CN118103396A

CN118103396A - IL-13 antibodies for the treatment of atopic dermatitis

Info

Publication number: CN118103396A
Application number: CN202280069245.2A
Authority: CN
Inventors: E·A·鲍尔; J·S·德鲁; R·G·利马; J·W·威彻
Original assignee: Dermira Inc
Current assignee: Dermira Inc
Priority date: 2021-08-13
Filing date: 2022-08-12
Publication date: 2024-05-28

Abstract

Provided herein are methods, uses, and pharmaceutical compositions of antibodies that bind human IL-13 ("anti-IL-13 antibodies") for the treatment of atopic dermatitis. Also provided herein are dosing regimens for methods and uses of anti-IL-13 antibodies for treating atopic dermatitis.

Description

IL-13 antibodies for the treatment of atopic dermatitis

Sequence listing

The present application is presented with a sequence table in st.26xml format. The sequence listing is provided in the form of a file named "X23063_ SequenceListing", created at 2022, 8, 3, and 15KB in size. Sequence table information in st.26xml format is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to methods, uses and pharmaceutical compositions of antibodies that bind to human IL-13 ("anti-IL-13 antibodies") for the treatment of atopic dermatitis. The invention also relates to methods and dosing regimens for the use of anti-IL-13 antibodies for the treatment of atopic dermatitis.

Background

Atopic Dermatitis (AD) is a chronic recurrent and palliative inflammatory skin condition affecting all age groups. Clinically, AD is characterized by xerosis, erythema crusting rash, lichenification, impaired skin barrier and severe itching (Bieber T., N Engl J Med 2008; 358:1483-94). The disease burden of AD patients is high, and the life quality is obviously affected. One study showed that AD has a greater negative effect on patient mental health than diabetes and hypertension (Zuberbier T et al, J ALLERGY CLIN Immunol2006; 118:226-32). The prevalence of social and sleep disorders is high in moderate to severe AD patients, which is directly related to the severity of the disease (WILLIAMS H, et al, J ALLERGY CLIN Immunol 2008; 121:947-54.e15). Depression, anxiety and social dysfunction affect not only AD patients, but also their caregivers (Zuberbier T, et al, J ALLERGY CLIN Immunol2006; 118:226-32).

Interleukin (IL) -13 is a key mediator of type 2 helper T (Th 2) inflammation and signals through the heterodimeric receptor IL-4Rα/IL-13Rα 1. Several lines of evidence suggest that IL-13 is a key pathogenic component in AD. Increased IL-13 expression has been reported in AD skin (Hamid Q, et al, J ALLERGY CLIN Immunol 98:225-31[1996]; jeong CW, et al, clin Exp Allergy33:1717-24[2003]; tazawa T, et al, arch Dermatol Res 295:295:459-64 [2004]; neis MM, et al, J ALLERGY CLIN Immunol118:930-7[2006]; M, et al, J ALLERGY CLIN Immunol132:361-70[2013]; choy DF, et al, J ALLERGY CLIN Immunol.130:1335-43[2012 ]), and some reports indicate a relationship between IL-13 expression and disease severity (La Grutta S, et al, allergy 60:391-5[2005 ]). IL-13 increase in serum of AD patients was reported (Novak N, d et al J Invest Dermatol2002;119:870-5; WO 2016149276), and several studies reported an increase in IL-13 expressing T cells in the blood of AD patients (Akdis M, et al J Immunol1997;159:4611-9; aleksza M, et al Br J Dermatol2002; 147:1135-41; la Grutta S, et al, allergy2005; 60:391-5).

Methods of treatment of AD mainly include avoiding triggers, skin hydration by bathing, and the use of emollients and anti-inflammatory therapies, such as Topical Corticosteroids (TCS). In many patients, treatment with TCS provides some measure of symptomatic relief, but does not adequately control the disease. Furthermore, the use of TCS is associated with a number of complications and limitations, including high patient burden. Long-term use of TCS is not recommended because of the risk of skin atrophy, pigmentation, acneiform rash, and the risks associated with systemic absorption (e.g., hypothalamic pituitary axis effects, cushing's disease). Local calcineurin inhibitors (TCIs) are generally effective and safe as short-term therapies, but concerns about increased risk of cutaneous malignancy and lymphoma have prompted regulatory authorities to alert in their prescription information of the long-term safety of local tacrolimus and pimecrolimus. Repeated application of any local treatment over a long period or large area can also lead to reduced patient compliance.

For patients with persistent moderate to severe AD and inadequate response to TCS, there are many therapeutic options for upgrades (Ring J, et al J Eur Acad Dermatol Venereol; 26:1176-93; schneider L, et al J ALLERGY CLIN Immunol 2013; 131:295-9.e1-27). Oral immunosuppressants (Schmitt et al, 2007,JEADV 21:606-619) and glucocorticoids are effective, but are sometimes associated with serious toxicity and side effects, thus limiting their use to short-term courses of treatment and/or intermittent therapy. Cyclosporin is approved in many european countries for the treatment of moderate to severe AD but has not been approved in the united states and its use is limited to patients aged 16 years and older (up to 8 weeks). Even in cases where cyclosporine has shown significant efficacy, approximately 50% of patients relapse within 2 weeks after discontinuation of treatment, 80% relapse within 6 weeks (Amor KT, et al, J Am Acad Dermatol 2010; 63:925-46). Cyclosporin a (CsA) is a potent immunosuppressant that affects both humoral and cellular immune responses, potentially leading to increased susceptibility to infection and decreased immune surveillance for cancer. Other common toxicities of CsA include hypertension and impaired renal and hepatic function. In addition, csA interacts with other commonly used drugs and may affect its metabolism and therapeutic effects.

The medical need for safer, more effective therapies and treatment regimens for moderate to severe AD remains unmet. There is also a need for methods of treatment and dosing regimens that provide patients with greater tolerability and convenience, as well as lower risk, thereby improving patient compliance and satisfaction.

Disclosure of Invention

Provided herein are methods, uses, and pharmaceutical compositions of anti-IL-13 antibodies (e.g., lebrikuizumab) for treating atopic dermatitis. Also provided herein are dosing regimens for methods and uses of anti-IL-13 antibodies (e.g., leirimumab) for treating atopic dermatitis. The methods and dosing regimens provided herein have one or more of the following advantages: optimized and improved dosing frequency, which enables higher patient compliance and higher patient satisfaction, while maintaining desired efficacy; reducing the risk of injection site reactions; and/or reduce manufacturing costs.

In one aspect, provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every four weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to the patient subcutaneously.

In some embodiments, provided herein are methods of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising administering to the patient an anti-IL-13 antibody for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein during the induction period (or first period), 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to the patient subcutaneously.

Also provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to an anti-IL-13 antibody after an induction period (or first period); if the patient has a response, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks or once every eight weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks); if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. The determination of whether a patient is responsive to an anti-IL-13 antibody may be assessed by assessing the patient's skin clearance, skin improvement and/or itch, sleep or quality of life improvement. For example, skin clearance and skin improvement may be measured by a researcher overall assessment (IGA) or an Eczema Area and Severity Index (EASI) score. Itching, hypopnea and quality of life may be measured by the itching rating scale (NRS), hypopnea score and DLQI (dermatological quality of life index) or CDLQI (pediatric dermatological quality of life index) scales, respectively. In some embodiments, the patient is responsive when the patient EASI score determined after the induction period (or first period) is reduced by 75% or more compared to the patient EASI score at baseline. In some embodiments, the patient responds when the patient's IGA score is 0 or 1 after the induction period (or first period). In some embodiments, the patient is responsive when the patient's IGA score is 0 or 1 after the induction period (or first period) and the patient's IGA score determined after the induction period (or first period) is reduced by 2 points or more compared to the patient's IGA score at baseline. In some embodiments, if the patient has a response, 250mg of anti-IL-13 antibody is administered once every four weeks during the maintenance period (or second period). In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

In some embodiments, provided herein are methods of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for a first period of 4 to 16 weeks, wherein during the first period 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg once every two weeks for 2 to 14 weeks; and administering 250mg of the anti-IL-13 antibody to the patient once every four weeks or once every eight weeks for a second period of 8 to 36 weeks, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO: 6.

In some embodiments, provided herein are methods of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient during a first period of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks during the first period; determining whether the patient is responsive to the anti-IL-13 antibody after the first period; if the patient is responsive, administering 250mg of the anti-IL-13 antibody to the patient once every four weeks or once every eight weeks during a second period of 8 to 36 weeks; if the patient does not respond, 250mg of the anti-IL-13 antibody is administered to the patient once every two weeks during the second period of 8 to 36 weeks, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO: 6.

In some embodiments, the patient has moderate to severe atopic dermatitis at baseline for at least one year. Moderate to severe atopic dermatitis may be determined by criteria known in the art, such as the american dermatological association with chronic atopic dermatitis consensus criteria. In some embodiments, the patient has an EASI score of 16 or more, an IGA score of 3 or more, and more than 10% of Body Surface Area (BSA) at baseline is affected by atopic dermatitis. In some embodiments, the patient is under-responsive to a local corticosteroid, a local calcineurin inhibitor, or crisaborole; or topical corticosteroids, topical calcineurin inhibitors or crisaborole are not medically recommended for the patient. In some embodiments, the patient is 12 years old and older.

In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient at baseline and during and after the induction period (or first period): EASI score; IGA score; percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD (atopic dermatitis score); a sleep deficiency score; poe (patient-oriented eczema measurement) total score; DLQI (dermatological quality of life index) or CDLQI (pediatric dermatological quality of life index) score; EQ-5D (european quality of life-5 dimension); ACQ-5 (asthma control questionnaire-5); proci (patient reported outcome measure information system) anxiety and depression symptoms.

In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient during and after the maintenance period (or second period): EASI score; IGA score; percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

In another aspect, provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering a loading dose of 500mg of an anti-IL-13 antibody (e.g., lerimumab) to the patient at baseline (week 0) and week 2, followed by a subsequent dose of 250mg once every two weeks. In some embodiments, the anti-IL-13 antibody is administered to the patient for a period of 4 to 52 weeks. In some embodiments, the anti-IL-13 antibody is administered to the patient for a period of 4 to 16 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody (e.g., leirimumab) to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every two weeks or once every four weeks or once every eight weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody (e.g., leirimumab) to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to the anti-IL-13 antibody after the induction period (or first period); if the patient has a response, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks or once every eight weeks for a maintenance period (or second period) of 8 to 36 weeks; if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline.

In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

In some embodiments, the anti-IL-13 antibodies bind IL-13 with high affinity and block signaling through active IL-4Rα/IL-13Rα1 heterodimers. In some embodiments, an anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an HCDR1 comprising SEQ ID NO.1, an HCDR2 comprising SEQ ID NO. 2, and an HCDR3 comprising SEQ ID NO. 3, and the VL comprises an LCDR1 comprising SEQ ID NO. 4, an LCDR2 comprising SEQ ID NO. 5, and an LCDR3 comprising SEQ ID NO. 6. In some embodiments, the anti-IL-13 antibody contains a VH comprising SEQ ID NO. 7 and a VL comprising SEQ ID NO. 8. In some embodiments, the anti-IL-13 antibody contains a heavy chain comprising SEQ ID NO. 9 and a light chain comprising SEQ ID NO. 10. In some embodiments, the anti-IL-13 antibody is Leimumab.

