Anti-thymic stromal lymphopoietin (TSLP) monoclonal antibodies and methods of treating atopic dermatitis

Abstract

The present disclosure relates to monoclonal antibodies that specifically bind to thymic stromal lymphopoietin (TSLP) and methods for treating atopic dermatitis. The antibodies block TSLP interaction with its receptor complex, preventing downstream inflammatory signaling. Administration involves weekly loading doses followed by biweekly maintenance doses, achieving superior clinical efficacy with >90% reduction in disease severity. The antibodies demonstrate favorable pharmacokinetics with a 25-day half-life, low immunogenicity, and a well-tolerated safety profile. This disclosure also covers methods for evaluating treatment efficacy and safety in moderate to severe atopic dermatitis patients.

Description

146588-005802ANTI-THYMIC STROMAL LYMPHOPOIETIN (TSLP) MONOCLONAL ANTIBODIES AND METHODS OF TREATING ATOPIC DERMATITISCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 721,235, filed November 15, 2024, and U.S. Provisional Application No. 63 / 869,888, filed August 25, 2025, which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates generally to methods for treating atopic dermatitis and more specifically to use of anti-thymic stromal lymphopoietin (TSLP) monoclonal antibodies to reduce inflammatory responses in patients with moderate to severe atopic dermatitis.BACKGROUND INFORMATION

[0003] Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease and the most common type of eczema, affecting more than 9.6 million children and about 16.5 million adults in the United States. Worldwide prevalence ranges from 0.2% to 24.6%, with the highest rates of atopic dermatitis seen in children in Africa and Latin America. Atopic dermatitis is a chronic relapsing and remitting condition that may overlap with other types of eczema and may progress through a process called atopic march to food allergies, asthma (up to 70%), and rhinitis.

[0004] Atopic dermatitis is characterized by recurrent eczematous lesions and intense itch. It is a major non-communicable disease that affects both children and adults and is the leading cause of the global burden from skin disease. It is estimated that 1 in 10 individuals will develop eczema during their lifetime, impacting people of all skin colors, races, and ethnicities (range 10 to 13%).

[0005] While various treatments exist for atopic dermatitis, there remains a need for more effective therapies that can target key inflammatory pathways involved in disease pathogenesis. Therapeutic approaches targeting TSLP represent a promising strategy, as this cytokine plays a central role in initiating and maintaining the inflammatory cascade in atopic dermatitis. Development of agents that can effectively block TSLP signaling could provide new options for patients with moderate to severe atopic dermatitis who have inadequate response to current treatments.11625938262.3146588-005802SUMMARY OF THE INVENTION

[0006] The present disclosure provides an isolated monoclonal antibody that specifically binds to TSLP and blocks its interaction with TSLP receptor complex, for treating atopic dermatitis. The antibody, or antigen-binding portion thereof, in a pharmaceutical (e.g., such a composition comprising a pharmaceutically acceptable carrier or diluent and the antibody or antigenbinding portion thereof, in an effective amount) is administered through a novel dosing regimen of weekly loading doses followed by biweekly maintenance doses, overcoming limitations of existing anti-TSLP therapies. Clinical studies demonstrate superior efficacy with >90% reduction in disease severity scores, favorable pharmacokinetics with a 25 -day half-life, and a well-tolerated safety profile characterized by mostly mild adverse events. The antibody prevents immune cells targeted by TSLP from releasing proinflammatory cytokines, providing an effective therapeutic approach for treating moderate to severe atopic dermatitis.

[0007] In one embodiment, the present disclosure provides a method of treating atopic dermatitis in a subject comprising administering to the subject a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) antibody or an antigen-binding portion thereof, advantageously in a pharmaceutical composition, the anti-TSLP antibody or the antigen-binding portion thereof having: (a) a heavy chain variable region comprising a VH CDR1, VH CDR2 and VH CDR3 regions having an amino acid sequence selected from SEQ ID NOs: 1, 2 and 3; and (ii) a light chain variable region comprising a VL CDR1, VL CDR2 and VL CDR3 regions having an amino acid sequence selected from SEQ ID NOs: 5, 6 and 7. In some embodiments, the anti-TSLP antibody or the antigen-binding portion thereof comprises: (a) a heavy chain variable region comprising a VH CDR1, a VH CDR2 and a VH CDR3 comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; and (ii) a light chain variable region comprising a VL CDR1, a VL CDR2 and a VL CDR3 comprising the amino acid sequences of SEQ ID NOs: 5, 6 and 7, respectively. The subject can also receive additional therapeutic agent(s), e.g., additional anti-atopic dermatitis therapeutic agent(s).

[0008] In an embodiment, the disclosure provides the antibody, or the antigen-binding portion thereof, comprising the antibody, e.g., an effective amount of the antibody, or the antigenbinding portion thereof, e.g., an effective amount of the antigen-binding portion, and a pharmaceutically acceptable carrier or diluent, for use in treating atopic dermatitis advantageously by the herein-disclosed dosing regimen or method.

[0009] Similarly in an embodiment the disclosure provides use of the antibody, or the antigenbinding portion thereof, or pharmaceutical composition comprising an effective amount of the21625938262.3146588-005802antibody, or the antigen-binding portion thereof and a pharmaceutically acceptable carrier or diluent, in treating atopic dermatitis by the herein-disclosed dosing regimen or method.

[0010] In one embodiment, the anti-TSLP antibody or the antigen-binding portion thereof includes a heavy chain variable region having the amino acid sequence of SEQ ID NO:4.

[0011] In one embodiment, the anti-TSLP antibody or the antigen-binding portion thereof includes a light chain variable region having the amino acid sequence of SEQ ID NO: 8.

[0012] In some embodiments, the administration and / or dosing regimen includes subcutaneous administration, intravenous administration, intramuscular administration, or intradermal administration.

[0013] In some embodiments, the administration and / or dosing regimen includes once every 7 days, once every 14 days, once every 28 days, once every 56 days, or once every 84 days administration of the anti-TSLP antibody or composition comprising the antibody. In some embodiments, the administration and / or dosing regimen includes once every 7 days administration of the anti-TSLP antibody or composition comprising the antibody.

[0014] In some embodiments, the administration and / or dosing regimen includes once every week, once every 2 weeks, once every 4 weeks, or once every 12 weeks administration of the anti-TSLP antibody or composition comprising the antibody.

[0015] In some embodiments, the administration and / or dosing regimen includes administration of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg or 720 mg of the anti-TSLP antibody.

[0016] In some embodiments, the administration and / or dosing regimen includes: (a) administering the anti-TSLP antibody or composition comprising the antibody weekly for 4 weeks as loading doses; and (b) administering the anti-TSLP antibody or composition comprising the antibody every two weeks thereafter as maintenance doses. In some embodiments, the administration and / or dosing regimen includes: (a) administering 300 mg of the anti-TSLP antibody weekly for four (4) weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every two weeks thereafter as maintenance doses; or (a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every four weeks thereafter as maintenance doses; or (a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every eight weeks thereafter as maintenance doses; or (a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every 12 weeks thereafter as maintenance doses; (a) administering 600 mg of the anti-TSLP antibody 31625938262.3146588-005802weekly for two weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every two weeks thereafter as maintenance doses; or (a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every 2 weeks thereafter as maintenance doses; or (a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every four weeks thereafter as maintenance doses; or (a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every eight weeks thereafter as maintenance doses; or (a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and (b) administering 300 mg of the anti-TSLP antibody every 12 weeks thereafter as maintenance doses.

[0017] In some embodiments, the treatment comprises or provides at least one of: (a) an improved Eczema Area and Severity Index (EASI); (b) an improved Investigator Global Assessment (IGA) score; (c) an improved Peak Prutitus Numerical Rating Scale (PP-NRS), (d) an improved Body Surface Estimate (BSA) score, (e) an improved Scoring Atopic Dermatitis (SCORAD) score; (f) an improved Patient-Oriented Eczema Measure (POEM) score, (g) an improved Dermatology Life Quality Index (DLQI) score; or (h) an improved Atopic Dermatitis Control Tool (ADCT).

[0018] In one embodiment, the EASI, IGA and / or PP-NRS score is improved by about 40-100%.

[0019] In one embodiment, the treatment comprises or provides: (a) an about >50% improvement in EASI score (EASI50); (b) an about >75% improvement in EASI score (EASI75); (c) an about >90% improvement in EASI score (EASI90); (d) an about >95% improvement in EASI score (EASI95); (e) an IGA score of 0 or 1; or (f) a Facial IGA score of 0 or 1.

[0020] In one embodiment, the treatment comprises or provides: (a) an about >50% improvement in EASI score (EASI50); (b) an about >75% improvement in EASI score (EASI75); (c) an about >90% improvement in EASI score (EASI90); (d) an about >95% improvement in EASI score (EASI95);(e) an IGA score of 0 or 1; or (f) a Facial IGA score of 0 or 1, by about two weeks after the final administration of the anti-TSLP antibody.

[0021] In some embodiments, the anti-TSLP antibody, or the antigen-binding portion thereof, is a humanized antibody or antigen-binding portion thereof.41625938262.3146588-005802

[0022] Additional therapeutic agent(s), e.g., additional anti-atopic dermatitis therapeutic agent(s), can be administered in a combination therapy involving the antibody, or antigenbinding portion thereof, in a pharmaceutical composition (e.g., such a composition comprising a pharmaceutically acceptable carrier or diluent and the antibody or antigen-binding portion thereof, in an effective amount); the antibody, or antigen-binding portion thereof, advantageously in a pharmaceutical (e.g., such a composition comprising a pharmaceutically carrier or diluent and the antibody or antigen-binding portion thereof, in an effective amount) is administered according to the dosing regimen.

[0023] In some embodiments, the method further includes administration of a therapeutic agent.

[0024] In one embodiment, the therapeutic agent is an anti-atopic dermatitis agent.

[0025] In one embodiment, the therapeutic agent is administered prior to, simultaneously or following the administration of the anti-TSLP antibody or antigen binding fragment thereof.

[0026] In some embodiments, the anti-atopic dermatitis drug is an anti-IL4 antibody, an anti-IL4R antibody, an anti-IL-13 antibody, an anti-IL13R antibody, an IL-5 antibody, and IL-5R antibody, an, IL-17 antibody, an IL-17R antibody, an IL-25 antibody, an IL-25R antibody, an IL-31 antibody, an IL-31R antibody, an IL-33 antibody, and IL-33R antibody, or combinations thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 illustrates the Phase 2a study design. The primary objective of the study was to evaluate the efficacy, safety, and tolerability of the anti-TSLP antibody as monotherapy in subjects with moderate to severe atopic dermatitis.

[0028] FIG. 2 illustrates a line graph showing the mean percent change from baseline in EASI score over time through 36 weeks, with vertical arrows indicating the last dose at Week 24 and 6 weeks post-dose timepoint.

[0029] FIG. 3 illustrates three line graphs showing the EASI50, EASI75, and EASI90 responder rates over time, with responder percentages on the y-axis and visit week on the x-axis.

[0030] FIG. 4 illustrates a line graph showing the mean percent change from baseline in IGA score over time, demonstrating progressive improvement during treatment and decline during follow-up.51625938262.3146588-005802

[0031] FIG. 5 illustrates the percentage of patients achieving IGA treatment success (IGA score of 0 or 1) over time through 36 weeks, with vertical arrows indicating the last dose at Week 24 and 6 weeks post-dose timepoint.

[0032] FIG. 6 illustrates a line graph showing the percent change in Peak Pruritus Numerical Rating Scale (PP-NRS) score over time, with vertical arrows indicating the last dose at Week 24 and 6 weeks post-dose timepoint.

[0033] FIG. 7 is a chart describing the baseline disease characteristics and treatment history for the subjects enrolled in the Phase 2a clinical trial. Fourteen (63.6%) participants had prior medication before screening, all of whom used corticosteroids for their dermatological conditions. As for systemic treatment for atopic dermatitis, 3 (13.6%) participants used other dermatological preparations, including 2 (9.1%) who used ruxolitinib phosphate and 1 (4.5%) who used abrocitinib, dupilumab and tralokinumab. Two (9.1%) participants used immunosuppressants, including 1 (4.5%) who used baricitinib and 1 (4.5%) who used Upadacitinib. Duration of atopic dermatitis disease since diagnosis (months) = (date of first dose - date of first diagnosis + l) / 30.4375. The baseline PP-NRS score is based on the average of daily PP-NRS scores for the 7 days immediately preceding Day 1. In order to calculate an average for the score, the subject must have completed the diary for a minimum of 4 days during the previous 7 days.

[0034] FIG. 8 illustrates the anti-TSLP antibody exposure and efficacy time profile. The results demonstrated sustained clinical response after last dose. A time lag in efficacy response relative to exposure was observed both while the drug was onboard and after the last dose.

[0035] FIGs. 9A-9B illustrates the anti-TSLP antibody improvement in efficacy measures (Week 26, N=7). FIG. 9A shows percent of patients with EASI 75%, EASI 90%, EASI 100% and IGA 0 / 1 at week 26. FIG. 9B shows the percent of patients achieving EASI75 or EASI90 week 0 to week 36.

[0036] FIG. 10 illustrates the Phase 2 study design, including the screening period (up to 30 days), the treatment period (24 weeks), and the follow-up period.DETAILED DESCRIPTION

[0037] The present disclosure provides compositions and methods for treating atopic dermatitis using an anti-TSLP monoclonal antibody. The approach utilizes a subcutaneous dosing regimen comprising weekly loading doses followed by biweekly monthly, or quarterly maintenance doses, offering a treatment for moderate to severe atopic dermatitis. The dosing61625938262.3146588-005802design allows for sustained clinical improvement with demonstrated efficacy in reducing disease severity as measured by EASI, IGA, and pruritus scores. The treatment shows a favorable safety profile with mostly mild adverse events and maintains efficacy for 6- 12 weeks after treatment discontinuation, providing a therapeutic option for patients with moderate to severe atopic dermatitis, such as those patients whose atopic dermatitis may be inadequately controlled with current treatments.

[0038] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0039] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, it will be understood that modifications and variations are encompassed within the spirit and scope of the instant disclosure. Preferred or advantageous methods and materials are now described.

[0041] Thymic stromal lymphopoietin (TSLP) protein is one of the molecules that mediate allergic reactions. TSLP belongs to the interleukin-2 (IL-2) cytokine family and has actions similar to IL-7. TSLP is mainly derived from the barrier surface of epithelial cells in skin, intestine, and lung tissues, and responds to danger signals by regulating type 2 inflammatory responses at mucosal barriers in allergic inflammation.

[0042] The protein acts on a variety of immune cells (e.g., dendritic cells) by forming complexes with the TSLP receptor (TSLPR) and IL-7 receptor on the cell surface to drive downstream helper T cell 2 (Th2) cytokine release. It also activates cells involved in non-Th2-driven inflammation and promotes the expression of inflammatory cytokines such as IL-4, IL-5, and IL- 13. Abnormally high TSLP protein expression is related to a variety of atopic diseases including asthma, atopic dermatitis, allergic rhinitis, eosinophilic esophagitis, and other diseases.71625938262.3146588-005802

[0043] Atopic dermatitis involves a complex interplay of inflammatory pathways with multiple cytokines and inflammatory and epithelial cells implicated, with atopic dermatitis lesions associated with underlying immune activation. Alarmins, which include TSLP, are endogenous, constitutively expressed chemotactic and immune activating peptides that are released following degranulation, cell injury or upon immune induction.

[0044] A common symptom of pruritis observed in atopic dermatitis can be attributed to TSLP signaling indirectly via the inflammatory cascade but also via direct activation by TSLP of a specific subset of sensory neurons expressing TSLPR and the ion-channel transient receptor potential ankyrin 1 (TRPA1). This validates targeting TSLP in atopic dermatitis therapies.

[0045] To ensure that the present disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0046] As used herein, the term “TSLP” refers to thymic stromal lymphopoietin, including its variants, isoforms, homologs, orthologs, and paralogs. For example, an antibody specific for a human TSLP protein may cross-react with TSLP proteins from other species, such as monkeys, or may be completely specific to human TSLP.

[0047] As used herein, the term “antibody” includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains thereof. Whole antibodies are glycoproteins comprising two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0048] The term “antigen-binding portion” of an antibody (or simply “antibody portion”), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a TSLP protein). It has been shown that the antigen-binding function 81625938262.3146588-005802of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F (ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment, which consists of a VH domain; (vi) an isolated complementarity determining region (CDR); and (viii) a nanobody, a heavy chain variable region containing a single variable domain and two constant domains. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0049] The terms “treat,” “treated,” “treating”, or “treatment” as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total, whether induction of or maintenance of), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects, or with clinically or therapeutically acceptable side effects, or without clinically or therapeutically unacceptable side effects (which may be to some extent subject-specific and are within the ambit of the skilled practitioner to assess). Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention 91625938262.3146588-005802of a disease may not mean complete foreclosure of any effect related to the diseases at any level but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable or acceptable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease and prolonging disease-free survival as compared to disease-free survival if not receiving treatment and prolonging disease-free survival as compared to disease-free survival if not receiving treatment.

[0050] The term “treatment” is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic conditions or disorder, and 2) and prophylactic / preventative measures. Those in need of treatment may include individuals already having a particular medical disorder as well as those who may ultimately acquire the disorder (i.e., those needing preventive measures).

[0051] The terms “therapeutically effective amount”, “effective dose,” “therapeutically effective dose”, “effective amount,” or the like refer to that amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Generally, the response is either amelioration of symptoms in a patient or a desired biological outcome (e.g., amelioration of symptoms of neuroinflammation). The effective amount can be determined as described herein.

[0052] The terms “administration of’ and or “administering” should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to the subject in need of treatment. Administration routes can be enteral, topical or parenteral. As such, administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intraarterial, intraorbital, intracardiac, intradermal, intraperitoneal, transdermal, subarachnoid, intraspinal, oral, sublingual, buccal, rectal, nasal administrations, as well infusion. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes, etc.

