, the improvement in AD-related parameters is selected from the following group of improvements: (i) IGA score decreased by at least 25% from baseline; (ii) BSA score decreased by at least 35% from baseline; (iii) EASI score decreased from baseline A decrease from baseline of at least 45%; (iv) a decrease in SCORAD score of at least 30% from baseline; (v) a decrease in the 5-D Pruritus Index of at least 15% from baseline; (vi) a decrease in Pruritus NRS score of at least 25% from baseline; and (vii) EASI improvement

50% (EASI50) percentage of responders.

In certain embodiments, the improvement of the above-mentioned AD-related parameters comprises a decrease in IGA from baseline by at least 25% from day 22 to at least day 85 after administration of the pharmaceutical composition. The preparation comprises an antibody or antigen-binding fragment thereof that binds to IL-4R. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in BSA score from baseline of at least 40% from day 29 to at least day 85 after administration of the pharmaceutical composition. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in EASI score from baseline by at least 50% from day 29 to at least day 85 after administration of the pharmaceutical composition. In certain embodiments, the improvement of the above-mentioned AD-related parameters includes at least 70% of the subjects having at least 50% decrease in EASI score from baseline on day 29 after administration of the pharmaceutical composition. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in the SCORAD score from baseline by at least 30% from day 29 to at least day 85 after administration of the pharmaceutical composition. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in the 5-D pruritus index from baseline by at least 15% from day 15 to at least day 85 after administration of the pharmaceutical composition. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in the NRS score from baseline by at least 25% from the end of the second week to at least the 10th week after the administration of the pharmaceutical composition.

In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in IGA from baseline of at least 45% from day 85 through at least day 197 after administration of a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist agent. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in BSA score from baseline of at least 50% from day 85 through at least day 197 after administration of a pharmaceutical composition comprising a therapeutic amount of IL-4R antagonist. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in EASI score from baseline of at least 60% from day 85 to at least day 197 after administration of a pharmaceutical composition comprising a therapeutic amount of IL-4R antagonist. In certain embodiments, the improvement of the aforementioned AD-related parameters comprises a decrease in SCORAD score from baseline of at least 45% from day 85 through at least day 197 after administration of a pharmaceutical composition comprising a therapeutic amount of IL-4R antagonist. In certain embodiments, the improvement of the above-mentioned AD-related parameters comprises a decrease of at least 30% from baseline in the 5-D pruritus index from day 85 to at least day 197 after administration of a pharmaceutical composition comprising a therapeutic amount of IL-4R antagonists. In certain embodiments, the improvement of the above-mentioned AD-related parameters includes at least a 50% decrease in the NRS score from the baseline from the 85th day to at least the 197th day after the administration of the pharmaceutical composition. The compositions comprise a therapeutic amount of an IL-4R antagonist.

According to other exemplary embodiments, the present invention provides methods of treating AD in a subject, the methods comprising: (a) selecting a subject exhibiting an elevated level of at least one AD-associated biomarker, and (b) administering to the subject a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist. In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4R. In the context of the present invention, exemplary AD-associated biomarkers that may be assessed and/or measured include, but are not limited to, thymus and activation-regulated chemokine (TARC, also known as CCL17), immunoglobulin E (IgE), Eotaxin-3, lactate dehydrogenase (LDH), eosinophils, antigen-specific IgE (eg, Phadiatop ^™ test), and osteoblast-specific factors. In certain embodiments, the methods of the invention comprise determining the level of an AD-associated biomarker in a patient in need of treatment, selecting a patient with an elevated level of an AD-associated biomarker, and administering to the patient a therapeutic amount of IL -An antibody or antigen-binding fragment thereof that specifically binds to 4R. In certain embodiments, the patient is selected by obtaining data on the levels of AD-associated biomarkers in the patient. In certain embodiments, the levels of AD-associated biomarkers are determined by assays or assays known in the art or disclosed elsewhere herein. In one embodiment, patients are selected for exhibiting IgE levels above about 1500 kU/L prior to or during treatment. In one embodiment, patients are selected for exhibiting TARC levels above about 1000 pg/mL prior to or during treatment. According to a related aspect of the present invention, there are provided methods of treating AD comprising administering to a subject a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist, wherein the pharmaceutical composition administered to the subject is, after administration, On the 4th, 8th, 15th, 22nd, 25th, 29th, 36th day or later, resulting in a decrease in the level of at least one AD-related biomarker in the subject. In certain embodiments, the patient experiences a decrease in IgE levels from baseline of 5% to 20% on day 36 or later after dosing. In certain embodiments, the patient exhibits a 25% to 70% decrease in TARC levels from baseline on day 4 or later after dosing.

The present invention also provides methods for reducing the level of one or more AD-related biomarkers in a subject, or improving the level of one or more AD-related parameters in a subject. wherein the method comprises administering to a subject in need of treatment an initial dose of a pharmaceutical composition comprising an IL-4R antagonist, and then administering one or more doses of a pharmaceutical composition comprising an IL-4R antagonist The second dose of the composition.

According to certain embodiments, the present invention provides methods for reducing the level of one or more AD-related biomarkers in a subject, or improving one or more AD-related parameters in a subject, wherein the methods include About 50 mg to about 600 mg of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds IL-4R is administered to the subject. In certain embodiments, the initial dose and one or more second doses each contain from about 75 mg to about 300 mg of the antibody or antigen-binding fragment thereof. According to this aspect of the invention, the pharmaceutical composition may be administered to the subject at a dosing frequency of, for example, once a week. In certain embodiments, each second dose is administered 1 to 8 weeks after the previous dose. In certain embodiments, at least 4 doses of the antibody or antigen-binding fragment thereof are administered. In one embodiment, each second dose is administered 1 week after the previous dose. In certain embodiments, said initial dose comprises a first dose of an antibody or antigen-binding fragment thereof, and said one or more second doses each comprise a second dose of an antibody or antigen-binding fragment thereof. In certain embodiments, the first dose of the antibody or antigen-binding fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times or 5 times the second dose. In certain embodiments, the pharmaceutical composition is administered subcutaneously or intravenously.

In certain embodiments, the present invention provides methods for treating moderate to severe AD comprising the simultaneous administration of an IL-4R antagonist and a topical corticosteroid (TCS). In certain embodiments, the method further comprises determining an improvement in an AD-related parameter. In certain embodiments, the present invention provides methods for improving one or more AD-related parameters comprising administering simultaneously an IL-4R antagonist and a TCS, wherein the improvement in AD-related parameters is selected from Improvement in one of the following groups: (i) IGA score decreased by at least 45% from baseline; (ii) BSA score decreased by at least 40% from baseline; (iii) EASI score decreased by at least 65% from baseline; (iv) SCORAD score decreased from baseline by at least 50%; (v) 5-D Pruritus Index decrease of at least 25% from baseline; and (vi) Pruritus NRS score decrease of at least 60% from baseline. In some embodiments, The improvement of the above-mentioned AD-related parameters is a decrease in IGA from baseline by at least 50% on day 29 after administration of the above-mentioned antibody or antigen-binding fragment thereof that binds to IL-4R. In certain embodiments, the improvement in the aforementioned AD-related parameters is a decrease in NRS of at least 65% from baseline on day 29 after administration. In certain embodiments, the improvement in the aforementioned AD-related parameters is a decrease in EASI from baseline of at least 70% on day 29 after administration. In certain embodiments, the improvement in the aforementioned AD-related parameters is a decrease in SCORAD of at least 60% from baseline on day 29 after administration.

In certain embodiments, the TCS is selected from Group I TCS, Group II TCS, and Group III TCS. In certain embodiments, the TCS is selected from the group consisting of methylprednisolone ethylpropionate, mometasone furoate, fluticasone propionate, betamethasone valerate, and hydrocortisone butyrate.

In some related embodiments, the present invention provides methods for reducing dependence on TCS in patients with moderate to severe AD, comprising administering an IL-4R antagonist and a TCS simultaneously; The dose of TCS was reduced by 50% when co-administered IL-4R antagonists compared to subjects with antagonists. In one embodiment, the present invention provides methods of reducing the dose of TCS in the treatment of moderate to severe AD comprising the simultaneous administration of an IL-4R antagonist and a reduced dose of TCS. The dose of TCS can be reduced by, for example, 10%, 20%, 30%, 40%, or more than 50%. In one embodiment, the dose of TCS may be reduced, eg, by 10%, 20%, 30%, 40%, or 50% or more, compared to the dose used by the subject prior to administration of IL-4R antagonist therapy.

The present invention also includes an IL-4R antagonist as disclosed herein for use in treating or preventing AD, improving AD-related parameters, reducing the level of at least one AD-related biomarker, and/or treating any of the other indications disclosed herein disease or condition.

In certain embodiments, the IL-4R antagonist used in the method is an antibody or antigen-binding fragment that specifically binds to IL-4R comprising heavy and light chain CDR sequences comprising a group of HCVR derived from The heavy chain and light chain CDR sequences of the /LCVR sequence pair, the sequence numbers of the HCVR/LCVR sequence pair are: 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/ 58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260, and 262/264. In one embodiment, the antibody or antigen-binding fragment specifically binding to IL-4R comprises heavy chain and light chain CDR sequences derived from the HCVR/LCVR sequence pair, and its sequence number is: 162/164. In one embodiment, the antibody or antigen-binding fragment specifically binding to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences respectively comprising the following sequences, and their sequence numbers are: 148, 150, 152, And three light chain complementarity determining (LCDR) sequences respectively comprising the following sequences, the sequence numbers of which are: 156, 158 and 160.

In certain embodiments, the pharmaceutical composition is administered to the patient by subcutaneous injection or intravenous injection. In certain embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of an antibody or antigen-binding fragment thereof that binds IL-4R. In other embodiments, the pharmaceutical composition comprises about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of an antibody or fragment thereof that binds IL-4R.

In certain embodiments, the pharmaceutical composition is administered to the patient before, after, or simultaneously with the administration of another therapeutic agent. In certain embodiments, said another therapeutic agent is a topical corticosteroid (TCS) or a calcineurin inhibitor.

2倍正常範圍上限(ULN)、QTc>=500ms、妊娠、藥物過量，以及第二型單純皰疹病毒感染；確定上述一個或多個事件已經發生，確定所述治療劑量是不安全的，以及可選地建議終止或減少治療劑量。 In another aspect, the present invention provides methods for monitoring the safety of a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject, the methods comprising adding the antagonist to Obtaining data on its safety after administration to human patients, wherein said data includes the occurrence of one or more events selected from the following group of events: anaphylaxis or acute allergic reaction requiring immediate treatment, lasting more than 24 hours Severe injection site reactions, serious infections, any parasitic infection, elevated alanine aminotransferase (ALT) levels

2 times the upper limit of normal range (ULN), QTc >= 500 ms, pregnancy, drug overdose, and herpes simplex virus type 2 infection; determination that one or more of the above events have occurred, determination that the therapeutic dose is unsafe, and Discontinuation or dose reduction of treatment is optionally recommended.

2倍正常範圍上限(ULN)、QTc>=500ms、妊娠、藥物過量，以及第二型單純皰疹病毒感染；確定上述一個或多個事件沒有發生；以及確定所述治療劑量是安全的。 In a related aspect, the invention provides methods for monitoring the safety of a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject, the methods comprising adding Data on the safety of antagonists are obtained after administration to human patients, wherein said data include the occurrence of one or more events selected from the following group of events: anaphylaxis or acute allergic reaction requiring immediate treatment, duration of more than Severe injection site reaction within 24 hours, severe infection, any parasitic infection, elevated alanine aminotransferase (ALT) level

2 times the upper limit of normal range (ULN), QTc>=500ms, pregnancy, drug overdose, and herpes simplex virus type 2 infection; determination that one or more of the above events have not occurred; and determination that the therapeutic dose is safe.

9mM。 In one embodiment, the infection is an upper respiratory tract infection, pharyngitis, or sinusitis. In one embodiment, said injection site reaction is erythema, pain, nodules, hematoma, or pruritus. In one embodiment, the pain level is higher than 2mm VAS, such as 3mm to 30mm VAS. In one embodiment, the erythema diameter

9mM.

In one embodiment, the safe therapeutic dose is equal to or less than 500 mg. In one embodiment, the safe therapeutic dose is selected from 75 mg, 150 mg and 300 mg.

In another aspect, the invention provides methods for quantifying or monitoring plasma concentrations of anti-drug antibodies in a human subject following administration, wherein the drug is an interleukin-4 receptor (IL-4R) antagonist , the method comprising: (a) obtaining said serum sample from a human subject who received a dose of said IL-4R antagonist; and (b) determining the plasma concentration of anti-drug antibody in said sample.

2倍正常範圍上限(ULN)、QTc>=500ms、妊娠、藥物過 量，以及第二型單純皰疹病毒感染；其中，如果所述第一製程製造的拮抗劑與所述第二製程製造的拮抗劑之相應資料無顯著不同，則確定可接受將這兩種製程用於製造等效的拮抗劑；如果所述第一製程製造的拮抗劑與所述第二製程製造的拮抗劑之相應資料有顯著不同，則確定不可接受將這兩種製程用於製造等效的拮抗劑。 In another aspect, the present invention provides methods for comparing interleukin-4 receptor (IL-4R) antagonists produced by the first process and the proposed second equivalent process, respectively, said The method comprises: after administering an antagonist produced by a first process to a first human patient and an antagonist produced by a second process to a second human patient, obtaining data on the safety of the antagonist, wherein The above data include the occurrence of one or more events selected from the following group of events: anaphylaxis or acute allergic reaction requiring immediate treatment, severe injection site reaction lasting more than 24 hours, serious infection, any parasitic infection, Elevated levels of alanine aminotransferase (ALT)

2 times the upper limit of normal range (ULN), QTc>=500ms, pregnancy, drug overdose, and herpes simplex virus type II infection; wherein, if the antagonist produced by the first process is antagonistic to the antagonist produced by the second process If the corresponding data for the agent produced by the first process are not significantly different, it is determined that the two processes are acceptable for the manufacture of equivalent antagonists; if the corresponding data for the antagonist produced by the first process and the antagonist produced by the second process are Significantly different, it is determined that the two processes are not acceptable for the production of equivalent antagonists.

In a related aspect, the present invention provides methods for comparing interleukin-4 receptor (IL-4R) antagonists produced by a first process and a proposed second equivalent process, respectively, so that The method comprises: obtaining information on a therapeutic amount of an antagonist after administering an antagonist produced by a first process to a first human patient and an antagonist produced by a second process to a second human patient, wherein The data include one or more of the following data: (a) from time zero to real time (AUC _last ), from about 4mg. h/ml to about 20mg. Area under the plasma concentration-time curve calculated using the trapezoidal method in the h/ml interval; (b) the maximum observed plasma concentration ( _Cmax ) in the interval from about 15 ug/mL to about 42 ug/mL; (c) Time to first attainment of maximum plasma concentration (t _max ) over the interval from about 40 hours to about 280 hours; (d) extrapolated plasma from about 5,000,000 ng/h*mL to about 25,000,000 ng/h*mL to infinity the area under the concentration-time curve (AUC), and (e) the time to reach the terminal half-life (t _1/2 ^z ) in the interval from about 50 hours to about 200 hours; wherein, if the antagonist produced by the first process is not significantly different from the corresponding data for the antagonist produced by the second process, it is determined acceptable to use both processes for the production of equivalent antagonists; if the antagonist produced by the first process is identical to the If the corresponding data for antagonists produced by the processes are significantly different, it is determined that the two processes are not acceptable for the production of equivalent antagonists.

In another aspect, the present invention provides a therapeutic dosage form of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, wherein administration of the dosage form to a human patient yields one or more of the following: Data: (a) From time zero to real time (AUClast), from about 4 mg˙h/ml to about 20 mg˙h/ml, the area under the plasma concentration-time curve calculated using the trapezoidal method; (b) from The maximum observed plasma concentration (Cmax) in the interval from about 15 ug/mL to about 42 ug/mL; (c) the time to first reach the maximum plasma concentration (tmax) in the interval from about 40 hours to about 280 hours; ( d) the area under the plasma concentration-time curve (AUC) extrapolated to infinity from about 5,000,000 ng/h*mL to about 25,000,000 ng/h*mL, and (e) achieved over the interval from about 50 hours to about 200 hours Time of terminal half-life (t _1/2 ^z );

In one embodiment, the safe therapeutic amount is equal to or less than 500 mg. In one embodiment, the safe therapeutic amount is selected from 75 mg, 150 mg and 300 mg.

Certain aspects of the invention relate to methods and compositions useful for vaccine applications. The present invention provides methods for increasing or enhancing the immune response of a subject to an antigen. In certain embodiments, the method of increasing or enhancing an immune response to an antigen in a subject comprises administering a pharmaceutical composition comprising the antigen and an IL-4R antagonist. Certain embodiments relate to methods comprising the steps of: (a) administering to a subject a vaccine composition comprising the antigen; and (b) administering to the subject a were administered an IL-4R antagonist. The present invention also provides some pharmaceutical compositions for improving or enhancing the immune response of a subject to an antigen, these pharmaceutical compositions comprising: (a) the antigen; and (b) an IL-4R antagonist. In an exemplary embodiment, the IL-4R antagonist is an anti-IL-4R antibody (as described in Example 1 below). In certain embodiments, the IL-4R antagonist is an anti-IL-4R antibody having the binding properties of a control antibody referred to herein as "mAb1" (e.g., an antibody comprising a complementarity determining region of mAb1 or an antigen-binding fragment thereof) .

Other embodiments of the invention will become apparent upon review of the detailed description that follows.

Figure 1 shows the mean (SD) plasma concentration-time profile of functional mAbl following a single subcutaneous injection in a Cartesian coordinate system.

Figure 2 shows a schematic representation of the injection procedure and pain assessment as described in Example 5.

Figure 3 shows the proportion of responders with IGA score (score of 0 or 1) - last observation forward (LOCF) for the study described in Example 6.

Figure 4 shows the mean IGA score change from baseline - LOCF in the study described in Example 6.

Figure 5 shows the percent change from baseline in mean IGA score - LOCF for the study described in Example 6.

Figure 6 shows the mean EASI score change from baseline - LOCF in the study described in Example 6.

Figure 7 shows the percent change from baseline in the mean EASI score for the study described in Example 6 - LOCF.

Figure 8 shows the proportion of EASI 50 responders - LOCF for the study described in Example 6.

Figure 9 shows the mean BSA score change from baseline - LOCF in the study described in Example 6.

Figure 10 shows the percent change from baseline - LOCF in mean BSA score for the study described in Example 6.

Figure 11 shows the mean 5-D index change from baseline - LOCF for the study described in Example 6.

Figure 12 shows the mean 5-D index percent change from baseline - LOCF for the study described in Example 6.

Figure 13 shows the mean NRS score change from baseline - LOCF in the study described in Example 6.

Figure 14 shows the percent change from baseline in the mean NRS score for the study described in Example 6 - LOCF.

Figure 15 shows the percent change from baseline in BSA score (compared to placebo) in patients dosed with 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 16 shows the percent change from baseline in IGA score (compared to placebo) for patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 17 shows the percent change from baseline in EASI scores (compared to placebo) for patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 18 shows the percent change from baseline in the NRS score of pruritus (compared to placebo) in patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 19 shows the time course of EASI response in moderate to severe AD patients administered 300 mg anti-IL-4R antibody in the study described in Example 8.

Figure 20 shows the percentage of EASI score responders (compared to placebo) among subjects dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 21 shows the EASI response (compared to placebo) at week 4 (day 29) of the study described in Example 8, given anti-IL-4R antibody doses of 75 mg, 150 mg or 300 mg.

1的患者比例。 Figure 22 shows the IGA achieved in the study described in Example 8

1 percent of patients.

Figure 23 shows the percent change in mean EASI score from baseline to last observation carried forward (LOCF) for the study described in Example 10.

Figure 24 shows the proportion of responders by IGA score up to LOCF (score of 0 or 1) in the study described in Example 10.

Figure 25 shows the proportion of responders (decrease in score of 2 points or more) by IGA score up to LOCF in the study described in Example 10.

Figure 26 shows the proportion of EASI score responders up to LOCF (50% decrease in score from baseline) in the study described in Example 10.

Figure 27 shows the change in mean EASI score from baseline up to LOCF in the study described in Example 10.

Figure 28 shows the change in mean IGA score from baseline up to LOCF in the study described in Example 10.

Figure 29 shows the percent change in mean IGA score from baseline up to LOCF for the study described in Example 10.

Figure 30 shows the change in mean BSA score from baseline up to LOCF in the study described in Example 10.

Figure 31 shows the change in mean SCORAD score from baseline up to LOCF in the study described in Example 10.

Figure 32 shows the change in mean NRS score from baseline up to LOCF in the study described in Example 10.

Figure 33 shows the change from baseline to LOCF in the mean 5-D pruritus index for the study described in Example 10.

Figure 34 shows the percent change from baseline in the mean EASI score for the study described in Example 11 - censored LOCF.

Figure 35 shows the change from baseline in mean EASI score in the study described in Example 11 - censored LOCF.

Figure 36 shows the proportion of EASI 50 responders in the study described in Example 11 - censored LOCF method.

Figure 37 shows the time to first attainment of EASI 50 as indicated by the Kaplan-Meier plot for the study described in Example 11 - censored LOCF.

Figure 38 shows the percent change from baseline in mean IGA score for the study described in Example 11 - censored LOCF.

Figure 39 shows the change from baseline in mean IGA score in the study described in Example 11 - censored LOCF.

Figure 40 shows the proportion of responders with IGA score (score of 0 or 1) - censored LOCF method for the study described in Example 11.

1的時間-截尾LOCF法。 Figure 41 shows the Kaplan-Meier curve in the study described in Example 11 showing the first attainment of IGA

1 time-truncated LOCF method.

1的無復發的患者比例-截尾LOCF法。 Figure 42 shows the IGA at each visit in the study described in Example 11

Proportion of patients free of recurrence by the 1-censored LOCF method.

2的患者比例-截尾LOCF法。 Figure 43 shows the decline in IGA from baseline at each visit in the study described in Example 11

Proportion of patients with 2-censored LOCF method.

Figure 44 shows the percent change from baseline in mean SCORAD score for the study described in Example 11 - censored LOCF.

Figure 45 shows the change from baseline in mean SCORAD score in the study described in Example 11 - censored LOCF.

Figure 46 shows the percent change from baseline in mean pruritus NRS scores for the study described in Example 11 - censored LOCF.

Figure 47 shows the change from baseline in mean pruritus NRS score for the study described in Example 11 - censored LOCF.

Figure 48 shows the median percent change in plasma concentrations of IgE at baseline (A) and in response to various doses of mAbl or placebo (B) in the study described in Example 12.

Figure 49 shows the mean percent change in baseline (A) TARC plasma concentrations and response to various doses of mAbl or placebo (B) in the study described in Example 12.

Figure 50 shows the change in TARC concentrations (compared to placebo) for the pooled mAbl groups in the study described in Example 12.

Figure 51 shows the baseline concentration profiles of (A) TARC, (B) total IgE plasma concentrations, and (C) lactate dehydrogenase (LDH) in patients from the study described in subparagraph B of Example 12.

Figure 52 shows the median percent change from baseline in IgE as described in subparagraph B of Example 12.

Figure 53 shows the median percent change from baseline in LDH as described in subparagraph B of Example 12.

Figure 54 shows the median percent change from baseline in TARC as described in Example 12, subparagraph B.

Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the present invention, since the scope of the present invention is only limited by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about", when applied to a specific listed value, means that the value may vary within a range of not more than 1% from the listed value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (eg, 99.1, 99.2, 99.3, 99.4, etc.). The term "treat" as used herein, whether a verb or a noun, means to relieve symptoms, eliminate the cause of symptoms, or prevent or slow the onset of symptoms of the disease or condition, either temporarily or permanently.

The invention provides methods comprising administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, the expression "subject in need of treatment" means a human or non-human animal exhibiting one or more symptoms or signs of atopic dermatitis and/or having been diagnosed with atopic dermatitis. In certain embodiments, the methods of the invention can be used to treat patients who exhibit elevated levels of one or more AD-associated biomarkers (described elsewhere herein). For example, the methods of the invention comprise administering an IL-4R antagonist to a patient with elevated levels of IgE or TARC or an osteoblast-specific factor. In certain embodiments, the methods of the present invention can be used to treat AD in children under the age of one. For example, the methods of the invention can be used to treat less than 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, Infants 10 months, 11 months, or younger than 12 months. In certain embodiments, the methods of the present invention may be used to treat children and/or adolescents under the age of 18. For example, the methods of the present invention can be used to treat children under the age of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 3 years old, 3 years old, or children or adolescents under 2 years old.

In the context of the present invention, "subjects in need of treatment" may include, for example, those subjects who exhibit (or have exhibited) one or more AD-related parameters prior to treatment, such as IGA, BSA, EASI , SCORAD, 5D-itch index, and/or NRS scores, and/or elevated levels of one or more AD-associated biomarkers such as IgE and/or TARC flat rise (as described elsewhere in this article). In certain embodiments, a "subject in need of treatment" may include a subpopulation of a population that is more susceptible to AD infection or may exhibit elevated levels of AD-associated biomarkers. For example, a "subject in need of treatment" can include a subpopulation defined by a race or ethnicity within the population.

The term "atopic dermatitis" (AD) as used herein means an inflammatory skin disorder characterized by extreme itching (eg severe pruritus) and scaly and dry eczematous lesions. The term "atopic dermatitis" includes, but is not limited to, epidermal barrier dysfunction, allergies (eg, allergies to certain foods, pollens, molds, dust mites, animals, etc.), radiation exposure, and/or asthma-induced or associated AD. The present invention includes methods of treating patients with mild, moderate to severe, or severe AD. The term "moderate-to-severe AD," as used herein, is characterized by extreme itching, widespread skin lesions, and often complicated by intractable bacterial, viral, or fungal infections. Moderate to severe AD also includes chronic AD. In many cases, chronic lesions include thickened skin plaques, lichenification, and fibrous papules. In general, patients affected by moderate-to-severe AD have more than 20% of their skin area affected, or 10% of their skin area in addition to those involving the eyes, hands, and body folds. Moderate to severe AD is also thought to be present in those patients who require frequent treatment with topical corticosteroids. A patient is also considered to have moderate to severe AD when the patient is resistant or refractory to topical corticosteroids or calcineurin inhibitors or any other commonly used therapeutic agent known in the art.

The present invention includes methods for treating both exogenous AD and endogenous AD. Exogenous AD associated with IgE-mediated sensitization and elevated Th2 cytokine levels is involved in 70% to 80% of AD patients. Endogenous AD without IgE-mediated sensitization is involved in 20% to 30% of patients; the levels of IL-4 and IL-13 are lower in these patients than in exogenous AD.

10%或IGA評分

3的慢性AD患者。 The present invention includes methods for treating AD patients who are resistant, unresponsive, or inadequately responsive to topical corticosteroid (TCS) or calcineurin inhibitor therapy. The term "resistant, unresponsive or insufficiently responsive to a TCS or a calcineurin inhibitor" as used herein refers to a subject or AD patient who has been treated with a TCS or a calcineurin inhibitor, wherein said TCS / Calcineurin inhibitors are not therapeutically effective. In certain embodiments, the above terms refer to decreased patient compliance and/or toxicity and side effects and/or ineffectiveness of TCS/calcineurin inhibitors administered to alleviate, ameliorate or reduce AD symptoms. In certain embodiments, the above terms refer to moderate to severe AD patients refractory to TCS/calcineurin inhibitors. In certain embodiments, the above terms refer to AD patients whose disease cannot be controlled despite treatment with TCS and/or calcineurin inhibitors. In certain embodiments, patients who are "resistant, non-responsive, or under-responsive" to TCS or calcineurin inhibitors may not show any improvement in one or more AD-related parameters. Examples of AD related parameters are described elsewhere in this document. For example, treatment with a TCS/calcineurin inhibitor may not result in a decrease in pruritus index or EASI or BSA scores. In certain embodiments, the present invention includes methods for the treatment of moderate to severe AD previously treated with a TCS/calcineurin inhibitor for more than one month without showing a decline in one or more AD-related parameters patient. For example, the methods of the invention can be used to treat BSA score patients who have been on a stable regimen of TCS/calcineurin inhibitors

10% or IGA score

3 of chronic AD patients.

In other embodiments, the above term "subject in need of treatment" includes having received one or more TCS treatments for more than 6 months, more than 1 year, more than 2 years, more than about 5 years, more than about 7 years, or Moderate to severe AD patients over about 10 years. Such patients may wish to minimize or avoid adverse side effects of TCS. The present invention includes methods for the long-term safer and more effective management of moderate-to-severe AD in patients comprising the simultaneous administration of an IL-4R antagonist with a TCS at doses adjusted to minimize or avoid Undesirable side effects of TCS. In certain embodiments, the present invention includes methods aimed at reducing the dependence of moderate to severe AD patients on TCS; said method comprising simultaneously administering a therapeutic amount of an IL-4R antagonist with an effective TCS, wherein the patient uses The amount of TCS was reduced by about 50% compared to patients not administered IL-4R antagonists. In certain embodiments, the present invention includes methods aimed at reducing the dependence of moderate to severe AD patients on TCS; said method comprising simultaneously administering a therapeutic amount of an IL-4R antagonist with an effective TCS, wherein the patient uses The amount of TCS compared with that before treatment with IL-4R antagonist reduced by about 50%. In certain embodiments, the combination of an IL-4R antagonist and a TCS results in an additive or synergistic effect in the treatment of AD compared to monotherapy.