In another aspect, provided herein are anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for use in treating moderate to severe atopic dermatitis in a patient.

In another aspect, provided herein are anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for use in a method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis. In another aspect, provided herein are anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for use in reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis.

In some embodiments, provided herein are anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, wherein the anti-IL-13 antibodies comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO: 6. And wherein the anti-IL-13 antibody or pharmaceutical composition is for administration at a loading dose of 500mg at baseline (week 0) and week 2, followed by administration at a subsequent dose of 250mg once every two weeks.

In some embodiments, provided herein are anti-IL-13 antibodies or pharmaceutical compositions comprising anti-IL-13 antibodies for reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, wherein the anti-IL-13 antibodies comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2, and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO: 6. And wherein the anti-IL-13 antibody or pharmaceutical composition is for administration during an induction period (or first period) of 4 to 16 weeks, and during the induction period (or first period), 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg once every two weeks for 2 to 14 weeks; and wherein 250mg of anti-IL-13 antibody is administered once every four weeks for a maintenance period (or second period) of 8 to 36 weeks.

In another aspect, provided herein is the use of an anti-IL-13 antibody in the manufacture of a medicament for treating moderate to severe atopic dermatitis in a patient. Also provided herein is the use of an anti-IL-13 antibody in the manufacture of a medicament for reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis.

In some embodiments, the methods, uses, and pharmaceutical compositions described herein further comprise administering one or more topical corticosteroids to the patient. In some embodiments, the topical corticosteroid is triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone. In some embodiments, the topical corticosteroid is administered concurrently with the anti-IL-13 antibody.

Drawings

FIG. 1 is a schematic representation of the phase 3 study design described in example 1.

Figures 2A and 2B show baseline demographics of participants in ADvocate a; figure 2C shows baseline disease characteristics for participants in ADvocate a. Ad=atopic dermatitis; ITT = intent-to-treat; leb=leisuri a group monoclonal antibody; q2w=1 every 2 weeks; PBO = placebo; SD = standard deviation; BMI = body mass index; BSA = body surface area; DLQI = dermatological quality of life index; EASI = eczema area and severity index; IGA = overall assessment of the investigator; iqr=quartile range; NRS = numerical rating scale; POEM = patient-oriented eczema measurement; SCORAD = atopic dermatitis score.

Fig. 3A shows an overview of adverse events from ADvocate to week 16. Figure 3B shows a serious adverse event from ADvocate to week 16. Figure 3C shows TEAE in the specific security topics from ADvocate to week 16. Figure 3D shows injection site response from ADvocate to week 16. AE = adverse event; leb=leisuri a group monoclonal antibody; q2w=1 every 2 weeks; PBO = placebo; TEAE = treatment emergency adverse event.

Figure 4A shows an overview of the key efficacy endpoint achievement in ADvocate a. FIG. 4B shows the IGA response at week 16 of ADvocate, which measures the percentage of IGA (0, 1), with an improvement of > 2 minutes at week 16 compared to baseline. FIG. 4C shows the EASI-75 response at week 16 in ADvocate. Fig. 4D shows the IGA response rate as a function of time up to week 16 in ADvocate a. FIG. 4E shows the EASI-75 response rate as a function of time up to week 16 in ADvocate. FIG. 4F shows the EASI-90 response over time from ADvocate to week 16. Fig. 4G shows the percent change in EASI from week 16 of ADvocate over time relative to baseline.

FIG. 5A shows that the pruritus NRS at ADvocate up to week 16 improves over baseline by ≡4 minutes over time. Fig. 5B shows the percent change over time of pruritic NRS from baseline by week 16 in ADvocate 1. FIG. 5C shows that the fraction of sleep insufficiency by week 16 in ADvocate 1 improves by ≡2 over time relative to baseline. Fig. 5D shows the score of sleep insufficiency from week 16 of ADvocate D versus baseline over time. FIG. 5E shows that DLQI improved by week 16 over baseline by ≡4 points over time. Fig. 5F shows DLQI from ADvocate up to week 16 over time relative to baseline.

Fig. 6A and 6B show the IGA response rates at week 52 in ADvocate (6A) and ADvocate (6B), which measure the percentage of patients reaching IGA (0, 1). FIGS. 6C and 6D show the EASI-75 response rates of ADvocate (6C) and ADvocate (6D) at week 52, which measure the percentage of patients who reached EASI-75. FIGS. 6E and 6F show the itch response rates of ADvocate (6E) and ADvocate (6F) at week 52, which measure the percent of patients with itch NRS at baseline of > 4 and achieve a score improvement of > 4.

Fig. 7 shows an overview of adverse events from week 16 to week 52 in ADvocate and ADvocate 2.

Fig. 8A is a graphical representation of the final PK-PD model in example 2. Fig. 8B shows model parameter estimation of the final PK-PD model.

Figure 9 shows the simulated EASI-75 response rate of the responders at week 16, who received various dosing maintenance regimens from week 16 to week 52. The line shows the median of 500 simulations.

FIG. 10 shows the simulated EASI-75 response rate of the responders at week 16, receiving either 250mg Q4W or 250mg Q8W maintenance regimen of Leirimumab at weeks 16 through 52. The line shows the median of 500 simulations and the shaded area shows 95% confidence interval.

FIG. 11 shows the simulated EASI-90 response rate of the responders at week 16, who received various dosing regimens from week 16 to week 52. The line shows the median of 500 simulations.

FIG. 12 shows the simulated EASI-90 response rate of the responders at week 16, receiving either 250mg Q4W or 250mg Q8W maintenance regimen of Leirimumab at weeks 16 through 52. The line shows the median of 500 simulations and the shaded area shows 95% confidence interval.

Detailed Description

Provided herein are methods, uses, and pharmaceutical compositions of anti-IL-13 antibodies for the treatment of atopic dermatitis. Also provided herein are dosing regimens for methods and uses of anti-IL-13 antibodies for treating atopic dermatitis. The methods and dosing regimens provided herein have one or more of the following advantages: optimized and/or improved dosing frequency, which enables higher patient compliance and higher patient satisfaction while maintaining a desired efficacy; reducing the risk of injection site reactions; the manufacturing cost is reduced.

In one aspect, provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every four weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period) of 16 weeks, 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

In one aspect, provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every eight weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period) of 16 weeks, 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

In some embodiments, provided herein are methods of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising administering to the patient an anti-IL-13 antibody for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein during the induction period (or first period), 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks; during the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

Also provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to an anti-IL-13 antibody after an induction period (or first period); if the patient has a response, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks); if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

Also provided herein is a method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising: administering an anti-IL-13 antibody to the patient for an induction period (or first period) of up to 16 weeks (e.g., 4 to 16 weeks), wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg of the anti-IL-13 antibody once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to an anti-IL-13 antibody after an induction period (or first period); if the patient has a response, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks or once every eight weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks); if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of up to 36 weeks (e.g., 8 to 36 weeks). In some embodiments, the induction period (or first period) is 16 weeks. During the induction period (or first period), 500mg of anti-IL-13 antibody was administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

The determination of whether a patient is responsive to an anti-IL-13 antibody may be assessed by assessing the patient's skin clearance, skin improvement and/or itch, sleep or quality of life improvement. For example, skin clearance and skin improvement may be measured by IGA or EASI scores. Itching, hypopnea, and quality of life may be measured by the itching NRS, hypopnea score, and DLQI or CDLQI scales, respectively. In some embodiments, the patient is responsive when the patient EASI score determined after the induction period (or first period) is reduced by 75% or more compared to the patient EASI score at baseline. In some embodiments, the patient responds when the patient's IGA score is 0 or 1 after the induction period (or first period). In some embodiments, the patient is responsive when the patient's IGA score is 0 or 1 after the induction period (or first period) and the patient's IGA score determined after the induction period (or first period) is reduced by 2 points or more compared to the patient's IGA score at baseline. In some embodiments, if the patient has a response, 250mg of anti-IL-13 antibody is administered once every four weeks during the maintenance period (or second period). In some embodiments, if the patient has a response, 250mg of anti-IL-13 antibody is administered once every eight weeks during the maintenance period (or second period).

In another aspect, provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering a loading dose of 500mg of an anti-IL-13 antibody (e.g., lerimumab) to the patient at baseline (week 0) and week 2, followed by a subsequent dose of 250mg once every two weeks. In some embodiments, an anti-IL-13 antibody is administered to a patient for a period of 4 to 52 weeks (e.g., about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, about 52 weeks). In some embodiments, an anti-IL-13 antibody is administered to a patient for a period of 4 to 16 weeks (e.g., about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks). In some embodiments, for example, as described above, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody (e.g., leirimumab) to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; and administering 250mg of anti-IL-13 antibody to the patient once every two weeks or once every four weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody (e.g., leirimumab) to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; and administering 250mg of the anti-IL-13 antibody to the patient once every eight weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to the anti-IL-13 antibody after the induction period (or first period); if the patient has a response, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks for a maintenance period (or second period) of 8 to 36 weeks; if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

Also provided herein are methods of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis; such methods comprise administering an anti-IL-13 antibody to a patient for an induction period (or first period) of 4 to 16 weeks, wherein 500mg of the anti-IL-13 antibody is administered at baseline (week 0) and week 2 during the induction period (or first period), followed by 250mg once every two weeks for 2 to 14 weeks; determining whether the patient is responsive to the anti-IL-13 antibody after the induction period (or first period); if the patient is responsive, 250mg of anti-IL-13 antibody is administered to the patient every eight weeks for a maintenance period (or second period) of 8 to 36 weeks; if the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient once every two weeks for a maintenance period (or second period) of 8 to 36 weeks. In some embodiments, the hypopnea is determined by a patient's hypopnea score. In some embodiments, the fraction of sleep insufficiency of the patient after anti-IL-13 antibody treatment is reduced by two or more compared to the fraction of sleep of the patient at baseline. In some embodiments, the induction period (or first period) is 16 weeks, during which 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg of anti-IL-13 antibody once every two weeks for 14 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks. In some embodiments, the anti-IL-13 antibody is administered to a patient subcutaneously.

In some embodiments, the patient has moderate to severe atopic dermatitis at baseline for at least one year. In some embodiments, the patient has an EASI score of 16 or more, an IGA score of 3 or more, and more than 10% BSA at baseline is affected by atopic dermatitis. In some embodiments, the patient is under-responsive to a local corticosteroid, a local calcineurin inhibitor, or crisaborole; or topical corticosteroids, topical calcineurin inhibitors or crisaborole are not medically recommended for the patient. In some embodiments, the patient is 12 years old and older. In some embodiments, the patient is 18 years old and older.