[0053] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans and non-human animals. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.101625938262.3146588-005802

[0054] As used herein, the term “pharmaceutical composition” refers to the combination of an active ingredient with a carrier, inert or active, making the composition especially suitable for therapeutic or diagnostic use in vitro, in vivo, or ex vivo.

[0055] As used herein, the terms “pharmaceutically acceptable” or “pharmacologically acceptable,” refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.

[0056] As used herein, the terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent”, “pharmaceutically acceptable carrier or diluent” or like terms, refer to any of the standard pharmaceutical carriers or diluents including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), glycerol, liquid polyethylene glycols, aprotic solvents such as dimethylsulfoxide, N-methylpyrrolidone and mixtures thereof, and various types of wetting agents, solubilizing agents, anti-oxidants, bulking agents, protein carriers such as albumins, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. Compositions of this disclosure that are “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent”, “pharmaceutically acceptable carrier or diluent” also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g. , Martin, Remington 's Pharmaceutical Sciences, 21st Ed., Mack Publ. Co., Easton, Pa. (2005), incorporated herein by reference in its entirety.

[0057] As used herein, the term “about” refers to a range that encompasses plus or minus 10% of a given value and plus or minus 1 week of a given time period.Clinical Studies

[0058] The disclosed anti-TSLP antibodies were the subject of several clinical trials to evaluate the efficacy, safety, tolerability, immunogenicity, pharmacokinetic (PK) profile, and activity of the anti-TSLP monoclonal antibodies after single and multiple doses in adult healthy volunteers (HVs) and patients with atopic dermatitis (AD). The anti-TSLP monoclonal antibody was administered via subcutaneous (SC) injection across all dosing regimens.

[0059] In a Single-Ascending Dose (SAD) Study in Healthy Volunteers (HVs), subjects received single SC administrations at doses of 120, 240, 480, and 780 mg as SC injections. Each dose level cohort included eight subjects (6 Active: 2 Placebo), totaling 32 subjects. In the Single-Dose Study in Patients with Atopic Dermatitis (AD), a single SC dose of 480 mg was administered as an SC injection. The cohort included a total of 5 atopic dermatitis patients 111625938262.3146588-005802(4 Active: 1 Placebo). In the Multiple -Ascending Dose (MAD) Study in Healthy Volunteers (HVs), subjects received weekly (Q7D) SC administrations of the anti-TSLP antibodies at doses of either 240 mg for 5 cycles or 480 mg for 3 cycles as SC injections weekly (Q7D). Each dose level cohort included eight subjects (6 Active: 2 Placebo). In an efficacy study, patients with moderate to severe atopic dermatitis were administered the anti-TSLP antibodies at 300 mg QW for weeks 1-4 and then 300 mg Q2W for weeks 5-24.

[0060] The primary objectives of the SAD and MAD studies were to evaluate the safety and tolerability of the administered anti-TSLP monoclonal antibody. The endpoints included assessing adverse events (AEs), clinical laboratory assessments, vital signs, electrocardiograms (ECGs), and physical examinations. The secondary objectives were to evaluate the pharmacokinetics (PK) of the administered anti-TSLP monoclonal antibody, with endpoints including Cmax, Tmax, ti / 2, AUCinf, and AUCiast. The study also aimed to evaluate the activity of the anti-TSLP monoclonal antibody in patients with moderate to severe atopic dermatitis over one dosing interval, with endpoints including 50% and 75% improvement from Day 1 in Eczema Area and Severity Index (EASI) scores. Additionally, the study aimed to evaluate the immunogenicity following administration of the anti-TSLP monoclonal antibody, with endpoints including assessing anti-drug antibodies (ADA). Additionally, pharmacodynamic (PD) biomarkers of the anti-TSLP monoclonal antibody target engagement, with endpoints including IL-4, IL-5, IL-13, IL-17, TARC / CCL-17, periostin, and IgE were assessed.

[0061] The results indicated that administration of the anti-TSLP monoclonal antibody was well-tolerated with favorable safety. The results suggested a low incidence of ADA following single and multiple dose administration. No serious TEAEs, >Grade 3 TEAEs, TEAEs leading to treatment interruption, or treatment-related TEAEs leading to death occurred. Following administration, the anti-TSLP monoclonal antibody exhibited a linear disposition over the dose range from 120 mg to 720 mg in the SAD cohort and dose proportionality was confirmed in the MAD cohort. A single SC dose administration of 480 mg in the SAD and atopic dermatitis patient cohorts exhibited nearly identical mean Cmax values. The ti / 2 following administration was approximately 25 days for subjects in the SAD and MAD cohorts. Results from the ADA assessment showed a low incidence of ADA following administration in both the SAD and MAD cohorts.

[0062] The primary end points for the efficacy study included a primary efficacy endpoint of the proportion of participants achieving EASI75 at Week 26. Additional efficacy outcomes included the proportion of participants achieving EASI50, EASI90, IGA 0 / 1, Facial IGA 0 / 1, and changes in PP-NRS scores. The pharmacokinetics (PK) and immunogenicity (ADA) of the 121625938262.3146588-005802anti-TSLP monoclonal antibody, as well as pharmacodynamic biomarkers, were also explored. The pharmacodynamic biomarkers including IL-4, IL-5, IL- 13, IL- 17, TARC / CCL-17, periostin, and IgE were measured to evaluate target engagement and biological activity.

[0063] The primary efficacy endpoint was achieved, with 94% of participants achieving EASI75 at Week 26. Additional efficacy outcomes showed that 100% of participants achieved EASI50, 65% achieved EASI90, 88% achieved IGA 0 / 1, and 88% achieved Facial IGA 0 / 1 at Week 26. The mean percent change from baseline in EASI score steadily improved at each visit, reaching 90% two weeks after the last dose (Week 26) and 95% at four weeks after the last dose (Week 28). The anti-TSLP monoclonal antibody was generally well-tolerated, with no serious treatment-emergent adverse events (TEAEs). The PK analysis showed that the anti-TSLP monoclonal antibody exhibited dose-proportional exposure and time-invariant clearance. The estimated terminal half-life was approximately 20 days. The occurrence of positive ADA was low and did not significantly impact the observed PK exposure.Methods of Treatment

[0064] In one embodiment, the present disclosure provides a method of treating atopic dermatitis in a subject comprising administering to the subject a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) antibody, the anti-TSLP antibody having: (a) a heavy chain variable region comprising a VH CDR1, VH CDR2 and VH CDR3 regions having an amino acid sequence selected from SEQ ID NOs: 1, 2 and 3; and (ii) a light chain variable region comprising a VL CDR1, VL CDR2 and VL CDR3 regions having an amino acid sequence selected from SEQ ID NOs: 5, 6 and 7.Anti-TSLP Monoclonal Antibodies

[0065] The invention pertains to anti-TSLP monoclonal antibodies with increased binding affinity to human TSLP and better blocking capacity on TSLP-TSLPR / IL7R interaction. The anti-TSLPantibody, or the antigen-binding portion thereof, specifically binds to human or cynomolgus TSLP with comparable, if not better, binding affinity as compared to previously described anti-TSLP antibodies, such as Tezepelumab. The antibody may also block human TSLP-TSLPR / IL7R interaction more effectively than prior art anti-TSLP antibodies. Preferred antibodies of the disclosure are humanized monoclonal antibodies. The anti-TSLP antibodies of the present invention are described in PCT / CN2020 / 113289, published as WO2021 / 043221, which is herein incorporated by reference.131625938262.3146588-005802

[0066] The amino acid sequence ID numbers of the heavy / light chain variable regions and the CDRs of the antibodies are summarized in Table 1 below. The heavy chain constant region for the antibodies may be a human IgGl heavy chain constant region having the amino acid sequence set forth in SEQ ID NO: 9, and the light chain constant region for the antibodies may be human kappa constant region having the amino acid sequence set forth in SEQ ID NO: 10.

[0067] Table 1: SEQ ID NOs for Anti-TSLP monoclonal antibody

[0068] In one embodiment, the anti-TSLP antibody includes a variable heavy region (VH) CDR1 having the amino acid sequence of SEQ ID NO: 1. In some embodiments, the disclosed of the anti-TSLP antibody, or the antigen-binding portion thereof, wherein the VH CDR1 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,141625938262.3146588-00580288%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 1.

[0069] In one embodiment, the anti-TSLP antibody includes a VH CDR2 having the amino acid sequence of SEQ ID NO:2. In some embodiments, the disclosed of the anti-TSLP antibody, or the anti gen -binding portion thereof, wherein the VH CDR2 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2.

[0070] In one embodiment, the anti-TSLP antibody includes a VH CDR3 having the amino acid sequence of SEQ ID NO:3. In some embodiments, the VH CDR3 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3.

[0071] In one embodiment, the anti-TSLP antibody includes a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO:4. In some embodiments, the VH includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 4.

[0072] In one embodiment, the anti-TSLP antibody or the antigen-binding portion thereof includes a heavy chain constant region, linked to the heavy chain variable region. The heavy chain constant region may be human IgGl, IgG2 or IgG4 heavy chain constant region. In some embodiments, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the heavy chain constant region comprises the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 9.

[0073] In one embodiment, the anti-TSLP antibody includes an IgG heavy chain constant region.

[0074] In one embodiment, the anti-TSLP antibody includes a light chain variable region (VL) CDR1 having the amino acid sequence of SEQ ID NO: 5. In some embodiments, the VL CDR1 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 5.

[0075] In one embodiment, the anti-TSLP antibody includes a VL CDR2 having the amino acid sequence of SEQ ID NO:6. In some embodiments, the VL CDR2 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 6.151625938262.3146588-005802

[0076] In one embodiment, the anti-TSLP antibody includes a VL CDR3 having the amino acid sequence of SEQ ID NO:7. In some embodiments, the VL CDR3 includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 7.

[0077] In one embodiment, the anti-TSLP antibody includes a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:8. In some embodiments, the VL includes an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 8.

[0078] In one embodiment, the anti-TSLP antibody or the antigen-binding portion thereof includes a light chain constant region, linked to the light chain variable region. The light chain variable region may be human K constant region. In some embodiments, the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the light chain constant region comprises the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 10.

[0079] In one embodiment, the anti-TSLP antibody includes a kappa light chain constant region.

[0080] In one embodiment, the anti-TSLP antibody is humanized.Administration of the Antibodies

[0081] The administration of antibodies can be performed through various routes, including intravenous (IV), subcutaneous (SC), intramuscular (IM), and intradermal (ID) injections. The choice of administration route depends on factors such as the nature of the antibody, the target disease, and patient-specific considerations. In certain embodiments, the anti-TSLP antibodies are administered by subcutaneous administration, intravenous administration, intramuscular administration, or intradermal administration. In one embodiment, the anti-TSLP antibodies are administered by subcutaneous administration.

[0082] The anti-TSLP antibody can be administered daily, weekly, monthly, or every three months. In certain embodiments, the anti-TSLP antibody is administered once every seven (7) days. In other embodiments, the anti-TSLP antibody is administered once every fourteen (14) days. In further embodiments, the anti-TSLP antibody is administered once every 28 days. In some embodiments, the anti-TSLP antibody is administered once every 84 days.

[0083] In certain embodiments, the anti-TSLP antibody is administered at a dose ranging from 100 mg to 800 mg. In some embodiments, the anti-TSLP antibody is administered at a dose 161625938262.3146588-005802ranging from 120 mg to 720 mg. In some embodiments, the anti-TSLP antibody is administered at a dose ranging from 300 mg to 500 mg. In particular embodiments, the anti-TSLP antibody is administered at a dose is selected from 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 660 mg, and 720 mg. In one embodiment, the anti-TSLP antibody is administered at 120 mg. In one embodiment, the anti-TSLP antibody is administered at 240 mg. In one embodiment, the anti-TSLP antibody is administered at 300 mg. In one embodiment, the anti-TSLP antibody is administered at 480 mg. In one embodiment, the anti-TSLP antibody is administered at 600 mg. In one embodiment, the anti-TSLP antibody is administered at 720 mg. In some embodiments, the administration includes administration of 120 mg, 240 mg, 300 mg, 480 mg, 600 mg or 720 mg of the anti-TSLP antibody, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks. In one embodiment 300 mg of the anti-TSLP anti-body is administered once every four weeks. In one embodiment 300 mg of the anti-TSLP antibody is administered once every two weeks. In one embodiment 600 mg of the anti-TSLP anti-body is administered once every two weeks for two loading doses and thereafter 300 mg of the anti-TSLP antibody is administered once every two weeks.

[0084] These dosages are based on an average human weighing from 60 to 80 kg, e.g., about 70 kg, with it understood that these dosages also envision that some humans can weigh as little as 45 or 50 kg. With this in mind, the skilled practitioner can adjust dosing for human subjects who may weigh less than 45 kg (such as human children or pre-pubescent humans or little humans or humans of short stature) or non-human mammal subjects or patients; and likewise, the skilled practitioner can adjust dosing for human or non-human subjects that may weigh more than 80 kg.

[0085] The anti-TSLP antibody can be administered in as one or more loading doses followed by one or more maintenance doses. In one embodiment, the anti-TSLP antibody is administered at 300 mg once every 7 days for 4 weeks as a loading dose. In one embodiment, the anti-TSLP antibody is administered at 300 mg every 14 days or 2 weeks after the first 4 weeks of administration as maintenance doses. In one embodiment, the anti-TSLP antibody is administered at 300 mg every 28 days or 4 weeks after the first 4 weeks of administration as maintenance doses. In one embodiment, the anti-TSLP antibody is administered at 300 mg every 48 days or 8 weeks after the first 4 weeks of administration as maintenance doses. In one171625938262.3146588-005802embodiment, the anti-TSLP antibody is administered at 300 mg every 84 days or 12 weeks after the first 4 weeks of administration as maintenance doses.Effective Amount

[0086] The term “effective amount” refers to an amount of the antibody that is sufficient to achieve the desired therapeutic effect. The effective amount may vary depending on factors such as the severity of the disease, the patient's age, weight, and overall health, as well as the specific characteristics of the antibody. In certain embodiments, the effective amount of the anti-TSLP antibody is from about 100 mg to 800 mg. In other embodiments, the effective amount of anti-TSLP antibody is from about 120 mg to 720 mg. In other embodiments, the effective amount of the anti-TSLP antibody is from about 240 mg to 480 mg. In other embodiments the effective amount of the anti-TSLP antibody is from about 300 mg to 500 mg. In particular embodiments, the effective amount anti-TSLP antibodies is selected from 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 660 mg, and 720 mg. In one embodiment the effective amount of the anti-TSLP antibody is 120 mg. In one embodiment, the effective amount of the anti-TSLP antibody is 240 mg. In one embodiment, the effective amount of the anti-TSLP antibody is 300 mg. In one embodiment, the effective amount of the anti-TSLP antibody is 480 mg. In one embodiment, the effective amount of the anti-TSLP antibody is 720 mg. These dosages are based on an average human weighing from 60 to 80 kg, e.g., about 70 kg, with it understood that these dosages also envision that some humans can weigh as little as 45 or 50 kg. With this in mind, the skilled practitioner can adjust dosing for human subjects who may weigh less than 45 kg (such as human children or pre-pubescent humans or little humans or humans of short stature) or non-human mammal subjects or patients; and likewise, the skilled practitioner can adjust dosing for human or non-human subjects that may weigh more than 80 kg.Atopic Dermatitis Control Tool (ADCT)

[0087] The Atopic Dermatitis Control Tool (ADCT) is a tool developed to assist patients and the investigators in comprehensively and efficiently understanding their atopic dermatitis. Its six concise questions allow patients and investigators to evaluate the different dimensions of patient-perceived atopic dermatitis control. The questions include patient-reported ratings of eczema-related symptoms, the frequency of intense episodes of itching, the degree of bother caused by eczema, the number of nights spent having trouble falling or staying asleep due to181625938262.3146588-005802eczema, the impact of eczema on daily activities, and the effect of eczema on mood or emotions.

[0088] An improvement in the ADCT is demonstrated by a decrease in the score as compared to baseline. In certain embodiments, the ADCT is improved by 40-100% after treatment. In specific embodiments, the ADCT is improved by 75-100% after treatment. In another embodiment, the ADCT is improved by 90-100% after treatment. In one embodiment, the ADCT is improved by 50%. In one embodiment, the ADCT is improved by 51%. In one embodiment, the ADCT is improved by 52%. In one embodiment, the ADCT is improved by 53%. In one embodiment, the ADCT is improved by 54%. In one embodiment, the ADCT is improved by 55%. In one embodiment, the ADCT is improved by 56%. In one embodiment, the ADCT is improved by 57%. In one embodiment, the ADCT is improved by 58%. In one embodiment, the ADCT is improved by 59%. In one embodiment, the ADCT is improved by 60%. In one embodiment, the ADCT is improved by 61%. In one embodiment, the ADCT is improved by 62%. In one embodiment, the ADCT is improved by 63%. In one embodiment, the ADCT is improved by 64%. In one embodiment, the ADCT is improved by 65%. In one embodiment, the ADCT is improved by 66%. In one embodiment, the ADCT is improved by 67%. In one embodiment, the ADCT is improved by 68%. In one embodiment, the ADCT is improved by 69%. In one embodiment, the ADCT is improved by 70%. In one embodiment, the ADCT is improved by 71%. In one embodiment, the ADCT is improved by 72%. In one embodiment, the ADCT is improved by 73%. In one embodiment, the ADCT is improved by 74%. In one embodiment, the ADCT is improved by 75%. In one embodiment, the ADCT is improved by 76%. In one embodiment, the ADCT is improved by 77%. In one embodiment, the ADCT is improved by 78%. In one embodiment, the ADCT is improved by 79%. In one embodiment, the ADCT is improved by 80%. In one embodiment, the ADCT is improved by 81%. In one embodiment, the ADCT is improved by 82%. In one embodiment, the ADCT is improved by 83%. In one embodiment, the ADCT is improved by 84%. In one embodiment, the ADCT is improved by 85%. In one embodiment, the ADCT is improved by 86%. In one embodiment, the ADCT is improved by 87%. In one embodiment, the ADCT is improved by 88%. In one embodiment, the ADCT is improved by 89%. In one embodiment, the ADCT is improved by 90%. In one embodiment, the ADCT is improved by 91%. In one embodiment, the ADCT is improved by 92%. In one embodiment, the ADCT is improved by 93%. In one embodiment, the ADCT is improved by 94%. In one embodiment, the ADCT is improved by 95%. In one embodiment, the ADCT is improved by 96%. In one embodiment, the ADCT is improved by 97%. In one embodiment, the ADCT is improved by 98%. In one embodiment,191625938262.3146588-005802the ADCT is improved by 99%. In one embodiment, the ADCT is improved by 50%. In one embodiment, the ADCT is improved by 100%.