The term "TCS" as used herein includes Group I, Group II, Group III and Group IV topical corticosteroids. According to the World Health Organization's anatomical therapeutic classification system, corticosteroids are classified as weakly potent (group I), moderately potent (group II), and potent (group III) based on activity compared with hydrocortisone and potent (Group IV). Group IV TCS (strong) can be up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (active) is 50 to 100 times more potent than hydrocortisone, including but not limited to betamethasone valerate, betamethasone dipropionate, diflumethasone valerate, hydrocortisone 17-butyl Mometasone furoate, mometasone furoate, and methylprednisolone ethanoate. Group II TCS (moderately active) are 2 to 25 times more potent than hydrocortisone, including but not limited to clobetasone butyrate and triamcinolone acetonide. Group I TCS (low potency) includes hydrocortisone.

Although any methods and materials similar or equivalent to those described herein find use in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

Method for improving parameters related to atopic dermatitis (AD)

The present invention includes a method of improving one or more parameters associated with atopic dermatitis (AD) in a subject in need thereof, the method comprising administering to the subject a drug comprising an interleukin 4 receptor (IL-4R) antagonist pharmaceutical composition.

Examples of "AD-related parameters" include: (a) Study Director's Global Assessment (IGA); (b) Atopic Dermatitis Involved Body Surface Area (BSA); (c) Eczema Area and Severity Index (EASI) ; (d) SCORAD; (e) 5-D Pruritus Index; and (f) Pruritus Numeric Rating Scale (NRS). "Improvement in AD-related parameters" means a decrease from baseline in one or more of IGA, BSA, EASI, SCORAD, 5-D Pruritus Index, or NRS. In terms of AD-related parameters, the term "baseline" as used herein means the values of AD-related parameters before or at the time of administration of the pharmaceutical composition of the present invention.

To determine whether an AD-related parameter has been "improved," the parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the invention. For example, AD-related parameters can be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 8 after initial treatment with the pharmaceutical composition of the present invention. Day 9, Day 10, Day 11, Day 12, Day 14, Day 15, Day 22, Day 25, Day 29, Day 36, Day 43, Day 50, Day 57 , Day 64, Day 71, Day 85; or Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9 Weekend, Weekend 10, Weekend 11, Weekend 12, Weekend 13, Weekend 14, Weekend 15, Weekend 16, Weekend 17, Weekend 18, Weekend 19, Weekend 20, Weekend 21, Measured after the end of the 22nd, 23rd, 24th or more time. The difference between the parameter value at a specific time point after initial treatment and the parameter value at baseline can be used to determine whether an AD-related parameter has been "improved" (eg, decreased).

Study Moderator Global Assessment (IGA). The IGA is a scoring scale, based on a 6-point scale ranging from 0 (none) to 5 (very severe), used to determine the severity of AD and the clinical response to treatment in clinical settings. According to certain embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the patient's IGA score. For example, some methods of treatment encompassed by the invention may be administered on day 4, day 4, day 4, day 4, or day 4 of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day or later, Causes a decrease in IGA score from baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or above. In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's IGA of at least 25% from baseline. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's IGA from baseline by at least 25% on day 15 after administration. In certain embodiments of the invention, administration of the IL-4R antagonist results in a decrease in IGA from baseline of at least 35% in the subject on day 22 following administration. In some other embodiments, the administration of the IL-4R antagonist results in the subject having 85-day IGA decreased by at least 40% or at least 45% from baseline.

Body surface area (BSA) involved in atopic dermatitis. BSA is assessed for each major body part (head, trunk, arms, and legs) and is reported as a percentage of the sum of the body surface area of all major body parts involved. According to certain embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the patient's BSA score. For example, some methods of treatment encompassed by the present invention may be administered on day 4, day 4, day 4, day 4, or day 4 of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day or later, Causes a decrease in BSA score from baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or above. In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's BSA score from baseline of at least 35% following administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's BSA score from baseline by at least 35% on day 29 after administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's BSA score from baseline by at least 40% on day 29 after administration. In certain embodiments, administration of the IL-4R antagonist results in a decrease in the subject's BSA score from baseline by at least 40%, or at least 50%, on day 85 following treatment.

Eczema Area and Severity Index (EASI). EASI is a validated measure used in clinical settings to assess the severity and extent of AD. (Hanifin et al. 2001, Exp. Dermatol. 10 : 11-18). Physicians or other qualified medical professionals assess the severity of AD disease in terms of four features, on a scale of 0 (none) to 3 (severe). In addition, the area involved in AD was assessed as a percentage of the sum of the body surface areas of the head, trunk, arms, and legs and converted to a scale of 0 to 6. According to certain embodiments of the invention, administration of an IL-4R antagonist results in a decrease in the patient's EASI score. For example, some methods of treatment encompassed by the present invention may be administered on day 4, day 4, day 4, day 4, or day 4 of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day or later, Results in a decrease in EASI score from baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or above. In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's EASI score of at least 45% from baseline. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's EASI score from baseline by at least 45% on day 15 after administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's EASI score from baseline by at least 50% on day 29 after administration. In certain embodiments, administration of the IL-4R antagonist results in a decrease in the subject's EASI from baseline by at least 55% or at least 60% at day 85 following treatment.

SCORAD. The Atopic Dermatitis Score (SCORAD) is a clinical assessment of the severity (eg, degree or intensity) of atopic dermatitis, developed by the European Task Force on Atopic Dermatitis (Consensus Report of the European Task Force on Atopic Dermatitis [Consensus Report of the European Atopic Dermatitis Task Force], 1993, Dermatology (Basel) 186 (1):23-31). The extent of AD was assessed as a percentage of each defined body surface area and reported as the sum of all areas, with a maximum score of 100% (designated "A" in the overall SCORAD calculation). The severity of the six specific symptoms of AD was assessed using the following scale: none (0), mild (1), moderate (2) or severe (3) (maximum total score of 18 points, designated in the overall SCORAD calculation as "B"). Subjective assessments of pruritus and insomnia were recorded by the patient or relatives by symptom on a visual analog scale (VAS), where 0 indicated no pruritus (or insomnia), 10 was the worst pruritus (or insomnia) imaginable, The highest possible score is 20 points. This parameter is designated as "C" in the overall SCORAD calculation. The calculation formula of SCORAD is: A/5+7B/2+C. According to certain embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the patient's SCORAD score. For example, some methods of treatment encompassed by the present invention may be administered on day 4, day 4, day 4, day 4, or day 4 of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day or later, Causes a decrease in SCORAD from baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more . In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's SCORAD score of at least 30% from baseline. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's SCORAD score from baseline by at least 30% on day 29 after administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's SCORAD score from baseline by at least 35% on day 29 after administration. In certain embodiments, administration of the IL-4R antagonist results in a decrease in the subject's SCORAD score from baseline by at least 40%, or at least 45%, on day 85 following treatment.

5-D pruritus index. The 5-D Pruritus Index Scale is a 1-page, 5-item form used to assess 5 measures of pruritus in a clinical setting: degree, duration, trend, disability, and distribution. (Elman and Hynan, 2010, Brit. J. Dermatol. 162 :587-593). Each question corresponds to one of 5 measures of pruritus; patients rate their symptoms as "present" or on a scale of 1 to 5, with 5 representing the most affecting symptom. According to certain embodiments of the invention, administration of an IL-4R antagonist results in a decrease in the patient's 5-D pruritus index. For example, some methods of treatment encompassed by the present invention may be administered on day 4, day 4, day 4, day 4, or day 4 of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). 8th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day or later, Causes a decrease in the 5-D Pruritus Index from baseline by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more. In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's 5-D Pruritus Index of at least 15% from baseline. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's 5-D pruritus index from baseline by at least 15% on day 15 after administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's 5-D pruritus index from baseline by at least 20% on day 15 after administration. In certain embodiments, administration of the IL-4R antagonist results in a decrease in the subject's 5-D Pruritus Index from baseline by at least 25% or at least 30% on day 85 following treatment.

Pruritus Numeric Rating Scale (NRS). The Pruritus NRS is a single-question assessment tool used to rate the subject's worst pruritus due to AD in the previous 12 hours on a scale of 1 to 10. According to certain embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the patient's NRS score. For example, some methods of treatment encompassed by the invention may be administered within the first weekend, on the second week of administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12 or later, leading to NRS score A decrease from baseline of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more. In certain exemplary embodiments of the invention, administration of the IL-4R antagonist results in a decrease in the subject's NRS score of at least 25% from baseline. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's NRS score from baseline by at least 25% by the end of the second week after administration. In one embodiment of the invention, the administration of the IL-4R antagonist results in a decrease in the subject's NRS score from baseline by at least 30% by the end of the second week after administration. In certain embodiments, administration of the IL-4R antagonist results in a decrease in the subject's NRS score from baseline by at least 45%, or at least 50%, on day 85 following treatment.

Global Single Symptom Score (GISS). The individual components of AD lesions (erythema, infiltration/spreading, abrasions, lichenification) were assessed globally on a 4-point scale (from 0 = none to 3 = severe) using the EASI severity scale (i.e. Each component is assessed from the whole body rather than anatomical regions).

Pruritus Categorical Scale. The Pruritus Categorical Scale, a 4-point scale for assessing symptoms, has been used in AD clinical studies with a small 'compromise' effect (Kaufmann 2006). The scale is scored as follows: 0: no pruritus; 1: mild pruritus (occasional mild itching/scratching); 2: moderate pruritus (persistent or intermittent itching/scratching, does not interfere with sleep); and 3: severe pruritus (disturbing itching/scratching, sleep disturbance).

Patient-specific Eczema Measure (POEM). POEM is a validated 7-question questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults (Charman 2004). Its format is responses to seven questions (dryness, itching, peeling, cracking, insomnia, bleeding, and crying) on a scoring system of 0 to 28, with higher scores indicating poorer quality of life (QOL).

Dermatology Life Quality Index (DLQI). The DLQI is a validated 10-question questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL) (Badia 1999). Its format is a simple response to 10 questions assessing quality of life during the past week on an overall scoring system of 0 to 30; higher scores indicate poorer quality of life (QOL).

Itching QOL. Itch QOL is a validated pruritus-specific tool addressing the symptomatic, emotional and functional impact of pruritus. Has a total score and sub-scores covering the 3 impacts above. It is a reliable, valid and quick questionnaire (Desai 2008).

EQ-5D. EQ-5D is a standardized health status scale developed by EuroQOl Group to provide a simple and universal health status measure for clinical and economic assessment. As a health-related quality-of-life (QOL) measure, the EQ-5D defines health along five dimensions: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression. Each aspect has 3 levels of severity in order: "no problem" (1), "some problem" (2), "serious problem" (3). Overall health status is defined by a 5-digit number. The health status defined by the above five categories can be converted into a corresponding index score that quantifies the health status, where 0 represents "death" and 1 represents "perfect health".

HADS. HADS is a generic Likert scale for detecting anxiety and depressive states (Bjelland 2002). There were 14 questions in the questionnaire, 7 of which were related to anxiety and 7 to depression. The questionnaire is scored for each question, whether it is anxiety or depression, and the score can be between 0 and 21 points.

Overall assessment of the patient's disease state and treatment response. Patient based on a serving of 5 points A Likert scale to rate their overall health from "poor" to "very good." The patient will be asked the following question: "Consider all the ways eczema has affected you, please tick the option that corresponds to your medical condition". The answer options are: "Poor", "Good", "Good", "Very good", "Very good".

For treatment efficacy, patients rated their satisfaction with study treatment on a 5-point Likert scale (from "poor" to "very good"). The patient will be asked the following question: "How would you rate the response of your eczema to the study drug?" The response options are: "Poor", "Fair", "Good", "Very good", "Very good".

Long-term management of atopic dermatitis

The present invention includes methods for the long-term management of moderate to severe AD in patients. In certain embodiments, the methods comprise administering an IL-4R antagonist concurrently with a traditional therapeutic agent, such as topical corticosteroids (TCS). In other embodiments, the IL-4R antagonist can be an anti-IL-4R antibody as described herein.

The term "traditional therapeutic agent" as used herein refers to therapeutic agents and drugs that are commonly or traditionally used to treat AD patients. Traditional therapeutic agents include systemic therapeutic agents and topical therapeutic agents. For example, the most commonly or commonly prescribed medications are topical corticosteroids (TCS). Other examples of such therapeutic agents include, but are not limited to, topical calcineurin inhibitors, antihistamines, oral immunosuppressants, corticosteroids, systemic immunosuppressants such as methotrexate, cyclosporine, and sulfur Azathioprine. Traditional therapeutic agents are used to alleviate the symptoms of AD, but also have a number of fairly serious side effects, including diabetes, hypertension, osteoporosis, myelosuppression, nephrotoxicity, hepatotoxicity, leukopenia, and increased risk of microbial infection. Long-term use of topical agents such as corticosteroids and calcineurin inhibitors is not recommended due to the risk of irreversible skin atrophy, depigmentation, acne outbreaks, and risks associated with systemic absorption including cutaneous malignancies and lymphomas. In addition, repeated application of any topical drug therapy over a long period of time can reduce patient compliance.

As used herein, the term "long-term management of AD" refers to Treatment or containment of one or more symptoms or disease conditions of AD, typically over about 2 years, about 5 years, about 10 years, or about 20 years. Long-term management of AD includes the implementation of a treatment method or method that improves one or more AD-related parameters over a period of more than 6 months, 1 year, 2 years, or 5 years; said method includes combination with a traditional therapeutic agent such as TCS was administered in conjunction with an anti-IL-4R antibody. The dosing regimen and dosage of the IL-4R antibody and TCS can be adjusted or changed, so that one or more parameters related to AD can be significantly improved, and the toxicity caused by traditional therapeutic agents can be avoided or minimized. In certain embodiments, the IL-4R antibody can be administered at a higher loading dose to significantly improve AD-related parameters, and then maintain or maintain the improvement at lower traditional doses. The concurrently administered TCS may be administered at a reduced dose, typically about 20%, about 30%, about 40%, about 50%, or about 60%, compared to patients not treated with the IL-4R antibody. Dosing regimens and dosages are described elsewhere herein. In certain embodiments, the present invention includes methods of reducing dependence on TCS in patients with moderate to severe AD.

In certain embodiments, the invention includes methods for treating a patient suffering from AD for more than 1 year, more than about 5 years, more than about 10 years, or more than about 15 years comprising combining with a traditional therapeutic agent such as TCS is administered in conjunction with a therapeutic amount of an IL-4R antagonist.

In another aspect, the present invention includes safer and/or more effective therapeutic methods for the long-term management of moderate to severe AD in patients. As used herein, the term "safer and/or more effective treatment" refers to treatment methods that include the administration of an IL-4R antagonist in combination with a traditional therapeutic agent such as TCS such that one or more AD-related parameters are significantly improved. Improvement, and the side effects and toxicity of traditional therapeutic agents are avoided or minimized. In certain embodiments, the improvement in an AD-related parameter is selected from the group consisting of improvements in: (a) a decrease from baseline in the Study Moderator's Global Assessment (IGA) score of at least 50%; (b) the Pruritus Numeric Rating Scale (NRS) (c) Eczema Area and Severity Index (EASI) score decreased by at least 70% from baseline; and (d) SCORAD score decreased by at least 60% from baseline. In certain embodiments, doses of conventional therapeutic agents are reduced or reduced to minimize adverse side effects. In certain embodiments, the methods of treatment described herein reduce or eliminate steroid taper or stop Risk of rebound after medication.

The present invention encompasses more effective and safer therapeutic approaches in the long-term management of AD in patients, including children or young adults who may be more susceptible or sensitive to traditional therapeutic agents.

In another aspect of the present invention, methods are provided for reducing or eliminating the dependence of AD patients on traditional therapeutic agents such as TCS during the treatment of moderate to severe AD. In an embodiment of the present invention, the method comprises: selecting a patient with moderate to severe AD that cannot be controlled or only partially controlled by background therapy; administering a predetermined dose of an IL-4R antagonist to the patient during initial treatment, Preferably an anti-IL-4R antibody while maintaining the patient's background therapy during this initial treatment period; then gradually reducing the dose of one or more components of the background therapy over a subsequent treatment period while continuing to administer the IL-4R antagonist. As used herein, the term "background treatment" refers to treatment with standard or traditional therapeutic agents (described elsewhere herein) known in the art for the treatment of AD. In certain embodiments, the background therapy includes a TCS, or a topical calcineurin inhibitor. In one embodiment, the background therapy is an effective Group III TCS such as mometasone furoate or methylprednisolone ethpropionate. In certain embodiments, doses of traditional therapeutic agents such as TCS are discontinued or discontinued entirely after the initial treatment period is complete. For example, a TCS is administered during the initial treatment period but is stopped or discontinued entirely during subsequent treatment periods. In certain embodiments, the TCS dose is reduced by about 10%, about 20%, about 30%, about 40%, about 50% or more compared to the dose during the initial treatment period.

In an example of a treatment regimen in which an IL-4R antagonist is administered to a patient with moderate to severe AD, a traditional therapy such as TCS is administered as a background therapy to the patient during the initial treatment period (also known as the "stable phase") . During the subsequent treatment period (also known as the "off period"), the dose of TCS is gradually reduced by approximately 5-60% compared to the initial treatment period. In one embodiment, the TCS is discontinued, ie the dose of the TCS is gradually reduced during subsequent treatment periods until discontinued or discontinued.

In a related aspect of the invention, there are provided methods of treating AD, These approaches consisted of an add-on therapy on top of background therapy, with systematic cessation of background therapy. In certain embodiments of the invention, an IL-4R antagonist is administered to a human subject who has received background therapy for a period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months , 12 months, 18 months, 24 months or longer) (also known as "stable phase") AD patients, as an add-on treatment. In certain embodiments, said background therapy includes a TCS. This stabilization period is followed by a background therapy withdrawal period in which one or more components that make up the background therapy are discontinued, or reduced or discontinued, while additional therapy continues. In certain embodiments, the background therapeutic agent may be reduced by about 5%, about 10%, about 20%, about 30%, about 40%, about 50% or more during the rest period. The rest period may last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or longer.

Biomarkers associated with atopic dermatitis

The invention also includes methods involving the use, quantification and analysis of AD-associated biomarkers. As used herein, the term "AD-associated biomarker" refers to any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or at a certain level or amount in an AD patient. Other biomolecules present or detectable at a level or amount different from (eg, higher or lower than) the level or amount of the marker present or detectable in a non-AD patient. In certain embodiments, the term "AD-associated biomarker" includes a biomarker associated with type 2 helper T cell (Th2) driven inflammation. Illustrative examples of AD-associated biomarkers include, but are not limited to, e.g., thymus and activation-regulated chemokine (TARC, also known as CCL17), immunoglobulin E (IgE), eotaxin-3 (also known as Known as CCL26), lactate dehydrogenase (LDH), eosinophils, antigen-specific IgE (eg, Phadiatop ^™ test), and osteoblast-specific factors. The term "AD-associated biomarker" also includes genes or gene probes known in the art that are differentially expressed in AD patients compared to subjects without AD . For example, genes that are significantly up-regulated in subjects suffering from AD include, but are not limited to, second type helper T cell (Th2)-related chemokines such as CCL13, CCL17, CCL18 and CCL26; epidermal proliferation markers such as K16 and Ki67; and T cell and dendritic cell antigens CD2, CD1b and CD1c (Tintle et al 2011; J. Allergy Clin. Immunol. 128:583-593). Alternatively, "AD-associated biomarkers" also include genes that are downregulated due to AD, such as terminal differentiation proteins (e.g., loricrin, filaggrin, and involucrin) (Tintle et al 2011; J. Allergy Clin. Immunol. 128:583-593). Certain embodiments of the invention relate to the use of these biomarkers to monitor disease reversal while administering an IL-4R antagonist. Methods for detecting and/or quantifying AD-associated biomarkers are known in the art; kits for measuring such AD-associated biomarkers are available from various commercial sources; various commercial diagnostics Laboratories also offer services to measure such biomarkers.

According to certain aspects of the present invention, there are provided methods of treating AD comprising: (a) selecting a subject who exhibits an abnormal level of at least one AD-associated biomarker before or during treatment, such The abnormality is indicative of a disease state, and (b) administering to the subject a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist. In certain embodiments, patients are selected based on determining whether an AD-associated biomarker level is elevated. AD-associated biomarker levels are determined or quantified by obtaining a sample from a patient for biomarker assays known in the art. In certain other embodiments, the patient is selected based on obtaining data on elevated levels of AD-associated biomarkers in the patient. In certain embodiments of this aspect of the invention, the subject is selected for elevated levels of IgE or TARC or an osteoblast-specific factor.

For purposes of the present invention, normal IgE levels in healthy subjects are below about 114 kU/L (eg, as measured with the ^ImmunoCAP® test [Phadia, Inc. Portage, MI]). Accordingly, the present invention relates to methods comprising selecting an IgE plasma concentration greater than about 114 kU/L, greater than about 150 kU/L, greater than about 500 kU/L, greater than about 1000 kU/L, greater than about 1500 kU/L , greater than about 2000 kU/L, greater than about 2500 kU/L, greater than about 3000 kU/L, greater than about 3500 kU/L, greater than about 4000 kU/L, greater than about 4500 kU/L, or greater than about 5000 kU/L and administering to the subject a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist.

TARC levels in healthy subjects ranged from 106 ng/L to 431 ng/L with a mean of 239 ng/L. (An exemplary assay system for measuring TARC levels is the TARC Quantitative ELISA Kit provided by R&D Systems [Minneapolis, MN], product number DDN00.) Accordingly, the present invention relates to methods comprising selecting a TARC plasma concentration Greater than about 431 ng/L, greater than about 500 ng/L, greater than about 1000 ng/L, greater than about 1500 ng/L, greater than about 2000 ng/L, greater than about 2500 ng/L, greater than about 3000 ng/L, high At about 3500 ng/L, greater than about 4000 ng/L, greater than about 4500 ng/L, or greater than about 5000 ng/L in a subject, and administering to the subject a medicament comprising a therapeutic amount of an IL-4R antagonist combination.

Another AD-associated biomarker is antigen-specific IgE. Phadiatop ^™ is a variant of a commercially available serum-specific or antigen-specific IgE test for screening for allergic sensitization (Merrett et al 1987, Allergy 17:409-416). The test simultaneously detects serum-specific IgE levels after challenge with a mixture of related allergens that cause common inhalant allergies. Depending on the fluorescent response produced, the test gives a positive or negative qualitative result. A positive test result is indicated when the fluorescent response level of the patient specimen is higher than or equal to that of the control. Low levels of fluorescence in patient specimens indicate a negative test result. The invention includes methods comprising selecting a subject exhibiting a positive test result, and administering to the subject a therapeutic amount of an IL-4R antagonist.

Osteoblast-specific factor is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Studies have found that the levels of osteoblast-specific factors are up-regulated in AD patients (Masuoka et al 2012 J Clin Invest. 122(7):2590-2600.doi:10.1172/JCI58978). The invention includes methods comprising administering an IL-4R antagonist for treatment of a patient having elevated levels of an osteoblast-specific factor.

Lactate dehydrogenase (LDH) is used as a marker of tissue damage, and studies have found elevated levels of lactate dehydrogenase in AD patients (Kou et al 2012; Arch.Dermatol.Res.304:305-312). The invention includes methods comprising administering an IL-4R antagonist for treatment of a patient with elevated LDH levels.

According to some other aspects of the present invention, some methods of treating AD are provided, which include administering to a subject a pharmaceutical composition comprising a therapeutic amount of an IL-4R antagonist; In contrast, administration of the pharmaceutical composition to a subject results in at least one AD-associated biomarker (e.g., IgE, TARC, eosinophils, eotaxin-3, Antigen-specific IgE, LDH, etc.) levels decreased.

As can be understood by those of ordinary skill in the technical field of the present invention, it can be determined whether the level of an AD-related biomarker is increased or decreased by comparing the following two values: (i) in the presence of a pharmaceutical composition containing an IL-4R antagonist The level of the biomarker in the subject measured at a given time after the drug, (ii) the level of the biomarker in the patient measured before the administration of the pharmaceutical composition comprising the IL-4R antagonist (i.e. "baseline measurement value") "). For example, the predetermined time for measuring the level of the biomarker can be about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days after administration of the pharmaceutical composition comprising the IL-4R antagonist. days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days or later.

According to certain embodiments of the invention, following administration of a pharmaceutical composition comprising an IL-4R antagonist (eg, an anti-IL-4R antibody), the subject may exhibit one or more TARC and/or A drop in IgE levels. For example, according to the present invention, on about day 4 after administration of the first, second, third or fourth dose of a pharmaceutical composition comprising about 75 mg, 150 mg or 300 mg of an anti-hIL-4R antibody (e.g., mAb1 ) , day 8, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71 or day 85, subject to Subjects may show a decrease in TARC from baseline of approximately 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or above (where "baseline" is defined as the TARC level in the subject before the first administration). Also, according to the present invention, the anti-hIL-4R antibody comprising about 75 mg, 150 mg or 300 mg (e.g. About day 4, day 8, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 43 after the pharmaceutical composition of mAb1) At Day 64, Day 71, or Day 85, subjects may demonstrate a decrease in IgE from baseline of approximately 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or above (where "baseline" is defined as the first IgE levels in the subjects before the drug).

The present invention also includes methods for determining whether a subject is a suitable subject who may benefit from a pharmaceutical composition comprising an IL-4R antagonist. For example, if a subject exhibits levels of AD-related biomarkers indicative of a disease state prior to receiving a pharmaceutical composition comprising an IL-4R antagonist, it can be determined that the subject will benefit from the present invention Suitable subjects for the pharmaceutical composition (a composition comprising an anti-IL-4R antibody). In a related embodiment, the invention includes methods for treating suitable subjects, who may, for example, be more susceptible to AD due to race or ethnicity. For example, the invention includes methods comprising administering an IL-4R antagonist to African-American subjects who may be more susceptible to AD. Such subject populations may have higher levels of AD-associated biomarkers.

According to certain exemplary embodiments, a subject may be determined to be a suitable candidate for anti-IL-4R therapy if the subject exhibits one or more of the following indications: (i) IgE levels greater than 114 kU /L, above about 150kU/L, above about 500kU/L, above about 1000kU/L, above about 1500kU/L, above about 2000kU/L, above about 2500kU/L, above about 3000kU/L L, greater than about 3500 kU/L, greater than about 4000 kU/L, greater than about 4500 kU/L, or greater than about 5000 kU/L; or (ii) TARC levels greater than about 431 ng/L, greater than about 500 ng/L , greater than about 1000 ng/L, greater than about 1500 ng/L, greater than about 2000 ng/L, greater than about 2500 ng/L, greater than about 3000 ng/L, greater than about 3500 ng/L, greater than about 4000 ng/L, Above about 4500 ng/L, or above about 5000 ng/L; or (iii) a positive Phadiatop ^™ test result. Other criteria, such as other clinical indicators of AD (eg, increased IGA, BSA, EASI, SCORAD, 5-D pruritus index, and/or NRS score indicative of AD), as described elsewhere herein, may also be combined with any of the aforementioned AD- Related biomarkers are used in combination to identify whether a subject is a suitable candidate for anti-IL-4R therapy.

Interleukin-4 receptor antagonist

As disclosed in detail above, the present invention encompasses methods comprising administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist. The term "IL-4R antagonist" as used herein refers to any IL-4R that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when IL-4R is expressed on the cell surface in vitro or in vivo. medicine. Non-limiting examples of classes of IL-4R antagonists include small molecule IL-4R antagonists, aptamers against IL-4R, peptidyl IL-4R antagonists (e.g. "peptibody" molecules), and human IL-4R antagonists. An antibody or antigen-binding fragment of an antibody that specifically binds to 4R.

The terms "IL-4R", "hIL-4R" and the like used herein refer to the α chain of the human cytokine receptor specifically binding to interleukin 4 (IL-4), i.e. IL-4Rα (sequence number: 274). Unless specifically stated to be of non-human origin, the term "IL-4R" as used herein should be understood to refer to the alpha chain of the human interleukin-4 receptor.

The term "antibody" as used herein means an immunoglobulin molecule composed of four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and polymers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or _VH ) and a heavy chain constant region. The heavy chain constant region comprises three domains, _CH1 , _CH2 and _CH3 . Each light chain comprises a light chain variable region (abbreviated herein as LCVR or _VL ) and a light chain constant region. The light chain constant region comprises one domain ( _CL1 ). The _VH and _VL regions can be further divided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each _VH and _VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the invention, the framework regions of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence can be defined based on the side-by-side analysis of two or more CDRs.