In some embodiments, moderate to severe atopic dermatitis may be determined by criteria known in the art, such as the Hanifin and Rajka criteria (Acta Derm Venereol (Stockh) 1980; suppl 92:44-7); rajka and LANGELAND (Rajka G AND LANGELAND T, acta Derm Venereol (Stockh) 1989;144 (Suppl): 13-4); or the American dermatological Condition of chronic atopic dermatitis (EICHENFIELD LF, et al, J Am Acad Dermatol.2014;70 (2): 338-351). In some embodiments, moderate to severe atopic dermatitis is determined by american dermatological association chronic atopic dermatitis consensus criteria. According to this standard, essential features of atopic dermatitis include itching; eczema (acute, subacute, chronic); typical morphology and age-specific patterns; history of chronic or recurrent. Typical morphology and age-specific patterns include facial, neck and extensor involvement in infants and children; current or previous bending injuries of any age group; the groin and armpit areas are reserved (sparing). Other important features that aid in diagnosis include early onset; allergy; personal and/or family history; immunoglobulin E reactivity; drying disease. May be helpful in suggesting a diagnosis of atopic dermatitis, but is a non-specific relevant feature for defining or detecting atopic dermatitis for research and epidemiological studies: atypical vascular reactions (e.g. pale face, whitened skin, delayed bleaching reactions); perikeratosis/pityriasis alba/increased palmprint/ichthyosis; eye/periorbital variation; perifollicular exacerbations/lichenification/prurigo lesions. Sometimes, skin biopsy specimens or other tests (e.g., serum immunoglobulin E, potassium hydroxide formulations, patch tests, and/or genetic tests) may help to exclude other or related skin disorders. Excluded disorders include scabies; seborrheic dermatitis; contact dermatitis (irritant or allergic); ichthyosis is a disease of fish; cutaneous T cell lymphoma; psoriasis; photosensitive skin diseases; immunodeficiency diseases; erythroderma caused by other causes.

Anti-IL-13 antibodies suitable for use in the methods and uses provided herein have been previously described, for example, in WO2005062967. In some embodiments, the anti-IL-13 antibodies bind IL-13 with high affinity and block signaling through active IL-4Rα/IL-13Rα1 heterodimers. In some embodiments, an anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an HCDR1 comprising SEQ ID NO.1, an HCDR2 comprising SEQ ID NO. 2, and an HCDR3 comprising SEQ ID NO. 3, and the VL comprises an LCDR1 comprising SEQ ID NO. 4, an LCDR2 comprising SEQ ID NO. 5, and an LCDR3 comprising SEQ ID NO. 6. In some embodiments, the anti-IL-13 antibody contains a VH comprising SEQ ID NO. 7 and a VL comprising SEQ ID NO. 8. In some embodiments, the anti-IL-13 antibody contains a heavy chain comprising SEQ ID NO.9 and a light chain comprising SEQ ID NO. 10. In some embodiments, the anti-IL-13 antibody is Leimumab. The amino acid sequence of Leir-group mab is shown in Table 1. C-terminal cleavage of an IgG antibody may occur, wherein one or two C-terminal amino acids are removed from the heavy chain of the IgG antibody. For example, if C-terminal lysine (K) is present, it may be truncated or sheared from the heavy chain. Penultimate glycine (G) may also be truncated or sheared off the heavy chain. Modification of the N-terminal amino acid of IgG may also occur. For example, N-terminal glutamine (Q) or glutamic acid (E) can spontaneously cyclize to pyroglutamic acid (pE). SEQ ID NO:9 reflects these potential modifications of the Lei-team mab heavy chain.

TABLE 1 Leir group mab sequence

Anti-IL-13 antibodies, such as Leirimumab, may be formulated with a suitable carrier or excipient into a pharmaceutical composition suitable for administration to a patient. For example, an anti-IL-13 antibody, such as Leirimumab, may be formulated in a pharmaceutical composition as described in WO 2013/066866. The pharmaceutical composition may comprise 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg or 500mg of the anti-IL-13 antibody. In some embodiments, the pharmaceutical composition comprises 250mg or 500mg of an anti-IL-13 antibody. In some embodiments, the concentration of anti-IL-13 antibody in the pharmaceutical composition is between 100mg/mL and 150mg/mL, e.g., 125mg/mL. The pharmaceutical composition may further comprise 5mM-40mM histidine acetate buffer, pH 5.4 to 6.0. In some embodiments, the pharmaceutical composition further comprises a polyol (e.g., sugar) at a concentration of 100mM to 200mM and/or a surfactant (e.g., polysorbate 20) at a concentration of 0.01% -0.1%. In one embodiment, the pharmaceutical composition comprises 125mg/mL of an anti-IL-13 antibody (e.g., leirimumab), 20mM histidine acetate buffer (pH 5.7), 175mM sucrose, and 0.03% polysorbate 20.

In some embodiments, an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody is administered to a patient subcutaneously. In some embodiments, the anti-IL-13 antibody or pharmaceutical composition comprising an anti-IL-13 antibody is administered to the patient once every two weeks or once every four weeks. In some embodiments, 250mg of an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody is administered to a patient once every two weeks or once every four weeks. In some embodiments, 250mg of an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody is administered subcutaneously to a patient once every two weeks. In some embodiments, 250mg of an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody is administered subcutaneously to a patient once every four weeks.

In some embodiments, the anti-IL-13 antibody or pharmaceutical composition comprising the anti-IL-13 antibody is administered to a patient using a subcutaneous administration device. The subcutaneous administration device may be selected from a prefilled syringe, a disposable pen injection device, a microneedle device, a micro-infuser device, a needleless injection device, or an auto-injector device. Various subcutaneous administration devices, including automatic injector devices, are known in the art and are commercially available. Exemplary devices include, but are not limited to, prefilled syringes (e.g., BDHYPAK from Becton DickinsonREADYFILL ^TM and STERIFILL SCF ^TM; CLEARSHOT ^TM copolymer prefilled syringe from Baxter; daikyo Seiko CRYSTAL/> from West Pharmaceutical ServicesA prefilled syringe); disposable Pen injection devices such as BD Pen of Becton Dickinson; ultra-sharp and micro-needle devices (e.g., INJECT-EASE ^TM and micro-infuser devices from Becton Dickinson; and H-PATCH ^TM from VALERITAS) and needleless injection devices (e.g., from Bioject)AndAnd/>, obtainable from MedtronicAnd a patch device). In some embodiments, the subcutaneous administration device is an automatic injector device described in WO 2008/112472, WO 2011/109205, WO 2014/062488, and/or WO 2016/089864.

In some embodiments, the patient may be treated with an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for a period of up to 52 weeks, such as about 4 to 52 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, about 52 weeks.

In some embodiments, the patient is treated with an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for an induction period (or first period) of up to 16 weeks (e.g., about 4 to 16 weeks, about 6 to 16 weeks, about 8 to 16 weeks, about 10 to 16 weeks, about 12 to 16 weeks, about 4 to 12 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 4 to 8 weeks, about 4 to 10 weeks, about 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks). During the induction period (or first period), a loading dose of 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by a subsequent dose of 250mg once every two weeks for 2 to 14 weeks (e.g., about 4 to 14 weeks, about 6 to 14 weeks, about 8 to 14 weeks, about 10 to 14 weeks, about 12 to 14 weeks, about 4 to 12 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 10 to 12 weeks, about 4 to 6 weeks, about 4 to 8 weeks, about 4 to 10 weeks, about 6 to 10 weeks, about 8 to 10 weeks, about 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks). In some embodiments, the induction period (or first period) is 4 to 16 weeks. In some embodiments, the induction period (or first period) is 16 weeks. In such embodiments, during the induction period (or first period), a 500mg loading dose of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by a 250mg subsequent dose once every two weeks for 14 weeks.

Before, during, and after anti-IL-13 antibody treatment, a patient may be assessed for one or more characteristics of an Atopic Dermatitis Disease Severity Measurement (ADDSM), which determines certain signs, symptoms, characteristics, or parameters associated with atopic dermatitis, and may be assessed quantitatively or qualitatively. Exemplary ADDSM include, but are not limited to, eczema Area and Severity Index (EASI), researcher general assessment (IGA), body Surface Area (BSA), atopic dermatitis Score (SCORAD), pruritus Numerical Rating Scale (NRS), sleep deficit scale, skin pain NRS score, patient-oriented total eczema measurement (poe m) score, dermatological quality of life index (DLQI) or pediatric dermatological quality of life index (CDLQI), DLQI-related (DLQI-R) score, patient reported outcome measure information system (prosis) anxiety and depression symptoms, EQ-5D (european quality of life-5 dimension), ACQ-5 (asthma control questionnaire 5), world health organization-five happiness index (WHO-5) score, atopic eczema Review (RECAP) score, medication satisfaction survey questionnaire-9 (TSQM-9) score. ADDSM may be measured at baseline and at one or more time points following administration of an anti-IL-13 antibody or pharmaceutical composition comprising an anti-IL-13 antibody. The difference between the ADDSM value at a particular time point after initiation of treatment and the ADDSM value at baseline was used to determine whether there was an "improvement" (e.g., a decrease) in ADDSM.

In some embodiments, the methods and therapeutic uses described herein further comprise determining one or more of the following characteristics of the patient during and after the baseline and induction periods (or first period): EASI score; IGA score; percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

In some embodiments, the EASI score of the patient is determined after the induction period (or first period). In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 50% or more compared to the baseline patient's EASI score, meaning that the patient has reached "EASI-50". In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 75% or more compared to the baseline patient's EASI score, meaning that the patient has reached "EASI-75". In some embodiments, the patient's EASI score determined after the induction period (or first period) is reduced by 90% or more compared to the baseline patient's EASI score, meaning that the patient has reached "EASI-90". When a patient reaches EASI-75 after the induction period (or first period), the patient is considered to be responsive to an anti-IL 13 antibody.

In some embodiments, the IGA score of the patient is determined after the induction period (or first period). When the IGA score of a patient is 0 or 1 after the induction period (or first period), the patient is considered to be responsive to an anti-IL 13 antibody. In some embodiments, a patient is considered to be responsive to an IL-13 antibody when the patient's IGA score after the induction period (or first period) is 0 or 1 and the patient's IGA score after the induction period (or first period) is reduced by 2 points or more compared to the patient's IGA score determined at baseline.

After the induction period (or first period) has ended, the patient enters a maintenance period (or second period). During the maintenance period (or second period), the patient is further treated with an anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody. The dosing regimen for the maintenance period (or second period) may be selected based on the ADDSM assessment of the patient and the response to the IL-13 antibody following the induction period (or first period), e.g., the IGA or EASI score of the patient following the induction period (or first period), and/or the characteristics of the patient itself (e.g., body weight, age, race).

The maintenance period (or second period) may be up to 36 weeks (e.g., about 4 to 36 weeks, about 8 to 36 weeks, about 12 to 36 weeks, about 16 to 36 weeks, about 20 to 36 weeks, about 24 to 36 weeks, about 28 to 36 weeks, about 4 to 32 weeks, about 8 to 32 weeks, about 12 to 32 weeks, about 16 to 32 weeks, about 20 to 32 weeks, about 24 to 32 weeks, about 28 to 32 weeks, about 4 to 24 weeks, about 8 to 24 weeks, about 12 to 24 weeks, about 16 to 24 weeks, about 20 to 24 weeks, about 4 to 20 weeks, about 8 to 20 weeks, about 12 to 20 weeks, about 16 to 20 weeks, about 4 to 16 weeks, about 12 to 16 weeks, about 4 to 12 weeks, about 8 to 12 weeks, about 4 to 12 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks). In some embodiments, the maintenance period (or second period) is 8 to 36 weeks. In some embodiments, the maintenance period (or second period) is 36 weeks.