[0089] In certain embodiments, the ADCT is improved by 5 to 24 points after treatment. In another embodiment, the ADCT is improved by 15 to 20 points after treatment. In one embodiment, the ADCT is improved by 5 points. In one embodiment, the ADCT is improved by 6 points. In one embodiment, the ADCT is improved by 7 points. In one embodiment, the ADCT is improved by 8 points. In one embodiment, the ADCT is improved by 9 points. In one embodiment, the ADCT is improved by 10 points. In one embodiment, the ADCT is improved by 11 points. In one embodiment, the ADCT is improved by 12 points. In one embodiment, the ADCT is improved by 13 points. In one embodiment, the ADCT is improved by 14 points. In one embodiment, the ADCT is improved by 15 points. In one embodiment, the ADCT is improved by 16 points. In one embodiment, the ADCT is improved by 17 points. In one embodiment, the ADCT is improved by 18 points. In one embodiment, the ADCT is improved by 19 points. In one embodiment, the ADCT is improved by 20 points. In one embodiment, the ADCT is improved by 21 points. In one embodiment, the ADCT is improved by 22 points. In one embodiment, the ADCT is improved by 23 points. In one embodiment, the ADCT is improved by 24 points.Body Surface Area (BSA) Assessment

[0090] The total percentage of atopic dermatitis-affected Body Surface Area (BSA) measures the severity of atopic dermatitis (eczema). BSA is estimated by the investigator or designee using the handprint method, which estimates that the area of a participant’s full handprint (fingers and thumbs together, palmar surface) constitutes 1% of their total BSA. The overall BSA affected by atopic dermatitis will be evaluated (from 0% to 100%). Maximum possible percentage (number of handprints) for each area is: 10 for the head and neck, representing 10% of the total body area; 30 for the trunk, representing 30% of the total body area; 20 for the upper extremities, representing 20% of the total body area, and 40 for the lower extremities, representing 40% of the total body area.

[0091] An improvement in the BSA is demonstrated by a decrease in the score as compared to baseline. In certain embodiments, the BSA is improved by 50-100% after treatment. In specific embodiments, the BSA is improved by 75-100% after treatment. In another embodiment, the BSA is improved by 90-100% after treatment. In one embodiment, the BSA is improved by 50%. In one embodiment, the BSA is improved by 51%. In one embodiment, the BSA is improved by 52%. In one embodiment, the BSA is improved by 53%. In one embodiment, the 201625938262.3146588-005802BSA is improved by 54%. In one embodiment, the BSA is improved by 55%. In one embodiment, the BSA is improved by 56%. In one embodiment, the BSA is improved by 57%. In one embodiment, the BSA is improved by 58%. In one embodiment, the BSA is improved by 59%. In one embodiment, the BSA is improved by 60%. In one embodiment, the BSA is improved by 61%. In one embodiment, the BSA is improved by 62%. In one embodiment, the BSA is improved by 63%. In one embodiment, the BSA is improved by 64%. In one embodiment, the BSA is improved by 65%. In one embodiment, the BSA is improved by 66%. In one embodiment, the BSA is improved by 67%. In one embodiment, the BSA is improved by 68%. In one embodiment, the BSA is improved by 69%. In one embodiment, the BSA is improved by 70%. In one embodiment, the BSA is improved by 71%. In one embodiment, the BSA is improved by 72%. In one embodiment, the BSA is improved by 73%. In one embodiment, the BSA is improved by 74%. In one embodiment, the BSA is improved by 75%. In one embodiment, the BSA is improved by 76%. In one embodiment, the BSA is improved by 77%. In one embodiment, the BSA is improved by 78%. In one embodiment, the BSA is improved by 79%. In one embodiment, the BSA is improved by 80%. In one embodiment, the BSA is improved by 81%. In one embodiment, the BSA is improved by 82%. In one embodiment, the BSA is improved by 83%. In one embodiment, the BSA is improved by 84%. In one embodiment, the BSA is improved by 85%. In one embodiment, the BSA is improved by 86%. In one embodiment, the BSA is improved by 87%. In one embodiment, the BSA is improved by 88%. In one embodiment, the BSA is improved by 89%. In one embodiment, the BSA is improved by 90%. In one embodiment, the BSA is improved by 91%. In one embodiment, the BSA is improved by 92%. In one embodiment, the BSA is improved by 93%. In one embodiment, the BSA is improved by 94%. In one embodiment, the BSA is improved by 95%. In one embodiment, the BSA is improved by 96%. In one embodiment, the BSA is improved by 97%. In one embodiment, the BSA is improved by 98%. In one embodiment, the BSA is improved by 99%. In one embodiment, the BSA is improved by 50%. In one embodiment, the BSA is improved by 100%.Dermatology Life Quality Index (DLQI)

[0092] The Dermatology Life Quality Index (DLQI) is a validated questionnaire that consists of 10 items addressing the patient’s perception of the impact of their skin disease on different aspects of their health-related quality of life over the last week, such as dermatology-related211625938262.3146588-005802symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment.

[0093] An improvement in the DLQI is demonstrated by a decrease in the score as compared to baseline. In certain embodiments, the DLQI is improved by 50-100% after treatment. In specific embodiments, the DLQI is improved by 75-100% after treatment. In another embodiment, the DLQI is improved by 90-100% after treatment. In one embodiment, the DLQI is improved by 50%. In one embodiment, the DLQI is improved by 51%. In one embodiment, the DLQI is improved by 52%. In one embodiment, the DLQI is improved by 53%. In one embodiment, the DLQI is improved by 54%. In one embodiment, the DLQI is improved by 55%. In one embodiment, the DLQI is improved by 56%. In one embodiment, the DLQI is improved by 57%. In one embodiment, the DLQI is improved by 58%. In one embodiment, the DLQI is improved by 59%. In one embodiment, the DLQI is improved by 60%. In one embodiment, the DLQI is improved by 61%. In one embodiment, the DLQI is improved by 62%. In one embodiment, the DLQI is improved by 63%. In one embodiment, the DLQI is improved by 64%. In one embodiment, the DLQI is improved by 65%. In one embodiment, the DLQI is improved by 66%. In one embodiment, the DLQI is improved by 67%. In one embodiment, the DLQI is improved by 68%. In one embodiment, the DLQI is improved by 69%. In one embodiment, the DLQI is improved by 70%. In one embodiment, the DLQI is improved by 71%. In one embodiment, the DLQI is improved by 72%. In one embodiment, the DLQI is improved by 73%. In one embodiment, the DLQI is improved by 74%. In one embodiment, the DLQI is improved by 75%. In one embodiment, the DLQI is improved by 76%. In one embodiment, the DLQI is improved by 77%. In one embodiment, the DLQI is improved by 78%. In one embodiment, the DLQI is improved by 79%. In one embodiment, the DLQI is improved by 80%. In one embodiment, the DLQI is improved by 81%. In one embodiment, the DLQI is improved by 82%. In one embodiment, the DLQI is improved by 83%. In one embodiment, the DLQI is improved by 84%. In one embodiment, the DLQI is improved by 85%. In one embodiment, the DLQI is improved by 86%. In one embodiment, the DLQI is improved by 87%. In one embodiment, the DLQI is improved by 88%. In one embodiment, the DLQI is improved by 89%. In one embodiment, the DLQI is improved by 90%. In one embodiment, the DLQI is improved by 91%. In one embodiment, the DLQI is improved by 92%. In one embodiment, the DLQI is improved by 93%. In one embodiment, the DLQI is improved by 94%. In one embodiment, the DLQI is improved by 95%. In one embodiment, the DLQI is improved by 96%. In one embodiment, the DLQI is improved by 97%. In one embodiment, the DLQI is improved by 98%. In one embodiment, the DLQI is 221625938262.3146588-005802improved by 99%. In one embodiment, the DLQI is improved by 50%. In one embodiment, the DLQI is improved by 100%.

[0094] In certain embodiments, the DLQI is improved by 4 to 30 points after treatment. In one embodiment, the DLQI is improved by 15 to 30 points after treatment. In one embodiment, the DLQI is improved by 2 to 8 points after treatment. In one embodiment, the DLQI is improved by 4 to 8 points after treatment. In one embodiment, the DLQI is improved by 5 to 10 points after treatment. In one embodiment, the DLQI is improved by 10 to 20 points after treatment. In one embodiment, the DLQI is improved by 20 to 30 points after treatment. In one embodiment, the DLQI is improved by 25 to 30 points after treatment. In one embodiment, the DLQI is improved by 2 points. In one embodiment, the DLQI is improved by 3 points. In one embodiment, the DLQI is improved by 4 points. In one embodiment, the DLQI is improved by 5 points. In one embodiment, the DLQI is improved by 6 points. In one embodiment, the DLQI is improved by 7 points. In one embodiment, the DLQI is improved by 53%. In one embodiment, the DLQI is improved by 8 points. In one embodiment, the DLQI is improved by 9 points. In one embodiment, the DLQI is improved by 10 points. In one embodiment, the DLQI is improved by 11 points. In one embodiment, the DLQI is improved by 12 points. In one embodiment, the DLQI is improved by 13 points. In one embodiment, the DLQI is improved by 14 points. In one embodiment, the DLQI is improved by 15 points. In one embodiment, the DLQI is improved by 16 points. In one embodiment, the DLQI is improved by 17 points. In one embodiment, the DLQI is improved by 18 points. In one embodiment, the DLQI is improved by 19 points. In one embodiment, the DLQI is improved by 20 points. In one embodiment, the DLQI is improved by 21 points. In one embodiment, the DLQI is improved by 22 points. In one embodiment, the DLQI is improved by 23 points. In one embodiment, the DLQI is improved by 24 points. In one embodiment, the DLQI is improved by 25 points. In one embodiment, the DLQI is improved by 26 points. In one embodiment, the DLQI is improved by 1 points. In one embodiment, the DLQI is improved by 28 points. In one embodiment, the DLQI is improved by 29 points. In one embodiment, the DLQI is improved by 30 points.Eczema Area and Severity Index (EASI)

[0095] The Eczema Area and Severity Index (EASI) is a tool used to measure the extent (area) and severity of atopic dermatitis (eczema). The EASI score ranges from 0 to 72 and is calculated based on the severity of four clinical signs: erythema (redness), edema / papulation (swelling), excoriation (scratching), and lichenification (thickening of the skin). Each of these 231625938262.3146588-005802signs is scored on a scale of 0 to 3, and the scores are then multiplied by the area of the body affected. The EASI score is used to assess the efficacy of treatments for atopic dermatitis. An improvement in EASI score is demonstrated by a decrease in the score as compared to baseline. In certain embodiments, the EASI score is improved by 50-100% after treatment. In specific embodiments, the EASI score is improved by 75-100% after treatment. In another embodiment, the EASI score is improved by 90-100% after treatment. In one embodiment, the EASI score is improved by 50%. In one embodiment, the EASI score is improved by 51%. In one embodiment, the EASI score is improved by 52%. In one embodiment, the EASI score is improved by 53%. In one embodiment, the EASI score is improved by 54%. In one embodiment, the EASI score is improved by 55%. In one embodiment, the EASI score is improved by 56%. In one embodiment, the EASI score is improved by 57%. In one embodiment, the EASI score is improved by 58%. In one embodiment, the EASI score is improved by 59%. In one embodiment, the EASI score is improved by 60%. In one embodiment, the EASI score is improved by 61%. In one embodiment, the EASI score is improved by 62%. In one embodiment, the EASI score is improved by 63%. In one embodiment, the EASI score is improved by 64%. In one embodiment, the EASI score is improved by 65%. In one embodiment, the EASI score is improved by 66%. In one embodiment, the EASI score is improved by 67%. In one embodiment, the EASI score is improved by 68%. In one embodiment, the EASI score is improved by 69%. In one embodiment, the EASI score is improved by 70%. In one embodiment, the EASI score is improved by 71%. In one embodiment, the EASI score is improved by 72%. In one embodiment, the EASI score is improved by 73%. In one embodiment, the EASI score is improved by 74%. In one embodiment, the EASI score is improved by 75%. In one embodiment, the EASI score is improved by 76%. In one embodiment, the EASI score is improved by 77%. In one embodiment, the EASI score is improved by 78%. In one embodiment, the EASI score is improved by 79%. In one embodiment, the EASI score is improved by 80%. In one embodiment, the EASI score is improved by 81%. In one embodiment, the EASI score is improved by 82%. In one embodiment, the EASI score is improved by 83%. In one embodiment, the EASI score is improved by 84%. In one embodiment, the EASI score is improved by 85%. In one embodiment, the EASI score is improved by 86%. In one embodiment, the EASI score is improved by 87%. In one embodiment, the EASI score is improved by 88%. In one embodiment, the EASI score is improved by 89%. In one embodiment, the EASI score is improved by 90%. In one embodiment, the EASI score is improved by 91%. In one embodiment, the EASI score is 241625938262.3146588-005802improved by 92%. In one embodiment, the EASI score is improved by 93%. In one embodiment, the EASI score is improved by 94%. In one embodiment, the EASI score is improved by 95%. In one embodiment, the EASI score is improved by 96%. In one embodiment, the EASI score is improved by 97%. In one embodiment, the EASI score is improved by 98%. In one embodiment, the EASI score is improved by 99%. In one embodiment, the EASI score is improved by 50%. In one embodiment, the EASI score is improved by 100%.

[0096] EASI50 is an EASI score that is improved by at least 50% compared to baseline. EASI75 is an EASI score that is improved by at least 75% compared to baseline. EASI90 is an EASI score that is improved by at least 90% compared to baseline. In one embodiment, the EASI score improvement may be at least 50% (EASI50), at least 75% (EASI75), or at least 90% (EASI90). In one embodiment, treatment achieves an EASI50 response. In one embodiment, treatment achieves an EASI75 response. In one embodiment, treatment achieves an EASI90 response.

[0097] In certain embodiments, the EASI is improved by 2 to 72 points after treatment. In one embodiment, the EASI is improved by 2 to 10 points after treatment. In one embodiment, the EASI is improved by 10 to 20 points after treatment. In one embodiment, the EASI is improved by 20 to 30 points after treatment. In one embodiment, the EASI is improved by 30 to 40 points after treatment. In one embodiment, the EASI is improved by 40 to 50 points after treatment. In one embodiment, the EASI is improved by 50 to 60 points after treatment. In one embodiment, the EASI is improved by 60 to 72 points after treatment. In one embodiment, the EASI is improved by 2 points. In one embodiment, the EASI is improved by 3 points. In one embodiment, the EASI is improved by 4 points. In one embodiment, the EASI is improved by 5 points. In one embodiment, the EASI is improved by 6 points. In one embodiment, the EASI is improved by 7 points. In one embodiment, the EASI is improved by 53%. In one embodiment, the EASI is improved by 8 points. In one embodiment, the EASI is improved by 9 points. In one embodiment, the EASI is improved by 10 points. In one embodiment, the EASI is improved by 11 points. In one embodiment, the EASI is improved by 12 points. In one embodiment, the EASI is improved by 13 points. In one embodiment, the EASI is improved by 14 points. In one embodiment, the EASI is improved by 15 points. In one embodiment, the EASI is improved by 16 points. In one embodiment, the EASI is improved by 17 points. In one embodiment, the EASI is improved by 18 points. In one embodiment, the EASI is improved by 19 points. In one embodiment, the EASI is improved by 20 points. In one embodiment, the EASI is improved by 21 points. In one embodiment, the EASI is improved by 22 points. In one 251625938262.3146588-005802embodiment, the EASI is improved by 23 points. In one embodiment, the EASI is improved by 24 points. In one embodiment, the EASI is improved by 25 points. In one embodiment, the EASI is improved by 26 points. In one embodiment, the EASI is improved by 27 points. In one embodiment, the EASI is improved by 28 points. In one embodiment, the EASI is improved by 29 points. In one embodiment, the EASI is improved by 30 points. In one embodiment, the EASI is improved by 31 points. In one embodiment, the EASI is improved by 32 points. In one embodiment, the EASI is improved by 33 points. In one embodiment, the EASI is improved by 34 points. In one embodiment, the EASI is improved by 35 points. In one embodiment, the EASI is improved by 36 points. In one embodiment, the EASI is improved by 37 points. In one embodiment, the EASI is improved by 38 points. In one embodiment, the EASI is improved by 39 points. In one embodiment, the EASI is improved by 40 points. In one embodiment, the EASI is improved by 41 points. In one embodiment, the EASI is improved by 42 points. In one embodiment, the EASI is improved by 43 points. In one embodiment, the EASI is improved by 44 points. In one embodiment, the EASI is improved by 45 points. In one embodiment, the EASI is improved by 46 points. In one embodiment, the EASI is improved by 47 points. In one embodiment, the EASI is improved by 48 points. In one embodiment, the EASI is improved by 49 points. In one embodiment, the EASI is improved by 50 points. In one embodiment, the EASI is improved by 51 points. In one embodiment, the EASI is improved by 52 points. In one embodiment, the EASI is improved by 53 points. In one embodiment, the EASI is improved by 54 points. In one embodiment, the EASI is improved by 55 points. In one embodiment, the EASI is improved by 56 points. In one embodiment, the EASI is improved by 57 points. In one embodiment, the EASI is improved by 58 points. In one embodiment, the EASI is improved by 59 points. In one embodiment, the EASI is improved by 60 points. In one embodiment, the EASI is improved by 61 points. In one embodiment, the EASI is improved by 62 points. In one embodiment, the EASI is improved by 63 points. In one embodiment, the EASI is improved by 64 points. In one embodiment, the EASI is improved by 65 points. In one embodiment, the EASI is improved by 66 points. In one embodiment, the EASI is improved by 67 points. In one embodiment, the EASI is improved by 68 points. In one embodiment, the EASI is improved by 69 points. In one embodiment, the EASI is improved by 70 points. In one embodiment, the EASI is improved by 71 points. In one embodiment, the EASI is improved by 72 points.Investigator Global Assessment (IGA)

[0098] The Investigator Global Assessment (IGA), or validated IGA (vIGA), is a scale used to assess the overall severity of atopic dermatitis. The IGA score ranges from 0 to 4, with 0261625938262.3146588-005802indicating clear skin, 1 indicating almost clear, 2 indicating mild disease, 3 indicating moderate disease, and 4 indicating severe disease. The IGA score is used to evaluate the efficacy of treatments for atopic dermatitis by assessing the overall improvement in the severity of the disease. Facial IGA is an IGA assessment limited to the skin of the facial region. An improvement in an IGA score or facial IGA score is demonstrated by a decrease in the score as compared to baseline. In certain embodiments, treatment results in an IGA score of 0 or 1. In certain embodiments, treatment results a facial IGA score of 0 or 1.