The term "antibody" as used herein also includes antigen-binding fragments of whole antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered compound that specifically binds to an antigen to form a complex. of polypeptides or glycoproteins. Antigen-binding fragments of antibodies can be produced, for example, from intact antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving manipulation and expression of DNA encoding antibody variable and constant regions (optional). . Such DNA is known and/or readily obtained, eg, from commercial sources, DNA libraries (including, eg, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by molecular biological techniques, such as arranging one or more variable and/or constant regions into a suitable configuration, or introducing codons, generating cysteine residues group, modification, addition or deletion of amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) consisting of amino acid residues that mimic the hypervariable region of the antibody (e.g., an isolated complementarity determining region CDR, such as a CDR3 peptide) or a FR3-CDR3-FR4 conformationally constrained peptide The smallest unit of identification. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies , bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also included in the expression "antigen-binding fragment" as used herein.

An antigen-binding fragment of an antibody typically comprises at least one variable region. A variable region may be of any size or of any amino acid composition, and generally comprises at least one CDR adjacent to or within one or more framework sequences. In an antigen-binding fragment comprising a _VH domain associated with a _VL domain, the relative positions of the _VH and _VL domains may be in any suitable arrangement. For example, the variable region may be dimerized _{and contain VH-VH, VH-VL or VL - VL dimers} . Alternatively, an antigen-binding fragment of an antibody may contain a single _VH domain or _VL domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable region covalently linked to at least one constant region. Non-limiting exemplary configurations of variable and constant regions that may be found within the antigen-binding fragments of the antibodies of the invention include: (i) _VH - _CH1 ; (ii) _VH - _CH2 ; ( iii) _VH - _CH3 ; (iv) _VH - _CH1 - _CH2 ; (v _{) VH} - _CH1 - _CH2 -CH3; (vi) _VH - _{CH2 -CH3} ; (vii) _VH - _CL ; (viii _{) VL} - _CH1 ; (ix) _VL - _CH2 ; (x)VL _{- CH3} ; _CH1 - _CH2 ; (xii) _VL - _CH1 - _CH2 -CH3; (xiii) _VL - _{CH2 - CH3} ; and (xiv) VL- _{CL .} In any configuration of the variable and constant regions, including any of the exemplary configurations described above, the variable and constant regions may be directly connected to one another or may be connected via a complete or partial hinge or linking region. A hinge region may contain at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that form between adjacent variable and/or constant regions in a single peptide molecule Flexible or semi-flexible connections. In addition, the antigen-binding fragment of the antibody of the present invention may comprise homodimers or heterodimers (or other multimers) of any configuration of the above-mentioned variable regions and constant regions, the variable regions and constant regions are separated by non- The covalent linkages are to each other and/or to one or more single _VH or _VL domains (eg, via disulfide bonds).

Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). A multispecific antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, wherein each variable domain is capable of specifically binding another antigen or a different epitope of the same antigen. As with any multispecific antibody format, conventional techniques available in the art can be used to adapt it for use involving antigen-binding fragments of the antibodies of the invention.

The constant regions of antibodies are important for the ability of antibodies to fix complement and regulate cell-dependent cytotoxicity. Therefore, the isotype of the antibody can be selected based on whether it is desired to modulate cytotoxicity by the antibody.

The term "human antibody" as used herein is intended to include antibodies comprising variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may still include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., by random induction in vitro). Mutation or site-specific mutagenesis or mutations introduced by in vivo somatic mutation), such amino acid residues may be included in the CDRs, especially in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from another mammalian species, such as mouse, have been grafted onto human framework sequences.

The term "recombinant human antibody" as used herein is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant methods, such as antibodies expressed by recombinant expression vectors transfected into host cells (further described below) ), antibodies isolated from recombinant, combinatorial human antibody libraries (described further below), antibodies isolated from human immunoglobulin gene transgenic animals (such as mice) (see, for example, Taylor et al. (1992) Nucl Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced or isolated by any other method involving the splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies contain variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using human Ig sequence transgenic animals, in vivo somatic mutagenesis) such that the _VH region and _VL region of the recombinant antibody The amino acid sequences of the domains become sequences that, although derived from and related to human germline _VH and _VL sequences, may not naturally _occur in vivo in _humans germline antibody library.

Human antibodies can exist in two forms related to hinge heterogeneity. In the first form, an immunoglobulin molecule consists of a stable four-chain construct of approximately 150-160 kDa in which two dimers are held together by an inter-heavy chain disulfide bond. In the second form, instead of being held together by inter-heavy chain disulfide bonds, the dimer forms an approximately 75-80 kDa antibody consisting of covalently coupled light and heavy chains (half antibodies). molecular. The isolation of these forms has been extremely difficult, even after affinity purification.

The frequency of occurrence of the second form among the various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody's hinge region isotype. Single amino acid substitutions within the hinge region of the human IgG4 hinge significantly reduced the frequency of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels normally observed with the human IgG1 hinge. The invention includes antibodies containing one or more mutations in the hinge, _CH2 , or _CH3 regions. Such mutations may be desirable, for example, in production to increase the yield of the desired antibody form.

As used herein, "isolated antibody" means an antibody that has been identified, isolated and/or collected from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism or from a tissue or cell in which the antibody exists or is naturally produced is an "isolated antibody" for the purposes of the present invention. "Isolated antibody" also includes antibodies in situ within recombinant cells. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.

"Specific binding" or similar terms means that an antibody or antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, including methods such as equilibrium dialysis, surface plasmon resonance, and the like. For example, the term "antibodies that specifically bind" IL-4R as used in the context of the present invention includes antibodies that bind IL-4R, or a portion thereof, with a K _of less than about 1000 nM, as measured by surface plasmon resonance techniques, Less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM. An isolated antibody that specifically binds human IL-4R may, however, have cross-reactivity to other antigens, such as IL-4R molecules derived from other (non-human) species.

Anti-IL-4R antibodies useful in the methods of the invention may comprise one or more amino acids in the framework and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody was derived substitutions, insertions and/or deletions. Such mutations can be readily confirmed by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. The invention includes methods involving the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions and/or CDR regions are mutated to The corresponding residues of the germline sequence from which the antibody was derived, or mutations to the corresponding residues of another human germline sequence, or mutations to conservative amino acid substitutions of the corresponding germline sequence residues (such sequence changes are described herein collectively referred to as "germline mutations"). One of ordinary skill in the art to which the present invention pertains can readily generate a variety of antibodies and antigen-binding fragments thereof comprising one or more single germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In certain embodiments, all framework and/or CDR residues within the aforementioned _VH and/or _VL regions are backmutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4, or only Mutated residues found in CDR1, CDR2, or CDR3 were backmutated to the original germline sequence. In certain embodiments, one or more framework and/or CDR residues are backmutated to the corresponding residues of a different germline sequence (ie, a germline sequence different from that from which the antibody was originally derived). In addition, antibodies of the invention may contain any combination of two or more mutations within the framework regions and/or CDR regions, for example, wherein some residues are mutated to the corresponding residues of a particular germline sequence, and some Other residues that differed from the original germline sequence were either left unchanged or mutated to correspond to a different germline sequence. Once antibodies and antigen-binding fragments containing one or more germline mutations are obtained, they can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved biological properties of antagonism or antagonism, or Enhancement (as the case may be), decreased immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner is within the scope of the present invention.

The invention also includes methods involving the use of anti-IL-4R antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein, the variants comprising one or more conservative amino acid substitutions. For example, the invention includes anti-IL-4R antibodies comprising HCVR, LCVR, and/or CDR amino acid sequences that, relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein, contain, for example, 10 or less, 8 or Less than, 6 or less, 4 or less, etc. conservative amino acid substitutions.

The term "surface plasmon resonance" as used herein refers to an optical phenomenon based on which protein concentration in a biosensor matrix can be detected using, for example, the BIAcore ^™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). changes in , allowing for the analysis of immediate interactions.

The term " _KD " as used herein means the equilibrium dissociation constant for a particular antibody-antigen interaction.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule called the paratope. A single antigen may have more than one epitope. Thus, different antibodies can bind to different regions of an antigen and can produce different biological effects. Epitopes can be conformational or linear. Conformational epitopes arise from the spatial juxtaposition of amino acids in different fragments of a linear polypeptide chain. Linear epitopes are formed by contiguous amino acid residues on a polypeptide chain. In some cases, an epitope may include carbohydrate, phosphonyl, or sulfonyl groups on the antigen.

Preparation of Human Antibody

Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods may be used in the context of the present invention to produce human antibodies that specifically bind human IL-4R.

Using VELOCIMMUNE ^TM technology (see, for example, U.S. Patent No. 6,596,541 of Regeneron Pharmaceuticals) or any other known technology for producing monoclonal antibodies, initially isolate a human variable region and a mouse constant region with high affinity for IL-4R. chimeric antibodies. VELOCIMMUNE® technology involves the development of a transgenic mouse whose genome contains human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, allowing the mouse to An antibody comprising human variable regions and mouse constant regions is produced. DNA encoding the variable regions of the heavy and light chains of the antibody is isolated and operably linked to DNA encoding the constant regions of the human heavy and light chains. The DNA is then expressed in cells capable of expressing fully human antibodies.

Typically, VELOCIMMUNE® mice are challenged with the antigen of interest and lymphocytes (eg, B cells) are recovered from the antibody-expressing mice. Lymphocytes can be fused with a myeloma cell line to produce an immortal hybridoma cell line, which is then screened to identify hybridoma cell lines that produce antibodies specific to the relevant antigen. DNA encoding the variable regions of the heavy and light chains can be isolated and ligated with the desired isotype constant regions of the heavy and light chains. The antibody protein can be produced in a cell such as CHO cells. Alternatively, DNA encoding antigen-specific chimeric antibodies or light and heavy chain variable domains can be isolated directly from antigen-specific lymphocytes.

First, a high-affinity chimeric antibody comprising a human variable region and a mouse constant region is isolated. The antibodies are identified and selected for desired properties, including affinity, selectivity, epitope, etc., using standard procedures known to those of ordinary skill in the art to which the invention pertains. Mouse constant regions are substituted with desired human constant regions to generate fully human antibodies of the invention, eg wild type or modified IgGl or IgG4. The chosen constant region can vary according to the particular application, while the high affinity antigen-binding and target-specific features are retained in the variable region.

In general, antibodies useful in the methods of the invention have high affinities, as described above, when assayed for binding to antigen immobilized on a solid or liquid phase. The mouse constant regions are substituted with the desired human constant regions to generate fully human antibodies of the invention. The chosen constant region can vary according to the particular application, while the high affinity antigen-binding and target-specific features are retained in the variable region.

Specific examples of human antibodies or antigen-binding fragments of antibodies that specifically bind IL-4R that can be used in the context of the methods of the invention include any that comprise three heavy chain CDRs (HCDR1) within the heavy chain variable region (HCVR). , HCDR2, HCDR3) antibody or antigen-binding fragment, and the amino acid sequence contained in the heavy chain variable region is selected from the following group of sequences, the sequence numbers of which are: 2, 18, 22, 26, 42, 46, 50 ,66,70,74,90,94,98,114,118,122,138,142,146,162,166,170,186,190,194,210,214,218,234,238,242,258 and 262. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCDR1, LCDR2, LCDR3) in the light chain variable region (LCVR), and the amino acid sequence contained in the light chain variable region is selected from the following group Serials with serial numbers: 10, 20, 24, 34, 44, 48, 58, 68, 72, 82, 92, 96, 106, 116, 120, 130, 140, 144, 154, 164, 168, 178 , 188, 192, 202, 212, 216, 226, 236, 240, 250, 260, and 264. Methods and techniques for identifying CDR regions within HCVR/LCVR amino acid sequences are well known in the art and can be used to identify CDR regions within specific HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR region boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of the structural loop region, and the AbM definition is a compromise between the Kabat method and the Chothia method. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al. , J. Mol. Biol. 273 : 927-948 (1997); and Martin et al. , Proc. Natl. Acad. Sci. USA 86 :9268-9272 (1989). Public databases are also available to identify CDR sequences within antibodies.

In certain embodiments of the present invention, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3), the amino acid sequence pair is selected from the following group of sequence pairs, and its sequence numbers are: 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/ 154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260 and 262/264.

In certain embodiments of the present invention, the antibody or antigen-binding fragment thereof comprises 6 CDRs comprising amino acid sequences (HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3), the amino acid sequence is selected from the following group of sequences, and its sequence number is: 4/6/8/12/14/16; 28/30/32/36 /38/40; 52/54/56/60/62/64; 76/78/80/84/86/88; 100/102/104/108/110/112; 124/126/128/132/134 /136; 148/150/152/156/158/160; 172/174/176/180/182/184; 196/198/200/204/206/208; 220/222/224/228/230/232 and 244/246/248/252/254/256.

In some embodiments of the present invention, the antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair selected from the following group of sequence pairs, whose sequence numbers are: 2/10, 18/20, 22 /24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120 , 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218 /226, 234/236, 238/240, 242/250, 258/260, and 262/264.

pharmaceutical composition

The invention includes methods comprising administering to a patient an IL-4R antagonist contained in a pharmaceutical composition. The pharmaceutical composition of the present invention is formulated together with suitable carriers, excipients and other agents that impart various desirable properties to the drug, such as transfer, delivery, tolerance. Many suitable formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA). These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, cationic or anionic liposomes (such as LIPOFECTIN ^™ ), DNA conjugates, anhydrous absorption pastes, oil-in-water Or water-in-oil emulsion, latex carbo wax (polyethylene glycol of various molecular weights), semi-solid gel and semi-solid mixture containing carbo wax. See also Powell et al. "Compendium of excipients for parenteral formulations", PDA (1998) J Pharm Sci Technol 52:238-311.

The dose of antibody administered to a patient according to the method of the present invention may vary according to the patient's age and weight, symptoms, conditions, route of administration, and other factors. The dosage is usually calculated by body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment may be adjusted. Effective doses and dosing schedules of pharmaceutical compositions comprising anti-IL-4R antibodies can be determined empirically; for example, changes in a patient's condition can be monitored through periodic assessments and doses adjusted accordingly. Furthermore, cross-species extrapolation of doses can be performed using methods well known in the art (eg Mordenti et al. , 1991, Pharmaceut. Res. 8 :1351). Specific exemplary dosages and dosing regimens of anti-IL4R antibodies useful in the context of the present invention are disclosed elsewhere herein.

Various drug delivery systems are known for administration of the pharmaceutical composition of the present invention, such as liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see e.g. Wu et al. al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral. The composition can be administered by any convenient route, for example, infusion or bolus injection, absorbed through the epithelium or mucosa (such as oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents.

The pharmaceutical compositions of this invention can be administered subcutaneously or intravenously using standard needles and syringes. In addition, for subcutaneous administration, a pen-type delivery device can be conveniently used for administering the pharmaceutical composition of the present invention. This pen type drug delivery device can be used repeatedly or disposablely. Reusable pen delivery devices typically employ a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge is conveniently discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen type drug delivery device can be used repeatedly. In a single-use pen delivery device, there is no replaceable cartridge. Instead, the single-use pen delivery device has a pre-filled reservoir of pharmaceutical composition. After the pharmaceutical composition in the reservoir is used up, the entire device is discarded.

A number of reusable pen-type and automatic injection delivery devices have been used for subcutaneous administration of the pharmaceutical compositions of the present invention. Examples include, but are not limited to, AUTOPEN ^™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC ^™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 ^™ pen, HUMALOG ^™ pen, HUMALIN 70/30 ^™ Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN ^™ Type I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ^™ (Novo Nordisk, Copenhagen, Denmark), BD ^™ Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ^™ , OPTIPEN PRO ^™ , OPTIPEN STARLET ^™ , and OPTICLIK ^™ (sanofi-aventis, Frankfurt, Germany), to name a few. Examples of single-use pen delivery devices for subcutaneous injection of pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR ^™ pen (sanofi-aventis), FLEXPEN ^™ (Novo Nordisk), KWIKPEN ^™ (Eli Lilly), SURECLICK ^TM autoinjector (Amgen, Thousand Oaks, CA), PENLET ^TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA ^TM pen (Abbott Labs, Abbott Park IL), to name a few.

In some instances, the pharmaceutical composition can be administered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials may be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed near the target of the composition so that only a fraction of the systemic dose needs to be used (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. .2, pp.115-138). Other controlled release systems are also discussed in the review by Langer, 1990, Science 249: 1527-1533.

Preparations for injection may include intravenous, subcutaneous, intradermal and intramuscular injection, as well as drip infusion and other dosage forms. These injection preparations can be prepared by known methods. For example, the above-mentioned antibody or a salt thereof can be dissolved, suspended or emulsified in a sterile aqueous or oily medium conventionally used for injection to prepare the injection preparation. The aqueous medium for injection includes, for example, physiological saline, isotonic solution containing glucose and other auxiliary agents, etc., and appropriate solubilizers, such as alcohol (such as ethanol), polysaccharide, etc., can be used in combination. Alcohols (such as propylene glycol, polyethylene glycol), non-ionic surfactants [such as polysorbate 80, HCO-50 (polyoxyethylene (50mol) adduct of hydrogenated castor oil)], etc. The oily medium can be, for example, sesame oil, soybean oil, etc., and a solubilizer, such as benzyl benzoate, benzyl alcohol, etc., can be used in combination. The injection solution thus prepared can be filled into a suitable ampule.

Advantageously, the above pharmaceutical compositions for oral or parenteral use are prepared in dosage unit form, so as to contain a dose of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (in ampoules), suppositories, and the like.

Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies useful in the context of the present invention are disclosed, for example, in US Patent Application Publication No. 2012/0097565.

dose

The amount of IL-4R antagonist (eg, anti-IL-4R antibody) administered to a subject according to the methods of the invention is generally a therapeutic amount. As used herein, the term "therapeutic amount" refers to a dose of an IL-4R antagonist that results in one or more of the following: (a) improvement of one or more AD-related parameters (as defined elsewhere herein); and/or ( b) Detectable improvement in one or more symptoms or signs of atopic dermatitis. "Therapeutic dose" also includes the dose of IL-4R antagonist that can inhibit, prevent, alleviate or delay the progression of AD in the subject.

For anti-IL-4R antibodies, the therapeutic amount can be from about 0.05 mg to about 600 mg, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, About 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg , about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In certain embodiments, the subject is administered 75 mg, 150 mg, or 300 mg of the anti-IL-4R antibody.

The amount of IL-4R antagonist contained in each dose can be expressed as milligrams of antibody per kilogram of patient body weight (ie, mg/kg). For example, an IL-4R antagonist can be administered to a patient at a dose of about 0.0001 mg/kg to about 10 mg/kg depending on the patient's weight.

combination therapy

According to certain embodiments, the methods of the invention comprise administering to a subject one or more additional therapeutic agents in combination with an IL-4R antagonist. The expression "combined" used herein means that the above-mentioned other therapeutic agent is administered before, after, or simultaneously with the administration of the pharmaceutical composition comprising the IL-4R antagonist. The term "combination" also includes sequential or simultaneous administration of an IL-4R antagonist and another therapeutic agent.

For example, when administered "before" the administration of the pharmaceutical composition comprising the IL-4R antagonist, the above-mentioned other therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 hours minute administration. For example, when administered "after" the administration of the pharmaceutical composition comprising the IL-4R antagonist, the other therapeutic agent described above may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours Hourly dosing. Administering "simultaneously" or together with the pharmaceutical composition comprising the IL-4R antagonist means that the above-mentioned other therapeutic agent is administered in a separate dosage form within 5 minutes (before, after) of the pharmaceutical composition comprising the IL-4R antagonist or simultaneously) to the subject, or administered to the subject as a single combined preparation containing the above-mentioned other therapeutic agent and IL-4R antagonist.

Such additional therapeutic agents may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, those described in US 6,927,044), an IL-6 antagonist, An IL-6R antagonist (including anti-IL-6R antibodies such as those described in US 7,582,298), an IL-13 antagonist, a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL -17 antagonist, an IL-5 antagonist, an IgE antagonist, a CD48 antagonist, an IL-31 antagonist (including, for example, those described in US 7,531,637), a thymic stromal lymphocyte (TSLP) antagonist ( These include, for example, those described in US 2011/027468), gamma-interferon (IFNγ) antibiotics, topical corticosteroids, tacrolimus, pimecrolimus, cyclosporine, azathioprine, methotrexate, chromosomal Sodium glycinate, a protease inhibitor, or a combination thereof. In certain embodiments, a pharmaceutical composition comprising an anti-IL4R antagonist is administered to a subject concurrently with a non-drug therapy, such as ultraviolet (UV) phototherapy.

The methods of the invention involve administering an IL-4R antagonist in combination with another therapeutic agent to produce an additive or synergistic effect in the treatment of AD. In one embodiment, the invention includes a method of treating moderate to severe AD. Certain embodiments of the invention include methods of administering an IL-4R antagonist concurrently with a TCS to treat moderate to severe AD. The TCS may be a valid TCS, such as a Class III TCS. Examples of Group II TCSs include methylprednisolone ethopropionate, mometasone furoate, fluticasone propionate, and betamethasone valerate. In certain embodiments, the TCS may be a moderately potent TCS such as a Group II TCS, or a weakly potent TCS such as a Group I TCS.

Dosing regimen

The invention includes methods comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a frequency of about four times a week, twice a week, once a week, once every two weeks, Once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently, as long as the therapeutic effect can be achieved. In certain embodiments, the administration of the pharmaceutical composition comprising the anti-IL-4R antibody may be administered at a dose of 75 mg, 150 mg or 300 mg once a week.

According to certain embodiments of the invention, multiple doses of an IL-4R antagonist may be administered to a subject within a given period of time. The method according to this aspect of the invention comprises sequentially administering to the subject multiple doses of the same IL-4R antagonist. "Sequential administration" as used herein means that each dose of IL-4R antagonist Antibiotics are administered to the subject at different points in time, eg, on different days at predetermined intervals (eg, hours, days, weeks or months). The invention includes methods comprising sequentially administering to a subject an initial dose of an IL-4R antagonist, followed by one or more second doses of an IL-4R antagonist, and then optionally One or more third doses of the IL-4R antagonist are administered.

The terms "initial dose", "second dose" and "third dose" refer to the temporal sequence of administration of the IL-4R antagonist. Thus, "initial dose" refers to the dose administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); "second dose" refers to the dose administered after the initial dose; "third dose" Refers to the dose administered after the second dose. The initial, second and third doses may all contain the same amount of IL-4R antagonist, but the frequency of dosing generally differs from one another. However, in certain embodiments, the initial, second and/or third doses contain different amounts of IL-4R antagonist (eg, may be up-regulated or down-regulated as appropriate) during the course of treatment. In certain embodiments, one or more (eg, 1, 2, 3, 4, or 5) "loading doses" are administered at the beginning of a treatment regimen, and subsequent doses are administered on a less frequent basis. dose (i.e. "maintenance dose"). For example, an IL-4R antagonist may be administered to an AD patient at a loading dose of about 300 mg or about 600 mg, followed by one or more maintenance doses of about 75 mg to about 300 mg. In one embodiment, the initial dose and one or more second doses each contain 50 mg to 600 mg of an IL-4R antagonist, such as 100 mg to 400 mg of an IL-4R antagonist, such as 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 500 mg of IL-4R antagonist. In certain embodiments, the initial dose and the one or more second doses each contain an equivalent amount of the IL-4R antagonist. In other embodiments, the initial dose contains a first amount of the IL-4R antagonist, and one or more second doses each contain a second amount of the IL-4R antagonist. For example, the first amount of IL-4R antagonist can be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times or 5 times or more than the second amount of IL-4R antagonist.

In an exemplary embodiment of the present invention, each dose of the second dose and/or the third dose is administered 1 to 14 weeks after the previous dose (for example, 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ weeks, or more). As used herein, the term "previous dose" refers to a dose of an IL-4R antagonist administered to a patient prior to the next dose in a sequential dose, with no other doses in between.

Methods according to this aspect of the invention may comprise administering to the patient any number of doses of the second and/or third IL-4R antagonist. For example, in certain embodiments, only one second dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. Also, in certain embodiments, only one third dose is administered to the patient. In other embodiments, the patient is administered two or more doses (eg, 2, 3, 4, 5, 6, 7, 8 or more doses) of a third dose.

In some embodiments involving multiple second doses, each second dose may be administered with the same frequency as the other second doses. For example, each second dose can be administered to the patient 1 to 2 weeks after the previous dose. Likewise, in some embodiments involving multiple third doses, each third dose may be administered with the same frequency as the other third doses. For example, each third dose can be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency at which the second and/or third dose is administered to the patient may be changed over the course of the treatment regimen. During the course of treatment, the frequency of administration can also be adjusted by the physician after the clinical examination according to the needs of each patient.

The present invention includes methods comprising the sequential administration of an IL-4R antagonist and another therapeutic agent to treat AD patients. In certain embodiments, the methods of the invention comprise administering one or more doses of an IL-4R antagonist followed by one or more doses of another therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-4R antagonist may be administered followed by one or more doses of another therapeutic agent (e.g., a topical corticosteroid or a calcineurin inhibitor or any Other therapeutic agents, as described elsewhere herein) to treat, alleviate, alleviate or ameliorate one or more symptoms of AD. In certain embodiments, administration of one or more doses of an IL-4R antagonist results in an improvement in one or more parameters associated with AD, followed by administration of another therapeutic agent to prevent recurrence of at least one symptom of AD. Some alternative embodiments of the invention relate to an IL-4R antagonistic A drug is administered concurrently with another therapeutic agent. For example, one or more doses of an IL-4R antagonist are administered and another therapeutic agent is administered alone at a similar or different frequency than the IL-4R antagonist. In certain embodiments, another therapeutic agent is administered before, after or simultaneously with the IL-4R antagonist.

IL-4R antagonists as vaccine adjuvants

The invention also includes certain compositions and methods useful for vaccine applications. For example, IL-4R antagonists (such as the anti-IL-4R antibodies disclosed herein) can be administered to a subject simultaneously with a vaccine to improve or enhance the immune response (including humoral immune response and cellular immune response) elicited by the vaccine , which is used as a vaccine adjuvant. In certain embodiments, the IL-4R antagonist is administered to a subject immediately before, simultaneously with, and/or after administration of a vaccine composition. For example, the present invention includes methods for eliciting or enhancing an immune response to an antigen comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist, followed by administering to the subject a vaccine composition comprising the antigen (alone or in combination with an IL-4R antagonist), and optionally an additional IL-4R antagonist is administered for a period of time after administration of the vaccine antigen to the subject.

The IL-4R antagonists of the present invention can be administered as adjuvants with any type of vaccines, such as live vaccines, live/attenuated vaccines, inactivated vaccines, subunit vaccines, DNA vaccines, and cancer immunotherapy vaccines. Vaccines that may be used in combination with IL-4R antagonists of the invention include vaccines against bacterial pathogens, viruses, parasites, and other infectious agents. Non-limiting examples of infectious agents and diseases against which the vaccine compositions and methods of the present invention are directed may include, for example, HIV, HCV, RSV, Neisseria meningitidis, Streptococcus, tuberculosis, malaria, smallpox, diphtheria, pertussis, Tetanus, polio, measles, rubella, mumps, influenza, anthrax, SARS, Ebola virus, Hanta virus, dengue virus, etc.

The invention also includes pharmaceutical compositions comprising an IL-4R antagonist and one or more vaccine antigens. The pharmaceutical composition according to this aspect of the present invention may include one or more other immune enhancers, such as MPL, MDP, CpG oligonucleotides, lipopeptides, saponins, dsRNA, small molecule immune enhancers and the like.

Inhibition of the IL-4/IL-13 signaling pathway other than IL-4R antagonists Agents (such as anti-IL-4 antibodies, anti-IL-13 antibodies, anti-IL-4/anti-IL-13 bispecific antibodies, etc.), can also be used in the vaccine methods and compositions disclosed herein.

Figure 1 shows the mean (SD) plasma concentration-time profile of functional mAbl following a single subcutaneous injection in a Cartesian coordinate system.

Figure 2 shows a schematic representation of the injection procedure and pain assessment as described in Example 5.

Figure 3 shows the proportion of responders with IGA score (score of 0 or 1) - last observation forward (LOCF) for the study described in Example 6.

Figure 4 shows the mean IGA score change from baseline - LOCF in the study described in Example 6.

Figure 5 shows the percent change from baseline in mean IGA score - LOCF for the study described in Example 6.

Figure 6 shows the mean EASI score change from baseline - LOCF in the study described in Example 6.

Figure 7 shows the percent change from baseline in the mean EASI score for the study described in Example 6 - LOCF.

Figure 8 shows the proportion of EASI 50 responders - LOCF for the study described in Example 6.

Figure 9 shows the mean BSA score change from baseline - LOCF in the study described in Example 6.

Figure 10 shows the percent change from baseline - LOCF in mean BSA score for the study described in Example 6.

Figure 11 shows the mean 5-D index change from baseline - LOCF for the study described in Example 6.

Figure 12 shows the mean 5-D index percent change from baseline - LOCF for the study described in Example 6.

Figure 13 shows the mean NRS score change from baseline - LOCF in the study described in Example 6.