In some embodiments, the methods and therapeutic uses described herein further comprise determining one or more of the following characteristics of the patient during and after the maintenance period (or second period): EASI score; IGA score; percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms. Similarly, the patient's EASI score during and after the maintenance period (or second period) may be evaluated to see if the patient has reached EASI-50, EASI-75 or EASI-90. The IGA score of the patient during and after the maintenance period (or second period) may be evaluated to see if the IGA score of the patient is 0 or 1 and if the IGA score of the patient decreases by 2 points or more.

"Researcher overall assessment" or "IGA" is an assessment measure for overall assessment of the severity of a patient's AD (Simpson E et al, J Am AcaDDermatol.2020;83 (3): 839-846). It selects the score based on a 5-score table from 0 (clean) to 4 (severe) and using a descriptor that best describes the overall appearance of the lesion at a given point in time (see table 2). All features under the morphological description need not be present. IGA may be performed prior to EASI and BSA evaluation.

TABLE 2 Overall evaluation by researchers (IGA)

Eczema area and severity index "or" EASI "is an effective measure in a clinical setting for assessing the severity and extent of AD (Hanifin et al, exp Dermatol.2001; 10:11-18). EASI is a composite index, with scores ranging from 0 to 72, with higher values indicating more severe and/or broader disease. Severity of plaques, induration/papules, epidermolysis and lichenification can be assessed by a clinician or other medical professional on a scale of 0 (none) to 3 (severe) for each of 4 body areas: head and neck, trunk, upper limbs, lower limbs, allowing half. Furthermore, the degree of AD involvement of each of the 4 body parts can be estimated as a percentage of the head, torso, upper and lower limb surface areas and converted to a fraction of 0 to 6. The total score (0-72) is assigned based on the sum of the total scores of each of the four body area scores.

Body Surface Area (BSA) assessment estimates the extent of disease associated with AD or the extent of skin involvement and is expressed as a percentage of the total surface area. BSA is determined by a clinician or other medical professional using a rule that the patient's palm is about 1% BSA.

"Atopic dermatitis severity score" or "SCORAD" is a validated clinical tool developed by the European atopic dermatitis working group for assessing the extent and intensity of AD (Consensus report of the European Task Force on Atopic Dermats. Dermatology.1993;186 (1): 23-31). There are 3 parts evaluated: (i) The range of AD is estimated as a percentage of each defined body region and reported as the sum of all regions, with a score range of 0 to 100 (designated "a" in the overall score calculation); (ii) severity of 6 symptoms of AD: redness, swelling, exudation/crusting, scaring, skin thickening/lichenification, dryness. Each item was rated as follows: none (0), mild (1), moderate (2) or severe (3) (total score up to 18 points, designated as "B" in the overall score calculation); (iii) Subjective assessment of itch and insomnia for each symptom was recorded using the Visual Analog Scale (VAS), where 0 represents no itch (or insomnia), 10 represents the most severe conceivable itch (or insomnia), and the highest possible score was 20 (designated as "C" in the overall score calculation). The SCORAD index formula is: A/5+7B/2+C. The SCORAD index highest score is 103.

The pruritus rating scale (NRS) is an 11-point scale for use by patients (with the help of parents/caregivers if applicable) to evaluate their severity of most severe pruritus over the last 24 hours, where 0 indicates "no itching" and 10 indicates "most severe pruritus conceivable" (Phan NQ et al Acta Derm Venereol 2012; 92:502-507). Patients were assessed daily using electronic diary recordings. The baseline pruritus NRS was determined from an average of daily pruritus NRS over 7 days prior to baseline. This calculation requires at least 4 daily scores for the 7 days before baseline.

Sleep deficit patients were evaluated for sleep deficit due to itch using a 5-point Likert scale (score ranges of 0[ none at all ], 1[ one point ], 2[ moderate ], 3[ considerable ], to 4[ unable to fall asleep at all ]). The patient will record the assessment results daily using an electronic diary.

Skin pain NRS is an 11-minute scale, performed by a patient (with the help of a parent/caregiver if applicable) to assess the severity of its most severe skin pain (e.g., discomfort or soreness) over the past 24 hours, 0 indicating "no pain", 10 indicating "the most severe pain conceivable" (Newton L, et al J PATIENT REP Outcomes.2019, day 7, 16; 3:42). Patients were assessed daily using an electronic diary record prior to week 16, and weekly using an electronic diary record starting at week 16. Baseline skin pain NRS was determined from the average of daily skin pain NRS over 7 days prior to baseline. This calculation requires at least 4 daily scores for the 7 days before baseline.

Patient-oriented eczema measurement (POEM) is a 7-item validated questionnaire, done by the patient (with the help of parents/caregivers if applicable) to evaluate disease symptoms in the past week (Centre of Evidence Based Dermatology. POEM-Patient Oriented Eczema measure. See https:// www.nottingham.ac.uk/research/groups/cebd/resources/asex). The patient was asked to answer 7 questions regarding skin dryness, itching, flaking, cracking, sleep insufficiency, bleeding and crying. All 7 answers are weighted the same, with a total possible score from 0 to 28 (answer score: none day = 0;1-2 days = 1, 3-4 days = 2, 5-6 days = 3; daily = 4). A high score indicates poor quality of life. Poe m answers were recorded weekly using an electronic diary.

The dermatological quality of life index (DLQI) is a validated questionnaire of 10 items completed by a patient or caregiver for assessing the effect of dermatological disorders on the patient's quality of life (Finlay, A.Y. and Khan, G.K.1994, clinical and Experimental Dermatology, 1993, 9, 23; 19:210-216). These 10 questions cover the following topics: symptoms of the last week, puzzles, shopping and home care, clothing, social and leisure, sports, work or learning, intimate, sexual and therapeutic. Each question was scored from 0 to 3 ("none at all", "one point", "many" and "very many"), with a total score ranging from 0 to 30 points. A high score indicates poor quality of life.

For teenagers under 16 years old, children DLQI (CDLQI) were used, which were based on a set of 10 questions different from DLQI (Lewis-Jones MS, finlay AY. British Journal of Dermatology,1995; 132:942-949).

DLQI correlation (DLQI-R) is a recently developed score, and the total score of the DLQI questionnaire can be adjusted according to the number of irrelevant answers (NRR) indicated by the patient (Rencz F et al Br J Dermatol.2020;182 (5): 1167-1175).

The patient reported outcome measure information system (proci) is a set of human-centered measurements that assess and monitor physical, psychological and social health of adults and children. Used in this studyMeasurements include anxiety and depression profiles that evaluate the symptoms of the patient for the past week. Patients aged 17 will complete the pediatric version during the study.

PROMIS anxiety profile v 1.0-anxiety 8a is a participant-managed questionnaire that evaluates adult human subjects for the following: self-reported fear (fear, panic); anxiety pain (fear ); oversleech (stress, nervous, restlessness) and somatic symptoms associated with arousal (acceleration of heart beat, dizziness) (PROMIS analysis 2019, published on month 3 of 2019, available at https:// www.healthmeasures.net/images/PROMIS/manuals/PROMIS_analysis_scanning_manual. Pdf). There are 5 answer options per question, with a score ranging from 1 to 5. The total score ranges from 8 to 40 scores, with higher scores indicating a higher anxiety level. Adult self-reporting assesses anxiety "over 7 days".

PROMIS depression profile v 1.0-depression 8a is a participant-managed questionnaire that evaluates adult human subjects for the following items: negative emotion of self-report (sadness, guilt); self-opinion (self criticism, no value); social cognition (autism, interpersonal distraction) and a decline in positive emotion and participation (loss of interest, meaning and purpose) (PROMISDepression 2019, published on 28 th 2 nd, 2021, 3 rd 8 th, accepted at https:// www.healthmeasures.net/images/procis/manuals/procis_ Depression _screening_manual. Somatic symptoms (e.g., changes in appetite or sleep patterns) are not included. This helps to eliminate the potential confounding effects of these items when assessing participants with co-morbid physical conditions. There are 5 answer options per question, with a score ranging from 1 to 5. The total score ranges from 8 to 40 scores, with higher scores indicating a higher level of depression. Adult self-reports evaluate "past 7 days" of depression.

EQ-5D (european quality of life-5 dimension) comprises five dimensions: mobility, self-care, daily activities, pain/discomfort and anxiety/depression. EQ VAS records the patient's health self-assessment on a vertical vision analog scale. The five-dimensional scores may be presented as a health profile or may be converted to a single aggregate index (utility) reflecting preferences compared to other health profiles. EQ-5D was completed by the patient at the study clinic.

European quality of life-5 dimension-5 grade (EuroQol-5D-5L or EQ-5D-5L) is a standardized measure of adult health status managed by participants, 5 questions plus 1 Visual Analog Scale (VAS), providing a simple, universal health measure for clinical and economic assessment. EQ-5D-5L consists of 2 parts: description of interviewee health system his or her current health status was rated using a 0 to 100mm VAS (20 cm). The description system includes the following 5 dimensions: locomotor ability, self-care, daily activities, pain/discomfort and anxiety/depression. There are 5 levels per dimension: no problems, mild problems, moderate problems, severe problems and extreme problems. The interviewee is required to mark (or cross) in the box associated with the most appropriate statement for each of the 5 dimensions to indicate his or her health condition. Note that the numbers 1 to 5 have no arithmetic attributes and no ordinal scores are applied. The EQ-5D-5L health defined by the EQ-5D-5L description system may be converted to a single summary index by applying a formula that essentially appends a value (also referred to as a weight) to each level of each dimension. The VAS records the interviewee's self-assessed health on a vertical VAS, with endpoints marked "conceivable best health status" and "conceivable worst health status". This information can be used as a quantitative measure of health outcome (Herdman et al, qual Life Res.2011;20 (10): 1727-1736;EuroQol Group,EQ-5D-5L version of the user guide 2.1, month 2015, accessed: month 1, month 14 of 2021; available from https:// euroqol.org/wp-content/uploads/2016/09/EQ-5D-5L_userGuide_2015. Pdf). The self-assessed health captured by EQ-5D-5L correlates with the condition at the completion of the participant. No attempt is made to recall the health condition over the past days or weeks (EuroQol Group, 2015).

ACQ-5 is an asthma control questionnaire. In addition to the results reported by other patients in this trial, patients reporting simultaneous asthma prior to group entry will also complete the asthma control questionnaire (ACQ-5). ACQ-5 has been shown to reliably weigh asthma control and distinguish well-controlled patients (score 0.75) from uncontrolled asthma patients (score 1.5). It consisted of 5 questions scored on a 7-point Likert scale with a1 week retrospective period. The total ACQ-5 score is the average of all questions; lower scores represent better asthma control. ACQ-5 was completed by the patient at the study clinic.

In another aspect, provided herein is the use of an anti-IL-13 antibody in the manufacture of a medicament for treating moderate to severe atopic dermatitis in a patient.