[0099] In certain embodiments, the IGA score is improved by 50-100% after treatment. In specific embodiments, the IGA score is improved by 75-100% after treatment. In another embodiment, the IGA score is improved by 90-100% after treatment. In one embodiment, the IGA score is improved by 50%. In one embodiment, the IGA score is improved by 51%. In one embodiment, the IGA score is improved by 52%. In one embodiment, the IGA score is improved by 53%. In one embodiment, the IGA score is improved by 54%. In one embodiment, the IGA score is improved by 55%. In one embodiment, the IGA score is improved by 56%. In one embodiment, the IGA score is improved by 57%. In one embodiment, the IGA score is improved by 58%. In one embodiment, the IGA score is improved by 59%. In one embodiment, the IGA score is improved by 60%. In one embodiment, the IGA score is improved by 61%. In one embodiment, the IGA score is improved by 62%. In one embodiment, the IGA score is improved by 63%. In one embodiment, the IGA score is improved by 64%. In one embodiment, the IGA score is improved by 65%. In one embodiment, the IGA score is improved by 66%. In one embodiment, the IGA score is improved by 67%. In one embodiment, the IGA score is improved by 68%. In one embodiment, the IGA score is improved by 69%. In one embodiment, the IGA score is improved by 70%. In one embodiment, the IGA score is improved by 71%. In one embodiment, the IGA score is improved by 72%. In one embodiment, the IGA score is improved by 73%. In one embodiment, the IGA score is improved by 74%. In one embodiment, the IGA score is improved by 75%. In one embodiment, the IGA score is improved by 76%. In one embodiment, the IGA score is improved by 77%. In one embodiment, the IGA score is improved by 78%. In one embodiment, the IGA score is improved by 79%. In one embodiment, the IGA score is improved by 80%. In one embodiment, the IGA score is improved by 81%. In one embodiment, the IGA score is improved by 82%. In one embodiment, the IGA score is improved by 83%. In one embodiment, the IGA score is improved by 84%. In one embodiment, the IGA score is improved by 85%. In one embodiment, the IGA score is improved by 86%. In one embodiment, the IGA score is improved by 87%. In one embodiment, the IGA score is improved by 88%. In one embodiment, the IGA score is improved by 89%. In one embodiment,271625938262.3146588-005802the IGA score is improved by 90%. In one embodiment, the IGA score is improved by 91%. In one embodiment, the IGA score is improved by 92%. In one embodiment, the IGA score is improved by 93%. In one embodiment, the IGA score is improved by 94%. In one embodiment, the IGA score is improved by 95%. In one embodiment, the IGA score is improved by 96%. In one embodiment, the IGA score is improved by 97%. In one embodiment, the IGA score is improved by 98%. In one embodiment, the IGA score is improved by 99%. In one embodiment, the IGA score is improved by 100%.

[0100] In certain embodiments, the IGA is improved by 1 to 4 points after treatment. In one embodiment, the IGA is improved by 1 point. In one embodiment, the IGA is improved by 2 points. In one embodiment, the IGA is improved by 3 points. In one embodiment, the IGA is improved by 4 points.

[0101] In certain embodiments, the facial IGA score is improved by 50-100% after treatment. In specific embodiments, the facial IGA score is improved by 75-100% after treatment. In another embodiment, the facial IGA score is improved by 90-100% after treatment. In one embodiment, the facial IGA score is improved by 50%. In one embodiment, the facial IGA score is improved by 51%. In one embodiment, the facial IGA score is improved by 52%. In one embodiment, the facial IGA score is improved by 53%. In one embodiment, the facial IGA score is improved by 54%. In one embodiment, the facial IGA score is improved by 55%. In one embodiment, the facial IGA score is improved by 56%. In one embodiment, the facial IGA score is improved by 57%. In one embodiment, the facial IGA score is improved by 58%. In one embodiment, the facial IGA score is improved by 59%. In one embodiment, the facial IGA score is improved by 60%. In one embodiment, the facial IGA score is improved by 61%. In one embodiment, the facial IGA score is improved by 62%. In one embodiment, the facial IGA score is improved by 63%. In one embodiment, the facial IGA score is improved by 64%. In one embodiment, the facial IGA score is improved by 65%. In one embodiment, the facial IGA score is improved by 66%. In one embodiment, the facial IGA score is improved by 67%. In one embodiment, the facial IGA score is improved by 68%. In one embodiment, the facial IGA score is improved by 69%. In one embodiment, the facial IGA score is improved by 70%. In one embodiment, the facial IGA score is improved by 71%. In one embodiment, the facial IGA score is improved by 72%. In one embodiment, the facial IGA score is improved by 73%. In one embodiment, the facial IGA score is improved by 74%. In one embodiment, the facial IGA score is improved by 75%. In one embodiment, the facial IGA score is improved by 76%. In one embodiment, the facial IGA score is improved by 77%. In one embodiment, the facial IGA score is improved by 78%. In one embodiment, the facial IGA score is improved by 79%. In 281625938262.3146588-005802one embodiment, the facial IGA score is improved by 80%. In one embodiment, the facial IGA score is improved by 81%. In one embodiment, the facial IGA score is improved by 82%. In one embodiment, the facial IGA score is improved by 83%. In one embodiment, the facial IGA score is improved by 84%. In one embodiment, the facial IGA score is improved by 85%. In one embodiment, the facial IGA score is improved by 86%. In one embodiment, the facial IGA score is improved by 87%. In one embodiment, the facial IGA score is improved by 88%. In one embodiment, the facial IGA score is improved by 89%. In one embodiment, the facial IGA score is improved by 90%. In one embodiment, the facial IGA score is improved by 91%. In one embodiment, the facial IGA score is improved by 92%. In one embodiment, the facial IGA score is improved by 93%. In one embodiment, the facial IGA score is improved by 94%. In one embodiment, the facial IGA score is improved by 95%. In one embodiment, the facial IGA score is improved by 96%. In one embodiment, the facial IGA score is improved by 97%. In one embodiment, the facial IGA score is improved by 98%. In one embodiment, the facial IGA score is improved by 99%. In one embodiment, the facial IGA score is improved by 100%.

[0102] In certain embodiments, the facial IGA is improved by 1 to 4 points after treatment. In one embodiment, the facial IGA is improved by 1 point. In one embodiment, the facial IGA is improved by 2 points. In one embodiment, the facial IGA is improved by 3 points. In one embodiment, the facial IGA is improved by 4 points.

[0103] IGA Treatment Success (IGA-TS) is defined as an IGA score of 0 or 1 with > 2 grade improvement from baseline. In certain embodiments, treatment results in a positive IGA-TS score. In one embodiment, IGA-TS score improvement may be a positive IGA-TS score. In one embodiment, treatment achieves an IGA-TS response.Patient-Oriented Eczema Measure (POEM)

[0104] The Patient-Oriented Eczema Measure (POEM) is a validated questionnaire used to assess disease symptoms in atopic eczema patients. It consists of 7 items, each addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and dryness).

[0105] An improvement in the POEM score is demonstrated as a decrease in the POEM score as compared to baseline. In certain embodiments, the POEM score is improved by 30-100% after treatment. In specific embodiments, the POEM score is improved by 40-80% after treatment. In another embodiment, the POEM score is improved by 40-50% after treatment. In one embodiment, the POEM score is improved by 30%. In one embodiment, the POEM score is improved by 31%. In one embodiment, the POEM score is improved by 32%. In one embodiment, the POEM score is improved by 33%. In one embodiment, the POEM score is 291625938262.3146588-005802improved by 34%. In one embodiment, the POEM score is improved by 35%. In one embodiment, the POEM score is improved by 36%. In one embodiment, the POEM score is improved by 37%. In one embodiment, the POEM score is improved by 38%. In one embodiment, the POEM score is improved by 39%. In one embodiment, the POEM score is improved by 40%. In one embodiment, the POEM score is improved by 41%. In one embodiment, the POEM score is improved by 42%. In one embodiment, the POEM score is improved by 43%. In one embodiment, the POEM score is improved by 44%. In one embodiment, the POEM score is improved by 45%. In one embodiment, the POEM score is improved by 46%. In one embodiment, the POEM score is improved by 47%. In one embodiment, the POEM score is improved by 49%. In one embodiment, the POEM score is improved by 50%. In one embodiment, the POEM score is improved by 51%. In one embodiment, the POEM score is improved by 52%. In one embodiment, the POEM score is improved by 53%. In one embodiment, the POEM score is improved by 54%. In one embodiment, the POEM score is improved by 55%. In one embodiment, the POEM score is improved by 56%. In one embodiment, the POEM score is improved by 57%. In one embodiment, the POEM score is improved by 58%. In one embodiment, the POEM score is improved by 59%. In one embodiment, the POEM score is improved by 60%. In one embodiment, the POEM score is improved by 61%. In one embodiment, the POEM score is improved by 62%. In one embodiment, the POEM score is improved by 63%. In one embodiment, the POEM score is improved by 64%. In one embodiment, the POEM score is improved by 65%. In one embodiment, the POEM score is improved by 66%. In one embodiment, the POEM score is improved by 67%. In one embodiment, the POEM score is improved by 68%. In one embodiment, the POEM score is improved by 69%. In one embodiment, the POEM score is improved by 70%. In one embodiment, the POEM score is improved by 71%. In one embodiment, the POEM score is improved by 72%. In one embodiment, the POEM score is improved by 73%. In one embodiment, the POEM score is improved by 74%. In one embodiment, the POEM score is improved by 75%. In one embodiment, the POEM score is improved by 76%. In one embodiment, the POEM score is improved by 77%. In one embodiment, the POEM score is improved by 78%. In one embodiment, the POEM score is improved by 79%. In one embodiment, the POEM score is improved by 80%. In one embodiment, the POEM score is improved by 81%. In one embodiment, the POEM score is improved by 82%. In one embodiment, the POEM score is improved by 83%. In one embodiment, the POEM score is improved by 84%. In one embodiment, the POEM score is improved by 85%. In one embodiment, the POEM score is 1625938262.3146588-005802improved by 86%. In one embodiment, the POEM score is improved by 87%. In one embodiment, the POEM score is improved by 88%. In one embodiment, the POEM score is improved by 89%. In one embodiment, the POEM score is improved by 90%. In one embodiment, the POEM score is improved by 91%. In one embodiment, the POEM score is improved by 92%. In one embodiment, the POEM score is improved by 93%. In one embodiment, the POEM score is improved by 94%. In one embodiment, the POEM score is improved by 95%. In one embodiment, the POEM score is improved by 96%. In one embodiment, the POEM score is improved by 97%. In one embodiment, the POEM score is improved by 98%. In one embodiment, the POEM score is improved by 99%. In one embodiment, the POEM score is improved by 50%. In one embodiment, the POEM score is improved by 100%.

[0106] In certain embodiments, the POEM is improved by 4 to 28 points after treatment. In one embodiment, the POEM is improved by 15 to 28 points after treatment. In one embodiment, the POEM is improved by 2 to 8 points after treatment. In one embodiment, the POEM is improved by 4 to 8 points after treatment. In one embodiment, the POEM is improved by 5 to 10 points after treatment. In one embodiment, the POEM is improved by 10 to 20 points after treatment. In one embodiment, the POEM is improved by 20 to 28 points after treatment. In one embodiment, the POEM is improved by 25 to 28 points after treatment. In one embodiment, the POEM is improved by 2 points. In one embodiment, the POEM is improved by 3 points. In one embodiment, the POEM is improved by 4 points. In one embodiment, the POEM is improved by 5 points. In one embodiment, the POEM is improved by 6 points. In one embodiment, the POEM is improved by 7 points. In one embodiment, the POEM is improved by 53%. In one embodiment, the POEM is improved by 8 points. In one embodiment, the POEM is improved by 9 points. In one embodiment, the POEM is improved by 10 points. In one embodiment, the POEM is improved by 11 points. In one embodiment, the POEM is improved by 12 points. In one embodiment, the POEM is improved by 13 points. In one embodiment, the POEM is improved by 14 points. In one embodiment, the POEM is improved by 15 points. In one embodiment, the POEM is improved by 16 points. In one embodiment, the POEM is improved by 17 points. In one embodiment, the POEM is improved by 18 points. In one embodiment, the POEM is improved by 19 points. In one embodiment, the POEM is improved by 20 points. In one embodiment, the POEM is improved by 21 points. In one embodiment, the POEM is improved by 22 points. In one embodiment, the POEM is improved by 23 points. In one embodiment, the POEM is improved by 24 points. In one embodiment, the POEM is improved by 25 points. In one embodiment, the POEM is improved by 26 points.311625938262.3146588-005802In one embodiment, the POEM is improved by 1 points. In one embodiment, the POEM is improved by 28 points.Peak Pruritus Numerical Rating Scale (PP-NRS)

[0107] The Peak Pruritus Numerical Rating Scale (PP-NRS) is a tool used to measure the intensity of itch (pruritus) in patients with atopic dermatitis. The PP-NRS score ranges from 0 to 10, with 0 indicating no itch and 10 indicating the worst itch imaginable. Patients are asked to rate their peak itch intensity over the past 24 hours. The PP-NRS score is used to assess the efficacy of treatments for atopic dermatitis by measuring the reduction in itch intensity. An improvement in PP-NRS score is demonstrated as a decrease in the PP-NRS score as compared to baseline. In certain embodiments, the PP-NRS score is improved by 30-100% after treatment. In specific embodiments, the PP-NRS score is improved by 40-80% after treatment. In another embodiment, the PP-NRS score is improved by 40-50% after treatment. In one embodiment, the PP-NRS score is improved by 30%. In one embodiment, the PP-NRS score is improved by 31%. In one embodiment, the PP-NRS score is improved by 32%. In one embodiment, the PP-NRS score is improved by 33%. In one embodiment, the PP-NRS score is improved by 34%. In one embodiment, the PP-NRS score is improved by 35%. In one embodiment, the PP-NRS score is improved by 36%. In one embodiment, the PP-NRS score is improved by 37%. In one embodiment, the PP-NRS score is improved by 38%. In one embodiment, the PP-NRS score is improved by 39%. In one embodiment, the PP-NRS score is improved by 40%. In one embodiment, the PP-NRS score is improved by 41%. In one embodiment, the PP-NRS score is improved by 42%. In one embodiment, the PP-NRS score is improved by 43%. In one embodiment, the PP-NRS score is improved by 44%. In one embodiment, the PP-NRS score is improved by 45%. In one embodiment, the PP-NRS score is improved by 46%. In one embodiment, the PP-NRS score is improved by 47%. In one embodiment, the PP-NRS score is improved by 49%. In one embodiment, the PP-NRS score is improved by 50%. In one embodiment, the PP-NRS score is improved by 51%. In one embodiment, the PP-NRS score is improved by 52%. In one embodiment, the PP-NRS score is improved by 53%. In one embodiment, the PP-NRS score is improved by 54%. In one embodiment, the PP-NRS score is improved by 55%. In one embodiment, the PP-NRS score is improved by 56%. In one embodiment, the PP-NRS score is improved by 57%. In one embodiment, the PP-NRS score is improved by 58%. In one embodiment, the PP-NRS score is improved by 59%. In one embodiment, the PP-NRS score is improved by 60%. In one embodiment, the PP-NRS score is improved by 61%. In one embodiment, the PP-NRS score 321625938262.3146588-005802is improved by 62%. In one embodiment, the PP-NRS score is improved by 63%. In one embodiment, the PP-NRS score is improved by 64%. In one embodiment, the PP-NRS score is improved by 65%. In one embodiment, the PP-NRS score is improved by 66%. In one embodiment, the PP-NRS score is improved by 67%. In one embodiment, the PP-NRS score is improved by 68%. In one embodiment, the PP-NRS score is improved by 69%. In one embodiment, the PP-NRS score is improved by 70%. In one embodiment, the PP-NRS score is improved by 71%. In one embodiment, the PP-NRS score is improved by 72%. In one embodiment, the PP-NRS score is improved by 73%. In one embodiment, the PP-NRS score is improved by 74%. In one embodiment, the PP-NRS score is improved by 75%. In one embodiment, the PP-NRS score is improved by 76%. In one embodiment, the PP-NRS score is improved by 77%. In one embodiment, the PP-NRS score is improved by 78%. In one embodiment, the PP-NRS score is improved by 79%. In one embodiment, the PP-NRS score is improved by 80%. In one embodiment, the PP-NRS score is improved by 81%. In one embodiment, the PP-NRS score is improved by 82%. In one embodiment, the PP-NRS score is improved by 83%. In one embodiment, the PP-NRS score is improved by 84%. In one embodiment, the PP-NRS score is improved by 85%. In one embodiment, the PP-NRS score is improved by 86%. In one embodiment, the PP-NRS score is improved by 87%. In one embodiment, the PP-NRS score is improved by 88%. In one embodiment, the PP-NRS score is improved by 89%. In one embodiment, the PP-NRS score is improved by 90%. In one embodiment, the PP-NRS score is improved by 91%. In one embodiment, the PP-NRS score is improved by 92%. In one embodiment, the PP-NRS score is improved by 93%. In one embodiment, the PP-NRS score is improved by 94%. In one embodiment, the PP-NRS score is improved by 95%. In one embodiment, the PP-NRS score is improved by 96%. In one embodiment, the PP-NRS score is improved by 97%. In one embodiment, the PP-NRS score is improved by 98%. In one embodiment, the PP-NRS score is improved by 99%. In one embodiment, the PP-NRS score is improved by 50%. In one embodiment, the PP-NRS score is improved by 100%.