Figure 14 shows the percent change from baseline in the mean NRS score for the study described in Example 6 - LOCF.

Figure 15 shows the percent change from baseline in BSA score (compared to placebo) in patients dosed with 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 16 shows the percent change from baseline in IGA score (compared to placebo) for patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 17 shows the percent change from baseline in EASI scores (compared to placebo) for patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 18 shows the percent change from baseline in the NRS score of pruritus (compared to placebo) in patients dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 19 shows the time course of EASI response in moderate to severe AD patients administered 300 mg anti-IL-4R antibody in the study described in Example 8.

Figure 20 shows the percentage of EASI score responders (compared to placebo) among subjects dosed with 75 mg, 150 mg or 300 mg of anti-IL-4R antibody in the study described in Example 8.

Figure 21 shows the EASI response (compared to placebo) at week 4 (day 29) of the study described in Example 8, given anti-IL-4R antibody doses of 75 mg, 150 mg or 300 mg.

1的患者比例。 Figure 22 shows the IGA achieved in the study described in Example 8

1 percent of patients.

Figure 23 shows the percent change in mean EASI score from baseline to last observation carried forward (LOCF) for the study described in Example 10.

Figure 24 shows the proportion of responders by IGA score up to LOCF (score of 0 or 1) in the study described in Example 10.

Figure 25 shows the proportion of responders (decrease in score of 2 points or more) by IGA score up to LOCF in the study described in Example 10.

Figure 26 shows the proportion of EASI score responders up to LOCF (50% decrease in score from baseline) in the study described in Example 10.

Figure 27 shows the change in mean EASI score from baseline up to LOCF in the study described in Example 10.

Figure 28 shows the change in mean IGA score from baseline up to LOCF in the study described in Example 10.

Figure 29 shows the percent change in mean IGA score from baseline up to LOCF for the study described in Example 10.

Figure 30 shows the change in mean BSA score from baseline up to LOCF in the study described in Example 10.

Figure 31 shows the change in mean SCORAD score from baseline up to LOCF in the study described in Example 10.

Figure 32 shows the change in mean NRS score from baseline up to LOCF in the study described in Example 10.

Figure 33 shows the change from baseline to LOCF in the mean 5-D pruritus index for the study described in Example 10.

Figure 34 shows the percent change from baseline in the mean EASI score for the study described in Example 11 - censored LOCF.

Figure 35 shows the change from baseline in mean EASI score in the study described in Example 11 - censored LOCF.

Figure 36 shows the proportion of EASI 50 responders in the study described in Example 11 - censored LOCF method.

Figure 37 shows the time to first attainment of EASI 50 as indicated by the Kaplan-Meier plot for the study described in Example 11 - censored LOCF.

Figure 38 shows the percent change from baseline in mean IGA score for the study described in Example 11 - censored LOCF.

Figure 39 shows the change from baseline in mean IGA score in the study described in Example 11 - censored LOCF.

Figure 40 shows the proportion of responders with IGA score (score of 0 or 1) - censored LOCF method for the study described in Example 11.

1的時間-截尾LOCF法。 Figure 41 shows the Kaplan-Meier curve in the study described in Example 11 showing the first attainment of IGA

1 time-truncated LOCF method.

1的無復發的患者比例-截尾LOCF法。 Figure 42 shows the IGA at each visit in the study described in Example 11

Proportion of patients free of recurrence by the 1-censored LOCF method.

2的患者比例-截尾LOCF法。 Figure 43 shows the decline in IGA from baseline at each visit in the study described in Example 11

Proportion of patients with 2-censored LOCF method.

Figure 44 shows the percent change from baseline in mean SCORAD score for the study described in Example 11 - censored LOCF.

Figure 45 shows the change from baseline in mean SCORAD score in the study described in Example 11 - censored LOCF.

Figure 46 shows the percent change from baseline in mean pruritus NRS scores for the study described in Example 11 - censored LOCF.

Figure 47 shows the change from baseline in mean pruritus NRS score for the study described in Example 11 - censored LOCF.

Figure 48 shows the median percent change in plasma concentrations of IgE at baseline (A) and in response to various doses of mAbl or placebo (B) in the study described in Example 12.

Figure 49 shows the mean percent change in baseline (A) TARC plasma concentrations and response to various doses of mAbl or placebo (B) in the study described in Example 12.

Figure 50 shows the change in TARC concentrations (compared to placebo) for the pooled mAbl groups in the study described in Example 12.

Figure 51 shows the baseline concentration profiles of (A) TARC, (B) total IgE plasma concentrations, and (C) lactate dehydrogenase (LDH) in patients from the study described in subparagraph B of Example 12.

Figure 52 shows the median percent change from baseline in IgE as described in subparagraph B of Example 12.

Figure 53 shows the median percent change from baseline in LDH as described in subparagraph B of Example 12.

Figure 54 shows the median percent change from baseline in TARC as described in Example 12, subparagraph B.

example

The following examples are given to provide a complete disclosure and description of how to use the methods and compositions of the present invention to those skilled in the art to which the present invention pertains, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (eg, doses, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1: Production of Human Antibodies against Human IL-4R

Anti-hIL-4R human antibodies were produced as described in US Patent No. 7,608,693. Table 1 lists the sequence identifiers of selected anti-IL-4R antibody heavy chain and light chain variable region amino acid sequence pairs and CDR amino acid sequences, as well as the corresponding antibody names.

An exemplary IL-4R antagonist used in the following examples is an anti-IL-4R human antibody, designated H1H098-b in Table 1 (also referred to herein as "mAbl").

Example 2: Clinical trial of single doses of anti-IL-4R antibody (mAb1 ) administered intravenously and subcutaneously to healthy subjects in increasing doses

A. Experimental design

This study was a randomized, double-blind, placebo-controlled, sequential, single ascending dose intravenous (IV) and subcutaneous (SC) administration of mAb1 in healthy subjects. Research. The primary objective of this study was to evaluate the safety and tolerability of intravenous and subcutaneous administration of mAb1 to healthy subjects.

Screening was performed from day 21 to day 3 before the start of the study. Subjects were randomized on study day 1 (baseline) to receive up to 2 hours of IV or SC infusion of study drug (mAb1 or placebo). Subjects returned to the clinic on Days 4, 8, 11, 15, 22, 29, 43, 57, and 85 (end of study) for safety assessments and blood collection for clinical laboratory testing.

A total of 48 subjects participated in this study. Arrange 4 groups of subjects to receive IV injection with sequentially increasing doses (1.0, 3.0, 8.0 and 12.0 mg/kg), and arrange 2 groups of subjects to receive SC injection with sequentially increasing doses (150 and 300 mg). Each dose cohort consisted of 8 subjects (if the cohort was not expanded): 6 subjects were randomized to receive mAb1 and 2 subjects were randomized to receive placebo. To optimize safety, the first 3 subjects in intravenous (IV) cohort 1 (1.0 mg/kg) were dosed at least 24 hours apart and the remaining 5 subjects were dosed 5 to 7 days later . In the subsequent intravenous (IV) group, 3 of 8 subjects were dosed on day 1 and the remaining 5 subjects were dosed 5 to 7 days later. All 8 subjects in subcutaneous (SC) cohort 1 (150 mg) were dosed on the same day, as were all 8 subjects in subcutaneous (SC) subsequent cohort (300 mg) . The SC group was administered after the end of the IV group.

Subject inclusion criteria are as follows: (1) male or female aged 18 to 65; (2) weighing 50 kg to 120 kg; (3) for women of childbearing potential, serum at screening (first visit) The pregnancy test was negative, and the urine pregnancy test was negative on the first day before the start of the study; (4) Willing to drink alcohol (standard alcoholic beverages) to less than 2 glasses within any 24 hours during the study. A so-called standard alcoholic drink is equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits; (5) willing to drink in moderation within 24 hours before each study visit; Willingness to use appropriate contraceptive measures to avoid pregnancy (or avoid making their partner pregnant) during the study. Appropriate contraceptive methods include: intrauterine device (IUD); bilateral tubal ligation; vasectomy; condom or diaphragm plus contraceptive sponge, foam, or gel; Willingness, commitment and ability.

Exclusion criteria for the study were as follows: (1) Starting a new exercise routine or making significant changes to a previous exercise routine within 4 weeks prior to screening (first visit). Subjects must be willing to maintain a considerable degree of fitness exercise during the study period, and avoid abnormally strenuous exercise during the clinical trial; (2) pregnant or breastfeeding women; (3) accompanying serious illness or history of serious illness, such as cardiac , renal, neurological, endocrine, metabolic or lymphatic diseases, or any other disease or condition that would adversely affect the subject's participation in this study; (4) Any clinically significant abnormalities were observed during the screening process; ( 5) Hospitalization for any reason within 60 days after screening (first visit); (6) Known history of the following: human immunodeficiency virus (HIV) infection, hepatitis B or C, and/or screening Hepatitis B surface antigen positive, hepatitis C antibody positive, or HIV serum test positive; (7) Has a history of drug or alcohol abuse within one year before screening, or a drug or alcohol screening test was positive Positive; (8) have a history of allergy to doxycycline or similar compounds; (9) participate in the evaluation of another study drug within 30 days before screening or within at least 5 half-lives of the relevant study drug (whichever is longer) (10) previous exposure to any therapeutic or investigational biological agent; (11) any physical or mental condition that, in the opinion of the study director, would put the subject at risk; Any physical or mental condition that participates in or interferes with the interpretation of the results of the study; (12) subjects who tested positive for the QuantiFERON tuberculin (TB) test; (13) have a history of parasitic infection or have recently (within the previous 6 months) Travel to parasite-endemic areas; (14) history of alcohol or drug abuse within the previous 5 years; (15) positive urine drug screen at screening (Visit 1) or baseline (Visit 2) and/or (16) Live/attenuated vaccine within 12 weeks prior to screening or during the study.

B study treatment

The drug product mAb1 is supplied as a lyophilized powder in 20 mg glass vials for intravenous or subcutaneous injection. For intravenous injection, the drug product mAb1 was prepared as a solution containing 50 mg/mL of mAb1 in a single-use vial with 7.8 mL of sterile water for injection. the pharmacist or his designee Draw the required amount of reconstituted mAb1 (depending on the subject's dose and body weight) or placebo, and inject it into the infusion bag together with 0.9% normal saline for intravenous infusion. The infusion takes about 2 hours.

For subcutaneous injection, prepare the mAb1 drug into a solution containing 150 mg/mL mAb1 with 2.3 mL sterile water for injection. The pharmacist or his/her designee administers this injection in the abdomen; do not administer from the extremities due to possible differences in absorption and bioavailability. If multiple injections are required on the same day, each injection needs to be injected at a different injection site.

The doses of mAb1 tested were: 1.0, 3.0, 8.0 and 12.0 mg/kg for intravenous injection, and 150 and 300 mg for subcutaneous injection.

A placebo corresponding to mAb1 was prepared in the same formulation as mAb1, but no antibody was added.

C. Results and conclusions

In general, mAb1 was both well tolerated and safe. The overall adverse event (AE) profile presented the characteristics of a healthy population. Less than 55% (19/36) of subjects treated with mAb1 experienced one or more treatment-related episodes compared to less than 59% (7/12) of subjects treated with placebo Emergent Adverse Events (TEAEs). The most commonly reported TEAEs were: increased blood creatine phosphokinase (CPK), increased blood pressure, nasopharyngitis, and toothache. Most subjects experienced TEAEs that were mild or moderate in intensity; only 3 subjects reported TEAEs considered severe. Only one case of serious TEAE (increased blood CPK) was considered by the study host to be related to treatment. One serious adverse event (SAE) was reported during the study, but was not considered by the study host to be related to the study drug. No subjects withdrew from the study due to AEs, and no deaths were reported. No other clinically significant laboratory test results (blood chemistry, hematology, or urinalysis) were reported during the study period. No trends were observed in the baseline mean/median for all laboratory parameters. Throughout the study period, no significant trends were observed in mean or median changes from baseline in body temperature or pulse. No clinically significant abnormalities were observed on physical examination, electrocardiogram, or vital signs.

A notable feature of this study was the black/African American subjects in the subject population accounted for a high proportion (Table 2).

Although the subjects were healthy volunteers, African Americans as a group may be more susceptible to atopic disease (Caggana et al 1999; Genet. Med. 1:267-271), so this group can be considered suitable for Evaluation of mechanistic evidence based on exploratory biomarker analysis.

Regarding the pharmacokinetic (PK) analysis, non-linear kinetics were observed. When the concentration of functional mAbl was above about 30 mg/L, the excretion pathway of the target vehicle appeared to be saturated at IV doses of 8 and 12 mg/kg. Low levels of anti-drug antibody (ADA) titers were observed in 9 subjects. Sudden and persistent decreases in functional mAb1 concentrations were not observed, indicating that ADA does not have a major effect on PK.

Example 3: Clinical trial of two different anti-IL-4R antibody (mAb1 ) drugs following subcutaneous injection of anti-IL-4R antibody (mAb1 ) in healthy patients

A. Experimental design

This study is a single-center, single-dose, double-blind, randomized, placebo-free study to evaluate the safety of subcutaneous injection of two different anti-IL-4R mAb (mAb1) produced from different cell lines and manufacturing processes and pharmacokinetic properties. Drugs are dosed in 2mL (150 mg/mL) was provided in the form of subcutaneous injection of 300 mg (2 mL) to 30 healthy adults in two parallel groups (15 subjects in each group). The study subjects included 30 subjects, 22 males (73.3%) and 8 females (26.7%), aged 19 to 45 years and weighing 54.8 to 94.3 kg.

mAb1 plasma concentrations were used to determine the following PK parameters: maximum plasma concentration (C _max ), time under the plasma concentration-time curve from time 0 to real time (corresponding to final concentration above the lower limit of quantification, t _last (AUC _last )) area, and the area under the plasma concentration-time curve (AUC) extrapolated from time 0 to infinity. The time to maximum plasma concentration (t _max ) and terminal half-life (t _1/2z ) were also measured.

B. Evaluation Criteria and Methods

Safety was assessed by measuring adverse events, including treatment-emergent adverse events (TEAEs), clinical laboratory assessments (biochemical, hematology, urinalysis), vital signs, automated-reading ECG up to two months after dosing (ECG), anti-mAb1 antibody (negative or titer), and local tolerability assessment (including evaluation of injection site pain, erythema [injection site, diameter mm ], and edema [injection site, diameter mm])

2倍正常範圍上限、QTc

500ms、懷孕，或藥物過量。 Adverse events of exceptional importance (AESI) are those AEs (regardless of severity) of scientific and medical concern that require special monitoring, documentation, and management as described in the protocol. The following AEs are defined as AESI: Hypersensitivity/anaphylaxis: anaphylaxis or acute anaphylaxis requiring immediate treatment, severe injection site reaction lasting longer than 24 hours, severe infection, any parasitic infection, alanine aminotransferase (ALT) level up

2 times upper limit of normal range, QTc

500ms, pregnancy, or drug overdose.

Blood samples were collected for hematology and biochemical evaluation on pre-study day 1, day 2 (i.e., 24 hours post-dose) and day 57, and on days 8, 15, 22, 29, 36, 43, and 50 Do biochemical tests limited to liver function every day.

Blood samples were collected on days 1 and 15, 29 and 57 for the determination of anti-mAb1 antibodies plasma concentration.

Administer mAb1 on day 1 before administration, 2 minutes, 2 hours, 6 hours and 12 hours after administration, and on day 2 (24 hours after administration), day 3, day 4 and day 8 A local tolerability assessment was then performed.

Blood samples were collected before and 12 hours after administration on day 1 and after administration of mAb1 on days 2, 3, 4, 8, 11, 15, 22, 29, 36, 43, 50, and 57 for pharmacological purposes. Kinetic and pharmacogenetic tests. Plasma concentrations of functional mAb1 were determined using a validated enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation (LLOQ) of 78 ng/mL.

Samples were collected at baseline (day 1 predose) for optional pharmacogenetic assay analysis.

Pharmacokinetic parameters of serum functional mAb1 by treatment group using descriptive statistics (mean, geometric mean, median, standard deviation (SD), coefficient of variation (CV), minimum and maximum) be summarized. For log-transformed _Cmax , _AUClast , and AUC, linear fixed-effects models were used with sex and treatment as fixed effects and body weight as a covariate to estimate study treatment/control treatment effect ratios. Estimates and 90% confidence intervals (CI) of treatment effect ratios are provided for _Cmax , _AUClast and AUC.

The safety assessment was based on a review of individual numerical and descriptive statistics. The frequency of treatment-emergent adverse events (TEAEs) was categorized and tabulated (number and percentage ). Potentially clinically significant abnormalities (PCSA; as defined in Version 2.0 September 14, 2009), such as clinical laboratory data, vital sign and ECG values, and values outside the normal range of clinical laboratory data, are flagged and Summarize.

According to the treatment group, subject and return date, the anti-mAb1 antibody result is listed as negative or the titer value (if the result of the confirmation test is positive). Summary by treatment group by number (number and percentage) of subjects who tested negative or positive for antidrug antibody (ADA) data.

By treatment group, descriptive statistics (mean, SD, minimum, median and maximum) pain VAS, erythema diameter and edema diameter are provided for each predetermined time point. Each of the above measurements was further summarized by treatment group as time mean (assessed from study drug administration to and including Day 8) and peak (assessed using post-dose).

C. Pharmacokinetic Results

These estimates were based on a linear fixed-effects model with sex, weight, and treatment as fixed terms.

D. Safety Results

Twelve of 15 subjects (80.0%) who received Drug A (Test Drug) and 8 of 15 subjects (53.3%) who received Drug B (Control Drug) experienced TEAEs . Apparent treatment imbalances were only seen in certain major system organs and appeared to be caused by events unrelated to the investigational medicinal product (IMP), as another cause was often found. Four serious adverse events (SAEs) experienced by two subjects were reported during the study.

A 23-year-old male subject in the drug 1 treatment group experienced "herpes simplex virus type II infection" with symptoms of blurred vision, sweating, fever, and headache starting on day 4 after drug use, followed by tongue swelling ( Day 6 after medication), cough, chest tightness, and calf muscle spasms on both sides (day 7 after medication). During the course of the event, the subject made multiple trips to the emergency room for a variety of treatments, including Solumedrol® (3 IV injections), Prednisone (9 days), Rocephin® (1 IV injection), and Zithromax® (5 days ). It is worth noting that the subject had a tongue nail pierced on his tongue 3 months before the medication. All symptoms disappeared 19 days after the medication. An initial herpes simplex virus (HSV) IgG titer for type 2 was negative on day 10 of dosing and was reassessed 7 weeks after dosing and was reassessed to be positive. This SAE incident was judged to be related to IMP by the study host and the company. More than 4 weeks after taking the drug, the subject was diagnosed with left-sided "Bell's palsy", which the research host believed was the result of herpes simplex virus type II infection. The event was managed with prednisone (6 days) and acyclovir (10 days). Repeated steroid administration due to the acute onset of HSV II infection, the investigators concluded that this SAE event was not related to IMP, and repeated steroid administration was considered as an alternative explanation. The company believes that a causal relationship with the IMP cannot be ruled out. Both events were recovering at the end of the study. The subject did not develop ADA at any time during the study.

A 22-year-old male subject in the drug A treatment group experienced "increased ALT levels" (ALT up to 11.4 times the upper limit of the normal range) and "rhabdomyolysis" (blood creatine phosphokinase up to 392 times the upper limit of the normal range), Both symptoms were detected by conventional laboratory tests 7 weeks after dosing. These events occurred during physical challenges (including swimming, push-ups, pull-ups, Sit-ups and other endurance-type fitness exercises; subject was a lifeguard) and after triceps injury (non-serious adverse event NSAE). The subject was admitted to the hospital for rehydration therapy. The possibility that the elevated liver function test results were caused by the liver was excluded, and it was judged that the elevated ALT level (and the elevated aspartate aminotransferase [AST] level, up to 50.5 times the upper limit of the normal range) were related to rhabdomyolysis. Creatinine and glomerular function remained within normal ranges during the event. Both events resolved within 3 weeks. The study moderators did not consider these two SAEs to be related to IMP. This subject also developed ADA, and positive titers were detected on day 29 (titer value = 120) and end-of-study visit (EOSV, titer value = 30) on day 58, respectively.

Apart from increased ALT levels, no other AESIs were observed during the study period.

Four (4) subjects experienced infections during the study. In addition to the above-mentioned herpes simplex virus infection, cases of mild upper respiratory tract infection, pharyngitis and sinusitis (1 case each) were also observed on the 54th day, 7th day and 1st day after administration. These latter three events were observed in subjects treated with C1P2.

Fifteen (15) injection site reactions occurred in 12 subjects: erythema (8 of 8 subjects, 4 in each group), pain (3, 2 treated with C2P1, 2 treated with C1P2 treated 1 case), small nodules (2 cases, 1 case in each group), hematoma (1 case treated with C1P2), and pruritus (1 case treated with C2P1). All were mild and resolved within 24 hours of injection.

Except for 2 cases of pruritus (not at the injection site) and 3 cases of headache in 2 subjects treated with C2P1 (in 1 subject treated with C2P1 and 2 cases treated with C1P2), no Other TEAEs were observed in more than 1 subject.

Except for the abnormal laboratory test results mentioned above, the rise of other laboratory test results did not exceed the predetermined PCSA threshold.

Six (22.22%) of 27 subjects who completed the study were positive for anti-mAb1 antibodies (no ADA was detected in subjects who did not complete the study). Of the 6 subjects with positive ADA titers, 4 were treated with C2P1 and 2 with C1P2. No association was observed between ADA production and TEAEs.

E. Specific Local Tolerance Assessment

On the pain VAS, mean peak values were 4.4 and 4.2 mm (100 mm scale) in the C2P1 and C1P2 treated groups, respectively, with a median of 2.0 mm in both groups. Five (5) of the 15 subjects in each group were "pain free" (0 mm peak). In the C2P1 and C1P2 treatment groups, the highest measurements were 17 mm and 18 mm, respectively, and were generally observed 2 minutes after dosing (2 minutes to 12 hours after dosing).

The mean peak measured erythema diameters were 12.5 mm and 10.9 mm in the C2P1 and C1P2 treated groups, respectively. Nine (9) of 15 subjects in each group were free of erythema at any time. The maximum value seen in both groups was 40mm, except for one subject whose maximum value (3mm) was observed 48 hours after administration, and the rest were all observed 2 minutes after administration.

The mean peak values of the measured edema diameters were 1.1 mm and 0 mm in the C2P1 and C1P2 treated groups, respectively. Thirteen (13) of 15 subjects in the C2P1 treatment group and 15 of 15 subjects in the C1P2 treatment group had no edema at any time. Two subjects in the C2P1 treatment group had maximum values of 15 mm and 1 mm, respectively, which were observed 2 hours after dosing.

F. Conclusion

Following a single subcutaneous dose of 300 mg of mAb1 to healthy subjects, functional mAb1 plasma concentrations were similar for both test products. The geometric means of treatment effect ratios (DP1/DP2) with 90% confidence intervals for _Cmax , _AUClast , and AUC were 1.10 (0.89 to 1.35), 0.90 (0.71 to 1.16) and 1.05 (0.86 to 1.29), respectively.

In general, mAbl was well tolerated. One subject treated with DP1 experienced a serious adverse event of "herpes simplex virus type 2 infection" followed by "Bell's palsy".

There were no clinically important local tolerability issues, and local tolerability parameters (eg, pain, erythema, edema) did not differ significantly between treatment groups.

The most common TEAE was injection site erythema (8 of 30 subjects), and was observed at the same rate in both treatment groups (4 of 15 subjects in each arm [26.7 %]).

In conclusion, following a single 300 mg subcutaneous dose of mAb1 in healthy subjects, no clinically important differences were found in the PK parameters, safety, and local tolerability of the two different medicinal products.

Example 4: Safety, tolerability, and pharmacokinetics of a clinical trial of dose-escalating single-dose subcutaneous injections of an anti-IL-4R antibody in healthy Japanese adult male subjects

A. Experimental design

This study was a randomized, double-blind, placebo-controlled study of single subcutaneous injections of an anti-IL-4R antibody (mAb1) in ascending doses in healthy Japanese adult male subjects. The primary objective was to assess the safety and tolerability of mAb1 following single subcutaneous injections of ascending doses in healthy Japanese male subjects. Secondary objectives were to evaluate the pharmacokinetics, immunogenicity and exploratory pharmacodynamics of mAb1 administered subcutaneously at ascending doses in healthy Japanese male subjects.

mAb1 is derived from cell line 2 and is supplied as a liquid formulation in vials at concentrations of 75 mg/mL or 150 mg/mL. mAbl was injected subcutaneously on day 1 in ascending single doses of 75, 150, 300 and 600 mg (one injection each of 75 mg and 150 mg; two injections each of 300 mg; four injections each of 600 mg). The observation period for each subject was approximately 11 weeks (including the screening period from day 2 to day 21 before dosing, 5 days in the clinic [from day 1 before the start of the study to day 4 of the study, including day 1 treatment], and outpatient follow-up up to day 57 after dosing).

B. Evaluation Criteria

Safety: adverse events (AEs), physical examination, clinical laboratory evaluation (hematology, biochemistry, urinalysis), vital signs (supine and standing positional blood pressure and heart rate, temperature), 12-lead electrocardiogram (ECG), and Anti-mAb1 antibody.

Pharmacokinetics: The following serum functional mAb1 pharmacokinetic parameters were calculated using non-compartmental assays - maximum observed plasma concentration ( _Cmax ), time to maximum plasma concentration ( _tmax ), dose-normalized _Cmax (C _max /dose), area under the plasma concentration-time curve from time 0 to real time (corresponding to final concentration above the lower limit of quantification, t _last (AUC _last )), dose-normalized AUC _last (AUC _last /dose ), area under the plasma concentration-time curve (AUC) extrapolated from time 0 to infinity, apparent volume of distribution at steady state (V _ss /F), apparent systemic clearance (CL/F), mean residence time (MRT), terminal half-life (t _½z )

Pharmacodynamics (PD): Pharmacodynamic effect of mAb1 on total IgE and TARC

Blood samples for PK assessment were taken before administration (day 1) and days 1, 2, 4, 8, 11, 15, 18, 22, 25, 29, 36, 43, 50, and 57 after administration of mAb1 ( collected on days 15 to 25 ± 1 day; days 29 to 57 ± 2 days). The plasma concentration of mAb1 was determined by a validated ELISA method with a lower limit of quantitation (LLOQ) of 78 ng/mL (0.078 mg/mL). Blood samples for PD assessment were taken predose (day 1 before study start) and study day 1, then on days 8, 15, 22, 29, 43, and 57 after mAb1 administration (days 15 to 25± 1 day; days 29 to 57 ± 2 days). Serum screening for total IgE and TARC was determined using a validated method.

C. Statistical Methods

The safety assessment was based on a review of individual numerical and descriptive statistics. All adverse events were coded using MedDRA version 15.1, and the frequency (number and percentage) of treatment-emergent adverse events (TEAEs) was categorized and tabulated by major system organ class, preferred term, and treatment group. Potentially clinically significant abnormalities, such as clinical laboratory data, vital signs and ECG values, and values outside the normal range of clinical laboratory data, were flagged and summarized by treatment group. In addition, raw data and changes from baseline for vital signs, ECG, and limited laboratory parameters were summarized with descriptive statistics.

Each dose group was summarized using descriptive statistics (mean, geometric mean, standard deviation of the mean (SEM), median, standard deviation (SD), coefficient of variation (CV), minimum and maximum) Pharmacokinetic parameters of serum functional mAb1. Dose proportionality was assessed using an efficacy model for C _max , AUC _last and AUC. The effect of dose on t _½z was assessed using a linear fixed-effects model. The distribution of t _max values is presented in a histogram. Using descriptive statistics, mAb1 PD biomarkers (total IgE and TARC:CCL17) were summarized for each dose group.

D. Safety Results

Single subcutaneous injections of mAb1 at doses up to 600 mg were well tolerated by healthy Japanese adult male subjects with a median body weight of 65.1 kg. There were no reports of serious TEAEs or premature withdrawals during the study period. During the observation period up to 57 days after dosing, a total of 3 TEAEs were reported in 32 subjects as follows: 1 of 8 subjects in the placebo group (influenza), 6 in the 150 mg dose group One of the subjects (influenza) and one of the 16 subjects in the 600 mg dose group (orthostatic hypotension).

There was no local skin reaction or discomfort at the injection site up to an injection volume of 2.0 ml x 4 sites (600 mg).

Five of the 32 subjects were positive for anti-mAb1 antibody (ADA) at low titer levels (1 case in the 75 mg dose group, 2 cases in the 150 mg dose group, 1 case in the 300 mg dose group, and 1 case in the 600 mg dose group). ADA was undetectable in all subjects in the baseline and placebo groups. None of the ADA positive subjects experienced any TEAEs.

Few PCSAs were found in the hematological and biochemical assay values in the mAb1-treated group, and no dose-incidence relationship was found. In particular, no changes in liver enzymes were observed. PCSA of vital signs or ECG was rare and independent of dose. No subject experienced prolonged QTcB (>450 ms), and no change from baseline greater than 60 ms was observed during the study.