In some embodiments, the methods and uses described herein further comprise administering one or more topical corticosteroids to the patient. Exemplary topical corticosteroids include, but are not limited to, triamcinolone acetonide, hydrocortisone, and combinations of triamcinolone acetonide and hydrocortisone. Triamcinolone acetonide is typically formulated in the cream at a concentration of 0.1% and hydrocortisone is typically formulated in the cream at a concentration of 1% or 2.5%. Certain topical corticosteroids are considered to be very potent, such as betamethasone dipropionate, clobetasol propionate, diflorasone diacetate, fluocinolone acetonide, and halobetasol propionate. Certain topical corticosteroids are considered to be highly potent, such as, for example, ambroxide, desoxymethasone, halcinonide, and triamcinolone acetonide. Certain topical corticosteroids are considered to be moderately potent, such as betamethasone valerate, chlorotolon valerate, anefluocinolone acetonide, fluoronolactone, fluocinolone acetonide, fluticasone propionate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and prednisolone acetonide. Certain topical corticosteroids are considered to be inefficient, such as acllomethasone dipropionate, budesonide, and hydrocortisone. TCS may be applied to the affected area once a day, twice a day, three times a day, or as desired. In some embodiments, the topical corticosteroid is not adequately controlled by the patient. In some embodiments, the topical corticosteroid is triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone. In some embodiments, the topical corticosteroid is administered simultaneously or sequentially with an anti-IL-13 antibody. In some embodiments, the topical corticosteroid is administered concurrently with the anti-IL-13 antibody.

As used herein, the terms "a," "an," "the," and similar referents used in the context of this disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The term "about" as used herein means within a reasonable range of the recited value, such as plus or minus 10% of the recited value.

As used herein, the term "antibody" refers to an immunoglobulin molecule that binds an antigen. Embodiments of antibodies include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugated antibodies. Antibodies can belong to any class (e.g., igG, igE, igM, igD, igA) and any subclass (e.g., igG1, igG2, igG3, igG 4).

Exemplary antibodies are immunoglobulin G (IgG) type antibodies consisting of four polypeptide chains: two Heavy Chains (HC) and two Light Chains (LC) crosslinked by interchain disulfide bonds. The amino terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 amino acids or more that is primarily responsible for antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains comprises a constant region primarily responsible for effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further divided into subclasses (e.g., igG1, igG2, igG3, and IgG 4).

VH and VL regions can be further subdivided into regions of high variability, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Framework Regions (FR). CDRs are exposed on the protein surface and are important regions of antibody binding specificity for antigen. Each VH and VL consists of 3 CDRs and 4 FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, three CDRs of the heavy chain are referred to as "HCDR1, HCDR2 and HCDR3", and three CDRs of the light chain are referred to as "LCDR1, LCDR2 and LCDR3". CDRs contain most of the residues that interact specifically with antigen formation. Amino acid residues may be assigned to CDRs according to well known protocols, including those described in Kabat (Kabat et al ,"Sequences of Proteins of Immunological Interest,"National Institutes of Health,Bethesda,Md.(1991)),Chothia(Chothia et al ,"Canonical structures for the hypervariable regions of immunoglobulins",Journal of Molecular Biology,196,901-917(1987);Al-Lazikani et al ,"StandarDconformations for the canonical structures of immunoglobulins",Journal of Molecular Biology,273,927-948(1997)),North(North et al ,"A New Clustering of Antibody CDR Loop Conformations",Journal of Molecular Biology,406,228-256(2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see LefranC et al Nucleic Acids Res.1999; 27:209-212).

Exemplary embodiments of antibodies of the present disclosure also include antibody fragments or antigen-binding fragments comprising at least a portion of an antibody that retains the ability to specifically interact with an antigen, such as Fab, fab ', F (ab') 2, fv fragments, scFv, scFab, disulfide-linked Fv (sdFv), fd fragments, and linear antibodies.

As used herein, the term "baseline" means prior to or at the time of administration of the first dose (week 0) of an anti-IL-13 antibody or pharmaceutical composition comprising an anti-IL-13 antibody. For example, the value of the Atopic Dermatitis Disease Severity Measurement (ADDSM) before or at the time of administration of the first dose of anti-IL-13 antibody or pharmaceutical composition comprising the anti-IL-13 antibody is considered to be the baseline value of ADDSM.

The term "bind" as used herein, unless otherwise indicated, means the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in the proximity of the two proteins or molecules, as determined by conventional methods known in the art.

The term "outbreak (flare)" as used herein refers to an increase in signs and/or symptoms that result in a therapeutic upgrade, which may be an increase in dosage, a switch to a higher efficacy class of drug, or the initiation of another drug.

The term "high affinity" as used herein refers to the binding strength of an antibody to human IL-13, wherein the equilibrium dissociation constant (K _D) is less than about 10 ^-8 M, e.g., 10 ^-15 M to 10 ^-8 M, or 10 ^-12 M to 10 ^-9 M.

The term "human IL-13" refers to human interleukin 13 (also known as P600), an immunomodulatory cytokine produced primarily by activated Th2 cells. There are two known isoforms of human IL-13: isoform a and isoform b. The term "human IL-13" as used herein refers collectively to all human IL-13 isoforms. The amino acid sequence of human IL-13 isoform a can be found in NCBI accession No. NP-002179.2. The amino acid sequence of human IL-13 isoform b can be found in NCBI accession No. NP-001341922.1.

The term "hypo-response" as used herein means that good disease control of atopic dermatitis (e.g., IGA.ltoreq.2 or EASI-75 cannot be achieved) or an outbreak of atopic dermatitis occurs during treatment after a duration of treatment recommended using product prescription information.

The term "intolerant" or "intolerant" as used herein refers to unacceptable toxicity (e.g., elevated creatinine, elevated liver function test, uncontrolled hypertension, paresthesia, headache, nausea, hirsutism) or the need for a drug that exceeds the dose or duration specified in the prescription information.

As used herein, the term "patient" refers to a human patient.

The term "topical corticosteroid" or "TCS" as used herein includes group I, group II, group III and group IV topical corticosteroids. Corticosteroids are classified according to the world health organization's Anatomical Therapeutic Chemistry (ATC) classification system into weak (first group), moderate (second group), strong (third group) and very strong (fourth group) based on their activity compared to hydrocortisone. TCS of group IV (very potent) was up to 600 times as potent as hydrocortisone, including clobetasol and halcinonide. TCS (potent) of group III is 50 to 100 times more potent than hydrocortisone, including but not limited to betamethasone valerate, betamethasone dipropionate, difluocortisone valerate, hydrocortisone 17-butyrate, mometasone furoate, and methylprednisolone acetate. Group II TCSs (intermediate potency) are 2 to 25 times more potent than hydrocortisone, including but not limited to clobetasol butyrate and triamcinolone acetonide. Group I TCSs (weak or mild potency) include hydrocortisone, prednisolone and methylprednisolone.

The term "topical calcineurin inhibitor" or "TCI" as used herein includes pimecrolimus, tacrolimus, and other inhibitors that inhibit calcineurin activity and which may be topically applied to the skin of a patient.

As used herein, "treatment" refers to all processes in which the progression of a disorder or disease disclosed herein can be slowed, controlled, delayed, or stopped, or the symptoms of the disorder or disease are ameliorated (but not necessarily all the symptoms of the disorder or disease are completely eliminated). Treatment includes administration of a protein or nucleic acid or vector or composition to treat a disease or condition in a patient, particularly a human.

Examples

Example 1. Two randomized, double-blind, placebo-controlled trials evaluate efficacy and safety of Leishmaniab in patients with moderate to severe atopic dermatitis.

Two identical phase 3, randomized, double-blind, placebo-controlled, parallel group studies were performed to assess the safety and efficacy of the treatment of moderate to severe atopic dermatitis with the Lei-group mab alone (ADvocate 1 and ADvocate, i.e., NCT04146363 and NCT 04178967). Each trial lasted 52 weeks, including an induction period (or first period) of 16 weeks and a maintenance period (or second period) of 36 weeks.

Patient population

Patients of eligible adults and adolescents (12 years or more to <18 years, body weight 40kg or more) who entered the group had moderate to severe atopic dermatitis for at least one year, with eczema area and severity index score (EASI) 16 or more, and with overall investigator assessment (IGA) score 3 or more and Body Surface Area (BSA) 10% or more, as defined by american dermatology consensus standards.

Inclusion criteria: the patient must meet all of the following criteria to be eligible to participate in the study:

1. adults and adolescents (. Gtoreq.12 years to <18 years and body weight.gtoreq.40 kg).

2. Chronic AD (according to the consensus standard of the american dermatological society for chronic atopic dermatitis) already exists for more than or equal to 1 year before the screening visit.

3. The Eczema Area and Severity Index (EASI) score at baseline visit is more than or equal to 16.

4. At baseline visit, the overall evaluation (IGA) score was > 3 (scale 0 to 4).

5. The Body Surface Area (BSA) affected by the AD at the time of baseline visit is more than or equal to 10 percent.

6. A history of inadequate response to topical drug treatment; or to determine that local treatment is medically not advisable.

7. A stable dose of non-pharmaceutical topical moisturizer is applied at least twice daily for no less than 7 days prior to the baseline visit.

8. Electronic diary recordings for itch and sleep insufficiency were completed at least 4 days out of the 7 days prior to random grouping.

9. Willing and able to follow all clinic visits, programs and questionnaires related to the study.

10. For women with fertility: the subjects agree to maintain abstinence or use a high-efficiency contraceptive regimen for at least 18 weeks during treatment and after the last dose of either Leiruses or placebo.

11. If male patients develop sexual behavior with fertility females, then an effective barrier contraceptive method must be agreed to be used during the study and at least 18 weeks after the last dose of study medication.

12. Signed informed consent/agreement is provided.

Exclusion criteria: patients meeting any of the following criteria were excluded from the study:

1. Participate in previous clinical studies of Leirelizumab.

The history of allergic reactions as defined by the Sampson standard (Sampson et al, J ALLERGY CLIN immunol 2006;117 (2): 391-397).

3. Treatment with a topical corticosteroid, calcineurin inhibitor, or phosphodiesterase 4 inhibitor (e.g., crisaborole) is performed within 1 week prior to baseline visit.

4. Prior to receiving excessive common Li Youshan anti (dupilumab) or Qu Luoshan anti (tralokinumab) therapy.

5. Treatment was performed within 4 weeks prior to baseline visit with any of the following agents:

a. Immunosuppression/immunomodulation drugs (e.g., systemic corticosteroids, cyclosporine, mycophenolate mofetil, IFN-gamma, janus kinase inhibitors, azathioprine, methotrexate).

B. Phototherapy and Phototherapy (PUVA) for AD.

6. The following treatments were performed prior to baseline visit:

Study drug within 8 weeks or within 5 half-lives (if known), whichever is longer.

B.6 months of B-cell depleting biologic including rituximab.

C.5 half-lives (if known) or other biological agents within 16 weeks, whichever is longer.

7. The formula moisturizer was used within 7 days of the baseline visit.

8. The solar bathroom/tanning chamber was used periodically (more than 2 visits per week) for 4 weeks of screening visit.

9. Planned live vaccine (attenuated) treatment within 12 weeks of baseline visit or during the study.

10. Uncontrolled chronic diseases that may require large amounts of oral corticosteroid, such as the incorporation of severe uncontrolled asthma (defined as ACQ-5 score ≡1.5 or history of ≡2 asthma exacerbations in the past 12 months, requiring systemic [ oral and/or parenteral ] corticosteroid treatment or hospitalization >24 hours).

11. Active chronic or acute infections requiring treatment with systemic antibiotics, antiviral, antiparasitic, antiprotozoal or antifungal agents within 2 weeks prior to baseline visit, or superficial skin infections within 1 week prior to baseline visit.

12. Evidence of active acute or chronic hepatitis (defined by the U.S. health and human services center for disease control and prevention) or known cirrhosis.