[0108] In certain embodiments, the PP-NRS is improved by 4 to 10 points after treatment. In one embodiment, the PP-NRS is improved by 6 to 100 points after treatment. In one embodiment, the PP-NRS is improved by 4 to 8 points after treatment. In one embodiment, the PP-NRS is improved by 8 to 10 points after treatment. In one embodiment, the PP-NRS is improved by 2 points. In one embodiment, the PP-NRS is improved by 3 points. In one embodiment, the PP-NRS is improved by 4 points. In one embodiment, the PP-NRS is improved by 5 points. In one embodiment, the PP-NRS is improved by 6 points. In one 331625938262.3146588-005802embodiment, the PP-NRS is improved by 7 points. In one embodiment, the PP-NRS is improved by 53%. In one embodiment, the PP-NRS is improved by 8 points. In one embodiment, the PP-NRS is improved by 9 points. In one embodiment, the PP-NRS is improved by 10 points.SCORing Atopic Dermatitis (SCORAD) Assessment

[0109] SCORAD stands for SCORing Atopic Dermatitis, and is a validated tool to evaluate the extent and severity of atopic dermatitis lesions, along with subjective symptoms. The assessment is based on the condition of the disease at the time of evaluation, and not in relation to the condition at a previous visit. The assessment consists of 3 components: A = extent or affected body surface area, B = severity, and C = subjective symptoms.

[0110] The extent of atopic dermatitis is assessed as an area score between 0 and 104 (assigned as “A” in the overall SCORAD calculation). The severity of 6 specific symptoms of atopic dermatitis (redness, swelling, oozing / crusting, excoriation, skin thickening / lichenification, dryness) is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation). Subjective assessment of itch and sleeplessness based on the average of the last 3 days / nights is recorded for each symptom by the patient or relative on a 10-cm visual analog scale, where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is assigned as “C” in the overall SCORAD calculation. The SCORAD is calculated as: A / 5 + 7B / 2 + C.[oni] An improvement in the SCORAD score is demonstrated as a decrease in the SCORAD score as compared to baseline. In certain embodiments, the SCORAD score is improved by 30-100% after treatment. In specific embodiments, the SCORAD score is improved by 40-80% after treatment. In another embodiment, the SCORAD score is improved by 40-50% after treatment. In one embodiment, the SCORAD score is improved by 30%. In one embodiment, the SCORAD score is improved by 31%. In one embodiment, the SCORAD score is improved by 32%. In one embodiment, the SCORAD score is improved by 33%. In one embodiment, the SCORAD score is improved by 34%. In one embodiment, the SCORAD score is improved by 35%. In one embodiment, the SCORAD score is improved by 36%. In one embodiment, the SCORAD score is improved by 37%. In one embodiment, the SCORAD score is improved by 38%. In one embodiment, the SCORAD score is improved by 39%. In one embodiment, the SCORAD score is improved by 40%. In one embodiment, the SCORAD score is improved by 41%. In one embodiment, the SCORAD score is improved by 42%. In one embodiment, the 341625938262.3146588-005802SCORAD score is improved by 43%. In one embodiment, the SCORAD score is improved by 44%. In one embodiment, the SCORAD score is improved by 45%. In one embodiment, the SCORAD score is improved by 46%. In one embodiment, the SCORAD score is improved by 47%. In one embodiment, the SCORAD score is improved by 49%. In one embodiment, the SCORAD score is improved by 50%. In one embodiment, the SCORAD score is improved by 51%. In one embodiment, the SCORAD score is improved by 52%. In one embodiment, the SCORAD score is improved by 53%. In one embodiment, the SCORAD score is improved by 54%. In one embodiment, the SCORAD score is improved by 55%. In one embodiment, the SCORAD score is improved by 56%. In one embodiment, the SCORAD score is improved by 57%. In one embodiment, the SCORAD score is improved by 58%. In one embodiment, the SCORAD score is improved by 59%. In one embodiment, the SCORAD score is improved by 60%. In one embodiment, the SCORAD score is improved by 61%. In one embodiment, the SCORAD score is improved by 62%. In one embodiment, the SCORAD score is improved by 63%. In one embodiment, the SCORAD score is improved by 64%. In one embodiment, the SCORAD score is improved by 65%. In one embodiment, the SCORAD score is improved by 66%. In one embodiment, the SCORAD score is improved by 67%. In one embodiment, the SCORAD score is improved by 68%. In one embodiment, the SCORAD score is improved by 69%. In one embodiment, the SCORAD score is improved by 70%. In one embodiment, the SCORAD score is improved by 71%. In one embodiment, the SCORAD score is improved by 72%. In one embodiment, the SCORAD score is improved by 73%. In one embodiment, the SCORAD score is improved by 74%. In one embodiment, the SCORAD score is improved by 75%. In one embodiment, the SCORAD score is improved by 76%. In one embodiment, the SCORAD score is improved by 77%. In one embodiment, the SCORAD score is improved by 78%. In one embodiment, the SCORAD score is improved by 79%. In one embodiment, the SCORAD score is improved by 80%. In one embodiment, the SCORAD score is improved by 81%. In one embodiment, the SCORAD score is improved by 82%. In one embodiment, the SCORAD score is improved by 83%. In one embodiment, the SCORAD score is improved by 84%. In one embodiment, the SCORAD score is improved by 85%. In one embodiment, the SCORAD score is improved by 86%. In one embodiment, the SCORAD score is improved by 87%. In one embodiment, the SCORAD score is improved by 88%. In one embodiment, the SCORAD score is improved by 89%. In one embodiment, the SCORAD score is improved by 90%. In one embodiment, the SCORAD score is improved by 91%. In one embodiment, the SCORAD score is improved by 92%. In one embodiment, the SCORAD score is improved by 93%. In one embodiment, the SCORAD score is improved by 94%. In one embodiment, the 351625938262.3146588-005802SCORAD score is improved by 95%. In one embodiment, the SCORAD score is improved by 96%. In one embodiment, the SCORAD score is improved by 97%. In one embodiment, the SCORAD score is improved by 98%. In one embodiment, the SCORAD score is improved by 99%. In one embodiment, the SCORAD score is improved by 50%. In one embodiment, the SCORAD score is improved by 100%.Pharmacokinetics and Pharmacodynamics

[0112] Pharmacokinetics (PK) refers to the study of the absorption, distribution, metabolism, and excretion of drugs. The PK profile of the anti-TSLP monoclonal antibody was evaluated by measuring parameters such as Cmax (maximum serum concentration), Tmax (time to reach Cmax), tl / 2 (half-life), AUCinf (area under the concentration-time curve from time zero to infinity), and AUCiast (area under the concentration-time curve from time zero to the last measurable concentration). The results indicated that the anti-TSLP monoclonal antibody exhibited a linear disposition over the dose range studied, with a half-life of approximately 25 days.

[0113] Pharmacodynamics (PD) refers to the study of the biochemical and physiological effects of drugs and their mechanisms of action. PD biomarkers such as IL-4, IL-5, IL-13, IL- 17, TARC / CCL-17, periostin, and IgE were measured to evaluate the target engagement and biological activity of the anti-TSLP monoclonal antibody. The results provided insights into the antibody's mechanism of action and its potential therapeutic effects in patients with atopic dermatitis. The level of the PD biomarkers may be increased or decreased as a result of treatment with the anti-TSLP antibodies. In one embodiment, treatment with the anti-TSLP antibodies results in an increase in the level of one or more of IL-4, IL-5, IL-13, IL-17, TARC / CCL-17, periostin, and IgE. In one embodiment, treatment with the anti-TSLP antibodies results in a decrease in the level of one or more of IL-4, IL-5, IL-13, IL-17, TARC / CCL-17, periostin, and IgE.

[0114] In certain embodiments, biomarker measurements include IL-4, IL-5, IL-13, IL-17, TARC / CCL-17, periostin, total IgE, and peripheral eosinophil count. In one embodiment, the biomarker is IL-4. In one embodiment, the biomarker is IL-5. In one embodiment, the biomarker is IL-13. In one embodiment, the biomarker is IL-17. In one embodiment, the biomarker is CCL-17. In one embodiment, the biomarker is periostin. In one embodiment the biomarker is total IgE. In one embodiment, the biomarker is peripheral eosinophil count.361625938262.3146588-005802Combination Therapy

[0115] As combinations are envisioned in this disclosure, the disclosure provides the antibody, or the antigen-binding portion thereof, or pharmaceutical composition comprising the antibody, e.g., an effective amount of the antibody, or the antigen-binding portion thereof, e.g., an effective amount of the antigen-binding portion, and a pharmaceutically acceptable carrier or diluent, and additional therapeutic agent(s), e.g., additional anti-atopic dermatitis therapeutic agent(s), for use in treating atopic dermatitis, by the herein-disclosed dosing regimen or method for administration of the antibody, or the antigen-binding portion thereof, or pharmaceutical composition comprising an effective amount of the antibody, or the antigen-binding portion thereof and a pharmaceutically acceptable carrier or diluent.

[0116] The disclosure also provides for use of the antibody, or the antigen-binding portion thereof, or pharmaceutical composition comprising an effective amount of the antibody, or the antigen-binding portion thereof and a pharmaceutically acceptable carrier or diluent, and additional therapeutic agent(s), e.g., additional anti-atopic dermatitis therapeutic agent(s), for use in treating atopic dermatitis in treating atopic dermatitis, the antibody, or the antigenbinding portion thereof, or pharmaceutical composition comprising an effective amount of the antibody, or the antigen-binding portion thereof and a pharmaceutically acceptable carrier or diluent is administered by the herein-disclosed dosing regimen. Considering further that embodiments of the disclosure can include anti-TSLP antibody or antigen-binding portion thereof, or a composition comprising the anti-TSLP antibody or antigen-binding portion thereof, used in combination with additional therapeutic agent(s), e.g., additional anti-atopic dermatitis therapeutic agent(s) or other drugs or treatments for treating skin disorders such as other drugs or treatment for atopic dermatitis, e.g., that the disclosure provides combination therapy comprising the administration of the anti-TSLP antibody or antigen-binding portion thereof or a composition comprising the anti-TSLP antibody or antigen-binding portion thereof (advantageously in the regimen discussed in this disclosure) with additional therapeutic agent(s), such as additional anti-atopic dermatitis therapeutic agent(s) or other drugs or treatments for treating skin disorders such as other drugs or treatment for atopic dermatitis, and that in such combination therapy the additional therapeutic agent(s) can be administered prior to, simultaneously with, or following administration of anti-TSLP antibody or antigen-binding portion thereof or a composition comprising the anti-TSLP antibody or antigen-binding portion thereof of this disclosure, kits of the this disclosure can also include such additional therapeutic agent(s), and instructions can include or additionally include instructions, such as for admixing any such additional therapeutic agent(s) and / or administration, for example amounts, routes,371625938262.3146588-005802timing of administration of such additional therapeutic agent(s), e.g., before simultaneously with or following administration of anti-TSLP antibody or antigen-binding portion thereof or a composition comprising the anti-TSLP antibody or antigen-binding portion thereof, as well as instructions as to any admixing and administration of the antibody, or the antigen-binding portion thereof, or pharmaceutical composition comprising an effective amount of the antibody, or the antigen-binding portion thereof and a pharmaceutically acceptable carrier or diluent (such as, for example, with respect to the herein-disclosed regimen).

[0117] In some embodiments, the anti-TSLP antibody can be administered in combination with one or more additional therapeutic agents. The phrases “combination therapy”, “combined with” and the like refer to the use of more than one medication or treatment simultaneously to increase the response. The anti-TSLP antibody(ies) or antigen-binding portion thereof of the present invention may, for example be used in combination with other drugs or treatment in use to treat skin disorders. Specifically, the administration of the anti-TSLP antibody(ies) or antigenbinding portion thereof of the present invention to a subject can be in combination with any anti-atopic dermatitis therapeutic agent. Such therapies can be administered prior to, simultaneously with, or following administration of the composition of the present invention.

[0118] In one embodiment, the method of treating atopic dermatitis includes administration of a therapeutic agent in combination with the anti-TSLP antibody. In one embodiment, the therapeutic agent is an anti-atopic dermatitis agent. In one embodiment, the anti-atopic dermatitis agent comprises an anti-IL4 antibody, an anti-IL4R antibody, an anti-IL-13 antibody, an anti-IL13R antibody, an IL-5 antibody, and IL-5R antibody, an, IL- 17 antibody, an IL-17R antibody, an IL-25 antibody, an IL-25R antibody, an IL-31 antibody, an IL-31R antibody, an IL-33 antibody, an IL-33R antibody, or a combination thereof. In one embodiment, the therapeutic agent is administered prior to, simultaneously or following the administration of the anti-TSLP monoclonal antibody or antigen binding fragment thereof.

[0119] The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.381625938262.3146588-005802EXAMPLES EXAMPLE 1Phase 1 Clinical Development of an Anti-TSLP monoclonal antibody

[0120] This example describes a Phase 1 study evaluating the safety, tolerability, immunogenicity, pharmacokinetic (PK) profile, and activity of an anti-TSLP monoclonal antibody injection after single and multiple doses in adult healthy volunteers (HVs) and patients with atopic dermatitis (AD).

[0121] The Phase 1 study employed a randomized, double-blind, placebo-controlled design comprising three parts: a single ascending dose (SAD) study in HVs, a single-dose study in AD patients, and a multiple ascending dose (MAD) study in HVs. An interim analysis was conducted with the following data availability: Part A (SAD) subjects and Part C (MAD) lowest dose cohort (240 mg weekly [Q7D] x 5 doses) completed through end of study; Part C second dose cohort (480 mg Q7D x 3 doses) completed through Day 84; and Part B (AD patients) completed through Day 43. Serum concentrations versus time data were available up to Day 56 for the second MAD cohort and up to Day 15 for AD patients. Table 2 presents the study objectives and endpoints.

[0122] Table 2: Objectives and Endpoints, Phase 1 Study391625938262.3146588-005802* ABBREVIATIONS: AD = atopic dermatitis; ADA = antidrug antibodies; AE = adverse event; AUCinf = area under the serum drug concentration-time curve from last dose extrapolated to infinity; AUCiast = area under the serum drug concentration-time curve from time last dose to the last quantifiable drug concentration; CCL-17 = C-C chemokine ligand 17; Cmax = maximum observed serum drug concentration; EASI = Eczema Area and Severity Index; ECG = electrocardiography; IgE = immunoglobulin E; IL = interleukin; NRS = Numerical Rating Scale; PD = pharmacodynamic; PK = pharmacokinetic; tl / 2 = apparent terminal elimination half-life; TARC = thymus and activation regulated chemokine; Tmax = time to maximum serum drug concentration.

[0123] The study design included three distinct parts. Part A (SAD) evaluated four dose levels (120, 240, 480, and 720 mg) in HVs, with eight subjects (6 active:2 placebo) per cohort. Part B assessed a single 480 mg dose in AD patients, with five patients enrolled (4 active: 1 placebo) versus twelve planned. Part C (MAD) evaluated multiple doses in HVs: 240 mg Q7D for 5 doses and 480 mg Q7D for 3 doses. In total, 55 subjects (49 HVs, 5 patients with AD, and 1 withdrawal) were enrolled at the time of the interim analysis. Table 3 details the treatment administration across cohorts.

[0124] Table 3: Treatments Administered per Cohort1. One subject in Cohort Cl withdrew from the study after the first dose and was replaced. AD = atopic dermatitis; HV = healthy volunteer; MAD = multiple ascending dose; Q7D = every 7 days; SAD = single ascending dose; SC = subcutaneous.401625938262.3146588-005802

[0125] The MAD portion was originally planned for three cohorts (240, 480, and 600 mg Q7D x 5 doses each). However, following a Safety Review Committee meeting on 30 August 2022, the 480 mg cohort was reduced to 3 doses, and the 600 mg cohort was cancelled due to drug accumulation, as the mean Cmax in the 240 mg MAD cohort exceeded that of the 720 mg SAD cohort.

[0126] Safety results showed no serious treatment-emergent adverse events (TEAEs) or deaths. One severe TEAE (increased transaminases) occurred in the SAD 240 mg cohort. In the MAD portion, one subject withdrew due to increased AST / ALT. TEAEs were common across dose levels in HVs, with injection site reactions being most frequent. In Part A, the frequency of study drug related TEAEs increased with dose level, indicating a potential relationship. In Part C, there was no increase in the frequency of study drug related TEAEs with dose level. The AD patient cohort showed lower TEAE frequency (40.0%) compared to HVs (87.5%) at the same dose level.

[0127] Pharmacokinetic analysis demonstrated typical IgG monoclonal antibody behavior. For the SAD cohort, mean semilogarithmic plots of serum concentration versus time profiles for 6 subjects at 4 dose levels showed a typical absorption pattern with mono-exponential decline and apparent linear disposition. The variability was typical of an IgG monoclonal antibody given the low number of subjects. Box plot analysis clearly determined dose proportionality and linear disposition for both Cmax and AUCinf. Cmax ranged from 10.2 to 53.8 pg / mL (120-720 mg), with Tmax between 128-164 hours. Mean AUCinf values showed dose proportionality, ranging from 362.8 to 2066 day* pg / mL. The elimination half-life was consistent (24.3-29.5 days).

[0128] In the MAD cohort, the mean profile for 240 mg multiple doses showed a typical PK profile for an IgG monoclonal antibody administered Q7D for 5 doses, with mean trough concentrations continuing to rise over the dosing period as expected. Steady-state was not attained with 5 doses. Following peak concentrations, there was a mono-exponential decline. The 480 mg Q7D dosing for 3 doses showed a similar profile.