E. Pharmacokinetic Results

The mean (SD) plasma concentration-time profiles of functional mAbl following a single subcutaneous dose are shown in Figure 1. The pharmacokinetic parameters of serum functional mAbl for all subjects treated with mAbl are summarized in Table 5.

Median _tmax was 7 days for all doses of mAbl. The mean terminal excretion half-life (t _½z ) was dose-dependent (p<0.01), ranging from 2.77 days at 75 mg to 8.77 days at 600 mg. An 8-fold increase in dose from 75 mg to 600 mg resulted in a 13.1-fold, 30.4-fold and 24.2-fold increase in geometric mean C _max , AUC _last and AUC, respectively.

F. Pharmacodynamic Results

IgE plasma concentration and TARC plasma concentration values varied widely across treatment groups. With respect to IgE plasma concentrations (percent change from baseline), no drug-related effects were observed over time when administered as a single subcutaneous dose at doses of 75 mg and 150 mg. When the dose is 300mg and 600mg, the IgE plasma concentration has a downward trend after treatment. An effect of treatment on TARC was observed. Single subcutaneous doses between 75 mg and 600 mg compared with placebo, compared with Correlates with decreased TARC plasma concentrations. More sustained declines were associated with dose increases.

G. Conclusion

Single subcutaneous injections of mAbl at doses up to 600 mg were well tolerated by healthy Japanese male subjects. There were no reports of serious TEAEs or premature withdrawals during the study period. A total of 3 TEAEs were reported among 32 subjects. There was no local skin reaction or discomfort at the injection site up to an injection volume of 2.0 ml x 4 sites (600 mg). Overall, the reported TEAEs and laboratory data, vital signs, and ECG assessments did not suggest a dose-related effect.

Following a single dose of healthy Japanese adult males, mAb1 was absorbed with a median t _max lasting 7 days and excreted according to a dose-dependent mean terminal excretion half-life (t _½z ) ranging from 2.77 days for the 75 mg dose to the 600 mg dose 8.77 days. Mean plasma concentrations of functional mAbl rose in a more than dose-proportional manner, with an 8-fold increase in dose from 75 mg to 600 mg resulting in a 13.1-fold, 30.4-fold, and 24.2-fold increase in geometric mean _Cmax , _AUClast , and AUC, respectively.

A pharmacodynamic effect was observed. TARC plasma concentrations decreased after treatment with mAb1. Longer-lasting declines were associated with increasing doses. Low ADA titers were detected in 5 of 32 subjects. ADA was undetectable in all subjects in the baseline and placebo groups. None of the ADA positive subjects experienced any TEAEs.

Example 5: Clinical Trial Evaluating the Effect of Injection Rate on the Safety and Tolerability of Healthy Volunteers Receiving Subcutaneous Injection of mAb1

A. Overview and Experimental Design

This study was performed to support the development of a large-volume injection device for mAb1 administration. This study comparatively evaluates two different injection rates that approximate the corresponding properties of two different subcutaneous (SC) drug delivery devices: one representing a rapid injection for an autoinjector and one representing a slow injection for a microinjector. The primary objective of this study was to compare the safety and tolerability of a single subcutaneous dose of 300 mg/2 mL of mAb1 administered to normal healthy volunteers at two different rates. this The secondary objectives of this study were: to compare the pharmacokinetic (PK) properties of a single 300mg/2mL subcutaneous injection of mAb1 at two different rates in two different groups of normal healthy volunteers; Rate Immunogenicity of mAb1 when a single dose of 300mg/2mL was injected subcutaneously into normal healthy volunteers.

This is an open-label, randomized, parallel-group, and single-dose study of the safety, tolerability, PK, and immunogenicity of mAb1 administered subcutaneously at 2 different injection rates. The study was randomized to avoid any possible bias in the assignment of subjects to study treatment and to minimize systematic differences between treatment groups with respect to baseline variables that could affect the results. Because the method and duration of injections could not be effectively concealed, this study was open-label. Thirty-six subjects (18 per treatment group) were recruited in the US and randomly assigned at 1 study site. The sample size for this study was chosen empirically. The sample size or test power calculation based on the main test index was not adopted. However, it was estimated that a sample size of 18 subjects per group would yield 80% power to detect a 20-point difference between the 2 groups on the pain VAS scale, assuming a two-sided test at the 0.05 significance level. The common standard deviation was 20.8 points on the pain VAS scale.

Subjects were screened from day 14 to day 2 before the start of the study. One day before the start of the study, subjects entered the clinic to attend training and familiarize themselves with the injection procedure, and were randomized into group 1 (fast injection) or group 2 (slow injection).

• Group 1 (bolus injection): Subjects received study drug by manual subcutaneous injection for 30 seconds.

●Group 2 (slow injection): Subjects received the study drug through a subcutaneous infusion device connected to a syringe pump, with a programmed infusion volume of 2 mL and an injection time of 10 minutes.

On day 1 before study initiation, all subjects received a mock injection during which the SC infusion set was briefly attached to the skin. This procedure involves inserting a 27G 6-mm needle, leaving it in place for about 10-15 seconds, and then withdrawing. Subjects rated their pain/discomfort associated with each step of the simulated injection procedure as follows:

針頭插入和拔出後，受試者立即(10秒內)評價他們與該模擬注射過程每一步驟相關的疼痛/不適。

Immediately (within 10 seconds) following needle insertion and withdrawal, subjects rated their pain/discomfort associated with each step of the simulated injection procedure.

總體評估(GA)：針頭拔出後1分鐘，受試者被要求根據回憶而提供GA，並評價在整個過程中經歷的疼痛/不適。

Global Assessment (GA): 1 minute after needle withdrawal, subjects were asked to provide a GA based on recall and rate the pain/discomfort experienced throughout the procedure.

比較評估(CA)：針頭拔出後約1分鐘(緊隨GA之後)，除了「視覺類比量表」(VAS)外，受試者還將經歷的總體疼痛/不適與熟悉的經歷如蜜蜂叮或打流感預防針相比而提供CA。

Comparative Assessment (CA): About 1 minute after needle withdrawal (immediately following GA), in addition to the "Visual Analog Scale" (VAS), the subject will compare the overall pain/discomfort experienced with a familiar experience such as a bee sting Or provide CA instead of getting a flu shot.

On day 1, all subjects received 300mg/2mL of mAb1 and completed the VAS assessment according to the diagram in Figure 2.

All subjects (Groups 1 and 2) were monitored for the incidence, extent and severity of injection site reactions (ISR), such as erythema, edema, induration, tenderness, and pruritus. Erythema, edema, induration extent (maximum diameter, mm) and severity of erythema and edema were assessed at 1, 2, 4 and 8 hours after injection and at each follow-up until the end of the study, or until after 2 consecutive assessments, when all injection site parameters assessed appear to have returned to normal. Subjects were also asked to rate the presence of any pruritus (itching) and tenderness (pain on palpation) using the VAS.

Subject left clinic on day 2. Subjects returned to the clinic on days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, and 64 (end of study) for outpatient follow-up. Callbacks on days 8, 11 and 15 are also possible within the range of +/- 1 day. Return visits from Day 22 to Day 64 may also be within the range of +/- 2 days. The total observation period for each subject was within 9 weeks after the first day of administration.

B. Analyzing Variables and Statistical Methods

The following demographic and baseline characteristic variables were summarized: age at screening (years), sex, ethnicity, race, baseline weight (kg), height (m), BMI (kg/m2), and pain/discomfort VAS. Primary variables included the following measures of safety and tolerability: (i) until Day 64 (end of study), incidence of treatment-emergent adverse events (TEAEs) and Severity; incidence, extent, severity and duration of ISR up to Day 64; (ii) overall pain/discomfort (GA) associated with the injection procedure; (iii) at time of needle insertion, study drug injection, respectively and pain/discomfort upon needle withdrawal; (iv) residual pain/discomfort over time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours, and pain/discomfort at subsequent study visits.

All subjects (Groups 1 and 2) were monitored for the incidence, extent and severity of injection site reactions (ISR), such as erythema, edema, induration, tenderness, and pruritus. The extent (maximum diameter, mm) of erythema, edema, and induration was assessed. In addition, the severity of erythema and edema was assessed qualitatively using a standard 0-4 cutaneous tolerance scale (Draize test) at 1, 2, 4, and 8 hours after injection and at each follow-up visit degree until the end of the study or until the injection site appears to have returned to normal on 2 consecutive assessments based on all parameters assessed.

The following scales are used to rate the severity of erythema and edema:

erythema:

0 = no erythema

1 = very slight erythema (almost imperceptible)

2 = well-defined erythema

3 = Moderate to severe erythema

4 = Severe erythema (beet redness) to mild eschar formation (deep injury)

Edema:

0 = no edema

1 = Very slight edema (almost imperceptible)

2 = Mild edema (well-defined borders)

3=moderate edema (protrusion>1mm)

4=severe edema (protrusion>1mm, and beyond the exposed area)

The VAS is a continuous rating scale (0-100 mm) that patients use to rate their pain/discomfort associated with study drug injections. The VAS ranges from "no pain/discomfort" on the left to "worst possible pain/discomfort" on the right. The same scale was also used to quantify itching and tenderness at the injection site, assessed as part of the ISR.

The safety and tolerability of mAb1 were assessed based on physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory evaluation. Subjects were required to monitor and report all adverse events (AEs) experienced from signing the informed consent until the end of the study visit on day 64. Adverse events, serious adverse events, and treatment-emergent adverse events have been defined elsewhere in this document.

Blood samples for PK analysis were collected at each visit from baseline (Day 1, pre-dose and post-dose [at end of injection and 1, 2, 4, 8, and 12 hours post-dose]). Blood samples were collected on Day 1 (pre-dose), Day 29 and Day 64 (end of study) for analysis of anti-mAbl antibody levels.

For continuous variables, descriptive statistics include the following: number of patients (n), mean, median, standard deviation, minimum and maximum values reflected in calculations. For categorical or ordinal data, frequencies and percentages for each category are shown.

C. Results

Injection pain and residual pain: Both injection modes - fast and slow - were well tolerated, which was associated with a relatively low degree of pain upon injection. For both modalities, the level of pain peaked approximately 15-30 seconds after the start of the injection. On the 0-100mm VAS scale, the average peak pain level was less than 15mm. Mean pain scores, including global assessment (overall pain recalled 1 min after injection), and residual pain over time, were comparable between bolus and slow injections; the observed differences were not clinically meaningful (i.e., at 0 -100 △<10 on the VAS scale). More subjects who received the slow injection reported little or no pain (VAS<5 mm) compared to those who received the bolus injection. Overall, it appears that injection pain was slightly better in the slow injection group, but there was no difference between the two injection methods Significance.

Injection site reactions: Overall, ISR rates were similar in both study groups (89% for bolus injections and 94% for slow injections). However, the objective ISR findings (erythema and/or induration) were more frequent in the slow injection group (83%) than in the rapid injection group (44%), especially injection site erythema (61% vs 11%, respectively). %). Subjective ISR included tenderness and itching at the injection site, and the incidence of ISR was slightly higher for rapid injection (72%) than for slow injection (56%), especially tenderness at the injection site (72% vs 39% for both groups, respectively). ). The onset of ISR can be noticed from 1 hour to several days after injection. The time to ISR resolution was also reported from 1 hour to several days after occurrence. Overall, it appeared that the ISR was slightly better in the bolus group, but the difference between the two injection modalities was not significant.

Adverse events: In terms of the number and incidence of treatment-emergent adverse events, the slow injection group (15 subjects reported 35 TEAEs) was higher than the rapid injection group (11 subjects reported 19 TEAEs). Most TEAEs were ISRs reported as adverse events based on the study host's assessment of clinical relevance. There were no TEAEs that resulted in discontinuation from the study. There were 3 serious TEAEs involving isolated conditions unrelated to the study drug or mode of injection. Overall, it appeared that the adverse event profile was slightly better in the bolus group, mainly due to the fact that ISR was also reported as an adverse event.

D. Conclusion

The research has achieved the primary and secondary objectives specified in the proposal. mAb1 was safe and well tolerated when administered as a bolus or slow injection. The study results did not provide a clear difference between the two injection methods.

Example 6: Clinical Trial of Subcutaneous Injection of Anti-IL-4R Antibody (mAb1) in Sequentially Ascending Repeated Doses in Patients with Moderate to Severe Atopic Dermatitis

A. Experimental design

This study is a Phase 1b, randomized, double-blind, placebo-controlled, sequentially ascending, repeated Dosage studies. Thirty patients were randomized into study groups (6 in the placebo group, 8 in each of the 75 mg, 150 mg and 300 mg dose groups). Twenty-eight patients received all treatments. The treatment period was 4 weeks; there was an 8-week follow-up period after the treatment period. Patients were randomly assigned in a 4:1 ratio to receive mAb1 or placebo in three escalating dose groups (75, 150, 300 mg mAb1). The primary purpose of the trial is to assess safety and tolerability, and PK is a secondary purpose. Exploratory objectives included trial indicators of efficacy and biomarkers. Exploratory efficacy variables included: (i) proportion of patients with an IGA score of 0 or 1 through week 4 and at each study visit; (ii) changes in BSA, EASI, and 5-D pruritus indices from baseline to each visit change and percent change; and (iii) weekly change in NRS score from baseline.

B. Efficacy variables

Efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Index, and Pruritus NRS Score are described elsewhere herein (see eg, Example 7).

IGA, BSA, EASI, and SCORAD scores were assessed at each visit. Patients were assessed for the 5-D Pruritus Index on the following follow-up days: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 43, 57, 71, and Day 85 (end of study) or earlier when terminated. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

The efficacy variable baseline was defined as the last nonmissing value on or before the random date. For a patient without a measured value on or before his/her randomization date, the last non-missing value on or before the day of the first drug injection will be used as baseline.

C. Statistical Methods

Summaries for safety and exploratory efficacy variables were generated by dose group and overall. The summary of safety and tolerability was based on the safety analysis set (SAF). Safety analyzes were based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 12-lead electrocardiograms.

All categorical variables were analyzed using the Fisher exact test with reported nominal p-values and confidence intervals.

All continuous variables were analyzed by ANalysis of COVAriance (ANCOVA). Unless otherwise stated, the assessment of change from baseline and the construction of confidence intervals for continuous measures were based on an ANCOVA model including treatment as the main factor and the baseline value as the covariate. Point estimates and 95% CIs for the difference between the two treatment groups in the adjusted mean change from baseline are provided. Due to the small sample size of this study, p-values for tests of exploratory efficacy variables are presented for descriptive purposes. Missing values were filled with last observation forward (LOCF).

D. Patient Configuration

Patients in the placebo group were the youngest, and 33% of patients in the placebo group were Hispanic or Latino, compared with all patients in the treatment group who were non-Hispanic. Table 6 summarizes the demographic characteristics of the patient population

Table 7 summarizes the baseline disease characteristics of the patient population

Mean baseline IGA, EASI, BSA, and pruritus NRS scores for study participants were approximately 3.8, 28.2, 48.5, and 6.4, respectively.

E. Results

In this study, subcutaneous administration of mAb1 to patients with moderate to severe AD was safe and well tolerated. The only serious adverse event recorded involved a patient in the 150 mg dose cohort who was diagnosed with exercise-related CPK elevations. No deaths were reported. Twenty-five or 83% of treated patients reported at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the treatment group were infections and parasitic infections (n=7 [29%], vs 1 [17%] in the placebo group), and headache (n=3 [13%] in mAb1-treated patients ], compared to 1 [17%] in the placebo group).

The baseline and exploratory efficacy results obtained from the studies are summarized in Figures 3-14. Administration of mAb1 did not result in statistically significant improvements in any of the exploratory AD trial parameters. This may be due to the small sample size and the fact that patients in the placebo group were less ill and younger than those in the active drug treatment group.

Example 7: Clinical Trial of Subcutaneous Injection of Anti-IL-4R Antibody (mAb1) in Moderate to Severe Atopic Dermatitis Patients

A. Experimental design

12且至少涉及10%體表面積。治療期為4週；治療期結束後有8週的追蹤期。患者在基線前至少1週停用局部藥劑(如吡美莫司、他克莫司及局部皮質類固醇)。口服皮質類固醇和免疫抑製劑(如環孢素、嗎替麥考酚酯、IFN-γ)從

基線4週前也被禁止。 This study was a 12-week, double-blind, randomized, placebo-controlled, sequentially ascending, repeat-dose study evaluating subcutaneous administration of an anti-IL-4R mAb to adult patients with moderate-to-severe atopic dermatitis (this article). known as "mAb1") safety and pharmacokinetic properties. Eczema Area and Severity Index (EASI) in Moderate to Severe AD Patients

12 and involve at least 10% of the body surface area. The treatment period was 4 weeks; there was an 8-week follow-up period after the treatment period. Patients discontinued topical agents (eg, pimecrolimus, tacrolimus, and topical corticosteroids) at least 1 week before baseline. Oral corticosteroids and immunosuppressants (eg, cyclosporine, mycophenolate mofetil, IFN-γ) from

Baseline 4 weeks ago was also prohibited.

Patients were randomly assigned in a 3:1 ratio to receive mAb1 or placebo in two ascending dose groups (150 or 300 mg). The study consisted of a screening period (days 14 to 3 before the start of the study), a treatment period (days 1 to 29) (no topical steroids allowed), and a follow-up period (day 29 to day 85) (topical steroids allowed). During the treatment period, patients will come to the clinic at least once a week on the 1st, 4th, 8th, 15th, 22nd, 25th and 29th day (week 4) to receive safety, laboratory tests and clinical effect evaluations. Patients received study drug on Days 1, 8, 15, and 22. Patients were observed at the study site for 2 hours after each dose of study drug. The follow-up visit at the end of the treatment period was on day 29 (week 4). During the follow-up period, patients visited the clinic for follow-up evaluations on days 36, 43, 50, 57, 64, 71, and 85 (end-of-study visits).

B Efficacy variables

The exploratory efficacy variables measured in this study included: (1) the proportion of patients with an Instructor's Global Assessment (IGA) score of 0 or 1 through Week 4 and at each study visit; Changes and percentage changes from baseline to each visit in Atopic Dermatitis Involved Body Surface Area (BSA), Eczema Area and Severity Index (EASI), SCORAD, and 5-D Pruritus Index; (3) Weekly change from baseline in Pruritus Numeric Rating Scale (NRS) score. (4) Changes from baseline in circulating eosinophils, TARC, eotaxin-3, and total IgE until week 4; (5) circulating eosinophils, TARC, eosinophils until week 12 Changes from baseline in chemokine-3 and total IgE; and (6) circulating eosinophils, TARC, eotaxin-3, Phadiatop ^TM assay results up to week 4 associated with treatment response and Change from baseline in total IgE.

The efficacy variable baseline was defined as the last nonmissing value on or before the random date. For a patient without a measured value on or before his/her randomization date, the last non-missing value on or before the day of the first drug injection will be used as baseline.

"Investigator's Global Assessment" (IGA): The IGA is a rating scale, based on a 6-point scale from 0 (none) to 5 (very severe), used in clinical studies to determine the severity and impact of treatment of AD. clinical response. The IGA score was assessed at each visit.

"Atopic Dermatitis Involved Body Surface Area" (BSA): BSA affected by AD is assessed for each major body part (head, trunk, upper and lower extremities) and is given as a percentage of the total for each body part Report. Patients were assessed for BSA on the following follow-up dates: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 36, 43, 57, 71, and Day 85 (end of study) or upon early termination .

"Eczema Area and Severity Index" (EASI): EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al 2001, Exp. Dermetol. 10: 11 -18). The calculation of the EASI score is based on the physician's assessment of various symptoms [erythema (E), induration/papule (I), exfoliation (X), and lichenification (L)], where each symptom is scored as 0=none, 1=mild, 2=moderate, or 3=severe, also based on area score [based on % affected (BSA)], where 0=0% BSA, 1=1-9% BSA, 2=10-29% BSA, 3=30-49% BSA, 4=50-69% BSA, 5=70-89% BSA, 6=90-100% BSA.

For each major body part (head, upper limbs, trunk and lower limbs), EASI Score = (E+I+X+L) x area score. The total EASI score is the weighted total of the EASI scores for each component, using weights of 10% = head, 20% = upper extremities, 30% = trunk, and 40% = lower extremities. The lowest possible EASI score is 0 and the highest possible EASI score is 72, with higher scores indicating increased severity of atopic dermatitis. Achieving EASI 50 (50% or greater improvement in EASI score) is considered clinically significant improvement by dermatology researchers and can be used as a test indicator.

Patients were assessed for EASI scores at the following visits: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 36, 43, 57, 71 and Day 85 (end of study) or early termination hour.

SCORAD: SCORAD is a validated tool used in clinical practice and clinical trials that was developed to standardize the assessment of the extent and severity of AD (Dermatology 1993, 186:23-31). The extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a maximum score of 100% (designated "A" in the overall SCORAD calculation). The severity of the six specific symptoms of AD (erythema, edema/papule, exfoliation, lichenification, exudate/crusting, and dryness) was assessed using the following scale: none (0), mild (1), moderate Degree (2) or Severe (3) (maximum overall score of 18, assigned a "B" in the overall SCORAD calculation). Subjective assessments of pruritus and insomnia are recorded by the patient or relatives on a "visual analog scale" (VAS) with various symptoms, where 0 indicates no pruritus (or insomnia) and 10 is the worst pruritus (or insomnia) imaginable. ), the highest possible score is 20. This parameter is designated as "C" in the overall SCORAD calculation. The calculation formula of SCORAD is A/5+7B/2+C. The highest SCORAD score is 103.

Patients were assessed for SCORAD score at the following visits: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 36, 43, 57, 71 and Day 85 (end of study) or early termination hour.

5-D Pruritus Index: The 5-D Pruritus Index Scale is a 5-question form used to evaluate 5 measures of pruritus in clinical research: degree, duration, trend, disability, and distribution (Elman et. al. 2010, Brit. J. Dermatol. 162:587-593). patient Their symptoms during the previous two weeks were rated as "present" or rated on a scale of 1 to 5, where 5 indicates the most affected in each question of degree, duration, tendency and disability. The individual scores (duration, extent and trend) are equal to the values indicated under the response options (range 1-5).

The disability component consists of four items that assess the impact of pruritus on daily activities: sleep, leisure/social activities, housework/errands, and work/school. The score for the disability component is the highest score for any of the four items.

For the distribution domain, the number of affected body parts is recorded (possible sums are 0-16) and this sum is divided into five scoring intervals: sum 0-2 = 1 point, sum 3-5 = 2 points , the sum is 6-10=3 points, the sum is 11-13=4 points, and the sum is 14-16=5 points.

Scores for each of the five intervals were obtained separately and then added together to obtain the overall 5-D score. The 5-D score may range between 5 (no pruritus) and 25 (worst pruritus).

Patients were assessed for the 5-D Pruritus Index on the following follow-up days: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 43, 57, 71, and Day 85 (end of study) or earlier when terminated.

Pruritus Numeric Rating Scale (NRS): The Pruritus NRS is a one-question assessment tool used to assess the worst severity of itch in patients as a result of AD within the past 12 hours. From the evening of the screening day onwards, the patient called the IVRS twice daily and answered the following question: "On a scale of 0-10, 0 being 'no itching' and 10 being 'worst itching imaginable' , "How would you rate the worst itching you experienced in the past 12 hours?" Patients were instructed to use the IVRS to record their NRS score for itching at screening and were asked at each next clinic visit if implement. Patients completed this rating scale twice daily until the last visit for the study.

Baseline NRS was defined as the mean of all NRS reported after screening and before the baseline visit. For post-baseline NRS, the average weekly NRS is the average of the daily reported NRS for the week Value calculation (scaled average).

C. Safety Assessment

Safety was assessed throughout the study period by monitoring adverse events and serious adverse events.

An adverse event (AE) refers to any adverse medical event that occurs in a subject receiving the drug or a subject of a clinical study. Thus, an AE can be any adverse, unexpected sign (including abnormal laboratory results), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal (investigational) product. AEs also include: any exacerbation of pre-existing conditions related to the use of the study drug in time (i.e. any clinically significant change in frequency and/or intensity); abnormal laboratory findings considered clinically significant by the study host; and any adverse medical events.

A serious adverse event (SAE) is any adverse medical event at any dose that results in death, is life-threatening, requires hospitalization or prolonged hospitalization, results in persistent or severe disability/incapacity; is a congenital anomaly/congenital defects, or major medical events.

In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and physical examination variables were measured throughout the study.

Clinical laboratory data included hematology, blood chemistry, and urinalysis. Blood samples for hematology testing were collected at each study visit; at Screening, Day 1/Baseline (pre-dose), Day 8, Day 15, Day 29, Day 36, Day 57, On day 85 (end of the study) or at early termination (in case the subject terminates the study), blood samples for blood biochemical tests and urine samples for urinalysis were collected to measure the general health status of the patients.

Vital sign parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg), and body temperature (°C). Vital signs (pre-dose, each dosing day) are at Screening, Day 1/Baseline, Days 4, 8, 15, 22, 25, 29, 36, and Day 85 (end of study) or early termination when collected. Vital signs on days 1, 8, 15 and 22 at Collected 1 hour and 2 hours after study drug injection.

12-lead ECG parameters include: ventricular heart rate, pulse interval, QRS complex interval, corrected QT interval (QTcF=QT/[RR ^0.33 ] and QTcB=QT/[RR ^0.5 ]) ECG status: normal, clinically insignificant abnormal or clinically significant abnormalities. A standard 12-lead ECG was tested at Screening, Days 29 and 85 (end of study) or early termination.

A complete physical examination will be performed at Screening, Days 29 and 85 (end of study) or early termination.

D. Data Analysis

1. Exploratory efficacy variable analysis

All categorical variables were analyzed using the Fisher exact test with reported nominal p-values and confidence intervals. All continuous variables were analyzed by ANalysis of COVAriance (ANCOVA). Unless otherwise stated, the assessment of change from baseline and the construction of confidence intervals for continuous measures were based on an ANCOVA model including treatment as the main factor and the baseline value as the covariate. Point estimates and 95% CIs for the difference between the two treatment groups in the adjusted mean change from baseline are provided. Missing values were filled with last observation forward (LOCF). In cases where the model assumptions were not warranted, rank-based analysis of covariates was used. Association analysis was performed using Spearman's correlation coefficient.

2. Analysis of safety data

Safety analyzes were based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 12-lead electrocardiograms. Thresholds for laboratory variables, vital signs and ECG potentially clinically significant values (PCSV) were defined in SAP. The time period for detection of any event or abnormality is from the start of the study drug infusion to the end of the study. Data collected outside this interval were excluded from calculations of descriptive statistics and detection of abnormalities in laboratory evaluations, vital signs and electrocardiograms.

E. Results

Patients received 150 mg or 300 mg subcutaneous injection of mAb1 as described above. treatment once a week for four weeks, or a placebo. Except for the older age at diagnosis in the 300 mg treatment group, the demographic and clinical characteristics of the treatment groups were generally similar (Table 8). The study population was mainly male (62.2%), white (94.6%), and the mean age was 43.6 (15.4) years. Of the 37 patients, 31 (83.8%) completed treatment and 25 (67.6%) completed the entire study. The most common reason for withdrawal from the trial was lack of efficacy (4 patients receiving placebo, 1 in each treatment group). No one withdrew from the trial due to adverse events associated with mAb1 administration.

The baseline and exploratory efficacy results obtained from the studies are summarized in Tables 9-14.

Table 9: Summary of percent change and absolute change from baseline in IGA score - all values are

E. Conclusion

Subcutaneous administration of an anti-IL-4R antibody (mAb1) at 150 mg or 300 mg once weekly for 4 weeks in adult patients with moderate to severe atopic dermatitis was generally safe and well tolerated; adverse events ( AE) rates were similar to placebo, and there were no dose-limiting toxicities or serious adverse events. The most common AEs caused by mAb1 were nasopharyngitis and headache. mAb1 rapidly (by day 8) reduced pruritus and improved dermatosis in a dose-dependent manner. Injection of mAb1 at doses of 150 mg and 300 mg resulted in significant improvements in mean and absolute percentage changes in IGA, EASI, BSA, SCORAD, and pruritus NRS scores from day 8 to day 85 compared to baseline (see Table 9- 14). On day 29, the 300mg dose group reached The proportion of patients who responded to EASI 50 was 71.4%, compared with 18.8% in the placebo group (p=0.0025); the pruritus NRS score decreased by 45.4%, compared with 18.6% in the placebo group (p=0.0016). This effect persisted until day 85 for EASI 50 and until day 75 for pruritus NRS score. For the 300 mg treatment group, the difference from the placebo group remained significant 6 weeks after the end of the treatment period. At day 29, mAb1 significantly improved other clinical outcomes: mean % change IGA (p=0.0002), EASI (p<0.0001), BSA (p=0.0037), and 5-D pruritus index (p<0.0001). These improvements were generally observed on Day 8 and persisted beyond the end of treatment. No rebound phenomenon was observed after the end of treatment.