13. Active endoparasite infections are diagnosed or at high risk for these infections.

14. A known or suspected history of immunosuppression, including a history of invasive opportunistic infections (e.g., tuberculosis [ TB ], histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis and aspergillosis), although the infection has resolved, or at the discretion of the researcher, the infection is abnormally frequent, recurrent or long-term.

15. Human Immunodeficiency Virus (HIV) infection history or HIV seropositivity at screening.

16. The researchers believe that any clinically significant laboratory result from chemical, hematology or urinalysis tests obtained at the time of the screening visit.

17. There are skin complications that may interfere with study evaluation.

18. A history of malignancy including mycosis fungoides was found within 5 years prior to the screening visit, except for fully treated carcinoma in situ of the cervix, fully treated and resolved non-metastatic squamous or basal cell skin cancer.

19. Researchers judge serious concomitant diseases that would adversely affect patient participation in the study. The researcher considers any other medical or psychological condition that may suggest a new and/or insufficiently understood disease, may carry an unreasonable risk to the research patient as he/she participates in the present clinical trial, may make patient participation unreliable, or may interfere with the research assessment.

20. Pregnant or lactating women, or women who are scheduled to become pregnant or lactating during the study.

Study drug:

pharmaceutical compositions or placebo containing 125mg/mL of Letrelimab are provided in the form of sterile pre-filled syringes with a pre-assembled needle safety device (PFS-NSD) for subcutaneous administration to patients. Leishmaniab sequences are provided in Table 1. The placebo solution was identical in appearance and volume to the active solution except that it did not contain Leirimumab.

Study design

The study design is shown in figure 1.

In each trial, during the induction period (or first period) of 16 weeks, about 400 patients were stratified and randomly assigned to either the 250mg Leirelizumab group (500 mg loading dose given at baseline (week 0) and week 2) or the placebo group at 2:1, once every 2 weeks (Q2W) Subcutaneous (SC) injection. All study drug injections were performed at the clinic.

After the visit at week 16 was completed, patients responding to treatment [ defined as IGA 0 or 1, or a 75% decrease in EASI from baseline to week 16 (EASI-75) ] entered the maintenance (or second) phase and were re-randomized to one of the following treatment groups at 2:2:1: leirimumab 250mg once every two weeks (Q2W), leimumab 250mg once every four weeks (Q4W), or placebo Q2W. Patients were instructed to self-administer study drugs at home.

Patients who received placebo in the first 16 weeks of the study and were re-randomized to the Lei-MAb group received a loading dose of Lei-MAb, either 500mg at week 16 or 500mg at weeks 16 and 18 based on the active treatment group assigned during the maintenance period.

Patients that did not reach IGA of 0 or 1 or EASI-75 at week 16, and patients that did not maintain EASI-50 response after re-randomization at weeks 24, 32, 40 or 48, were assigned to escape groups and received 250mg q2w of Leucomumab as long-term treatment until week 52. Patients who did not reach EASI-50 response 8 weeks after escape group treatment terminated the study.

Efficacy was measured by IGA, EASI, BSA, SCORAD, itch and sleep deficit scores.

Safety was assessed by monitoring adverse events, serum chemistry, hematology and urinalysis laboratory tests, physical examination, pulse and blood pressure. The independent data safety monitoring committee monitors patient safety by regularly officially reviewing the accumulated safety data throughout the course of the trial. In addition, hormonal levels in adolescents are monitored.

Using POEM, DLQI/CDLQI, EQ-5D andAnxiety and depression measurements assess quality of life and disease effects. Patients with simultaneous asthma were reported to complete ACQ-5 at the time of study entry.

Serum samples were collected for pharmacokinetic analysis and immunogenicity.

Patients who completed this 52 week study may choose to continue treatment in a separate long-term extension study. Patients who were prematurely terminated or selected not to participate in the long-term extension study received safety follow-up about 12 weeks after the last study drug injection.

Target and endpoint

The main objective of this study was to evaluate the safety and efficacy of Leirimumab compared to placebo in patients with moderate to severe AD.

For the United states, the primary efficacy endpoint is the percentage of patients with an IGA score of 0 or 1 and a decrease of ≡2 from baseline to week 16. Secondary objectives include: (1) The percentage of patients who reached EASI-75 (EASI score decreased by ≡75% from baseline) at week 16; (2) The percentage of patients who reached EASI-90 (EASI score decreased by 90% or more from baseline) at week 16; (3) Percent change from baseline to week 16 pruritus rating scale (NRS); (4) The percentage of patients with pruritus NRS being more than or equal to 4 minutes at baseline and decreasing more than or equal to 4 minutes at 16 weeks compared with baseline; (5) Percent change from baseline EASI score at week 16; (6) change in percentage BSA from baseline at week 16; (7) the percentage of patients who reached EASI-90 at week 4; (8) Percent change from baseline hypopnea score at week 16; (9) Changes in the fraction of sleep insufficiency compared to baseline at week 16; (10) The percentage of patients with pruritus NRS being more than or equal to 4 minutes at baseline and decreasing more than or equal to 4 minutes at week 4 compared with baseline; (11) The percentage of patients with pruritus NRS being more than or equal to 4 minutes at baseline and decreasing more than or equal to 4 minutes at week 2 compared with baseline; (12) The percentage of patients with pruritus NRS at baseline at 4 or more decreased at week 1 compared to baseline at 4 or more. During maintenance, secondary objectives include: (1) The percentage of patients in the re-randomized group reached EASI-75 at week 16 and continued to exhibit EASI-75 at week 52 (EASI-75 calculated relative to baseline EASI score); (2) The percentage of patients that reached IGA 0 or 1 in the patient re-randomized group and improved by ≡2 compared to baseline at week 16 continued to show IGA 0 or 1 and improved by ≡2 compared to baseline at week 52.

For europe, the common primary endpoints are: (1) IGA score of 0 or 1, and a decrease of ≡2 compared to baseline at week 16; (2) The percentage of patients who reached EASI-75 (EASI score was > 75% reduced from baseline) at week 16. Secondary objectives include: (1) The percentage of patients who reached EASI-90 (EASI score decreased by 90% or more from baseline) at week 16; (2) Percent change in pruritus Number Rating Scale (NRS) score compared to baseline at week 16; (3) The percentage of patients with pruritus NRS being more than or equal to 5 minutes at baseline and being less than or equal to 4 minutes at 16 weeks compared with baseline; (4) The percentage of patients with pruritus NRS being more than or equal to 4 minutes at baseline and decreasing more than or equal to 4 minutes at 16 weeks compared with baseline; (5) Percent change from baseline EASI score at week 16; (6) patient percentage reaching EASI-90 at week 4; (7) change from baseline DLQI at week 16; (8) Percentage of patients reaching DLQI improvement greater than or equal to 4 score at week 16 compared to baseline; (9) Percent change from baseline hypopnea score at week 16; (10) Changes in the fraction of sleep insufficiency compared to baseline at week 16; (11) The percentage of patients with pruritus NRS at baseline at 5 or more and decreased at 1, 2, and 4 weeks at 4 or more compared to baseline at 4 or more; (12) The percentage of patients with pruritus NRS at baseline at 4 score or more, decreased at weeks 1, 2, and 4 compared to baseline at 4 score or more. During maintenance, secondary objectives include: (1) The percentage of patients in the re-randomized group reached EASI-75 at week 16 and continued to exhibit EASI-75 at week 52 (EASI-75 calculated relative to baseline EASI score); (2) The percentage of patients that reached IGA 0 or 1 in the patient re-randomized group and improved by ≡2 compared to baseline at week 16, continued to show IGA 0 or 1 and improved by ≡2 compared to baseline at week 52; (3) Patients with pruritus NRS > 4 score at baseline were re-randomized, reaching a > 4 score decrease compared to baseline at week 16, and continuing to exhibit a > 4 score decrease compared to baseline at week 52; (4) Patients with pruritus NRS > 5 score at baseline were re-randomized, reaching a > 4 score decrease compared to baseline at week 16, and continuing to exhibit a > 4 score decrease compared to baseline at week 52; (5) Percent change in SCORAD at week 52 compared to baseline (EASI-75 was reached at week 16).

To evaluate the pharmacokinetics of the Lei-group mab, the mean serum Lei-group mab concentration was measured.

Other secondary endpoints include: patient proportions of EASI-75, EASI-90 and EASI-50 at visit; the IGA score at visit is 0 or 1 and the proportion of patients with a score of > 2 is reduced from baseline; percentage change in EASI score from baseline at visit; percentage change in pruritic NRS from baseline at visit; the percentage of patients with pruritus NRS at the time of visit, compared with the baseline change, is more than or equal to 4; the pruritus NRS fraction at the baseline is more than or equal to 4 minutes, and the patient percentage is reduced by more than or equal to 4 minutes compared with the baseline when the patient visits; changes in the fraction of sleep insufficiency compared to baseline at the visit; changes in the reference versus baseline DLQI/CDLQI; changes in the consultation relative to baseline EQ 5D; changes in the phase of visit relative to baseline poe m; changes in the baseline proci anxiety measurements relative to the visit; changes in the baseline proci depression measurements relative to the visit; changes in the ACQ-5 score compared to baseline on week 16 from patients with concurrent asthma; percent change from baseline SCORAD at week 16.

Statistical analysis was performed on primary and secondary endpoints. Estimation and missing data interpolation methods include Markov chain Monte Carlo multiple interpolation (MCMC-MI) and non-responder interpolation (NRI).

Results

In the ADvocate 1 trial, all major and critical minor endpoints, including skin and itch improvement, were reached at week 16 (figures 4A-4G and 5A-5F).

Figures 2A-2C show baseline demographics and baseline disease characteristics for ADvocate a 1 participants. Figures 3A-3C show adverse events by week 16. Figure 3D shows injection site response to week 16.

The participants in the Lei-mab treated group achieved a statistically significantly higher proportion of skin clearance and skin improvement as early as week 4 than the placebo group, as measured by IGA 0/1, EASI-75 and EASI-90 (see FIGS. 4D-4G). The participants in the Lei-bang treatment group achieved a statistically significantly higher proportion of improvement in pruritus as measured by pruritus NRS as early as week 2 (FIGS. 5A-5B). The participants of the Leishmaniab-treated group experienced a statistically significantly higher proportion of improvement in sleep and quality of life, as measured by the undersleep score and the DLQI scales, respectively (FIGS. 5C-5F).

During the 16 th week of evaluation, the Leirimumab remained well tolerated, with the frequency of adverse events comparable to placebo, including lower frequency of injection site reactions. There was no mortality due to the lower overall frequency of SAE and withdrawal caused by AE.

Similar results were seen in ADvocate test, reaching all major and critical minor endpoints at week 16, including skin and itch improvement.

Thus, the treatment with Leirimumab achieved major and all critical secondary endpoints in two critical phase 3 clinical trials, including itch at week 16, interference of itch with sleep, and quality of life.