[0129] For the 240 mg MAD cohort, the first dose produced mean Cmax 17.6 pg / mL at Tmax 147 hours, comparable to SAD results. After five weekly doses: mean Cmax was 76 pg / mL (at 776 hours), mean Cmin 54.9 pg / mL, mean Cave 65.6 pg / mL, mean AUCt 458.9 day*pg / mL, and mean 11 / 223.8 days. The mean RCmax and Rauc values of 5.1 and 6.1 respectively (expected 5.0) supported linear disposition.

[0130] For the 480 mg MAD cohort, eight subjects completed Cohort C2 first dose with 6 subjects providing PK data. The first dose achieved mean Cmax 37.5 pg / mL at Tmax 124 hours 411625938262.3146588-005802(comparable to SAD Cmax of 42.0 pg / mL and Tmax of 128 hours), with mean AUCtau 214.3 day* pg / mL. After three weekly doses in 6 subjects: mean Cmax was 98.6 pg / mL (at 432 hours), slightly below the expected 112.5 pg / mL (mean Cmax from first dose * 3 doses); mean Cmin 65.2 pg / mL; mean Cave (AUCt / t) 89.2 pg / mL; mean AUCt 624.2 day*pg / mL (close to expected 643 day* pg / mL from first dose * 3); mean AUCiast 2454 day* g / mL; and mean tl / 222.1 days (similar to SAD and MAD Cl cohorts). The mean RCmax (Cmax of third dose / Cmax) and Rauc (AUCTof third dose / AUC0-7) values of 2.7 and 3.1 respectively (expected 3.0) further supported linear disposition.

[0131] In the AD patient cohort, five patients were enrolled in the ongoing Part B study. Four of the 5 patients had serum drug concentration vs time data up to Day 15. Patients received a single SC dose of 480 mg. The mean Cmax from 4 patients was 41.0 pg / mL and was nearly identical to the mean Cmax value of 42.0 pg / mL determined in the SAD cohort and is close to the mean Cmax value of 37.5 pg / mL determined in the 480 mg first dose in the MAD cohort.The Tmax mean value was 108 hours, shorter than the mean half-life of 128 hours and 124 hours reported in healthy volunteers following a 480 mg dose in the SAD cohort and following the first 480 mg SC dose in the MAD cohort.

[0132] The presence of ADAs in patients with AD enrolled in Part B has not been evaluated at the present time. In Part A (SAD), ADA was detected in 1 subject at the 120 mg, 240 mg and 720 mg dose levels. There were no occurrences of ADA at the 480 mg dose. In total, 3 subjects out of 24 subjects in Part A had ADA present and in 2 out of 3 occurrences, ADA appeared late in the study. In Part C, 2 out of 6 subjects developed ADA at the last scheduled PK sampling on Day 124 following administration of 5 doses of 240-mg Q7D. Following administration of 480 mg SC Q7D for 3 doses, no ADA was detected over the 124-day study period. The results suggest a low incidence of ADA following single and multiple dosing.

[0133] In general, the PK analysis has shown that the anti-TSLP monoclonal antibody is well behaved following single and multiple doses in subjects. While there were minor apparent differences among various cohorts in their PK parameters, given the sample sizes and individual variances, the assessment of dose proportionality clearly showed a linear disposition over the dose range from 120 mg to 720 mg in the SAD cohort and dose proportionality was also confirmed in the MAD cohort. A single SC dose of 480 mg in the SAD and AD patient cohorts exhibited nearly identical mean Cmax values. In general, the tl / 2 is approximately 25 days for subjects in the SAD and MAD cohorts. Results from the ADA assessment show a low incidence of ADA in both the SAD and MAD cohorts. The consistent and reliable PK profiles421625938262.3146588-005802observed in the SAD and MAD cohorts have provided a basis for designing a dose regimen in the proposed proof-of-concept Phase 2 study.EXAMPLE 2Study Objectives and Endpoints for Phase 2 Development of an Anti-TSLP monoclonal antibody

[0134] This example describes the objectives and endpoints for a Phase 2 clinical study evaluating the efficacy and safety of an anti-TSLP monoclonal antibody in patients with moderate to severe atopic dermatitis (AD). Table 4 presents the comprehensive set of primary, secondary, and exploratory objectives and their corresponding endpoints.

[0135] Table 4: Objectives and Endpoints>431625938262.3146588-005802>>> >>> >

[0136] The study incorporates dual primary objectives focusing on both efficacy and safety. The primary efficacy objective aims to evaluate the treatment effect in moderate to severe AD patients, with success measured by the proportion of patients achieving at least 75% improvement in the Eczema Area and Severity Index (EASI75) at Week 26, assessed 2 weeks after the final dose at Week 24.

[0137] The primary safety objective focuses on comprehensive safety and tolerability assessment through multiple parameters including adverse events (AEs), antidrug antibody (ADA) formation, clinical laboratory evaluations, 12-lead electrocardiography (ECGs), vital signs, and physical examinations. Investigators evaluate the relationship between study drug and any observed AEs.

[0138] Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity. The PK assessment will provide detailed pharmacokinetic listings with potential compartmental modeling and exploration of PK / efficacy relationships. Immunogenicity is assessed through measurement of ADA during and after treatment.

[0139] The study includes multiple exploratory objectives to assess additional efficacy and safety outcomes. These include evaluation of EASI90 and EASI50 responses at Week 26, percent changes in EASI scores throughout the study, achievement of Investigator's Global Assessment (IGA) 0 or 1, changes in Peak Pruritus Numerical Rating Scale (PP-NRS) scores, attainment of Facial IGA 0 / 1, and monitoring for conjunctivitis. Additionally, pharmacodynamic biomarkers including thymus and activation regulated chemokine / C-C chemokine ligand 17 (TARC / CCL-17), periostin, and immunoglobulin E (IgE) are evaluated during and after treatment.441625938262.3146588-005802EXAMPLE 3Clinical Study Assessments and Safety Monitoring Procedures

[0140] This example describes the specific procedures and assessments for patient monitoring and safety evaluation in a clinical study of an anti-TSLP monoclonal antibody.General Study Considerations

[0141] Patients are assigned a screening identification number once they have signed the ICF and are then considered enrolled into the study if they have been determined to satisfy all inclusion and exclusion criteria (and after washout if requiring washout).

[0142] When collecting PK samples, immunogenicity, PD / biomarker, and clinical laboratory samples, vital signs, and / or ECG assessments are scheduled to occur at the same time point, ECG and vital signs testing are performed prior to blood collections. The preferred order of assessments is:1. ECG2. Vital signs3. PK, Immunogenicity, PD / biomarker sampling4. Clinical laboratory sampling

[0143] Samples for serum PK (collected at nominal times), ADA, and PD / biomarker assessments are collected for PK and ADA assessments using GLP validated assays and for PD / biomarker assessments using fit-for-purpose, qualified assays with commercial kits. Refer to the laboratory manual for additional details on laboratory assessment and sample processing. Screening Procedures and Assessments

[0144] Screening assessments are performed after the patients signed the ICF. After all screening results are obtained, eligible patients who require no washout are enrolled to the study directly; eligible patients who require washout start washout and repeat some screening assessments during Day- 14 to Day-1.

[0145] Rescreening is allowed after a delay of at least 4 weeks from the initial screening assessment. Any rescreening should be approved by the Sponsor.

[0146] A complete history is recorded at Screening and includes medical history, surgical history, smoking history, alcohol use history, drug abuse history, prior and current medication, blood donation history, allergy history, and other demographic information.

[0147] Physical examinations at Screening include weight, height, and body mass index (BMI), as well as a complete examination. Symptom-driven examinations are performed at other time points.451625938262.3146588-005802

[0148] Other screening assessments include 12-lead ECG, blood pregnancy test (females of childbearing potential only), and vital signs (blood pressure, pulse, temperature, and respiratory rate). A subset of these tests is completed at other time points, as detailed in the Schedule of Activities.

[0149] A screening for drugs of abuse is optional (per the discretion of the Investigator).

[0150] Clinical laboratory assessments at Screening include those listed in Table 5 and are conducted as site policy requires.

[0151] Table 5: Clinical Laboratory AssessmentsEfficacy Assessments

[0152] Patients are assessed to determine an EASI score at Screening, prior to dosing on Day 1 (baseline), at subsequent visits, and at the time of early withdrawal from the study.

[0153] The EASI score is a composite index that measures the severity of AD based on the average intensity of four clinical signs (erythema, edema / papulation, excoriations, and lichenification) at four body areas (head, neck, upper extremities, and trunk and lower extremities), and the percentage of affected area for each of the four body areas (Hanifin and Rajka, 1980). The primary efficacy endpoint is the proportion of patients with > EASI75 at Week 26 (2 weeks after last dose at Week 24).

[0154] The IGA and facial IGA require the Investigator to rate the severity of AD on a scale from 0 (clear) to 4 (severe).

[0155] The assessment tool for itching is the PP-NRS, on which the patient rates the maximum severity of the itch from AD on a scale from 0 (no itch) to 10 (worst itch imaginable) over a 24-hour period. The baseline PP-NRS score is based on the average of daily PP-NRS scores461625938262.3146588-005802for the 7 days immediately preceding Day 1. Patients complete the rating scale daily using the patient diary beginning on Day -8, throughout the last study visit, and at the time of early withdrawal from the study. In order to calculate an average for the score, the patient is to have completed the diary for a minimum of 4 days during the previous 7 days.

[0156] Exploratory efficacy and safety assessments include the following. At each visit, the percentage of patients who achieve 50%, 75%, and 90% improvement in the EASI score from Day 1 and the change in EASI score from Day 1 is calculated. Detailed analysis of all exploratory endpoints is described in the Statistical Analysis Plan (SAP).• Proportion of patients with EASI90 at Week 26 (2 weeks after last dose at Week 24) • Proportion of patients with EASI50 at Week 26 (2 weeks after last dose at Week 24) • Percent change from baseline in EASI at each visit• Proportion of patients achieving IGA 0 or 1 Week 26 (2 weeks after last dose at Week 24)• Percent changes in PP-NRS scores at Week 26 (2 weeks after last dose at Week 24) • Proportion of patients achieving Facial IGA 0 / 1 at Week 26 (2 weeks after last dose at Week 24)• Occurrence of conjunctivitisSafety Assessments and Monitoring

[0157] The safety of the anti-TSLP monoclonal antibody is assessed by the incidence of AEs, anti-drug antibody formation, clinical laboratory evaluations, 12-lead ECGs, vital signs, physical examinations, occurrence of conjunctivitis, as well as injection site reactions. The relationships between study medication and AEs are evaluated by the Investigators.

[0158] Assessments occur during visits to the study sites or via videoconference or telephone conference. Adverse events are collected throughout the Treatment Period and the Follow-Up Period to determine whether there are ongoing AEs, SAEs, worsening of AEs or SAEs, or development of new AEs or SAEs. Follow-up of AEs and SAEs occur during clinic visits and whenever abnormal, clinically significant findings are observed. Concomitant medications taken after the final dose are recorded throughout the Follow-Up Period. At the Investigator’s discretion, patients may be brought back to the study sites at other times for re-evaluation.

[0159] For the assessment of conjunctivitis, conjunctivitis history is asked at screening visit, and all patients are asked if they had been diagnosed as conjunctivitis at every visit during study treatment period. For patients who have been diagnosed as conjunctivitis, the conjunctivitis severity is asked, and the severity grades include: 0 = no conjunctivitis; 1= mild 471625938262.3146588-005802conjunctivitis; 2 = moderate conjunctivitis requiring treatment; 3 = severe conjunctivitis that may require an ophthalmic exam. Investigators should also check the patients' eyes and record any findings.Pharmacokinetic Assessments

[0160] Assessments of the PK are evaluated throughout the Treatment Period and Follow-up Period as outlined in Table 6 and Table 7. Blood sample for the analysis of the PK is collected at the time points indicated in the PK Sample Collection in Table 6 and Table 7. Refer to the laboratory manual for additional details on laboratory assessment and sample processing.Immunogenicity Assessments

[0161] Assessments of the ADA status (negative or positive with titer) is evaluated throughout the Treatment Period and Follow-up Period as outlined in Table 6 and Table 7. Blood sample for the analysis of the ADA is collected at the time points indicated in the Immunogenicity Sample Collection in Table 6 and Table 7.

[0162] Table 6: Screening and Treatment481625938262.3146588-005802AE = adverse event; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; CCL-17 =C-C chemokine ligand 17; EASI = Eczema and Severity Index; ECG = electrocardiography; GGT = gamma glutamyl transferase; IGA = Investigator’s Global Assessment; IgE = immunoglobulin E; IL = interleukin; INR = international normalized ratio; LDH = lactate dehydrogenase; PD = pharmacodynamic; PK = pharmacokinetic; PP- NRS = Peak Pruritus Numerical Rating Scale; PT = prothrombin time; RBC = red blood cell; TARC = thymus and activation regulated chemokine; W = week; WBC = white blood cell1. Early withdrawal: Early withdrawal assessments are completed within 7 days after the last treatment with the anti-TSLP antibody or within 7 days after the patient’s decision to discontinue study treatment, whichever occurs first. When medically feasible, the Medical Monitor should be consulted prior to study drug discontinuation.2. Order of assessments: When collecting PK, immunogenicity, biomarker, and clinical laboratory samples, vital signs, and / or ECG assessments are scheduled to occur at the same time point, ECG and vital signs testing are performed prior to blood collections. The preferred order of assessments is: 1) ECG, 2) vital signs, 3) PK, immunogenicity, and PD / biomarker sampling, 4) clinical laboratory sampling.3. Clinical laboratory assessments:• Hematology. Hemoglobin, hematocrit, WBC count and differential, RBC count and indices, platelet count• Chemistry: Sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, glucose, BUN, creatinine, uric acid, ALT, AST, GGT, alkaline phosphatase, total protein, albumin, globulin, total bilirubin, LDH, total cholesterol, triglycerides, CK, CK isoenzymes• Coagulation: PT, aPTT, fibrinogen, INR• Urinalysis: Protein, glucose, ketones, occult blood, urobilinogen, urine sediment microscopy (if other parameters abnormal)4. Efficacy assessments: EASI, IGA, facial IGA, and PP-NRS. Patients complete the PP-NRS daily throughout the last study visit, and at the time of early withdrawal from the study, and scores for each timepoint are the average of scores over the past 491625938262.3146588-0058027 days. In order to calculate an average for the score, the patient is to have completed the diary for a minimum of 4 days during the previous 7 days. Investigator should also assess Facial IGA.5. PK blood sample collection: At each visit during the Follow-up Period, and at the time of early withdrawal from the study drug.6. Immunogenicity blood sampling: Blood samples are to be collected at FU2, FU4, and FU6 during the Follow-up Period, and at the time of early withdrawal from the study drug.7. Biomarker blood sample collection: Assessments are TARC / CCL-17, periostin, and IgE. Samples are to be obtained at FU2, FU4, and FU6 during the Follow-up Period, and at the time of early withdrawal from the study drug.

[0163] Table 7: Follow-up, End of Study, and Early Withdrawal501625938262.3146588-005802Pharmacodynamic Biomarker Assessments

[0164] Blood samples (4 ml) for TARC / CCL-17, periostin, and IgE concentrations are collected at W1D1, W2, W3, W4, W8, W12, W16, W20, and W24 within 1 h before each dose during the Treatment Period, on every visit during the Follow-up Period, and at the time of early withdrawal from the study drug.EXAMPLE 4Study Eligibility Criteria for Clinical Evaluation of an Anti-TSLP monoclonal antibody

[0165] This example describes the comprehensive inclusion and exclusion criteria for patient selection in a clinical study of an anti-TSLP monoclonal antibody in atopic dermatitis.Study Inclusion Criteria

[0166] Patients are to meet all of the following criteria for study entry:1. In the opinion of the Investigator, the patient is capable of understanding and complying with protocol requirements.2. The patient signs and dates a written ICF prior to the initiation of any study procedures.3. The patient has a diagnosis of atopic dermatitis(according to the criteria established by Hanifin and Rajka, 1980). The diagnosis of atopic dermatitis is to have been present for at least 6 months.4. The patient is aged 18 to 65 years, inclusive at the time of consent. Patients of any gender are eligible.5. A female patient weighs at least 45 kg and a male patient weighs at least 50 kg. The patient has a BMI between 18.0 and 32.0 kg / m2 inclusive at Screening.6. The EAST is >12 at Screening and on Day 1.7. The score on the IGA is >3 (scale of 0 to 4) at Screening and on Day 1.8. The total body surface area (BSA) affected by atopic dermatitis is >10% as assessed by the physical examination at Screening and on Day 1.9. The patient has: (a) not received prior treatment with topical or systemic medications OR (b) the patient has active disease despite topical or systemic treatment as per the Investigator at the time of screening. Prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products can be allowed if the patient agrees to continue using at the current dose during the study.511625938262.3146588-00580210. A male patient who is non-sterilized and sexually active with a female partner of childbearing potential agrees to use highly effective contraception from the time of signing the ICF throughout the duration of the study treatment and for 90 days (~5 half-lives) after the last dose of study drug (See Section 8.3).11. A female patient of childbearing potential who is sexually active with a non-sterilized male partner agrees to use highly effective contraception from the time of signing the ICF throughout the duration of the study treatment and for 90 days after the last dose of study drug (See Section 8.3).12. The patient has a negative urine / blood result for drugs of abuse (if there are concerns in the opinion of the Investigators regarding the use of illicit drugs, including cannabinoid products).Study Exclusion Criteria

[0167] Any patient who meets any of the following criteria is excluded from the study:1. The patient has received any of the following treatments but did not finish the required washout period as stated in the following table. After the washout period, the patients can be considered for study treatment.