Therefore, the results shown in this example demonstrate that mAbl is safe and effective for the treatment of atopic dermatitis.

Example 8: Treatment of Moderate to Severe Atopic Dermatitis Patients with Anti-IL-4R Antibodies: Pooled Analysis of Phase 1b Studies

AD efficacy parameters were measured and pooled for analysis in two separate clinical trials in patients with moderate-to-severe atopic dermatitis. "Study A" is a 12-week double-blind, randomized, placebo-controlled, sequentially ascending dose study to evaluate the safety and tolerability of anti-IL-4R antibody (mAb1) in patients with atopic dermatitis sex. The treatment period was 4 weeks, and there was an 8-week follow-up period after the treatment period. Patients were randomly assigned in a 4:1 ratio to receive mAb1 or placebo in three ascending dose groups (75mg, 150mg or 300mg). The study included a screening period (day 14 to day 3 prior to study initiation), a treatment period (day 1 to day 29), and a follow-up period (day 29 to day 85). During the treatment period, the patients came to the clinic once a week on the 1st, 4th, 8th, 15th, 22nd, 25th and 29th day (week 4) to receive safety, laboratory tests and clinical effect evaluations. Patients received one dose of mAbl or placebo on days 1, 8, 15 and 22. The end of the treatment period was Day 29 (Week 4). Patients were observed at the study site for 6 hours after injection (mAbl or placebo) on day 1 and for 3 hours after injection on days 8, 15 and 22. During the follow-up period, patients were treated on days 36, 43, 50, 57, 64, 71, and 85 (study Follow-up at the end of the study) to the clinic for follow-up evaluation.

"Study B" was a 12-week double-blind, randomized, placebo-controlled, sequentially ascending, repeat-dose study in patients with moderate-to-severe AD. AD subjects were administered 150 or 300 mg of mAb1 or placebo (see Example 3 herein) on days 1, 8, 15 and 22 of the study (ie weekly dosing for a total of 4 times). All dosing in both studies was by subcutaneous injection.

18歲的男性或女性；(2)患有慢性異位性皮膚炎達3年；(3)EASI

12；(4)IGA

3；(5)AD涉及之BSA

15%(美國)，或AD涉及之BSA

10%(美國以外)；以及(6)對於局部皮質類固醇(TCS)或鈣調磷酸酶抑製劑的穩定給藥方案有響應不足史。 The inclusion criteria of the research objects are: (1) should be

18-year-old male or female; (2) with chronic atopic dermatitis for 3 years; (3) EASI

12; (4) IGA

3; (5) BSA involved in AD

15% (USA), or BSA involved in AD

10% (outside the US); and (6) history of inadequate response to a stable dosing regimen of topical corticosteroids (TCS) or calcineurin inhibitors.

The exclusion criteria of the research subjects are: (1) WBC<3.5 x 10 ³ /μl; (2) platelets <125 x 10 ³ /μl; (3) neutrophils <1.75 x 10 ³ /μl; (4) AST/ALT >1.5x ULN; (5) positive for hepatitis B or C; and (6) treated with TCS or calcineurin inhibitor within 1 week of baseline.

The primary trial endpoint of the study is monitoring the incidence of treatment-emergent adverse events (TEAEs) from baseline to week 12. The exploratory trial measures for efficacy variables were: (i) percent IGA achieved 0 or 1 at week 4; (ii) percent improvement from baseline in BSA and EASI; and (iii) change from baseline in NRS score.

Efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Index, and Pruritus NRS Score are described elsewhere herein (see eg, Example 4).

IGA, BSA, EASI, and SCORAD scores were assessed at each visit. Patients were assessed for the 5-D Pruritus Index on the following follow-up days: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 43, 57, 71, and Day 85 (end of study) or earlier when terminated. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

Efficacy variable baseline was defined as the last random date on or before the random date non-missing value. For a patient without a measured value on or before his/her randomization date, the last non-missing value on or before the day of the first drug injection will be used as baseline.

The baseline statistical characteristics of the patient population are summarized in Table 15.

Mean baseline disease characteristics are shown in Table 16.

The results of the exploratory efficacy obtained from the pooled studies are summarized in Tables 17-25 and Figures 15-22.

50%，安慰劑組則為(18.8%；兩劑量組均為p<0.05)(圖19和20)。與 安慰劑組相比，mAb1治療組有較多患者在第4週達到EASI-25、EASI-50和EASI-75(圖21)。 mAb1 was well tolerated and effective in adults with moderate to severe AD. Administration of mAbl significantly improved AD disease activity and severity. In the 4th week, the 150mg and 300mg mAb1 treatment groups compared with the placebo group, in %BSA (p<0.05) (Figure 15), IGA (p<0.001) (Figure 16), EASI (p<0.001) (Figure 17 ) and Pruritus NRS (p<0.01, 300mg) (Figure 18) achieved significant improvement in change from baseline. More patients in the 150mg mAb1 dose group (54.5%) and 300mg dose group (71.4%) had decreased EASI scores

50%, compared with the placebo group (18.8%; both dose groups p<0.05) (Figures 19 and 20). More patients in the mAbl treated group achieved EASI-25, EASI-50 and EASI-75 at week 4 compared to the placebo group (Figure 21).

For the 300mg mAb1 dose group, significant improvements were seen in %BSA (p<0.02), IGA (p<0.05) and EASI (p<0.0001) within 2 weeks. Improvements in BSA, IGA and EASI (p<0.05 vs. placebo) were sustained for 8 weeks. At week 4, the proportion of patients with an IGA of 0 or 1 was significantly higher than placebo, but not statistically significant (Figure 22).

The most common treatment-emergent adverse events (AEs) in the mAb1-treated group were nasopharyngitis (19.6% vs. 12.5% in the placebo group) and headache (11.8% vs. 6.3% in the placebo group).

Example 9: Parallel group, dose-ranging clinical trial of subcutaneous injection of an anti-IL-4R antibody (mAb1 ) in adult patients with moderate to severe atopic dermatitis

A. Experimental design

This study was a 32-week randomized, double-blind, placebo-controlled, parallel-group study to evaluate the dose-response curve of weekly mAb1 in adult patients with moderate-to-severe atopic dermatitis. The primary objective of the study was to evaluate the efficacy of a multiple-dose mAb1 dosing regimen compared with placebo in adult patients with moderate-to-severe AD. Secondary objectives were: (1) to assess the safety of the multiple dose mAb1 dosing regimen in adult patients with moderate to severe AD compared with placebo; (2) to assess the safety of the multiple dose mAb1 dosing regimen in adult patients with moderate to severe AD Pharmacokinetics (PK); (3) compared with placebo, to evaluate the potential immune response of using multiple doses of mAb1 dosage regimen in adult patients with moderate to severe AD.

The target population includes adult patients with moderate-to-severe AD for whom topical medications are not adequately controlling the disease or for which topical therapy is not appropriate (eg, because of side effects or safety risks). Approximately 240 to 288 patients were enrolled. Eligible patients were randomized in a 1:1:1:1:1:1 ratio to receive 1 of 6 weekly regimens (5 active drugs, 1 placebo). Randomization was based on disease severity (moderate versus severe AD) and location District (Japan relative to the rest of the world) classification. The dosing schedule followed is shown in Table 26:

All patients received 2 injections (loading dose) on day 1, followed by weekly injections. For the every 2-week (q2w) and every 4-week (q4w) dosing regimens, the next dose of study drug was administered at weeks 2 and 4, respectively. Patients assigned to the once-every-two-week (q2w) and once-every-four-week (q4w) dosing regimens received an equivalent volume of placebo weekly when mAbl was not administered. After patients provided informed consent, they were assessed for study eligibility at screening. Eligible patients underwent Day 1/baseline assessment, randomization, and then weekly study drug injections from Day 1 through Week 15. During this time, patients return to the clinic for weekly visits, some weeks only by phone. Patients (and/or caregivers) were trained to inject study drug at visits 2, 3, 4, 5, and 6 and self-injected study drug at subsequent visits by phone only training. After receiving weekly doses of study drug for the first 5 weeks, patients were closely observed at the study site for at least 1 hour. Safety, laboratory results and clinical effect evaluations will be carried out at the stipulated return time. The end of the treatment period was at week 16, 1 week after the last dose of study drug, at which time the primary trial outcome was assessed. From week 18 to week 32, every 2 Follow up once a week. The end-of-study visit was at week 32. AD salvage therapy (drugs and/or phototherapy) was offered to study patients, if necessary, at the discretion of the study host. Patients requiring rescue therapy were immediately discontinued from study drug, but were asked to continue to follow the schedule of study assessments. Efficacy measures ("Study Director's Global Assessment" [IGA], Eczema Area and Severity Index [EASI], etc.) were obtained before any rescue treatment was to be administered. From patients who consented to participate in the optional genomic substudy, one sample for DNA analysis and multiple samples for RNA analysis were collected.

Study treatment: mAb1 subcutaneously: 300 mg (once per week), 300 mg (once every 2 weeks), 300 mg (once every 4 weeks), 200 mg (once every 2 weeks), or 100 mg (once every 2 weeks) from day 1 to week 15 4 weeks), or placebo subcutaneously once a week from day 1 to week 15. A substantially non-irritating topical moisturizer was applied twice daily from day 7 before the start of the study to day 8 after the start of the study.

2的患者比例；(3)從基線起至第16週EASI評分的絕對變化；(4)在第16週達到EASI-50、EASI-75和EASI-90(EASI評分從基線下降50、75和90%)的患者比例；(6)在第16週達到SCORAD-50、SCORAD-75和SCORAD-90(SCORAD評分從基線下降50、75和90%)的患者比例；(7)瘙癢指數(NRS和4級分類量表)從基線的絕對變化和百分比變化；(8)POEM評分從基線的絕對變化和百分比變化；(9)GISS組成部分(紅斑、浸潤/丘疹、表皮脫落、苔蘚化)從基線的變化；(10)GISS累積評分從基線的變化；(11)從基線起至第32週治療相關突發不良事件(TEAE)的發生率；以及(12)多劑量mAb1劑量方案的藥代動力學特性。 Trial Outcome: The primary trial outcome of this study was the percent change in EASI score from baseline to week 16. Secondary trial measures included: (1) proportion of patients achieving an IGA of 0 (none) or 1 (almost none) at week 16; (2) achieving an IGA score reduction at week 16

2; (3) Absolute change in EASI score from baseline to week 16; (4) EASI-50, EASI-75 and EASI-90 achieved at week 16 (EASI scores decreased from baseline by 50, 75 and 90%); (6) proportion of patients achieving SCORAD-50, SCORAD-75 and SCORAD-90 (50, 75 and 90% decrease in SCORAD score from baseline) at week 16; (7) pruritus index (NRS and 4-level categorical scale) absolute change and percent change from baseline; (8) absolute change and percent change from baseline in POEM score; (9) GISS components (erythema, infiltrates/papules, exfoliation, lichenification) from baseline Change from Baseline; (10) Change from Baseline in GISS Cumulative Score; (11) Incidence of Treatment-Emergent Adverse Events (TEAEs) from Baseline to Week 32; and (12) Pharmacokinetics of Multiple-Dose mAb1 Dosing Regimen dynamic properties.

2的患者比例；(5)從基線起至第16週各時間點，達到IGA評分下降

3的患者比例；(6)從第16週至第32週療效參數的變化；(7)mAb1 ADA的發生率和曲線(滴度隨時間推移的變化)(8)mAb1血漿濃度對ADA的形成和持續性之影響；(9)ADA對mAb1血漿濃度之影響；(14)ADA對臨床結果(安全性和療效)之影響；(10)PK參數(C_max和AUC)對臨床結果之影響；以及(11)體重對藥物作用和臨床結果之影響。 Other exploratory test indicators include: (1) distribution of disease severity scores (such as IGA, EASI, SCORAD) and changes at various time points from baseline to week 16; Table score, SCORAD (itch VAS and sleep disturbance VAS), overall assessment of patient disease status, overall assessment of patient treatment effect, DLQI, POEM, EQ-5D, pruritus quality of life, and HADS, from baseline to second Changes at each time point at 16 weeks; (3) Absolute changes and percentage changes at each time point from baseline to week 16 in terms of % BSA, SCORAD score, EASI and pruritus NRS; (4) Changes from baseline to week 16 At each time point of 16 weeks, the IGA score decreased

The proportion of patients was 2; (5) From the baseline to the 16th week at each time point, the IGA score decreased

3; (6) Changes in efficacy parameters from week 16 to week 32; (7) incidence and curve of mAb1 ADA (change in titer over time) (8) mAb1 plasma concentration on ADA formation and Effects of persistence; (9) effects of ADA on mAb1 plasma concentrations; (14) effects of ADA on clinical outcomes (safety and efficacy); (10) effects of PK parameters ( _Cmax and AUC) on clinical outcomes; (11) The effect of body weight on drug action and clinical outcome.

Rationale for Trial Design: The purpose of this study was to find an optimal dosing regimen that will be further investigated during the Phase 3 validation study. The design of this Phase 2b study builds on the results of a previous mAb1 study investigating the safety and efficacy of 300 mg mAb1 administered once weekly for 12 weeks in patients with moderate-to-severe AD . The selection of the phase 2b dosing regimen was also supported by observations and simulations of the correlation between pharmacokinetic (PK) and pharmacodynamic (PD) parameters (PK/PD model) obtained in early clinical trials. Using 300 mg once weekly (i.e., the dose regimen studied in phase 2a) as the upper end of the dose range, the aim was to find the lowest dose regimen with the highest or near-maximum efficacy and/or to rely on the demonstrated safety profile of mAb1 , to find the dosage regimen with the best benefit/risk ratio. Thus, five mAb1 dosing regimens were selected to reasonably cover the range between a potentially overtherapeutic regimen (ie, the upper limit) and a clearly suboptimal dose regimen (ie, the lower limit). The plan also includes a placebo group to compare the dosing regimen of each active drug with a control.

Use of Loading Dose: Most patients receive a loading dose on Day 1, the The loading dose was twice the nominal dose received at subsequent visits. This allows systemic mAb1 concentrations to reach steady state and target systemic concentrations more quickly and may shorten the time to clinical benefit. Administration of the study treatment continued for 16 weeks such that systemic concentrations of functional mAbl reached a steady state for all dose regimens investigated. Pharmacokinetic modeling suggests that a once-every-four-week (q4w) dosing regimen may result in decreased trough concentrations following the initial loading dose. Therefore, the immunogenic potential of these regimens may not be fully manifested in a shorter course of treatment. All patients were followed for 16 weeks after the last dose of study drug to ensure that the mAb1 clearance process was substantially complete (plasma concentration below the lower limit of quantification) before the end-of-study visit.

Mechanism for dose selection: The highest mAb1 dose regimen implemented in this study was 300 mg once weekly. This dosage regimen was safe when administered as a short course (4 weeks) and appeared to be most effective in an early phase 1b clinical trial; once a week and 75mg once a week) survey together. Pharmacokinetic modeling suggests that 300 mg (once weekly) may be supratherapeutic if administered chronically: mAb1 plasma concentrations did not reach a steady state until week 4 and are expected to stabilize above saturation targets (i.e., membrane bound IL-4 receptor α subunit) required level. However, this needs to be confirmed in the context of a longer study treatment (12 weeks or longer) comparing the 300 mg (once weekly) dose regimen to a lower dose regimen, so that for all investigated Dosage regimen, plasma concentration can reach a steady state. Although in an earlier study (e.g. Phase 2a proof-of-concept), 300 mg dose (once weekly) was administered for 12 weeks, this dosing regimen was repeated in Phase 2b to confirm Phase 2a phase results and enabled direct comparison with low-dose regimens in the same study. Therefore, 300 mg (once a week) was the upper end of the dose range in this study.

The lower end of the range for this dosage regimen is 100 mg administered every 4 weeks. Based on the PK/PD model, the resulting steady-state mAb1 plasma concentration is expected to be consistently lower than the target-induced clearance (i.e., a concentration low enough that excretion of mAb1 is primarily through its binding to the IL-4 receptor ), which suggests that the clinical response associated with this dosage regimen is incomplete. other Three dosage regimens were chosen between the upper and lower limits. These dosage regimens and the main reasons for their selection are summarized below:

●300mg, once a week (qw): high limit. The dose regimen was the same as in the Phase 2a study.

●300mg, once every 2 weeks (q2w): Based on PK/PD data and models, the probability of success is high. May be sufficient to maintain therapeutic drug levels between doses.

300 mg every 4 weeks (q4w): PK modeling suggests that mAb1 plasma concentrations rise rapidly to >60 mg/L following a rapidly acting loading dose administered every 4 weeks (q4w) over time The dose is sufficient to maintain the therapeutic effect. Since the 300 mg dose is the highest dose available, this regimen has the best chance of showing efficacy when administered every 4 weeks (q4w).

●200mg, once every 2 weeks (q2w): some efficacy is expected, but the optimal therapeutic effect cannot be achieved. Useful for dose response assessment and further PK/PD modeling. Helpful in evaluating q2w regimens for the full dose range.

●100mg, once every 4 weeks (q4w): the lower limit. Possibly a suboptimal effective dose.

• Placebo: Provides a reliable reference for any apparent drug effect.

16；(4)在篩檢和基線就診時，IGA評分

3(0-4分IGA量表)；(5)在篩檢和基線就診時，AD涉及的體表面積(BSA)

10%；(6)最近(在篩檢前3個月內)有文件記載的病史，對使用局部藥物的門診治療響應不足，或不宜採用局部治療(例如因嚴重副作用或安全風險)*的患者；(7)在基線就診前，患者必須已經以穩定劑量每日兩次敷用一種無添加劑、基本無刺激性的局部潤膚乳，達至少7天；(8)願意並能夠遵守所有回診安排及研究相關程序；(9) 能夠理解和完成研究相關問卷；以及(10)提供已簽署的知情同意書。*注：出於本計劃書的目的，響應不足表示儘管已用中效至高效局部皮質類固醇治療(酌情±局部鈣調磷酸酶抑製劑)，每日敷用達至少28天或達產品處方說明書所推薦的最長時間(例如超強效局部皮質類固醇為14天)(以時間較短者為準)，仍未能達到和維持緩解狀態，或疾病的低活性狀態(例如IGA為0=無至2=輕度)。如研究主持人或患者的治療醫生所評估，嚴重副作用或安全風險是指那些弊處大於潛在治療效益的副作用或風險(如過敏反應、顯著的皮膚萎縮、全身影響等，或即時風險)。 Inclusion and Exclusion Criteria: Patients must meet the following criteria to be eligible for inclusion in the study: (1) male or female over the age of 18; (2) pre-existing chronic AD (according to the American Academy of Dermatology (AAD) consensus criteria , [Eichenfeld 2004]) for at least 3 years; (3) EASI score at screening and baseline visits

16; (4) IGA score at screening and baseline visit

3 (0-4 point IGA scale); (5) body surface area (BSA) involved in AD at screening and baseline visit

10%; (6) Patients with a recent (within 3 months prior to screening) documented medical history who have had an inadequate response to outpatient treatment with topical agents, or who are not candidates for topical treatment (e.g. because of serious side effects or safety risks)* (7) Before the baseline visit, the patient must have applied an additive-free, essentially non-irritating topical moisturizer twice daily at a stable dose for at least 7 days; (8) Willing and able to comply with all return visit arrangements and study-related procedures; (9) be able to understand and complete study-related questionnaires; and (10) provide signed informed consent. *Note: For the purposes of this protocol, underresponse means despite treatment with moderate to high potency topical corticosteroids (± topical calcineurin inhibitors, as appropriate), applied daily for at least 28 days or up to the product prescribing insert Failure to achieve and maintain a state of remission for the longest time recommended (eg, 14 days for superpotent topical corticosteroids), whichever is shorter, or a low activity state of disease (eg, 0 for IGA = none to 2=mild). Serious side effects or safety risks are those for which the harm outweighs the potential benefit of the treatment (eg, allergic reaction, significant skin atrophy, systemic effects, etc., or immediate risk), as assessed by the study sponsor or the patient's treating physician.

9%)、心血管病患者(例如根據紐約心臟協會分類為第III期或第IV期心臟衰竭)、嚴重腎病(例如接受透析治療的患者)、肝膽疾病(如Child-Pugh B級或C級)、神經系統疾病(如脫髓鞘疾病)、活動性嚴 重自身免疫性疾病(如紅斑狼瘡、炎症性腸病、風濕性關節炎等)，其他嚴重的內分泌、胃腸道、代謝疾病、肺病或淋巴疾病。根據這一標準排除患者的確切理由將記錄在研究文件(圖表註釋、病例報告表[CRF]等)中；(22)任何其他身體或心理狀況，包括篩檢時有關實驗室異常結果，依研究主持人的意見，提示一種新的和/或未充分理解的疾病，對於參與研究的患者作為其參與此項臨床試驗的結果可能會構成一種不合理的風險、可能會使患者的參與不可靠，或可能會干擾研究評估。根據這一標準排除患者的確切理由將記錄在研究文件(圖表註釋、CRF等)中；(23)在患者參與此項研究期間，計劃中的重大外科手術；(24)患者是研究小組成員或其直接家庭成員；(25)孕婦或哺乳期婦女；以及(26)具有生殖能力且性生活活躍，卻不願採用適當的避孕措施者。適當的避孕措施之定義為，同意在整個研究期間和最後一劑研究藥物給藥後16週內，始終如一地實行一種有效且可接受的避孕方法。 Patients meeting any of the following criteria were ineligible to participate in this study: (1) previously treated with mAb1; (2) within 8 weeks or 5 half-lives (if known) prior to baseline visit (whichever is longer) (3) have received the following treatments within 4 weeks prior to the baseline visit, or have any condition that may require the following treatments within the first 4 weeks of study treatment: systemic corticosteroids, immune Suppressive/immunomodulatory drugs (eg, cyclosporine, mycophenolate mofetil, gamma-interferon (IFN-γ), azathioprine, or methotrexate), or AD phototherapy; (4) before baseline visit Within 1 week, treat with topical corticosteroids, tacrolimus, and/or pimecrolimus; (5) treat with the following biologics: any cell-depleting agent, including but not limited to rituximab (6 days before baseline visit) months, or until lymphocyte and CD 19+ lymphocyte counts return to normal [whichever is longer]); infliximab, adalimumab, golimumab, cerizumab , abatacept, etanercept, anakinra (for any indication within 16 weeks prior to baseline visit, or for dermatological indications within 5 years); or other biologics (5 half-lives [if known ] or within 16 weeks [whichever is longer]); (6) used a prescription body lotion listed as a medical device within 1 week before the baseline visit (such as Atopiclair®, MimyX®, Epicerum®, Cerave®, etc. ) treatment of AD; (7) frequent use (more than 2 times a week) of artificial sun cabins/artificial sun chairs within 4 weeks before the baseline visit; (8) planned or expected use of any illegal drugs and methods during the study treatment (including But not limited to topical tacrolimus and pimecrolimus, corticosteroids; prescription body lotions listed as medical devices (e.g., Atopiclair®, MimyX®, Epicerum®, Cerave®, etc.); allergen immunotherapy; Systemic AD with suppressive/immunomodulators; vaccine with live (attenuated) bacteria or treatment with study drug (except mAb1); larger elective surgery; (9) treatment with live (attenuated) bacteria within 12 weeks prior to baseline visit ) vaccine treatment; (10) Chronic or acute infection requiring treatment with antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to screening, or superficial skin infection within 1 week prior to screening Infections; (11) Known or suspected immunosuppression, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillus, although infection has resolved) , or other recurrent infections with unusual frequency, or as judged by the study host, long-term infection showing an immunocompromised state; (12) Known history of human immunodeficiency virus (HIV) infection or HIV seropositive at screening ; (13) At the time of screening, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody was positive or the result was uncertain; (14) At the time of screening, the transaminase (ALT and/or AST) was higher than normal upper limit (>3 xULN); (15) History of clinical endoparasites other than treated vaginal trichomoniasis within 12 months prior to baseline visit; (16) Presence of skin complications that may interfere with study assessment ; (17) History of malignant tumor within 5 years before baseline visit, except for completely cured cervical carcinoma in situ, completely resected non-metastatic squamous cell or basal cell skin cancer; (18) History of non-malignant lymphoproliferative disease; (19) High risk of parasitic infection, such as living in an endemic area of endoparasites or recently (within 12 months before the baseline visit) to an endemic area of endoparasites, where the environment is prone to contact with parasites (such as long-term stay, Rural or poor areas, lack of running water, consumption of undercooked or undercooked or potentially contaminated food, close contact with vectors and vectors, etc.), unless subsequent medical evaluation (e.g. stool examination, blood test, etc.) has ruled out (20) There is a history of alcoholism or drug abuse within 2 years before the screening; (21) According to the judgment of the research director, serious complications that will seriously affect the patient's participation in the study. Examples include, but are not limited to, patients with short life expectancy, patients with uncontrolled diabetes (HbA1c

9%), patients with cardiovascular disease (such as New York Heart Association stage III or IV heart failure), severe renal disease (such as patients receiving dialysis), hepatobiliary disease (such as Child-Pugh class B or C ), neurological diseases (such as demyelinating diseases), active severe autoimmune diseases (such as lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, etc.), other serious endocrine, gastrointestinal, metabolic diseases, pulmonary diseases or Lymphatic disease. The exact reason for excluding patients based on this criterion will be documented in the study documentation (chart notes, case report form [CRF], etc.); (22) any other physical or psychological condition, Moderator's opinion, suggesting a new and/or poorly understood disease that may pose an unreasonable risk to patients participating in the study as a result of their participation in this clinical trial, that may render the patient's participation unreliable, or may interfere with the evaluation of the study. Exact reasons for excluding patients based on this criterion will be documented in the study documentation (chart notes, CRF, etc.); (23) planned major surgical procedures during the patient's participation in this study; (24) the patient was a member of the study team or (25) Pregnant or breastfeeding women; and (26) Reproductive and sexually active persons who are unwilling to use appropriate contraceptive measures. Adequate contraception was defined as consent to consistently practice an effective and acceptable method of contraception throughout the study period and for 16 weeks after the last dose of study drug.

BSecurity

Safety was assessed throughout the study period by monitoring adverse events and serious adverse events.

An adverse event (AE) refers to any adverse medical event that occurs in a subject receiving the drug or a subject of a clinical study. Thus, an AE can be any adverse, unexpected sign (including abnormal laboratory results), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal (investigational) product. AEs also include: any exacerbation of pre-existing conditions related to the use of the study drug in time (i.e. any clinically significant change in frequency and/or intensity); abnormal laboratory findings considered clinically significant by the study host; and any adverse medical events.

A serious adverse event (SAE) is any adverse medical event at any dose that results in death, is life-threatening, requires hospitalization or prolonged hospitalization, results in persistent or severe disability/incapacity; is a congenital anomaly/congenital defects, or major medical pieces.

In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and physical examination variables were measured throughout the study.

Clinical laboratory data included hematology, blood chemistry, and urinalysis. Blood samples for hematology testing were collected at each study visit; at Screening, Day 1/Baseline (pre-dose), Day 15, Day 29, Day 43, Day 57, Day 71, On day 85, day 99, day 113, day 141, day 169, and day 197 (the end of the study) or early termination (if the subject terminates the study), blood samples for blood biochemical tests and urine test samples were collected, respectively. A urine sample to measure the patient's general health.

Vital sign parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg), and body temperature (°C). Vital signs (before medication, each medication day) are at screening, day 1/baseline, day 4, 8, 15, 22, 25, 29, 43, 64, 71, 85, 99, 113, 127, 141 , 155, 169, 183, 197 days, and 211 days (end of study) or early termination. Vital signs were collected on Days 1, 8, 15, and 22 at 1 hour and 2 hours after study drug injection.

12-lead ECG parameters include: ventricular heart rate, pulse interval, QRS complex interval, corrected QT interval (QTcF=QT/[RR ^0.33 ] and QTcB=QT/[RR ^0.5 ]) ECG status: normal, clinically insignificant abnormal or clinically significant abnormalities. A standard 12-lead ECG was tested at Screening, Days 29 and 113 (end of treatment) or early termination.

A complete physical examination was performed at Screening, Days 29 and 113 (end of treatment) or early termination.

B. Efficacy variables

Efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Index, and Pruritus NRS Score are described elsewhere herein (see eg, Example 7).

IGA, RSA, EASI, and SCORAD scores were assessed at each visit. Patients were assessed for the 5-D Pruritus Index on the following return days: Screening, Day 1/Baseline (using Pre-dose), Day 113 (end of treatment) and Day 211 (end of study) or early termination. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

In addition, other variables such as Global Single Symptom Score (GISS), Pruritus Classification Scale, Patient-Centered Eczema Measure (POEM), Dermatology-Life Quality Index (DLQI), Pruritus QOL, EQ-50, HADS As well as an overall assessment of the patient's disease state and treatment effectiveness.

The efficacy variable baseline was defined as the last nonmissing value on or before the random date. For a patient who did not have a measured value on or before his/her randomization date, the last non-missing value on or before the day of the first drug injection was used as baseline.