From the mid-term analysis of the 16 th week data, in ADvocate 1, the proportion of patients treated with 250mg (n=283) of rituximab and placebo (n=141) reached IGA 0/1 at 16 th week was 43.0% and 12.8%, respectively (p < 0.001); EASI-75 reactions were 59.3% and 16.4% (p < 0.001), respectively; the ratio of > 4 minutes (P > 4) of NRS improvement compared to baseline pruritus was 46.3% and 12.7% (P < 0.001), respectively. Patients treated with 250mg (n=283) of revascularizumab and placebo (n=141) had average DLQI scores of 15.3 and 15.7, respectively, at baseline. The corresponding baseline averages for EQ-5D VAS scores were 68.2 and 67.0, respectively; the corresponding baseline averages for the EQ-5D-5L U.S. health index were 0.7 and 0.7, respectively. Of those patients with a baseline DLQI score of ≡4, the proportion of patients with an improvement of ≡4 compared to the baseline DLQI score in the Lei-group mab and placebo group at week 16 was 71.2% and 29.3%, respectively. Of those with baseline DLQI >1, the proportion of DLQI (0, 1) responses in patients receiving Leirimumab and placebo was 26.3% and 4.2%, respectively. Patients treated with Leir-group mab improved the DLQI total score average CFB by-10.0 at week 16, while placebo-treated patients improved by-4.4. All DLQI analyses reached statistical significance as early as week 4 (first evaluation after baseline) and continued until week 16. For patients assigned to Lei-group mab and placebo, there was also a significant difference between EQ-5D VAS fractional average CFB (10.5 and 2.2, respectively) and EQ-5D-5L US health index CFB (0.13 and 0.03, respectively) at week 16.

According to the mid-term analysis of week 16 data, in ADvocate 2 (leidomab, n=281, placebo, n=146), the corresponding IGA 0/1 ratios were 33.1% and 10.9%, respectively (p < 0.001); EASI-75 reactions were 50.8% and 18.2% (p < 0.001), respectively; the ratio of > 4 minutes (P > 4) of NRS improvement compared to baseline pruritus was 38.3% and 11.3% (P < 0.001), respectively. Baseline averages for DLQI scores were 15.4 and 15.9, respectively; the EQ-5D VAS scores were 66.7 and 68.6, respectively; EQ-5D-5L U.S. health index was 0.8 and 0.7, respectively. Of those patients with a baseline DLQI score of > 4, the proportion of patients with an improvement of > 4 compared to the baseline DLQI score in the Lei-mab group and placebo group at week 16 was 60.5% and 31.3%, respectively. Of those with baseline DLQI >1, the proportion of patients assigned to the Leirimumab and placebo reached a DLQI (0, 1) response of 16.1% and 7.7%, respectively. Patients treated with Leir-group mab improved the DLQI total score average CFB by-9.3 at week 16, while placebo-treated patients improved by-4.9. Improvements in DLQI > 4 score and total score CFB reached statistical significance as early as week 4 (first assessment after baseline) and continued until week 16. For patients receiving Leishmaniab and placebo, a significant difference was also observed between EQ-5D VAS score average CFB (9.0 and 5.2, respectively) and EQ-5D-5L US health index CFB (0.08 and 0.03, respectively) at week 16.

The percentage of patients reported to be 1TEAE or more in ADvocate1 (Lei Rui Fu MAB 45.4%, placebo 51.1%) and ADvocate2 (Lei Rui Fu MAB 53.0%, placebo 66.2%) was comparable.

After the final database is locked, some updates with concomitant medications (e.g., rescue medications) are considered for efficacy and safety endpoints. Patients receiving 250mg of Leirimumab reached IGA (0, 1) at week 16 compared to placebo, and were statistically higher than the baseline improvement by > 2 points, in ADvocate1, (43.1% vs.12.7% [ p <0.001 ]), in ADvocate, (33.2% vs.10.8% [ p <0.001 ]). The proportion of patients who reached EASI-75 response in the Lei mab group at week 16 was also higher compared to placebo group, in ADvocate1, (58.8% vs.16.2% [ p <0.001 ]), in ADvocate2, (52.1% vs.18.1% [ p <0.001 ]); the corresponding proportion to achieve EASI-90 at week 16 was 38.3% vs.9.0% (p < 0.001) in ADvocate1 and 30.7% vs.9.5% (p < 0.001) in ADvocate 2. The percentage change in Least Squares Mean (LSM) was significantly greater for patients treated with Learelizumab (ADvocate, -64.3; ADvolcate 2, -61.5; p < 0.001) compared to placebo-treated patients (ADvocate, -26.0; ADvolcate 2, -28.0; p < 0.001) at week 16 compared to the baseline EASI score. Patients receiving 250mg of Leirimumab reached a significantly higher proportion (p < 0.001) than baseline at week 16 than the following: the pruritic NRS score was improved by at least 4 score ((ADvocate: 45.9% vs.13%; ADvocate: 39.8% vs.11.5%); improvement in sleep deficit scale > 2 score (ADvocate: 39% vs.4.7%; ADvocate: 28% vs.8.2%); and improvement in DLQI > 4 score. Furthermore, lereoxygenation mab showed significant clinical improvement compared to placebo in week 16 in terms of percentage change in pruritic NRS score compared to baseline, change in LSM compared to baseline, and DLQI.

Leir-group mab 250mg showed rapid onset. In both studies, an improvement of IGA (0, 1). Gtoreq.2 score, EASI-90, and an improvement of pruritus NRS.gtoreq.4 score were achieved from week 4 compared to placebo, all of which were subject to multiple controls.

There was an approximately 3-fold and 2-fold increase in rescue drug usage in ADvocate and ADvocate-treated patients, respectively, compared to the Leishmaniab-treated patients. Patients assigned to placebo treatment require rescue treatment earlier than patients receiving Leirimumab treatment. Placebo-treated patients required a proportion of local and/or systemic rescue treatments as early as week 2, 5.0% in ADvocate (1.4% for the patients treated with Leir-MAb) and 10.3% in ADvocate (3.9% for the patients treated with Leir-MAb). The patient being rescued is primarily receiving local treatment rather than systemic treatment.

In ADvocate1 and ADvocate2, 51.8% (n=73) and 66.2% (n=96) of Treatment Emergency Adverse Events (TEAE) were reported in placebo patients, respectively, while 45.7% (n=129) and 53.4% (n=150) in patients receiving 250mg of Leirimumab, respectively. Most TEAEs are mild to moderate in severity, resulting in less frequent treatment interruptions. In both studies, the frequency of injection site responses reported for patients treated with 250mg of remimumab (ADvocate 1,1.1%; ADvocate, 2.1%), severe adverse events (ADvocate, 2.1%; ADvocate, 2, 0.7%) and TEAE (ADvocate, 1.1%; ADvocate, 3.2%) that led to discontinuation of the study were lower, comparable to the proportion of placebo-group patients. The placebo group in ADvocate had 1 death. The most common TEAE (Lei's mab group incidence > 5% and reporting frequency consistently higher than placebo) is conjunctivitis, in ADvocate 1.4%; in ADvocate (7.5%). All TEAEs associated with conjunctivitis were mild to moderate in severity.

Improvement in anxiety and depression in ADvocate and ADvocate was measured using the adult anxiety and depression patient report results measurement information system (PROMIS) scale. Missing data was estimated by last observation push (LOCF). In ADvocate1, the patient baseline anxiety scores for either 250mg (n=246) or placebo (n=123) received Lei-group mab were 52.9 and 54.3, respectively; baseline depression scores were 49.8 and 50.0, respectively. The anxiety-related Changes (CFB) of the 250mg group of herceptin versus the placebo group at week 16 were-3.99 and-0.62 (p < 0.001), respectively, while depressed CFB was-3.16 and-0.40 (p=0.002), respectively. In ADvocate2, the baseline anxiety scores for the Lei-group mab 250mg group (N=251) and placebo group (N=129) were 54.4 and 55.0, respectively, and the depression scores were 51.3 and 51.2, respectively. Anxiety CFBs in the 250mg and placebo groups were-3.00 and-0.43 (p < 0.001), respectively, and depressed CFBs were-2.38 and 0.19 (p=0.13), respectively, at week 16.

For the maintenance period, surprisingly, the maintenance doses of both Leucomumab Q4W and Q2W maintained the response at week 52 in similar ratios for patients receiving Leucomumab treatment during the induction period (or first period) and considered responders at week 16, as measured by IGA, EASI-75, pruritic NRS, and in clinically significant patient percentages (see FIGS. 6A-6F). In ADvocate 1, 79% of patients receiving Leuconostoc Q4W and 79% of patients receiving Leuconostoc Q2W maintained EASI-75 at week 52 (see FIG. 6C); 74% of patients receiving Leuconostoc Q4W and 76% of patients receiving Leuconostoc Q2W maintain IGA at 0 or 1 at week 52, improving by ≡2. In addition, in ADvocate2, 85% of patients receiving Leuconostoc Q4W and 77% of patients receiving Leuconostoc Q2W maintained the EASI-75 response at week 52 (see FIG. 6D); 81% of patients receiving Leuconostoc Q4W and 65% of patients receiving Leuconostoc Q2W maintain IGA at 0 or 1 at week 52, improving by ≡2. In ADvocate 1 and ADvocate, 81.2% and 90.3% of patients in the Leuconostoc Q2W group, respectively, remained an improvement of > 4 minutes in the pruritus digital rating scale (NRS) at week 52 compared to baseline, while 80.4% and 88.1% in the Leuconostoc Q4W patients, respectively. Overall, in ADvocate 1 and 2, about 80% of patients who respond to Leirimumab at week 16 maintained improvement in skin clearance and disease severity at week 52; sustained improvement in itch was also observed at week 52 in patients receiving Leishmaniab treatment. Unexpectedly, the loss of response after the withdrawal of the Lei-group mab was relatively slow, with approximately half of patients re-randomized to placebo during the maintenance period ("Lei-group mab withdrawal group") still responding at week 52 (see FIGS. 6A-6F). In ADvocate 1 and ADvocate2, 61% and 72% of patients in the Leirimumab withdrawal group, respectively, continued to reach EASI-75 at week 52. The proportion of NRS response to maintenance of itching in the patients in the Leir group was 65.4% (ADvocate 1) and 67.6% (ADvocate 2). The proportion of patients using any rescue therapy in each treatment group was 14.0% (ADvocate 1) and 16.4% (ADvocate 2), respectively.

The overall safety profile of the Lei-group mab Q2W and Q4W was comparable, and no new safety problems were found during maintenance (see FIG. 7). Low frequency SAE and AE resulted in withdrawal and no mortality was reported. Most of the reported adverse events were mild to moderate in severity. In all studies, the conjunctivitis of the Leucomumab treated group was 14.5%. Only one injection site response was reported.

After 16 weeks of induction with Leucomumab Q2W, both Leucomumab Q2W and Leucomumab Q4W maintained an improvement in moderate to severe atopic dermatitis signs and symptoms with a good safety profile.

Example 2 exposure-response modeling and simulation

The exposure-response relationship of Leirimumab was evaluated in a combined PK-PD analysis of 5 randomized, double-blind, placebo-controlled studies in AD patients with induction period data (week 16) from ADvocate and ADvocate 2, NCT04250337, NCT03443024, NCT 02340234. From the data of these double-blind placebo-controlled phase 2 and 3 AD studies, the relationship between the exposure of the Leishmaniab and the Eczema Area and Severity Index (EASI) response was evaluated. EASI was chosen for modeling because it is a continuous variable. In the Leishmaniab phase 3 data, there was 88% high consistency between EASI 90 and IGA (0, 1), further confirming the suitability and practicality of the EASI endpoint for such modeling.

The indirect effect model, which well describes the longitudinal EASI response to the leuprolide, includes the leuprolide drug effect, the placebo effect, and the time-varying TCS effect. No significant effect of the following covariates was found in the E-R model: age, sex, body weight (continuous and definite), race and baseline IGA (moderate and severe). The model diagram is shown in fig. 8A, and the model parameters are shown in fig. 8B.