[0168] Table 8: Treatment and Required Washout Durations2. The patient has another dermatologic condition that may confound a diagnosis of atopic dermatitis or a treatment assessment.3. The patient has any clinically significant illness that may affect the safety, increase the risk for seizure or lower the seizure threshold, or potentially confound the study results, such as cardiovascular, neurologic, pulmonary, hepatic, renal, metabolic, gastrointestinal,521625938262.3146588-005802immunologic, endocrine, or psychiatric disease or disorder, or other abnormality. It is the responsibility of the Investigator to assess the clinical significance of a patient’s condition; however, consultation with the Sponsor’s Medical Monitor may be warranted.4. The patient has abnormal laboratory values during the Screening Period: ALT and / or AST > 1.5 times the upper limit of normal (ULN), total bilirubin > 1.5 mg / dL, estimated glomerular filtration rate (GFR) < 60 mL / min (based on Cockcroft-Gault calculation), hemoglobin (Hgb) < 10 g / dL, platelet count < 150 x 103 / pL. Individual exceptions may be granted with the agreement of the Sponsor and the Investigator.5. The patient has a history of anaphylaxis following biologic therapy.6. The patient has a history of allergy to corticosteroids, diphenhydramine, hydroxyzine, cetirizine, or fexofenadine.7. The patient has a history of a clinically significant infection within 4 weeks prior to Screening.8. The patient has been diagnosed with a helminthic parasitic infection within 6 months prior to Screening.9. The patient has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to Screening or is unwilling to agree to abstain from excessive alcohol consumption and drugs (including cannabinoids) throughout the study.10. The patient had a major surgical or major dental procedure within 8 weeks prior to Screening.11. The patient is pregnant or lactating or intends to donate ova before, during, or within 90 days (~ 5 half-lives) since the last dose of study drug.12. If male, the patient intends to donate sperm during this study or within 90 days (~ 5 half-lives) since the last dose of study drug.13. The patient has a history of neurologic abnormalities including abnormal electroencephalography, brain injury including traumatic injury, perinatal cerebropathy, postnatal brain damage, blood-brain barrier abnormality, and cavernous angioma.14. The patient has a history of cerebral arteriosclerosis.15. The patient has a history of cancer, except for adequately treated basal or squamous cell skin cancer or in situ cancers; or any other cancer from which the patient has been disease- free for at least 5 years prior to the first dose of study drug.16. The patient has a positive test result for HbsAg, anti-HCV, a history of active tuberculosis, a positive test result for HIV, or a known history of HIV infection at Screening.531625938262.3146588-00580217. The patient has poor peripheral venous access.18. The patient has donated or lost > 450 mL of blood (including plasmapheresis) or had a transfusion of any blood product within 90 days prior to the first dose of study drug. 19. The patient has an abnormal (clinically significant) ECG at Screening and / or on Dayl. Entry of any patient with an abnormal (not clinically significant) ECG is to be approved and documented by signature of the Investigator. In the case of a corrected QT interval (Fridericia) (QTcF) > 450 ms or > 470 ms (patients with bundle branch block) or PR interval outside the range of 115 to 220 ms, assessment may be repeated once for eligibility determination at Screening and / or on Dayl.20. The patient has poorly controlled hypertension and is not considered suitable for participation in this study in the judgement of the Investigators at Screening and / or on Dayl.21. The patient has abnormal resting heart rate and is not considered suitable for participation in this study in the judgement of the Investigator at Screening and / or on Day 1. Assessment is allowed to be repeated once for eligibility determination at Screening and / or on Dayl if deemed necessary.22. The patient plans to use any other prohibited medication or undergo any prohibited procedure during the study. Oral antibiotics are permitted. Bleach baths are not permitted.23. The patient has a risk of suicide on the Patient Health Questionnaire-2 (PH-2) or in the judgment of the Investigator, or the patient has made a suicide attempt or has a history of deliberate self-harm within 6 months prior to Screening.24. The patient is compulsorily detained for a medical or psychiatric illness.25. The patient or their immediate family are personnel at the study site.26. The patient is unable to comply with restrictions and prohibited activities / treatments as listed in the study protocol.EXAMPLE 5Phase 2a Clinical Study Results for Anti-TSLP Monoclonal Antibody

[0169] This example describes the results of a Phase 2a proof-of-concept study evaluating the efficacy and safety of an anti-TSLP monoclonal antibody in patients with moderate to severe atopic dermatitis (AD) (see FIG. 1).

[0170] The Phase 2a study employed an open-label design to evaluate anti-TSLP monoclonal antibody at 300 mg administered subcutaneously every week (QW) for the first 4 weeks as loading doses, followed by every 2 weeks (Q2W) through Week 24 as maintenance doses. A 541625938262.3146588-00580212-week follow-up period was conducted after the final dose. Key inclusion criteria included: diagnosis of atopic dermatitis present for at least 6 months, EASI score >12, IGA score >3, and BSA affected by atopic dermatitis >10% at screening and Day 1. Prescription moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products were allowed if patients continued using at the current dose during the study.

[0171] A total of 36 patients were screened, with 22 patients enrolled and treated. Of these, 17 patients (77.3%) completed the 24-week treatment period, while 5 discontinued early due to: pregnancy (Week 10, n=l), patient request (Week 18, n=l), corticosteroid use with allergic contact dermatitis (Week 14, n=l), withdrawal of consent (Week 14, n=l), and adverse event (hepatic steatosis, Week 1 Day 1, n=l). The mean age was 43.5 years, with 14 males and 8 females enrolled. The racial distribution included 11 Black / African American, 8 White, and 3 Asian patients. Mean baseline values included: height 169 cm, weight 80.4 kg, and BMI 28.2 kg / m2. Baseline values are included in FIG. 7.Summary of the ResultsPatient Disposition:

[0172] A total of 22 patients received at least one administration of an anti-TSLP monoclonal antibody 300 mg via SC injection. Seventeen patients (77.3%) completed the required treatment, and 5 patients (22.7%) discontinued treatment early.Demography and Baseline Characteristics:

[0173] Among the enrolled 22 patients, the mean (SD) duration of atopic dermatitis disease was 314.39 (180.13) months, ranging from 19.2 to 732.3. Median baseline EASI score was 17.85, with a range of 12.0 to 22.2. Twenty-one patients (95.5%) had a baseline IGA score of 3 (moderate), and 1 patient (4.5%) had a score of 4 (severe). Median baseline PP-NRS score was 7.1, with a range of 2.0 to 9.0. Median baseline total BSA affected by atopic dermatitis was 29.5%, with a range of 12.0% to 60.0%.Efficacy Results:

[0174] Results for all efficacy endpoints analyzed at Week 26 were the same in the Efficacy Analysis Set and the Per Protocol Analysis Set because both populations had the same patients with available data at Week 26 for analysis.

[0175] The primary efficacy of the anti-TSLP monoclonal antibody was demonstrated by the percentage of patients achieving EASI75 at Week 26 (2 weeks after the last dose at Week 24),551625938262.3146588-005802which was 94% (16 of 17 patients [95% CI: 71.3, 99.9]) in the Efficacy Analysis Set (and the same in the Per Protocol Analysis Set).

[0176] The efficacy of anti-TSLP monoclonal antibody was further supported by the achievement of EASI90 in 65% of patients, EASI50 in 100% of patients, IGA 0 / 1 in 88% of patients, and facial IGA 0 / 1 in 88% of patients at Week 26 (Efficacy and Per Protocol Analysis Sets). Mean percent reduction from baseline in PP-NRS score at Week 26 was -42.6% (SD: 24.1%) (Efficacy and Per Protocol Analysis Sets).

[0177] Initial rapid onset of disease improvement was demonstrated by a ~50% reduction in mean EASI score by Week 4, continuing to improve to a ~90% reduction at Week 26 (2 weeks after the last dose at Week 24) and a ~95% reduction at Week 28. This suggests that the effect of anti-TSLP monoclonal antibody on the underlying TSLP pathway requires time to build up to achieve the observed high efficacy.

[0178] Mean percent change in EASI score slightly declined to ~90% at 6 weeks after last dose (Week 30) and gradually decreased to ~75% at 12 weeks after the last dose (Week 36). This suggests that drug exposure may have been approaching the clinical threshold by the end of the Follow-up Period.Pharmacokinetic Results:

[0179] Key PK characteristics observed included: (1) dose dependency, where exposure was shown to be proportional to dose, consistent with findings from the anti-TSLP monoclonal antibody PK study; and (2) time-invariant clearance, suggesting the absence of target-mediated clearance; and (3) an estimated terminal half-life of 20 days.Pharmacodynamic Results:

[0180] The most commonly assessed PD biomarkers for therapeutics targeting the Th2 pathway in atopic dermatitis are serum levels of CCL17, periostin, total serum IgE, and peripheral eosinophil count. In the present study, anti-TSLP monoclonal antibody treatment did not result in significant reduction of these biomarkers. This might be the result of a collective impact including blocking the most upstream target in the Th2 pathway and complex cross talk of several Th pathways in the atopic dermatitis context.Immunogenicity Results:

[0181] Immunogenicity results were favorable: the occurrence of positive ADA was low (1 patient [4.5%]) and ADAs developed later in the study, during the Follow-up period, and did not significantly impact the observed PK exposure.561625938262.3146588-005802Safety Results:

[0182] A total of 13 of 22 patients (59.1%) hadTEAEs, of whom 3 patients (13.6%) had TEAEs assessed as related to the anti-TSLP antibody. No serious TEAEs, >Grade 3 TEAEs, TEAEs leading to interruption of treatment with the anti-TSLP monoclonal antibody, or anti-TSLP monoclonal antibody -related TEAEs leading to death occurred.

[0183] One (4.5%) patient had an unrelated TEAE of allergic contact dermatitis leading to anti-TSLP monoclonal antibody treatment withdrawal. Headache was the most common TEAE by PT (5 patients, 22.7%). Among the 13 patients with TEAEs, 2 patients (9.1%) had Grade 2 TEAEs, all assessed as not related to the anti-TSLP antibody. Treatment-emergent conjunctivitis only occurred in 1 patient (4.5%), and this was assessed as not related to anti-TSLP monoclonal antibody. There were no clinically meaningful changes from baseline or observable trends in hematology, chemistry, coagulation, and vital signs parameters during the study. The majority of patients did not experience any type of injection site reaction. Tenderness was the most common type of injection site reaction (10 patients, 47.6%), and all of these were Grade 1. Overall, anti-TSLP monoclonal antibody 300 mg treatment showed an acceptable safety profile in moderate to severe atopic dermatitis patients.Overall Conclusions:

[0184] In this Phase 2a proof-of-concept study in patients with moderate to severe atopic dermatitis, anti-TSLP monoclonal antibody demonstrated a favorable efficacy profile (FIG. 8, FIG. 9A and FIG. 9B) and a generally well tolerated safety profile. Drug exposure was observed to be dose-proportional, with no evidence of target-mediated disposition, and an estimated terminal half-life of 20 days. Immunogenicity occurrence was low, appeared late, and did not significantly impact drug exposure. These data support advancing to a Phase 2b study, which aims to provide a more comprehensive evaluation of anti-TSLP monoclonal antibody in a placebo-controlled, dose-ranging, randomized, and double-blind way in atopic dermatitis patients.Detailed Results

[0185] Efficacy assessments included EASI score, IGA, PP-NRS, and facial IGA. FIG. 2 presents the mean percent change from baseline in EASI score over time. Progressive improvement was observed, with mean percent changes of -13.6% at Week 2, -31.3% at Week 3, -50.9% at Week 4, -59.8% at Week 6, -64.6% at Week 8, -66.2% at Week 10, -71.4% at Week 12, -76.2% at Week 14, -77.3% at Week 16, -82.0% at Week 18, -85.7% at Week 20, -571625938262.3146588-00580288.2% at Week 22, and -89.2% at Week 24. During follow-up, the improvement was maintained at -90.8% at Week 26 and -95.9% at Week 28 before declining to -90.8% at Week 30, -88.5% at Week 32, -84.7% at Week 34, and -75.6% at Week 36.

[0186] FIG. 3 shows the EASI50, EASI75, and EASI90 responder rates over time. The EASI50 response plateaued after Week 6 at approximately 100% of patients and maintained briefly after treatment cessation. EASI75 response reached 94.1% (16 / 17 patients) at Week 26. EASI90 showed progressively increasing response reaching 64.7% (11 / 17 patients) at Week 26, lasting approximately 4 weeks after the final dose before declining.

[0187] FIG. 4 illustrates the mean percent change from baseline in IGA score, showing >70% reduction that increased progressively over 24 weeks. The IGA treatment success rate (achievement of IGA 0 / 1) reached 88.2% (15 / 17 patients) at Week 26. Similar to EASI scores, the effect persisted for 6-8 weeks post-treatment before declining. FIG. 5 demonstrates the IGA treatment success rate (achievement of IGA 0 / 1) over time, showing progressive improvement reaching >70% of participants by Week 24. The percentage of patients achieving IGA 0 / 1 peaked at 88.2% (15 / 17 patients) at Week 26, before gradually declining after treatment discontinuation. Similar to EASI scores, the effect persisted for approximately 6 weeks post-treatment before declining. This pattern of sustained efficacy followed by gradual decline after treatment cessation was consistent across multiple efficacy endpoints.

[0188] FIG. 6 depicts the change in Peak Pruritus Numerical Rating Scale (PP-NRS). The mean baseline PP-NRS score was 6.5 (SD 2.0). At Week 26, the mean PP-NRS score was 3.5 (SD 2.1) among 14 evaluable patients, representing a mean percent change of -42.6% (SD 24.1%). The improvement maintained for approximately 6 weeks post-treatment. Facial IGA showed similar progressive improvement with 88.2% (15 / 17 patients) achieving facial IGA 0 / 1 at Week 26, though efficacy was not sustained beyond 12 weeks after treatment discontinuation.

[0189] Regarding safety, 13 patients (59.1%) experienced treatment-emergent adverse events (TEAEs), with 3 patients (13.6%) having treatment-related TEAEs. Headache was the most common TEAE (n=5, 22.7%). Other TEAEs occurred in single patients. No serious TEAEs or TEAEs >Grade 3 were reported. One patient discontinued due to a TEAE (allergic contact dermatitis). The most common TEAEs by System Organ Class included Nervous System Disorders (31.8%), Infections and infestations (18.2%), and Gastrointestinal disorders (13.6%).

[0009] Injection site reactions were monitored through the study. Tenderness was the most common reaction (11 / 22, 52.4%, all Grade 1), followed by induration / swelling (7 / 22, 33.4%, 6 Grade 1, 1 Grade 2), erythema / redness (6 / 22, 28.6%, 5 Grade 1, 1 Grade 2), and pain (3 / 22,581625938262.3146588-00580214.3%, all Grade 1). Grade 2 reactions were limited to erythema / redness and induration / swelling in one patient each. No severe injection site reactions were reported.

[0190] Laboratory assessments showed isolated cases of increased alanine aminotransferase and blood creatine phosphokinase (one patient each, Grade 1 ). No clinically significant changes in 12-lead ECG were observed. Anti-drug antibody development was low, with one patient developing antibodies during the follow-up period (positive at Weeks 28, 32, and 36) without significant impact on drug exposure.

[0191] The results of this Phase 2a study demonstrated that the anti-TSLP monoclonal antibody provided substantial clinical benefit in moderate-to-severe atopic dermatitis patients, with effects generally maintained for 6-8 weeks after treatment discontinuation. The safety profile was favorable, with mostly mild adverse events and injection site reactions. These findings support further development in a formal Phase 2b dose-ranging study.EXAMPLE 6Study to Evaluate the Efficacy and Safety of the Anti-TSLP Monoclonal Antibody in Atopic Dermatitis

[0192] This example describes a Phase 2 randomized, two-arm blinded clinical study evaluating the efficacy and safety of an anti-TSLP monoclonal antibody in patients with moderate to severe atopic dermatitis.Study Rationale

[0193] This Phase 2 study is planned to compare the efficacy of the anti-TSLP antibody with that of placebo in patients with moderate-to-severe atopic dermatitis, and this study will enable further clinical development of the anti-TSLP antibody in atopic dermatitis. Atopic dermatitis is a T-helper type 2 (Th-2)-driven inflammatory disease. Evidence from published literature has implicated TSLP as a component of atopic dermatitis pathobiology. Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine shown to be elevated in skin lesions of patients with atopic dermatitis.

[0194] TSLP protein is one of the molecules that mediate allergic reactions. The TSLP protein belongs to the interleukin-2 (IL-2) cytokine family, which has actions similar to IL-7. TSLP is mainly derived from the barrier surface of epithelial cells in skin, intestine, and lung tissues, and responds to danger signals by regulating Th-2 inflammatory responses at mucosal barriers in allergic inflammation. The protein acts on a variety of immune cells (e.g., dendritic cells) by591625938262.3146588-005802forming complexes with the TSLP receptor (TSLPR) and IL-7 receptor on the cell surface to drive downstream helper T cell 2 (Th2) cytokine release.

[0195] TSLP activates cells involved in non-Th2-driven inflammation and promotes the expression of inflammatory cytokines such as IL-4, IL-5, and IL-13.

[0196] Abnormally high TSLP protein expression is related to a variety of atopic diseases including asthma, atopic dermatitis, allergic rhinitis, eosinophilic esophagitis, cancer, arthritis, intestinal parasites, and other diseases, TSLP plays several roles in the triad of atopic diseases: asthma, allergic rhinitis, and atopic dermatitis.

[0197] The symptom of pruritis observed frequently in atopic dermatitis can be attributed to TSLP signaling, indirectly via the inflammatory cascade, but also via direct activation by TSLP of a specific subset of sensory neurons expressing the TSLP receptor and the ion-channel TRPA1.

[0198] Tezepelumab is a TSLP inhibitor, which has been approved for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. As for atopic dermatitis, the investigation showed a trend toward a superior EASI75 response and stronger improvement in IGA response in Tezepelumab plus topical corticosteroids (TCS)- treated patients versus placebo plus TCS. Numerical improvements were seen across several clinical and patient reported endpoints, and greater efficacy in biomarker-defmed subgroups suggest potential benefits in TSLP blockade.