Example 10: Repeated Dose Clinical Trial of Subcutaneous Injection of Anti-IL-4R Antibody (mAb1) in Adult Patients with Moderate to Severe Atopic Dermatitis

A. Experimental design

This study was a 28-week randomized, double-blind, placebo-controlled study of subcutaneous injection of an anti-IL-4R mAb (referred to herein as "mAb1") in patients with moderate to severe atopic dermatitis. The treatment period was 12 weeks, and there was a 16-week follow-up period after the treatment period.

150kU/L)，以檢驗mAb1對於外源性或內源性AD患者的療效。符合標準的患者接受第1天/基線的評估、隨機分組，然後接受300mg mAb1或安慰劑的皮下注射。每週給藥一次的研究藥物可作為一劑2mL注射液注射，或分為兩劑1mL注射液注射。患者每週回診一次，並於第8、15、22、29、36、43、50、57、64、71和78天接受研究藥物注射。每次接受研究藥物後，患者在研究現場接受嚴密觀察至少2小時。治療期於第85天結束。於第99、113、127、141、155、169、183天進行追蹤回診，並於第197天進行研究 結束回診。 One hundred and nine patients were enrolled and randomized 1:1 into study groups (54 placebo and 55 300 mg antibody). Forty-three patients withdrew from the study (30 in the placebo group and 13 in the 300 mg dose group). Randomization was stratified according to IgE level (IgE<150kU/L or

150kU/L), to test the curative effect of mAb1 on patients with exogenous or endogenous AD. Eligible patients underwent Day 1/baseline assessment, randomization, and then received subcutaneous injections of 300 mg mAb1 or placebo. Weekly doses of study drug can be injected as one 2 mL injection or divided into two 1 mL injections. Patients returned weekly and received study drug injections on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. After each dose of study drug, patients were closely observed at the study site for at least 2 hours. The treatment period ended on day 85. Follow-up visits were conducted on days 99, 113, 127, 141, 155, 169, and 183, and the end-of-study visits were conducted on day 197.

16；(4)在篩檢和基線就診時，IGA評分

3；(5)在篩檢和基線就診時，

10% BSA受AD影響；(6)在篩檢前最後3個月內，對一種以局部皮質類固醇或鈣調磷酸酶抑制劑治療AD的穩定(

1個月)治療方案響應不足；(7)在基線就診前至少7天，患者必須已經以穩定劑量敷用一種無添加劑、基本無刺激性的潤膚乳，每日兩次；以及(8)具有返回診所參加全部臨床試驗並完成全部研究相關程序的意願、承諾和能力；以及願意並能夠簽署知情同意書(ICF)。 Subject inclusion criteria are as follows: (1) male or female patients over 18 years old; (2) diagnosed according to Eichenfield's revised Hannifin and Rajka criteria, suffering from chronic AD for at least 3 years before screening; (3) at screening and baseline At visit, EASI score

16; (4) IGA score at screening and baseline visit

3; (5) At screening and baseline visits,

10% BSA was affected by AD; (6) in the last 3 months before the screening, a stable (

1 month) insufficient response to treatment regimen; (7) patient must have been applying an additive-free, essentially non-irritating body lotion at a stable dose twice daily for at least 7 days prior to the baseline visit; and (8) Willingness, commitment, and ability to return to the clinic to participate in the full clinical trial and complete all study-related procedures; and willing and able to sign an Informed Consent Form (ICF).

25U/mL的促卵泡激素水平。若適用，必須記錄子宮切除術、雙側卵巢切除術，或雙側輸卵管結紮術史。 The exclusion criteria of the study are as follows: (1) previously treated with mAb1; (2) at the time of screening, any of the following laboratory abnormal results: white blood cell count <3.5 x 10 ³ /μL; platelet count <125 x 10 ³ /μL; Neutrophil count <1.75 x 10 ³ /μL; aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >1.5 x ULN; and CPK >2x ULN; (3) at screening, hepatitis B Surface antigen, hepatitis B core antibody, or hepatitis C antibody were positive or the results were inconclusive; (4) Started a new routine fitness program within 4 weeks before screening (visit 1), or made changes to the previous routine fitness program Big change. Subjects must be willing to maintain a comparable degree of exercise during the study period, and avoid abnormally strenuous exercise during the clinical trial; (5) within 8 weeks or 5 half-lives (if known) before the baseline visit (whichever is more (Elder prevails), treated with a study drug; (6) treated with a live (attenuated) vaccine within 12 weeks before the baseline visit; (7) received allergen immunotherapy within 6 months before the baseline visit; ( 8) Treatment with leukotriene inhibitors within 4 weeks before the baseline visit; (9) Treatment with systemic corticosteroids within 4 weeks before the baseline visit; (10) Treatment with topical corticosteroids, Tacrolimus and/or pimecrolimus treatment; (11) Using an immunosuppressive/immunomodulatory drug within 4 weeks before the baseline visit, such as cyclosporine, mycophenolate mofetil, IFN-γ, photoelectric Treatment (narrow-spectrum uvB, uvB, uvA1, positron + uvA), azathioprine, methotrexate, or biologics for systemic AD therapy; (12) washed three times in any week within 4 weeks prior to baseline visit or more than three sterilization baths; (13) treatment with medical equipment (such as Atopiclair®, MimyX®, Epicerum®, Cerave®, etc.) within 1 week before the baseline visit; (14) oral or IV treatment within 4 weeks before screening Chronic or acute infection treated with injected antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals, or superficial skin infection within 1 week before screening; (15) Known history of HIV infection ; (16) history of allergic reaction to doxycycline or related compounds; (17) history of clinical parasitic infection other than vaginal trichomoniasis; (18) history of malignancy within 5 years before baseline visit, but with the following medical history Exceptions for patients with: completely cured carcinoma in situ of the cervix, non-metastatic squamous cell or basal cell skin cancer; (19) planned surgical procedures during the patient's participation in this study; (20) 4 days before the screening visit Use artificial sun cabins/artificial sun chairs within a week; (21) Accompanying serious illness or serious illness history, such as mental illness, heart, kidney, nerve, endocrine, metabolism or lymphatic diseases, or the participation of subjects in this research meeting Any other disease or condition that adversely affects; (22) pregnant or breastfeeding women; and/or (23) unwilling to use appropriate contraceptive measures. Adequate contraception was defined as consent to consistently practice an effective and acceptable method of contraception throughout the study period and for 16 weeks after the last dose of study drug. For women, an appropriate birth control method is defined as: hormonal contraceptives, intrauterine device (IUD), or double barrier method (ie, condom + diaphragm, condom or diaphragm + spermicidal gel or foam) . For men, an appropriate method of contraception is defined as a double barrier method (ie, condom + diaphragm, condom or diaphragm + spermicidal gel or foam). For women, menopause is defined as 24 months without menstruation; in case of doubt, it must be documented

FSH level of 25U/mL. History of hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, if applicable.

B Efficacy variables

50%的患者比例；(3)從基線起至第12週EASI評分的變化；(4)從基線起至第12週，IGA評分、「異位性皮膚炎涉及之體表面積」(BSA)、「濕疹面積和嚴重程度指數」(EASI)、SCORAD、瘙癢NRS和5-D瘙癢指數的變化和百分比變化；(5)從基線直至第28週TEAE的發生率；(6)與響應相關的嗜酸性粒細胞、TARC、Phadiatop^TM試驗結果，以及總IgE從基線起的變化；(7)從基線起至第12週QoLIAD的變化；(8)從基線起至第12週，達到IGA評分下降

2的患者比例；(9)從基線起至第12週，達到IGA評分下降

3的患者比例；以及(10)循環嗜酸性粒細胞、TARC和總IgE的藥效動力學(PD)響應。 The primary trial outcome was the percent change in EASI score from baseline to week 12. Secondary trial outcomes measured in this study included: (1) the proportion of patients with an Instructor's Global Assessment (IGA) score of 0 or 1 at week 12; (2) from baseline to week 12, An overall improvement in the EASI score (also known as EASI 50) of

50% of patients; (3) Changes in EASI score from baseline to week 12; (4) From baseline to week 12, IGA score, "body surface area involved in atopic dermatitis" (BSA), Changes and percent changes in the Eczema Area and Severity Index (EASI), SCORAD, Pruritus NRS, and 5-D Pruritus Index; (5) incidence of TEAEs from baseline to week 28; (6) response-related Eosinophils, TARC, Phadiatop ^TM test results, and change from baseline in total IgE; (7) change in QoLIAD from baseline to week 12; (8) reduction in IGA score achieved from baseline to week 12

2% of patients; (9) from baseline to week 12, achieved a decrease in IGA score

3; and (10) pharmacodynamic (PD) responses of circulating eosinophils, TARC, and total IgE.

The efficacy variable baseline was defined as the last nonmissing value on or before the random date. For a patient without a measured value on or before his/her randomization date, the last non-missing value on or before the day of the first drug injection will be used as baseline.

research program

Efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Index, and Pruritus NRS Score are described elsewhere herein (see eg, Example 7).

IGA, BSA, EASI, and SCORAD scores were assessed at each visit. Patients were assessed for the 5-D Pruritus Index on the following follow-up days: Screening, Day 1/Baseline (pre-drug) and Days 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183, and Day 197 (end of study) or upon early termination. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

Atopic Dermatitis Quality of Life Index (QoLIAD): QoLIAD is a validated 25-question questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL) . It is formatted as simple yes or no answers to 25 questions on a scale of 0 to 25; high scores indicate poor quality of life. The questionnaire was administered at Screening, Day 1/Baseline (pre-drug) and Days 29, 57, 85, 99, 113, 127, 141, Completed at Days 155, 169, 183, and at Day 197 (end of study) or early termination.

C. Research Treatment

The drug product mAb1 is supplied as a lyophilized powder in 5 mg glass vials for subcutaneous injection. For subcutaneous injection, prepare the mAb1 drug into a solution containing 150 mg/mL mAb1 with 2.5 mL sterile water for injection. The dose level of mAbl tested was 300 mg for subcutaneous injection. mAb1 or placebo was given as 1 dose (2 mL) or 2 doses (1 mL) subcutaneously in the clinic on Day 1/Baseline and Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 day injection. Although weekly doses of study drug are best administered as a single 2-mL injection, the weekly dose can also be divided into two 1-mL injections. Subcutaneous injection sites alternate between: the back of the arm, the abdomen (except the navel or waist), and the thigh. Do not administer via the extremities due to possible differences in absorption and bioavailability. If multiple injections are required on the same day, each dose should be injected at a different injection site (for example, one dose in the right lower quadrant and the other in the left lower quadrant). The subcutaneous injection sites are so alternated that no injections are given at the same site for 2 weeks in a row.

A placebo corresponding to mAb1 was prepared in the same formulation as mAb1, but no antibody was added.

Patients were observed at the study site for at least 2 hours after each dose of study drug.

In addition, patients were asked to apply an additive-free, substantially non-irritating body lotion at a steady dose twice daily for at least 7 days at the baseline visit and throughout study participation. Patients reported compliance with background treatment during the study using the IVRS or IWRS. The system prompts patients to answer the following question about body lotion: "Have you used a study doctor-approved body lotion on the affected areas of your skin?"

D. Safety Assessment

Safety was assessed throughout the study period by monitoring adverse events and serious adverse events.

An adverse event (AE) is defined as an adverse event in a subject receiving the drug or a subject in a clinical study Any adverse medical events that occurred. Thus, an AE can be any adverse, unexpected sign (including abnormal laboratory results), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal (investigational) product. AEs also include: any exacerbation of pre-existing conditions related to the use of the study drug in time (i.e. any clinically significant change in frequency and/or intensity); abnormal laboratory findings considered clinically significant by the study host; and any adverse medical events.

A serious adverse event (SAE) is any adverse medical event at any dose that results in death, is life-threatening, requires hospitalization or prolonged hospitalization, results in persistent or severe disability/incapacity; is a congenital anomaly/congenital defects, or major medical events.

In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and physical examination variables were measured throughout the study.

Clinical laboratory data included hematology, blood chemistry, and urinalysis. Blood samples for hematology testing were collected at each study visit; at Screening, Day 1/Baseline (pre-dose), Day 15, Day 29, Day 43, Day 57, Day 71, On day 85, day 99, day 113, day 141, day 169, and day 197 (the end of the study) or early termination (if the subject terminates the study), blood samples for blood biochemical tests and urine test samples were collected, respectively. A urine sample to measure the patient's general health.

Vital sign parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg), and body temperature (°C). Vital signs (before medication, each medication day) are at screening, day 1/baseline, day 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 99, 113 , 141, 169 days, and 197 days (end of study) or early termination. Vital signs on days 1, 8, 15, 22, 29, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 99, 113, 141, 169, and 78 Collected at 1 hour and 2 hours after study drug injection.

12-lead ECG parameters include: ventricular heart rate, pulse interval, QRS complex interval, corrected QT interval (QTcF=QT/[RR ^0.33 ] and QTcB=QT/[RR ^0.5 ]) ECG status: normal, clinically insignificant abnormal or clinically significant abnormalities. A standard 12-lead ECG was tested at Screening, Days 141 and 197 (end of study) or early termination.

Study test samples were collected at Screening and at Day 1/Baseline (pre-dose), and at Days 8, 15, 22, 29, 57, 85, and 197 (end of study) or at premature termination, and at unscheduled return visits. Sample (serum/RNA/plasma).

A complete physical examination will be performed at Screening, Days 85 and 197 (end of study) or early termination.

E data analysis

1. Exploratory efficacy variable analysis

150kU/L)進行分析。除非另有說明，對於從基線變化的評估和連續測量信賴區間的設立是基於ANCOVA模型，其包括作為主要因素的治療，作為共變數的基線值。提供了點估計值和兩個治療組之間在調整後從基線平均變化方面的差異的95%CI。缺失值將以最後觀察值前推法(LOCF)填補。倘若該模型假設得不到保證，則使用基於秩次的共變數分析。 All categorical variables were analyzed using the Fisher exact test with reported nominal p-values and confidence intervals. All continuous variables were stratified according to baseline IgE (IgE<150kU/L or

150kU/L) for analysis. Unless otherwise stated, the assessment of change from baseline and the construction of confidence intervals for continuous measures were based on an ANCOVA model including treatment as the main factor and the baseline value as the covariate. Point estimates and 95% CIs for the difference between the two treatment groups in adjusted mean change from baseline are provided. Missing values will be filled with last observation forward (LOCF). In cases where the model assumptions were not warranted, rank-based analysis of covariates was used.

2. Analysis of safety data

Safety analyzes were based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 12-lead electrocardiograms. Thresholds for laboratory variables, vital signs and ECG potentially clinically significant values (PCSV) were defined in SAP. The time period for detection of any event or abnormality is from the start of the study drug infusion to the end of the study. Data collected outside this interval were excluded from calculations of descriptive statistics and detection of abnormalities in laboratory evaluations, vital signs and electrocardiograms.

F. Security: Results

In general, mAb1 was both well tolerated and safe. The overall adverse event (AE) profile presented the characteristics of a healthy population. No deaths were reported. There were 8 serious adverse events, of which 1 (facial bone fracture) occurred in the mAb1 group and 7 (angina pectoris, cellulitis, eczematous herpes, bacterial skin infection, renal failure, asthmatic crisis, pulmonary disease, and dysentery Atopic dermatitis) occurred in the placebo group. TEAEs led to discontinuation of study drug in 7 patients, 1 in the mAb1 group and 6 in the placebo group. Eighty-five patients experienced at least one TEAE (n=42 [76.4%] in the mAb1 group vs n=43 [79.6%] in the placebo group). The most common TEAE was nasopharyngitis infection in subjects in the mAb1 group (n=22 [40%], compared to n=10 [18.5%] in the placebo group). Other TEAEs in the treatment group included ocular infection, neurological disturbance, and general disease and administration site conditions. No other clinically significant laboratory test results (blood chemistry, hematology, or urinalysis) were reported during the study period. No trends were observed in the baseline mean/median for any laboratory parameter. Throughout the study period, no significant trends were observed in mean or median changes from baseline in body temperature or pulse. No clinically significant abnormalities were observed in physical examination results, electrocardiograms, or vital signs.

Subcutaneous administration of mAb1 to adult patients with moderate-to-severe AD was generally safe and well tolerated.

G. Efficacy: Results

The baseline and exploratory efficacy results obtained from the study are summarized in Figures 23-33 and Tables 27-33. Patients were treated with 300 mg subcutaneous injection of mAbl once a week for 12 weeks, or with placebo, as described above.

Table 30: Summary of Absolute Change from Baseline in BSA Score - All Values Mean (SD)

E. Conclusion

Subcutaneous administration of anti-IL-4R antibody (mAb1) at a dose of 300 mg once weekly for 12 weeks in adult patients with moderate to severe atopic dermatitis was generally safe and well tolerated sex is good. Injection of mAbl at a dose of 300 mg resulted in significant improvements in mean and absolute percent changes in IGA, EASI, BSA, SCORAD, and pruritus NRS scores up to Day 85 compared to baseline levels (see Tables 27-33). At Day 85, the proportion of patients achieving a 50% percent reduction in EASI score ("EASI-50") in the 300 mg dose group was 85.5% compared to 35.2% of patients treated with placebo at Day 85. At day 85, 40.0% of patients in the 300 mg dose group achieved an IGA score of 0 or 1 compared to 7.4% in the placebo group. The percent change in EASI score from baseline to Week 12 of mAbl dosing was statistically significant compared to the placebo group (-74.0% vs -23.0%, p-value<0.0001). All secondary efficacy trial measures were statistically significantly different between the treatment groups compared with the placebo group. The following are the p-values for: IGA responders (0 or 1) (<0.0001), EASI responders (<0.0001), absolute change from baseline to week 12 in EASI (<0.0001), IGA Absolute Change (<0.0001), Percent Change in IGA (<0.0001), Absolute Change in BSA (<0.0001), Absolute Change in SCORAD (<0.0001), Absolute Change in Pruritus NRS (<0.0001), and 5-D Pruritus Index absolute change (<0.0001).

Example 11: Clinical Trial Evaluating the Safety of mAbl Administered Concomitantly with Topical Corticosteroids in Patients with Moderate to Severe Atopic Dermatitis

A. Experimental design

This study is a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the safety of repeated subcutaneous injections of mAb1 in patients with moderate-to-severe AD while using topical corticosteroids (TCS), and to explore its curative effect. Patients were randomized in a 2:1 ratio to receive 300 mg mAb1 or placebo by subcutaneous injection (on days 1, 8, 15, and 22, respectively) once a week for 4 weeks. All patients simultaneously received open-label daily treatment for up to 28 days with an effective TCS product (50-100 times stronger than hydrocortisone), such as methylprednisolone ethpropionate 0.1%, mometasone furoate 0.1%, or betamethasone valerate 0.1%. Other topical agents, such as the less potent TCS or topical calcineurin inhibitors (TCIs), respectively, are used to treat AD lesions on the face, skin folds, and genital area.

Beginning at Screening, patients began applying an additive-free, essentially non-irritating body lotion at least 7 days prior to their baseline visit twice daily and continued throughout the study (applied to TCS on treatment days). site of application, once a day). Environmental controls and non-drug treatment modalities, such as allergen avoidance and antiseptic baths, were at the discretion of the study host.

Screening was carried out from the 21st day to the day before the start of the test. Patients received their first drug injection (300 mg mAb1 or placebo) on Day 1, and then returned to the clinic on Days 8, 15, and 22 (+/- 1 day) for further drug injections weekly A total of 4 times at a time. From the first day, the patient applied the above topical drugs once a night, and continued to apply until all parts affected by AD (that is, active AD lesions) were controlled, up to 28 days. Once under control, TCS application to AD-prone sites without active lesions (ie, lesions had resolved) was limited to 2 days per week until study day 28. After day 28, topical medications were continued to treat any residual AD lesions as needed. Patients continued to apply an additive-free, essentially non-irritating body lotion twice daily (once daily on topical treatment days) throughout the study period. Patients returned to the clinic for follow-up visits on Days 29, 36, 50, 64, and 78 (end of study).

3和SCORAD>20，提示需用有效TCS治療一個或多個AD活動性病變；(4)在篩檢和基線就診時，至少10% BSA受AD影響；(5)在基線就診前至少7天，患者必須敷用一種無添加劑、基本無刺激性的潤膚乳，每日兩次；(6)願意並能夠遵守就診和研究相關程序；以及(7)能夠閱讀和理解並願意簽署知情同意書。 The inclusion criteria for the study subjects were: (1) male/female patients over 18 years old; (2) diagnosed according to Eichenfield's revised Hannifin and Rajka criteria, with chronic AD for at least 2 years before screening; (3) diagnosed at screening and baseline visits When , the active AD assessment result is the IGA score

3 and SCORAD >20, suggesting the need to treat one or more AD active lesions with effective TCS; (4) at least 10% BSA affected by AD at screening and baseline visit; (5) at least 7 days before baseline visit , patients must apply an additive-free, essentially non-irritating body lotion twice daily; (6) be willing and able to follow procedures related to visits and studies; and (7) be able to read and understand and be willing to sign an informed consent form .

50%累積病變面積)位於面部、皮膚褶皺和生殖器 部位，(4)可能存在會干擾研究評估的皮膚併發症；(5)在基線就診前4週內，或在研究期間可能需要用以下藥物治療的任何狀況：全身性皮質類固醇、免疫抑製劑或免疫調節藥物，如環孢素、嗎替麥考酚酯、γ-干擾素(IFN-γ)、硫唑嘌呤或甲氨蝶呤；(6)用如下生物製劑治療：(a)基線就診前6個月內，或直至淋巴細胞和CD19+淋巴細胞計數恢復正常(以時間較長者為準)，任何細胞消耗劑，包括但不限於利妥昔單抗；(b)基線就診前8週內，英夫利昔單抗、阿達木單抗、戈利木單抗、培化舍珠單抗、阿巴西普、依那西普、阿那白滯素；以及(c)在5個半衰期(若已知)或8週內(以時間較長者為準)，其他生物製劑；(7)基線就診前4週內，任何治療皮膚病的光電治療(如窄譜UVB、UVB、UVA1、正電子+UVA；(8)基線就診前4週內經常使用(每周超過2次)人工日曬艙/人工日曬椅；(9)基線就診前12週內用減毒活疫苗治療；(10)在基線就診前8週內或5個半衰期內(以時間較長者為準)，用一種研究藥物治療過；(11)篩檢前4週內需要口服或IV注射抗生素、抗病毒藥、抗寄生蟲藥、抗原蟲藥或抗真菌藥治療的慢性或急性感染，或篩檢前1週內淺表皮膚感染；(12)侵入性機會性感染史，如組織漿菌病、李斯特菌病、球黴菌病、傑氏肺囊蟲病、麴菌病(儘管感染已消退)，以及JC病毒(導致進行性多處腦白質病)；(13)已知的HIV感染史；(14)篩檢時，乙肝表面抗原、乙肝核心抗體，或丙肝抗體呈陽性或結果不確定；(15)篩檢時，存在以下任何實驗室異常結果：肌酸磷酸激酶>2倍正常範圍上限(ULN)，天冬胺酸轉氨酶(AST)和/或丙胺酸轉氨酶(ALT)>2倍ULN；嗜中性粒細胞計數<1.75×10³/ul；血小板計數<100×10³/ul；(16)在隨機分組前2週內，開始一套新的例行健身計劃，或對於先前的例行健身計劃作出重大改變，或在參與研究的整個期間不願維持(不增加)目前的體育活動水平；(17)對強力黴素或其他四環素有過敏反應史；(18)基線就診前12個月內，除已治療的陰道滴蟲病以外的臨床體內寄生蟲感染史；(19) 基線就診前5年內有惡性腫瘤史，徹底治愈的子宮頸原位癌、完全切除的非轉移性鱗片狀細胞或基底細胞皮膚癌除外；(20)非惡性淋巴增生症病史；(21)孕婦或哺乳期婦女；(22)不願意採取避孕措施的有生育能力的男性或女性；(23)篩檢前2年內有酗酒或藥物濫用史；(24)近期(隨機分組前12個月內)曾去寄生蟲感染的疫區旅行，如非洲的發展中國家或亞洲的熱帶/亞熱帶地區；(25)以前或目前病史中會嚴重影響患者參與研究的嚴重併發症，例如，第III期或第IV期心臟衰竭、嚴重腎病、神經系統疾病、內分泌疾病、胃腸道疾病、肝膽疾病、代謝疾病、肺病或淋巴疾病；以及(26)任何對參與研究的患者可能會構成一種不合理的風險，或可能會使患者的參與不可靠，或可能會干擾研究評估的其他狀況。 The exclusion criteria for the study were as follows: (1) previous treatment with mAb1; (2) hypersensitivity to corticosteroids, or hypersensitivity to any other ingredients contained in TCS products used during the study; (3) AD lesions mainly (

50% of the cumulative lesion area) located on the face, skin folds, and genital areas, (4) may have skin complications that would interfere with the study assessment; (5) may require treatment with the following medications within 4 weeks before the baseline visit, or during the study Any condition: systemic corticosteroids, immunosuppressant or immunomodulatory drugs such as cyclosporine, mycophenolate mofetil, gamma-interferon (IFN-γ), azathioprine or methotrexate; (6 ) Treatment with biologics: (a) any cell depleting agent, including but not limited to rituximab, within 6 months prior to baseline visit, or until lymphocyte and CD19+ lymphocyte counts return to normal, whichever is longer Monoclonal antibody; (b) within 8 weeks before the baseline visit, infliximab, adalimumab, golimumab, pecizumab, abatacept, etanercept, anakinra and (c) within 5 half-lives (if known) or 8 weeks, whichever is longer, other biologics; (7) within 4 weeks prior to the baseline visit, any phototherapy ( Such as narrow-spectrum UVB, UVB, UVA1, positron+UVA; (8) Frequent use (more than 2 times a week) of artificial sun cabins/artificial sun chairs within 4 weeks before the baseline visit; (9) 12 weeks before the baseline visit Internal treatment with live attenuated vaccine; (10) treated with a study drug within 8 weeks or 5 half-lives (whichever is longer) before the baseline visit; (11) oral administration within 4 weeks before screening Or chronic or acute infection treated with IV antibiotics, antivirals, antiparasitics, antiprotozoals or antifungals, or superficial skin infection within 1 week before screening; (12) History of invasive opportunistic infection, Examples include histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis jirovecii, aspergillus (although infection has resolved), and JC virus (causing progressive multifocal leukoencephalopathy); (13) have (14) Hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody is positive or the result is indeterminate at the time of screening; (15) There are any of the following laboratory abnormal results at the time of screening: creatine phosphokinase >2 times upper limit of normal (ULN), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2 times ULN; neutrophil count <1.75×10 ³ /ul; platelet count <100 ×10 ³ /ul; (16) Within 2 weeks before randomization, start a new routine fitness program, or make major changes to the previous routine fitness program, or do not want to maintain during the entire period of participation in the study ( No increase) current level of physical activity; (17) history of allergic reaction to doxycycline or other tetracyclines; (18) clinical endoparasitic infection other than treated vaginal trichomoniasis within 12 months prior to baseline visit (19) history of malignancy within 5 years prior to baseline visit, except for cured carcinoma in situ of the cervix, completely resected non-metastatic squamous cell or basal cell skin cancer; (20) history of non-malignant lymphoproliferative disease ; (21) pregnant or breastfeeding women; (22) unwilling to take avoidance (23) have a history of alcohol or drug abuse within 2 years before screening; (24) recently (within 12 months before randomization) have traveled to endemic areas for parasite infection, Such as developing countries in Africa or tropical/subtropical regions in Asia; (25) serious complications in previous or current medical history that would seriously affect the patient's participation in the study, for example, stage III or stage IV heart failure, severe kidney disease, nervous system disease, endocrine disease, gastrointestinal disease, hepatobiliary disease, metabolic disease, pulmonary disease, or lymphatic disease; and (26) any that may pose an unreasonable risk to the patient participating in the research, or may render the patient's participation unreliable, or Other conditions that may interfere with the study assessment.

50%的二元反應變數；(2)在第29天以及基線後其他觀察時間點達到IGA評分

1(無或幾乎無)；(3)達到IGA

1和EASI 50的時間；(4)從基線起至第29天以及基線後其他觀察時間點，IGA、EASI和SCORAD評分的變化；以及(5)第4週時IGA

1且直至觀察期結束仍保持未復發的患者比例。 The primary trial outcome of the study was the incidence and severity of adverse events. Secondary trial measures were exploratory in nature and included: (1) EASI 50 Index - from baseline to day 29 and at other observed time points after baseline, whether the EASI decline reached

50% of binary response variables; (2) achieved IGA score at day 29 and other observed time points after baseline

1 (none or almost none); (3) reached IGA

1 and time to EASI 50; (4) changes in IGA, EASI, and SCORAD scores from baseline to day 29 and other observed time points after baseline; and (5) IGA at week 4

1 and the proportion of patients who remained recurrence-free until the end of the observation period.

B. Efficacy variables

Efficacy variables IGA, BSA, EASI, SCORAD, and Pruritus NRS scores are described elsewhere herein (see eg, Example 7). IGA, BSA, EASI, pruritus NRS, and SCORAD scores were assessed at each visit.