After the final E-R model was developed, the model was used to explore different aspects of the exposure and dose response of the Leishmaniab. Simulations were performed using the E-R model to explore maintenance dose selection by participants who reached EASI-75 at week 16 by induction dosing regimen (500 mg loading dose at weeks 0 and 2, followed by 250mg q2w until week 14). Each dosing regimen was simulated for n=125 patients and the simulation was repeated 500 times. N=125 was selected based on the typical sample size for each treatment group in the phase 3 study. In the simulations, patients who reached EASI-75 response at week 16 were classified as either responsive or non-responsive, and data for either responsive or non-responsive patients were summarized for each dosing regimen, respectively.

From the simulation, responders at week 16 were predicted to have high levels of EASI response by receiving 250mg q2w (once every two weeks) or 250mg q4w (once every four weeks) maintenance regimens at weeks 16 to 52. The EASI-75 and EASI-90 simulations are shown in FIGS. 9 through 12. These simulations were consistent with the data observed in phase 3 (comparative data not shown).

From the simulation, it was predicted that responders receiving placebo at week 16 will develop a persistent EASI response (figures 9 and 11). The observed efficacy data for placebo (the Lei-group mab withdrawal group) are consistent with the simulation using the E-R model (data not shown). Its long lasting effect is attributed to the long PK half-life and indirect E-R relationship of Yu Lairui group mab.

Other dosing regimen selections not studied in stage 3 were explored, including 250mg of 8w (once every eight weeks) maintenance regimen after week 16. The responders at week 16 were predicted to continue to receive 250mg of the maintenance regimen of 8w with a high level of efficacy. The EASI-75 and EASI-90 simulations are shown in FIGS. 9-12. There was a slight decrease in the EASI-75 and EASI-90 simulations for Q8W administration compared to Q4W, but Q8W still showed high levels of response (FIGS. 9-12). There is some overlap in the 95% confidence interval between Q4W and Q8W (fig. 10 and 12), also indicating that both dosing regimens will produce high levels of efficacy and are comparable to each other.

Claims

1. A method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising:

Administering an anti-IL-13 antibody to the patient for an induction period of 4 to 16 weeks, wherein during the induction period 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2 followed by 250mg once every two weeks for 2 to 14 weeks; and

250Mg of anti-IL-13 antibody was administered to the patient once every four weeks for a maintenance period of 8 to 36 weeks,

Wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an HCDR1 comprising SEQ ID NO. 1, an HCDR2 comprising SEQ ID NO. 2 and an HCDR3 comprising SEQ ID NO. 3, and the VL comprises an LCDR1 comprising SEQ ID NO. 4, an LCDR2 comprising SEQ ID NO. 5, and an LCDR3 comprising SEQ ID NO. 6.

2. A method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising:

Administering 250mg of anti-IL-13 antibody to the patient once every two weeks for a maintenance period of 8 to 36 weeks,

3. A method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising:

Administering an anti-IL-13 antibody to the patient for an induction period of 4 to 16 weeks, wherein during the induction period 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2 followed by 250mg once every two weeks for 2 to 14 weeks;

Determining whether the patient is responsive to an anti-IL-13 antibody after an induction period; and

If the patient is responsive, 250mg of anti-IL-13 antibody is administered to the patient once every four weeks for a maintenance period of 8 to 36 weeks;

If the patient does not respond, 250mg of anti-IL-13 antibody is administered to the patient every two weeks for a maintenance period of 8 to 36 weeks,

4. A method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, the method comprising:

Administering to the patient a 500mg loading dose of anti-IL-13 antibody at baseline (week 0) and week 2, followed by a subsequent dose of 250mg once every two weeks;

5. A method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, the method comprising:

6. A method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, the method comprising:

7. A method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising:

Administering 250mg of anti-IL-13 antibody to the patient once every eight weeks for a maintenance period of 8 to 36 weeks,

8. A method of treating moderate to severe atopic dermatitis in a patient in need thereof, the method comprising:

If the patient is responsive, 250mg of anti-IL-13 antibody is administered to the patient every eight weeks for a maintenance period of 8 to 36 weeks;

9. A method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, the method comprising:

10. A method of reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, the method comprising:

11. The method of any one of claims 1-10, wherein the patient has moderate to severe atopic dermatitis at baseline for at least one year.

12. The method of any one of claims 1-10, wherein the moderate to severe atopic dermatitis is determined by american society of dermatology chronic atopic dermatitis consensus criteria.

13. The method of any one of claims 1-10, wherein the patient has an EASI score of 16 or more, an IGA score of 3 or more, and more than 10% of Body Surface Area (BSA) affected by atopic dermatitis at baseline.

14. The method of any one of claims 1-13, wherein the patient is under-responsive to a local corticosteroid, a local calcineurin inhibitor, or crisaborole; or a topical corticosteroid, a topical calcineurin inhibitor, or crisaborole are not medically recommended for the patient.

15. The method of any one of claims 1-14, wherein the patient is 12 years old and older.

16. The method of any one of claims 1-3, 5-15, further comprising determining the EASI score of the patient at baseline and during and after induction period.

17. The method of any one of claims 1-3, 5-15, further comprising determining an IGA score for the patient at baseline and during and after an induction period.

18. The method of any one of claims 1-3, 5-17, further comprising determining one or more of the following characteristics of the patient during and after a baseline and an induction period: percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

19. The method of any one of claims 3 and 6-18, wherein the patient is responsive when the patient EASI score determined after the induction period is reduced by 75% or more compared to the patient EASI score at baseline.

20. The method of any one of claims 3 and 6-18, wherein the patient is responsive when the patient's IGA score is 0 or 1 after an induction period.

21. The method of claim 20, wherein the patient IGA score determined after the induction period is reduced by 2 points or more compared to the patient IGA score at baseline.

22. The method of any one of claims 1-3, 5-21, wherein the induction period is 16 weeks.

23. The method of claim 22, wherein 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg once every two weeks for 14 weeks during the induction period.

24. The method of any one of claims 1-3, 5-23, wherein the maintenance period is 36 weeks.

25. The method of any one of claims 1-3, 5-24, further comprising determining the patient's EASI score during and after a maintenance period.

26. The method of any one of claims 1-3, 5-25, further comprising determining an IGA score for the patient during and after the maintenance period.

27. The method of any one of claims 1-3, 5-26, further comprising determining one or more of the following characteristics of the patient during and after a maintenance period: percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

28. The method of claim 4, further comprising determining an EASI score for the patient.

29. The method of claim 4, further comprising determining an IGA score for the patient.

30. The method of claim 4, further comprising determining one or more of the following characteristics of the patient: percentage of BSA affected by atopic dermatitis; a pruritic NRS score; score of SCORAD; a sleep deficiency score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; proci anxiety and depression symptoms.

31. The method of claim 4, wherein the anti-IL-13 antibody is administered to the patient for a period of 4 to 52 weeks.

32. The method of claim 4, wherein the anti-IL-13 antibody is administered to the patient for a period of 4 to 16 weeks.

33. The method of any one of claims 4-32, wherein the hypopneas are determined by a patient's hypopneas score.

34. The method of claim 33, wherein the patient's fraction of hypopneas following anti-IL-13 antibody treatment is reduced by two or more compared to the patient's fraction of sleep at baseline.

35. The method of any one of claims 16, 25, 28, further comprising determining whether the patient's EASI score is reduced by 50%, 75%, 90% or more as compared to the patient's EASI score at baseline.

36. The method of any one of claims 17, 26, 29, further comprising determining whether the patient's IGA score is 0 or 1 and whether the patient's IGA score is reduced by 2 points or more compared to the patient's IGA score at baseline.

37. The method of any one of claims 1-36, wherein the antibody comprises a VH comprising SEQ ID No. 7 and a VL comprising SEQ ID No. 8.

38. The method of any one of claims 1-37, wherein the antibody comprises a heavy chain comprising SEQ ID No. 9 and a light chain comprising SEQ ID No. 10.

39. The method of any one of claims 1-38, wherein the antibody is leuprolide.

40. The method of any one of claims 1-39, wherein the patient is subcutaneously administered an anti-IL-13 antibody.

41. The method of any one of claims 1-40, wherein the patient is administered an anti-IL-13 antibody using a subcutaneous administration device.

42. The method of claim 41, wherein the subcutaneous administration device is selected from the group consisting of a prefilled syringe, a disposable pen injection device, a microneedle device, a microinjection device, a needleless injection device, or an auto-injector device.

43. The method of any one of claims 1-42, wherein the method further comprises administering one or more topical corticosteroids to the patient.

44. The method of claim 43, wherein the one or more topical corticosteroids are triamcinolone acetonide, hydrocortisone, or a combination of triamcinolone acetonide and hydrocortisone.

45. The method of claim 43 or 44, wherein the one or more topical corticosteroids are administered concurrently with the antibody.

46. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in treating moderate to severe atopic dermatitis in a patient, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO: 6. And wherein the anti-IL-13 antibody or pharmaceutical composition is for administration during an induction period of 4 to 16 weeks, and during the induction period, 500mg of anti-IL-13 antibody is administered at baseline (week 0) and week 2, followed by 250mg once every two weeks for 2 to 14 weeks; and wherein 250mg of anti-IL-13 antibody is administered once every four weeks for a maintenance period of 8 to 36 weeks.

47. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6, and wherein the anti-IL-13 antibody or pharmaceutical composition is for administration of a loading dose of 500mg at baseline (week 0) and week 2, followed by administration of a subsequent dose of 250mg once every two weeks.

48. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6, and wherein the anti-IL-13 antibody or pharmaceutical composition is for administration for an induction period of 4 to 16 weeks, and during the induction period 500mg of anti-IL-13 antibody is administered once every two weeks for 2 to 14 weeks at baseline (week 0) and week; and wherein 250mg of anti-IL-13 antibody is administered once every four weeks for a maintenance period of 8 to 36 weeks.

49. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in treating moderate to severe atopic dermatitis in a patient, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6, and wherein the anti-IL-13 antibody or pharmaceutical composition is for administration during the induction period of 4 to 16 weeks, and 500mg of the anti-IL-13 antibody is administered once every two weeks for 2 to 14 weeks at baseline (week 0) and week; and wherein 250mg of anti-IL-13 antibody is administered once every eight weeks for a maintenance period of 8 to 36 weeks.

50. An anti-IL-13 antibody or a pharmaceutical composition comprising an anti-IL-13 antibody for use in reducing sleep insufficiency in a patient suffering from moderate to severe atopic dermatitis, wherein the anti-IL-13 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1 comprising SEQ ID NO:1, HCDR2 comprising SEQ ID NO:2 and HCDR3 comprising SEQ ID NO:3, and the VL comprises LCDR1 comprising SEQ ID NO:4, LCDR2 comprising SEQ ID NO:5, and LCDR3 comprising SEQ ID NO:6, and wherein the anti-IL-13 antibody or pharmaceutical composition is for administration for an induction period of 4 to 16 weeks, and during the induction period 500mg of anti-IL-13 antibody is administered once every two weeks for 2 to 14 weeks at baseline (week 0) and week; and wherein 250mg of anti-IL-13 antibody is administered once every eight weeks for a maintenance period of 8 to 36 weeks.