C. Procedures and Assessments

Based on an assessment of the incidence of adverse events (AEs) (described elsewhere in this document) from Day 1 to Day 78, and based on a detailed medical history, thorough physical examination, vital signs, electrocardiogram (EVG), and clinical laboratory tests, Safety was assessed. Ongoing blinded review of safety data was performed. From Screening to Day 78 (end of study) or early termination (if applicable), Data on contemporaneous medications and procedures were collected. Safety, laboratory test results, and efficacy evaluations are made at each return visit. At each study visit prior to initiation of treatment at baseline (Day 1), blood samples were collected to determine systemic trough concentrations of functional mAbl. Blood samples were collected at predetermined time points for analysis of anti-mAbl antibody levels. Study samples and samples for exploratory biomarker analysis were also collected. The efficacy of mAb1 was evaluated according to EASI, IGA, SCORAD, Pruritus Numerical Rating Scale (NRS), and % body surface area involved in AD (BSA). Blood samples were collected at predetermined time points for pharmacokinetic (PK) analysis and anti-mAbl antibody level analysis. Study samples and samples for exploratory biomarker analysis were also collected.

C. Statistical Methods

Since all statistical analyzes described in this section were exploratory, no multiplicity adjustments were made for type I errors. A 5% significance level was used for each test. All categorical variables (EASI-50 and IGA responders at each post-baseline visit, IGA responders at day 29 and no relapse thereafter) were calculated from the comparison between mAb1 and placebo For nominal p values, analyzes were performed using Fisher's exact test. Confidence intervals for point estimates and proportions are provided. A graph of the ratio versus time is provided. All continuous variables (changes or percent changes in IGA, EASI, SCORAD, and NRS from baseline to each post-baseline visit) were analyzed by ANalysis of COVAriance (ANCOVA). Unless otherwise stated, the assessment of change from baseline and the construction of confidence intervals for continuous measures were based on an ANCOVA model including treatment as the main factor and the baseline value as the covariate. Point estimates and 95% CIs for the difference between the two treatment groups in the adjusted mean change from baseline are provided. Nominal p-values obtained from the comparison between the mAb1 and placebo groups will be presented. In cases where the model assumptions were not warranted, rank-based analysis of covariates was used. A plot of mean change from baseline over time is provided. Time to event variables (time to EASI 50 and time to IGA response) were analyzed using the log-rank test to compare the placebo group to the mAbl group. Kaplan-Meier survival curves across the two treatment groups are presented. For this study, the following analysis methods were implemented: (a) censored LOCF method: after the patient used the illicit drug or terminated After participating in the study, the efficacy data were set as missing. All missing values were filled by simple LOCF. (b) Simple observed case (OC) approach: only observed cases are analyzed.

E. Security

Overall, mAb1 was safe and well tolerated in this study. No deaths were reported. A serious adverse event (SAE) was recorded for one patient in the placebo group, who became unconscious and was withdrawn from the study as a result. No other patients experienced adverse events leading to treatment discontinuation. A total of 19 of the 31 patients enrolled in the study reported at least one treatment-emergent adverse event (TEAE)—seven (70%) in the placebo group and 12 (57%) in the mAb1 group. By system and organ class (SOC), the most commonly reported TEAEs in the mAb1-treated group were infections and parasitic infections (12 [57%] vs 3 [30%] in the placebo group). The most common infection was nasopharyngitis—5 patients (24%) in the mAb1 group compared to 2 patients (20%) in the placebo group. No serious or opportunistic infections. Other TEAEs reported by more than one patient included non-specific symptoms such as headache in 3 (14%) in the mAb1 group compared to 1 (10%) in the placebo group; somnolence in 2 (9.5% in the mAb1 group). ), compared to 0% in the placebo group; 3 patients (14%) in the oropharyngeal pain-mAb1 group, compared to 1 patient (10%) in the placebo group; and 2 patients (9.5%) in the cough-mAb1 group , compared to 0% in the placebo group. Most AEs were mild to moderate and generally resolved within 2 weeks. One serious AE was reported in the mAb1 arm: bacterial bronchitis, with onset on Day 63 (the last dose of study drug was administered on Day 22), but was considered unrelated to study treatment. There were no adverse events in the mAb1 group that would suggest an adverse drug-to-drug (mAb1-TCS) interaction at the skin level. Analysis of on-treatment safety laboratory test results, vital signs, and potentially clinically significant values (PCSV) of ECC showed that the rates of PCSV were roughly balanced between the two study groups, with no systematic distribution or clear trend, suggesting that PCSV Occurrence was incidental and unrelated to study treatment.

F. Results

In this study, mAb1 was administered concurrently with TCS to patients with moderate to severe AD. Following the current standard of care for AD, a controlled TCS dosing regimen (i.e., concurrently with study treatment) is required for the first 4 weeks, as described elsewhere in this paper. Table 34 lists the participating TCS drugs used by the patient. Patients should apply TCS to all active lesions once a day until the lesions are resolved, and then apply TCS to lesion-prone (ie, resolved) areas once a day, two days a week. An effective TCS (Group III) needs to be applied to at least 50% of the lesions. For lesions located on the face, skin folds, or genital area (where effective TCSs are generally not appropriate), less potent TCSs (group I or group II) are permitted. The amount of TCS used per week was calculated by measuring the weight of the TCS container when it was issued to the patient and when the container was returned at the next visit. Table 35 and Table 36 summarize the TCS dosage from day 1 to day 29.

Demographic and disease characteristics were substantially similar between the two treatment groups (Table 37 and Table 38). The mean baseline AD disease severity scores (IGA, EASI, SCORAD, BSA and Pruritus NRS) were also reasonably balanced.

The results of the exploratory efficacy obtained from the study are summarized in Figures 34-47 and Tables 39-42. Despite a relatively small sample size and limited treatment period, this analysis revealed a statistically significant and clinically relevant effect of mAb1 versus placebo on key efficacy trial measures, including EASI-50 response rate and EASI, SCORAD, IGA Some improvements in change from baseline and percent change in NRS and pruritus were maintained for several weeks after study treatment was stopped. Regarding the EASI-50, 100% of patients in the mAb1 plus TCS group met the response criteria at day 29, compared to 50% in the placebo plus TCS group (p-value 0.0015). Other trial measures such as IGA 0-1 response rate showed numerical superiority over placebo, but did not reach statistical significance (47.6% vs. 30.0% for placebo). Notably, patients treated with mAb1 had an average reduction in TCS of about 50%, which may underestimate the therapeutic effect of mAb1 relative to the placebo (TCS only) comparator group.

Table 41: Summary of Percent Change and Absolute Change in SCORAD Score from Baseline to Day 29

Subcutaneous administration of mAb1 to adult patients with moderate-to-severe AD concomitantly treated with TCS was generally safe and well tolerated. The treatment modality of mAbl administered concurrently with TCS had significantly superior results compared to treatment with TCS alone. The proportion of patients achieving the EASI-50 score is numerically much greater compared to some recent results of mAb1 monotherapy (the best EASI-50 to date is 75%), suggesting that mAb1 is used with TCS have additive or synergistic effects. However, this may also be partly due to small sample sizes and subtle differences in patient populations between studies.

This study demonstrates the additional efficacy of mAb1 in moderate-to-severe AD patients treated with TCS. These results suggest that combination therapy may provide additional clinical benefit in patients with moderate-to-severe AD compared with either monotherapy. These results also show a sparing effect of mAb1 on TCS, which may contribute to safer long-term management of AD patients.

Example 12: Biomarker Analysis

Samples for biomarker analysis were taken from subjects participating in the mAb1 clinical trial. In particular, samples for determination of IgE, thymus, and activation-regulated chemokine (TARC) levels were taken from patients at baseline and at various time points after initiation of study treatment. A Phadiatop ^TM test was performed to detect antigen-specific IgE. In addition, molecular characterization was performed on skin lesions of patients enrolled in mAb1 clinical trials.

A. Administration of mAb1 to healthy subjects

In the first clinical trial, subjects were given single doses of mAb intravenously (IV) (1.0, 3.0, 8.0, and 12.0 mg/kg) or subcutaneously (SC) (150 and 300 mg), or placebo (see Example 2). Samples for biomarker analysis will be collected from antibody-treated and placebo-treated subjects on Day 1 (Baseline), Day 8, 29, and 85 (or early termination date). The levels of IgE and TARC were determined in each sample. A p-value <0.10 was considered statistically significant to allow the use of smaller sample sizes. A mixed-effects repeated-measures model was used to analyze means, and nonparametric tests were used to analyze medians. Median percent changes in IgE and TARC levels in samples taken from patients are summarized in Tables 43 and 44, respectively.

Baseline IgE levels varied widely, as shown by comparison of mean and median baseline IgE across treatment groups (Fig. 48A). The laboratory reference range for the IgE assay used was 0-114 kU/L, and 15 of 40 subjects had baseline total IgE levels >114 kU/L. As shown in Table 43 and Figure 48B, the decrease in IgE levels was approximately proportional to mAb1 dose and duration of treatment. On day 85 post-dose, subjects receiving subcutaneous mAb1 showed a median reduction in IgE levels of 16.5% (150mg) and 17.2% (300mg), respectively. In patients receiving mAb1 intravenously, a significant decrease in IgE was also observed, with 10.7% and 25.6% decreases in IgE levels in the 8 mg/kg and 12 mg/kg groups, respectively. In contrast, IgE levels increased over time in placebo-treated subjects.

Median baseline TARC plasma concentrations were roughly comparable between treatment groups (Figure 49A) and higher than levels reported in the literature. The baseline TARC mean was 616 pg/mL with a range of 134-1327 pg/mL. The range of TARC levels in healthy subjects has been reported to be 106-431 ng/L (Hijnen et al 2004, J. Allergy Clin. Immunol. 113:334-340). A significant reduction in TARC was observed in samples of patients treated with both subcutaneous doses of mAb1 compared to the placebo group (p=0.044 for the 150 mg dose group and p=0.047 for the 300 mg dose group) (Figure 49B and Table 44). For example, a single subcutaneous dose of mAb1 at a dose of 300 mg resulted in a median decrease in TARC levels of nearly 35% at day 8 (p=0.052), compared with a 7.7% increase in placebo-treated patients. Significant reductions in TARC levels were observed from day 29 and continued until the end of the study (day 85) in patients treated with both SC and IV injections of mAbl. When pooling data from all subjects treated with mAbl, the overall difference in percent change from baseline in TARC was significant (p=0.004) between the mAbl and placebo groups (Figure 50). Significant differences were also observed on day 8 (p=0.012) and day 29 (p=0.022).

B. Administration of mAbl to Atopic Dermatitis Subjects

For two independent clinical trials involving atopic dermatitis (AD) patients, the levels of the biomarkers were also determined in patient samples. In "Study A", AD subjects were administered mAb1 (75, 150 or 300 mg) or placebo on the 1st, 8th, 15th and 22nd day of the study (ie once a week, 4 times in total). In "Study B", respectively, in Study 1, AD subjects were administered 150 or 300 mg mAb1 or placebo on days 8, 15 and 22 (ie once a week, 4 times in total) (see Example 7 herein). All dosing in both studies was administered subcutaneously (SC). On Day 1 (baseline), Day 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, and Day 85 (or early termination date), from both studies Samples were collected from antibody- and placebo-treated subjects for biomarker analysis. The levels of IgE, TARC, lactate dehydrogenase (LDH) and antigen-specific IgE (Phadiatop test) were determined in each sample.

TARC plasma concentrations were determined using a validated assay (Human CCL17/TARC Quantikine ELISA Kit, R&D Systems; validated and analyzed by Quest Diagnostics). Total IgE plasma concentrations were determined using the ImmunoCAP® Total IgE Assay (FDA-approved assay from Thermo Scientific; performed by Quest Diagnostics). Lactate dehydrogenase (LDH) was tested using the Roche modular assay (FDA approved; tested by Covance Central Laboratories). Phadiatop® (an FDA-approved assay from Thermo Scientific) assays were performed by Viracor-IBT. A two-sample median test was used to compare the changes from baseline in biomarkers between the mAbl group and the placebo group.

All AD patients participating in "Study B" had mean baseline levels of TARC plasma concentrations, total IgE and LDH above the reported upper limit of normal (ULN) (Table 45 and Figure 51 ).

Mean baseline eosinophil levels were at the upper end of the reference range (Table 45). All but two patients with available data had positive Phadiatop test results. Total IgE plasma concentrations were also normal in both patients. One of the patients had no Phadiatop trial results available.

150kU/L(一個常被用來區分外源性和內源性AD的截止點)(圖51B)。37名患者中有17名患者的LDH水平高於234U/L(圖51C)。沒有LDH水平低於100U/L的患者。 A broad spectrum of baseline TARC and IgE levels was observed in the moderate-to-severe AD population enrolled in the study. Twenty-seven of 36 patients had plasma concentrations of TARC >1000 pg/mL (approximately twice the average level of healthy volunteers) (Figure 51A). IgE levels in 32 of 36 patients

150kU/L (a cut-off point commonly used to distinguish exogenous from endogenous AD) (Fig. 51B). LDH levels were higher than 234 U/L in 17 of 37 patients (Fig. 51C). There were no patients with LDH levels below 100 U/L.

Using local linear regression, an overall treatment effect (percent change from baseline) of mAbl on total IgE plasma concentrations was observed in both dose groups compared to the placebo group (p<0.0001) (Figure 52). Total IgE plasma concentration levels decreased in the mAb1-treated group, whereas an increase in total IgE plasma concentration was observed at the end of the study in the placebo group.

The median percent change from baseline in IgE levels for each group in Study A and Study B (combined data) is summarized in Table 46.

As shown in Table 46 and Figure 52, a statistically significant decrease in IgE levels was observed in samples from subjects treated with mAbl compared to placebo. Median percent IgE at day 85 decreased by 23.9% in patients treated with 300 mg mAb1, compared to a 41.7% increase in the placebo group (p<0.0001). The median percent change from baseline was significant (p<0.03) for the 150 mg dose group at all time points from Day 29 to Day 85 compared to the placebo group. The median percent change from baseline was significant (p<0.04) for the 300 mg dose group at all time points from Day 15 to Day 85 compared to the placebo group.

Using local linear regression, the overall treatment effect on LDH was observed. In the 300 mg treatment group, there was a statistically significant decrease in LDH (p=0.0051) (Figure 53). The median percent change was not statistically significant at any one time point, but a time-dependent trend was observed (p=0.008).

Treatment with mAbl rapidly suppressed plasma concentrations of TARC in AD patients (Figure 54). The median percent change from baseline in TARC levels for each group in both studies (combined data) is summarized in Table 47.

A statistically significant decrease in TARC plasma concentrations was observed in patients treated with 300 mg mAbl compared to placebo (p<0.0001; local linear regression analysis). In patients treated with 300 mg mAbl, statistically significant inhibition was maintained until Day 50, approximately one month after the last dose (on Study Day 21). The 150mg dose group achieved a considerable degree of inhibition, but compared with the 300mg dose group, it was observed that the TARC level began to rise earlier. Statistically significant inhibition was observed in the 150 mg dose group (p<0.03) on days 36 and 43, and in the 300 mg dose group (p<0.04) on days 22, 25, 29, 36 and 50 Effect (median percent change from baseline in TARC compared to placebo).

In patients treated with placebo, an anteroposterior change in the patient's own TARC levels over the course of the study was observed. At the end of the study, data were available for only 4 of the placebo-treated patients due to the high drop-out rate in the placebo group.

In summary, biomarkers such as TARC, IgE, and LDH associated with Th2 inflammation and/or AD disease activity in AD patients were all inhibited by mAb1 treatment. Compared with placebo, mAb1 rapidly reduced TARC plasma concentrations in AD patients. The duration of the inhibitory effect appears to be dose-related, and the data suggest that this effect persists even after discontinuation of the drug. Total IgE plasma concentrations were significantly decreased in patients treated with mAb1. After the treatment period, IgE levels continued to decline in the 300 mg dose group (median percent change), indicating that the suppression of IgE had not yet reached its maximum. In patients treated with mAb1, a consistent decrease in LDH levels from baseline was observed. The direct link between LDH and IL-4 and IL-13 is unknown, but its association with disease severity suggests that LDH may be a marker of the extent of skin damage in AD patients. The results of TARC and IgE inhibition showed that mAb1 is a potent inhibitor of Th2-type inflammation.

Associations between biomarkers and AD-related parameters

In "Study B" (see Example 7), 150 mg or 300 mg mAb1 or placebo (PBO) were administered to patients with severe AD, respectively, once a week for four weeks. Pruritus levels were measured twice daily using the Pruritus Numeric Rating Scale (NRS, ranging from 0 to 10) to generate mean weekly NRS scores and mean biweekly 5-D Pruritus Index assessments. The 5-D Pruritus Index Scale is a 5-question form used to assess pruritus on multiple measures: degree, duration, trend, disability, and distribution. Mean baseline NRS and 5-D scores were 5.5 and 19, respectively. Mean weekly NRS scores decreased rapidly (mean percent change from baseline) in the 300 mg dose group, decreasing by 31.9% (p<0.02) at week 2 and week 2 The 7-week reduction was 55.2% (p=0.01), compared to +1.3% and -17.3% in the PBO group. A rapid decrease in 5-D score was also observed in patients treated with 300 mg mAb1 (mean percent change at day 15 was -28.2%, p=0.0009; at day 29 was -37.1%, p=0.0007; at -42.5% on day 43, p=0.012; compared to +3.6%, +8.1% and -9.4% in the PBO group). CCL17 plasma concentrations, a marker of IL4/IL13 activity, also decreased rapidly upon treatment. Both CCL17 and the pruritus index were suppressed for several weeks after the end of treatment. Table 48 shows the association of pruritus scores (5D and NRS) with dermatitis outcomes (EASI) and CCL17.

Overall, the 5-D pruritus index was significantly associated with CCL17 for all treatment groups in this study (r=0.46, p=0.004 at baseline; r=0.55, p=0.002 at day 29), Also significantly correlated with EASI score (r=0.41, p=0.011 at baseline; day 29 , r=0.62, p<0.0001). For all treatment groups, the percent change in the 5-D Pruritus Index at Days 15 and 29 compared with EASI (r=0.65, p<0.0001 at Day 15; and r=0.61, p<0.0001 at Day 29) and CCL17 (r=0.46, p=0.0089 at day 15; and r=0.48, p=0.0105 at day 29) The percent change from baseline was significantly correlated. For each treatment group, the association of the 5-D pruritus index with EASI and CCL17 was assessed separately. At day 15, only the 150 mg dose group showed a strong and significant association between the percent change in EASI and the percent change in the 5-D Pruritus Index (r=0.81, p=0.0005). Likewise, at day 29, only the 150 mg dose group showed a significant association (r=0.57, p=0.0036). While there was a significant overall association between percent change in CCL17 and percent change in the 5-D Pruritus Index at Days 15 and 29, no such association was shown for either treatment group on either day.

Pruritus severity, assessed by NRS, showed a moderate to strong significant association with EASI. However, NRS values showed an association with CCL17 values only at baseline, while percent change from baseline was not significantly associated. The rapid and sustained improvement in pruritus observed in adult AD patients treated with mAbl suggests that IL-4/IL-13 signaling is a key mechanism of AD pruritus. The association between pruritus and CCL17 levels highlights the relationship between IL-4/IL-13-mediated inflammation, AD disease activity, and pruritus in severe AD.

C. Repeated administration of mAb1 to subjects with moderate to severe atopic dermatitis (AD)

In a clinical trial involving subjects with moderate to severe atopic dermatitis (AD), the levels of IgE and TARC were measured in their samples. On days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of the study (i.e. once a week, 12 times in total), AD subjects were given 300 mg mAb1 or placebo agent (see Example 10 herein). All dosing in both studies was administered subcutaneously (SC). On Day 1 (baseline), Day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 99, 113, 127, 141, 155, 169, 183, and 197 Serum samples for biomarker analysis were collected from subjects treated with antibody and placebo in both studies on the day (end of study) or early termination day. The levels of IgE, TARC and antigen-specific IgE (Phadiatop ^™ test) were determined in each sample.

TARC, an IL-4/IL-13-induced chemokine, has shown a strong association with AD disease severity and may be involved in disease pathogenesis. Baseline TARC levels were assessed for potential predictors of treatment response. Samples taken after the treatment period were evaluated for the pharmacodynamic effect of mAbl on TARC.

AD patients tend to have elevated IgE levels. Total IgE levels have been found to correlate with AD severity and may be involved in disease pathogenesis. Baseline IgE levels were assessed for potential predictors of response to treatment. Samples taken after the treatment period were assessed for the pharmacodynamic effect of mAbl on total IgE levels.

The Phadiatop ^TM test is an in vitro diagnostic screening tool for the detection of antigen-specific IgE levels after challenge with common inhalants. Baseline Phadiatop ^TM trial results were assessed for potential predictors of treatment response. Samples taken after the treatment period were evaluated for the pharmacodynamic effect of mAbl on the Phadiatop ^™ antigen.

According to the results of early clinical trials (see subsections A and B above), TARC and IgE levels should decrease after treatment with 300 mg IL-4R antibody, and the Phadiatop ^TM test results should be negative.

It is intended that the scope of the invention not be limited by the specific examples described herein. Indeed, various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art to which the invention pertains from the foregoing description and accompanying drawings. These modifications will also be included in the scope of the appended patent application.

<110> REGENERON PHARMACEUTICALS, INC. SANOFI BIOTECHNOLOGY

<120> Method for treating atopic dermatitis by administering IL-4R antagonist

<130> 9150A

<150> 61/697,972

<151> 2012-09-07

<150> 61/738,715

<151> 2012-12-18

<150> 61/748,588

<151> 2013-01-03

<150> 61/764,624

<151> 2013-02-14

<150> 61/768,229

<151> 2013-02-22

<150> 61/770,091

<151> 2013-02-27

<150> 61/782,420

<151> 2013-03-14

<150> 61/816,191

<151> 2013-04-26

<150> 1356759

<151> 2013-07-10

<160> 275

<170> FastSEQ software for Windows version 4.0

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<210> 147

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 147

<210> 148

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 148

<210> 149

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 149

<210> 150

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 150

<210> 151

<211> 54

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 151

<210> 152

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 152

<210> 153

<211> 339

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 153

<210> 154

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 154

<210> 155

<211> 33

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 155

<210> 156

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 156

<210> 157

<211> 9

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 157

<210> 158

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 158

<210> 159

<211> 27

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 159

<210> 160

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 160

<210> 161

<211> 372

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 161

<210> 162

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 162

<210> 163

<211> 336

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 163

<210> 164

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 164

<210> 165

<211> 373

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 165

<210> 166

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 166

<210> 167

<211> 337

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 167

<210> 168

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 168

<210> 169

<211> 375

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 169

<210> 170

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 170

<210> 171

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 171

<210> 172

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 172

<210> 173

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 173

<210> 174

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 174

<210> 175

<211> 54

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 175

<210> 176

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 176

<210> 177

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 177

<210> 178

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 178

<210> 179

<211> 18

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 179

<210> 180

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 180

<210> 181

<211> 9

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 181

<210> 182

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 182

<210> 183

<211> 27

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 183

<210> 184

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 184

<210> 185

<211> 372

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 185

<210> 186

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 186

<210> 187

<211> 321

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 187

<210> 188

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 188

<210> 189

<211> 373

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 189

<210> 190

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 190

<210> 191

<211> 322

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 191

<210> 192

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 192

<210> 193

<211> 355

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 193

<210> 194

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 194

<210> 195

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 195

<210> 196

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 196

<210> 197

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 197

<210> 198

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 198

<210> 199

<211> 33

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 199

<210> 200

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 200

<210> 201

<211> 322

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 201

<210> 202

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 202

<210> 203

<211> 18

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 203

<210> 204

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 204

<210> 205

<211> 9

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 205

<210> 206

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 206

<210> 207

<211> 27

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 207

<210> 208

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 208

<210> 209

<211> 355

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 209

<210> 210

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 210

<210> 211

<211> 322

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 211

<210> 212

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 212

<210> 213

<211> 355

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 213

<210> 214

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 214

<210> 215

<211> 322

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 215

<210> 216

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 216

<210> 217

<211> 363

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 217

<210> 218

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 218

<210> 219

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 219

<210> 220

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 220

<210> 221

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 221

<210> 222

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 222

<210> 223

<211> 42

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 223

<210> 224

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 224

<210> 225

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 225

<210> 226

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 226

<210> 227

<211> 18

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 227

<210> 228

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 228

<210> 229

<211> 9

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 229

<210> 230

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 230

<210> 231

<211> 27

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 231

<210> 232

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 232

<210> 233

<211> 363

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 233

<210> 234

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 234

<210> 235

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 235

<210> 236

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 236

<210> 237

<211> 363

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 237

<210> 238

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 238

<210> 239

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 239

<210> 240

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 240

<210> 241

<211> 366

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 241

<210> 242

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 242

<210> 243

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 243

<210> 244

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 244

<210> 245

<211> 24

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 245

<210> 246

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 246

<210> 247

<211> 45

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 247

<210> 248

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 248

<210> 249

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 249

<210> 250

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 250

<210> 251

<211> 18

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 251

<210> 252

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 252

<210> 253

<211> 9

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 253

<210> 254

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 254

<210> 255

<211> 27

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 255

<210> 256

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 256

<210> 257

<211> 366

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 257

<210> 258

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 258

<210> 259

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 259

<210> 260

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 260

<210> 261

<211> 366

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 261

<210> 262

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 262

<210> 263

<211> 324

<212>DNA

<213> Artificial sequence

<220>

<223> Synthetic

<400> 263

<210> 264

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 264

<210> 265

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(8)

<223> Xaa=any amino acid

<400> 265

<210> 266

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(8)

<223> Xaa=any amino acid

<400> 266

<210> 267

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(18)

<223> Xaa=any amino acid

<400> 267

<210> 268

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(11)

<223> Xaa=any amino acid

<400> 268

<210> 269

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(3)

<223> Xaa=any amino acid

<400> 269

<210> 270

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<220>

<221> variant

<222> (1)...(9)

<223> Xaa=any amino acid

<400> 270

<210> 271

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 271

<210> 272

<211> 327

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 272

<210> 273

<211> 327

<212> PRT

<213> Artificial sequence

<220>

<223> Synthetic

<400> 273

<210> 274

<211> 207

<212> PRT

<213> Homo sapiens

<400> 274

<210> 275

<211> 231

<212> PRT

<213> Cynomolgus macaque

<400> 275

Claims (23)

Use of an anti-interleukin-4 receptor (IL-4R) antibody or an antigen-binding fragment thereof for the manufacture of a medicament for reducing atopic dermatitis (AD) in patients who are resistant to topical therapy , unresponsive or underresponsive AD or the patient has AD for which topical therapy is not suitable for the patient, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDRs) and three light chain CDRs (LCDRs), the three The three heavy chain CDRs include SEQ ID NO: 148, 150, and 152, respectively, and the three light chain CDRs include SEQ ID NO: 156, 158, and 160, respectively. The use of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 162 and the amino acid of SEQ ID NO: 164 sequence of the light chain variable region (LCVR). Such as the application of item 1 or 2 of the patent scope, wherein the patient has moderate to severe AD. Such as the use of claim 1 or 2, wherein the patient has a medical history of side effects or safety risks associated with topical treatment. Such as the application of item 1 or 2 of the patent scope, where the patient is an adult. If the use of item 1 or 2 of the patent scope is applied, the patient is a teenager. As the use of item 1 or 2 of the scope of the patent application, wherein the local treatment is a local corticosteroid. As the use of claim 1 or 2, wherein the local treatment is a local calcineurin inhibitor. The use of claim 1 or 2, wherein each dose of the drug administered to the patient comprises about 50 mg to about 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. The use of claim 1 or 2, wherein the patient is administered an initial dose of the anti-IL-4R antibody or antigen-binding fragment thereof, and then administered one or more subsequent doses of the anti-IL-4R antibody or an antigen-binding fragment thereof. The use according to claim 10, wherein each dose of the drug administered to the patient comprises 300 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. The use of claim 10, wherein the patient is administered an initial dose of 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof, followed by one or more subsequent doses of 300 mg. The use of claim 10, wherein each subsequent dose is administered 1 to 4 weeks after the previous dose. Such as the use of claim 13, wherein each subsequent dose is administered 1 week after the previous dose. Such as the use of claim 13, wherein each subsequent dose is administered 2 weeks after the previous dose. The use of claim 1 or 2, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is administered subcutaneously. The use of claim 1 or 2, wherein topical corticosteroids and/or topical calcineurin inhibitors are administered to the patient at the same time. The use of claim 1 or 2, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in a container selected from the group consisting of syringes, pre-filled pen-type drug delivery devices, auto-injectors, glass Vials, and groups consisting of microinfusion sets. The use according to claim 18, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in a syringe. As the use of claim 18, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in a pre-filled pen-type drug delivery device. The use according to claim 18, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in an automatic injector. The use according to claim 18, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in a glass vial. As the use of claim 18, wherein the anti-IL-4R antibody or antigen-binding fragment thereof is contained in a microinfusion set.

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