[0199] The anti-TSLP antibody has good in vitro binding affinity to HuTSLP ( D (mol / L) <1.08E"12) and to cynoTSLP ( D (mol / L) <7.14E"13) and has a higher affinity than tezepelumabIn vitro studies demonstrated that the anti-TSLP antibody inhibits the TSLP pathway and production of downstream cytokines. In animal models, the anti-TSLP antibody reduced levels of inflammatory factors and eosinophil production in a dose-dependent manner. In preclinical studies, the anti-TSLP antibody was safe and well tolerated, and no treatment-related abnormal changes were observed during administration and recovery. The anti-TSLP antibody is not associated with irritation at the injection site and has a low incidence of immunogenicity.

[0200] In the proof-of-concept Phase 2a study, clinical benefits were seen in patients with moderate-to-severe atopic dermatitis in terms of EASI, IGA, and PP-NRS improvements. At Week 26 (2 weeks after last dose at Week 24), 75.0% patients achieved EASI75 improvement (95% CI, 50.9-91.3).601625938262.3146588-005802Rationale for Study Design

[0201] A subcutaneous dose of 300 mg Q2W demonstrated substantial activity in the small, open-label study of the anti-TSLP antibody conducted in patients with moderate to severe atopic dermatitis. The current study aims to expand on these findings by evaluating the efficacy of 300 mg Q2W as a maintenance dose in a larger, double-blind study designed to assess the difference between the active and placebo arms, as described in FIG. 10.

[0202] To achieve the target concentration more rapidly, a loading dose of 600 mg Q2W for two doses was selected. The safety of this regimen has been previously established. Pharmacokinetic modeling indicates that the Cmax and area under the serum drug concentration-time curve (AUC) values for 600 mg Q2W><2 are comparable to or lower than those observed during the Phase 2a induction period or the 480 mg QW><3 regimen in the previous study.

[0203] The time points for the primary and secondary endpoints were selected based on simulation results and observed responses from the previous study. Week 24 was chosen as the primary endpoint because data from the previous study indicated that near-maximal improvement in EASI score from baseline was achieved by this time.

[0204] A 12-week follow-up period (14 weeks after the final dose) is included to improve understanding of the PK / PD relationship and to provide greater confidence in predicting the duration of sustained efficacy, as well as providing the safety data for five half-lives after the last dose.Benefits and Risks of the Anti-TSLP Antibody in Patients with Atopic Dermatitis

[0205] The study drug is an anti-TSLP mAb being investigated to treat moderate to severe atopic dermatitis. Anti-TSLP therapy has been clinically validated as an effective treatment for allergic inflammatory diseases such as severe asthma and has also shown clinical activity in patients with moderate to severe atopic dermatitis.

[0206] Preclinical studies have demonstrated the efficacy of the anti-TSLP antibody in binding, in a highly specific manner, to human TSLP in vitro. The binding of the anti-TSLP antibody to TSLP was also shown to inhibit TSLP binding to the TSLP receptor in an in vitro model. No evidence of the anti-TSLP antibody induced cytokine release was observed after in vitro incubation with human PBMCs. Tissue cross-reactivity studies confirmed on-target only binding of the anti-TSLP antibody in human tissues.611625938262.3146588-005802Potential Benefits

[0207] It is anticipated that the anti-TSLP antibody will provide a much-needed treatment option for patients with moderate to severe atopic dermatitis. The primary efficacy of the anti-TSLP antibody was demonstrated in the previous study by the fact that, at Week 26 (two weeks after the last dose at Week 24), 94% of participants achieved EASI75 improvement in both the Efficacy and Per Protocol Analysis Sets. Additionally, the efficacy was further supported by the achievement of EASI90 (65%), EASI50 (100%), IGA 0 / 1 (88%), and facial IGA 0 / 1 (88%) at Week 26.Study Objectives, Endpoints, and Estimands

[0208] The primary and secondary estimands are intended to provide population level estimates of the treatment effect of 300 mg Q2W of the anti-TSLP monoclonal antibody in comparison with placebo after 24 weeks of treatment, in absence of rescue and prohibited medications / therapies for the treatment of atopic dermatitis as if all patients completed treatment, except those who discontinued due to lack of efficacy and disease-related adverse events.

[0209] The primary objectives were to evaluate the efficacy of the anti-TSLP monoclonal antibody compared to placebo, as measured by the change in Eczema Area and Severity Index (EASI) score in patients with moderate-to-severe atopic dermatitis. The primary endpoint is the percent change from baseline in EASI at week 24. The secondary objectives were to evaluate the treatment effect of the anti-TSLP monoclonal antibody compared to placebo, on additional clinical outcome measures.

[0210] Secondary endpoints included the proportion of patients with validated Investigator Global Assessment (IGA) treatment success (IGA-TS) (defined as score 0 / 1 and a reduction >2 points from baseline), at Week 24, the proportion of patients with EASI reduction of 75% (EASI75) relative to baseline score at Week 24, and the change and percent change from baseline in weekly average of the daily Peak Pruritus Numerical Rating Scale (PP-NRS) score at Week 24. In addition, secondary endpoints include the proportion of patients with a 4-point improvement or greater from baseline in weekly average of the daily Peak Pruritus Numerical Rating Scale (PP-NRS) at Week 24, the proportion of patients with EASI reduction of 50% (EASI50) relative to baseline score at Week 24, and the proportion of patients with EASI reduction of 90% (EASI90) relative to baseline score at Week 24. Secondary endpoints also include the change from baseline in body surface area (BSA) at Week 24.621625938262.3146588-005802

[0211] To evaluate the safety and tolerability, including characterization of the immunogenicity profile of the anti-TSLP monoclonal antibody in patients with moderate-to-severe atopic dermatitis, the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) after first study drug dose until the patient’s last visit. Any abnormalities of clinical laboratory evaluations such as 12-lead ECGs and vital signs will be measured, in addition to measuring any antibodies against the anti-TSLP monoclonal antibody.

[0212] Exploratory objectives will guide evaluation of the treatment effect of the anti-TSLP monoclonal antibody compared to placebo on additional clinical outcome measures and include the change and percent change from baseline in EASI, IGA, PP-NRS, BSA, facial IGA, and SCORAD, over time. The proportion of patients with EASI50, EASI75, EASI90, IGA-TS, and PP-NRS 4-point reduction over time will be measured, in addition to the change from baseline in dermatology life quality index (DLQI) at Week 24 and over time. Additional exploratory endpoints include the change from baseline in Patient-Oriented Eczema Measure (POEM) score at Week 24 and over time and the change from Atopic Dermatitis Control Tool (ADCT) score at Week 24 and over time.

[0213] To assess the PK profiles, as well as any exposure-response relationships of the anti-TSLP monoclonal antibody in patients with moderate-to-severe atopic dermatitis, pharmacokinetic listings will be provided. PK parameters might be estimated through compartmental modeling. If sufficient data are available, the exposure-response relationship can be explored. To evaluate the pharmacodynamic (PD) biomarkers of the anti-TSLP monoclonal antibody, PD markers may include endogenous cytokines / chemokines and inflammation markers in plasma and serum. To evaluate the effect of a subject’s genetic profile on the efficacy and safety of the anti-TSLP monoclonal antibody, genetic marker profiling will be conducted with biomarkers.Overall Study Design

[0214] This is a randomized, double-blinded, placebo-controlled, phase 2 study to assess the efficacy of the anti-TSLP monoclonal antibody as compared to placebo in patients with moderate-to-severe atopic dermatitis. There will be a screening period (up to 30 days), a treatment period (24 weeks), and a 12-week follow-up (FU) period.

[0215] After providing informed consent, patients will be assessed for study eligibility at the screening visit. Patients will undergo screening within 30 days prior to randomization. After screening, eligible patients, as confirmed by the Independent Medical Reviewer and the 631625938262.3146588-005802Investigator, will be randomized 2: 1 to the anti-TSLP monoclonal antibody 300 mg group and placebo group respectively. Randomization will be stratified by baseline severity (vIGA 3, moderate; vIGA 4, severe). The study population will include at least 33% (approximately) of severe patients. Approximately 96 patients will be randomized in the study. Dropout rates in the study will be monitored to achieve target number of patients who complete the treatment period (Week 24 visit).

[0216] The treatment period is planned for 24 weeks (last dose at Week 22), which includes an initial period of loading doses on the first day of Week 0 and Week 2, and subsequent maintenance doses, every 2 weeks (Q2W), on the first day of Week 4 through Week 22. The loading dose is 600 mg for the anti-TSLP monoclonal antibody 300 mg group; placebo group will receive matching placebo loading dose. During the maintenance treatment, patients in each group will receive the study treatment Q2W for a total of 10 doses from Week 4 to Week 22.

[0217] The study will be double-blinded to avoid the Investigator and the patients knowing about the treatment allocation, for the comparation between the anti-TSLP monoclonal antibody and placebo treatment. The primary endpoint is percent change from baseline in EASI score at Week 24 compared to placebo.

[0218] Clinical outcome measures include EASI, vIGA, facial IGA, BSA, SCORAD, PP-NRS, DLQI, POEM and ADCT. Efficacy assessments will be conducted at each scheduled study visit. All patients will have photographs taken during screening visit and at specified visits during treatment and follow-up period.

[0219] Safety will be assessed by monitoring AEs, physical examination, vital signs, serum hematology, chemistry and urinalysis laboratory testing. AEs will be collected after signing the Informed Consent Form (ICF) and throughout the treatment period and the FU period. Concomitant medications that were used 6 months prior to screening through follow-up will be recorded. However, for atopic dermatitis treatments, all prior systemic treatments for atopic dermatitis should be recorded, including biologies or JAK inhibitors.Numbers of Patients

[0220] Approximately 96 patients will be randomized 2: 1 active or placebo arms respectively in the study. Patients who are withdrawn or removed from treatment or study will not be replaced.641625938262.3146588-005802Inclusion Criteria

[0221] Patients must meet the several criteria to be entered into the study. They must be male or female adults aged > 18 and < 70 years, inclusive at the time of consent, with chronic atopic dermatitis that has been present for >6 months before the screening visit and with no significant atopic dermatitis flares during the past 4 weeks before screening. Patients must have an EASI score > 16 at the screening and the baseline visit (W0D1), a vIGA score >3 (scale of 0 to 4) at the screening and the baseline visit, and with a minimum weekly average of the daily PP-NRS score >4 in the 7 days before the baseline visit. Greater than 10% of the body surface area (BSA) of the patient should have atopic dermatitis involvement at the screening and baseline visit. Photographs at screening are representative of the disease diagnosis and extent (as judged by the Independent Medical Reviewer). Patients should have a history of inadequate response to treatment for atopic dermatitis with topical medications, or determination that topical treatments are otherwise medically inadvisable (e.g., because of important side effects or safety risks). A history of inadequate response to or lack of tolerability will be assessed by the investigator based on information obtained from medical chart, patient’s physician, or directly from the patient, and include a stable regimen (>4 weeks or for the duration recommended by the product prescribing information) of one or more topical treatments (e.g., moderate to high potency TCSs and / or TCIs) before the Screening visit, or for whom topical treatments are otherwise inadvisable.

[0222] Patients eligible for the study must have applied a stable dose of non-medicated topical moisturizer (ideally once or twice daily) for > 7 days prior to the baseline visit and they will agree to continue using the same moisturizer daily at the same frequency throughout the study. Moisturizer containing urea is prohibited. The patient should not use an emollient for 12 hours before any clinic visit.Study Treatment Description

[0223] The anti-TSLP monoclonal antibody is the investigational product (IP) for this study, and placebo will also be used. The study drug substance and drug product will be manufactured in compliance with Good Manufacturing Practice. All study drugs sent to the study sites will be labeled according to current Good Clinical Practice (GCP) and local Therapeutic Goods Administration requirements. Refer to Table 1 for further details.651625938262.3146588-005802

[0224] TABLE 1 is a description of the study drug.Administration of Study Drugs

[0225] The Interactive Web Response Systemwill assign the required IP identification numbers for each patient visit. The preferred SC injection site is the abdomen. The thigh can be used as an alternative site for SC injections. The date and time of study drug administration, and site of injection will be documented at each visit, when applicable. More details on the administration method are described in separate study manual.

[0226] As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be immediately available at the study sites, and study personnel should be trained to recognize and respond to anaphylaxis according to local guidelines.

[0227] Patients participating in the study will be under careful supervision of a dermatologist or allergist. The investigators must be experienced in treating atopic dermatitis and have documented experience and / or training in use of the assessment required by the study protocol. Treatments in the Induction Treatment Period

[0228] During the induction treatment period, one patient group will be dosed with 300 mg of the anti-TSLP monoclonal antibody. The dose will be administered via two injections of 2.5 mL of 120 mg / mL drug product for a total dose of 600 mg drug product at W0D1 and W2D1. In the Placebo group, patients will be dosed with two injections of 2.5 mL placebo at W0D1 and W2D1 each.661625938262.3146588-005802Treatments in the Maintenance Treatment Period

[0229] During the maintenance treatment period, one patient group will be administered 300 mg of the anti-TSLP monoclonal antibody. The dose will be given as one injection of 2.5 mL of 120 mg / mL of the drug product at each dosing, Q2W. In the placebo group, patients will be given one injection of 2.5 mL placebo at each dosing, Q2W.Study Assessments and Procedures

[0230] As protocol waivers or exemptions are not allowed if an enrolled patient is subsequently determined to be ineligible for the study, this must be discussed with the sponsor immediately upon occurrence or awareness to determine if the patient is to continue or discontinue study treatment. Adherence to the study design requirements is required for study conduct. Assessments / procedures at any study visits are to be performed in the following preferred order.

[0231] First, patient reported outcomes, including POEM, DLQI, and ADCT, will be assessed. These assessments will be conducted at the study center at the designated visits during the study. These assessments should be conducted before the Investigator assessments.

[0232] Second, the SCORAD component C should also be completed before Investigator assessments.

[0233] Third, investigator assessments (performed only by adequately trained Investigators; the same Investigator should preferably perform all the evaluations for a given patient throughout the entire study period, whenever possible) in the following order:a. vIGAb. Facial IGAc. BSAd. SCORAD components A and Be. EASIf. Take photographs of representative areas with atopic dermatitis involvement.

[0234] Fourth, safety and laboratory assessments should be performed. When collecting PK, immunogenicity, PD biomarkers, and clinical laboratory samples when vital signs and / or ECG assessments are scheduled to occur at the same time point, the preferred order of assessments is ECG first, then vital signs, and then blood draws (the order of blood tubes should be drawn per the study-specific laboratory manual). Fifth, administration of study drugs should occur. Sixth, assess for injection site reaction.671625938262.3146588-005802

[0235] Demographic data collection, including sex, age, race, and ethnicity, will be collected in order to study their possible association with patient safety and treatment effectiveness. Additionally, demographic data will be used to study the impact on biomarker variability and PK of the protocol-required therapies, if needed.

[0236] A complete medical history will be collected as part of the screening assessment and will include all clinically relevant past or coexisting medical conditions or surgeries. Extensive information on the patient’s atopic dermatitis, asthma, and allergies will be collected as part of the disease history form. Information on the patient’s atopic dermatitis will be collected as part of the screening assessment and will include the date of onset of AD, anatomical areas affected by atopic dermatitis, number of AD flares in the prior 12 months (as per the history), and past treatments for atopic dermatitis.

[0237] Physical examination will be performed as per standard of care. Clinically significant physical examination findings should be recorded on the appropriate eCRF (e.g., medical history if onset is before ICF signature; AEs if onset is after ICF signature). Physical examinations at Screening will be a complete examination, while symptom-driven focused examinations will be performed at other time points. Complete physical examination will include the following body systems: general appearance; dermatological (except AD); head, eyes, ears, nose, and throat (HEENT); respiratory; cardiovascular; abdominal, neurological, musculoskeletal, and lymphatic systems. Height, weight, and BMI information will be collected as well, in addition to a detailed history of the use of alcohol, tobacco, and recreational drugs.Efficacy Assessment and ProceduresEczema Area and Severity Index

[0238] EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of atopic dermatitis. The EASI score is a composite index with scores ranging from 0 to 72, with higher value indicating more severe and / or mor extensive condition. The Investigator will assess the severity of 4 atopic dermatitis disease characteristics (erythema, edema / papulation, excoriations, and lichenification) on the four body areas (head / neck, trunk, upper extremities, and lower extremities). For each body region, a severity sum score will be calculated which will be multiplied by an area score and by a weighting factor. The EASI score equals the sum of the scores obtained for each body region.681625938262.3146588-005802Validated IGA (vIGA) and Facial IGA

[0239] The vIGA is a validated instrument used in clinical trials to rate the severity of the patient’s global atopic dermatitis and is based on a 5 -point scale ranging from 0 (clear) to 4 (severe). The vIGA is a global assessment of the current state of the disease, as assessed by the investigator. It is a 5-point morphological assessment of overall disease severity. The vIGA score ranges from 0 to 4. A higher vIGA score means higher atopic dermatitis severity. A score of 0 is given when atopic dermatitis is clear, a score of 1 is given when atopic dermatitis is almost clear, a score of 2 is given when atopic dermatitis is mild, a score of 3 is given when atopic dermatitis is moderate, and a score of 4 is used when atopic dermatitis is severe.

[0240] The IGA-TS is defined as a vIGA score of 0 or 1 with >2 grade improvement from baseline. Facial IGA assessment will be conducted using the vIGA scale focusing the atopic dermatitis lesions on the face and neck.Body Surface Area Estimates

[0241] The total percentage of the participant’s atopic dermatitis -affected body surface area (BSA) will be estimated by the investigator or designee using the handprint method, which estimates that the area of a participant’s full handprint (fingers and thumbs together, palmar surface) constitutes 1% of their total BSA.

[0242] The overall BSA affected by atopic dermatitis will be evaluated (from 0% to 100%). Maximum possible percentage (number of handprints) for each area are:Head and Neck: 10 (ie 10% of total body area)Trunk (including genitalia): 30 (ie 30% of total body area)Upper extremities: 20 (ie 20% of total body area)Lower extremities: 40 (ie 40% of total body area)SCORAD

[0243] SCORAD is a validated tool to evaluate the extent and severity of atopic dermatitis lesions, along with subjective symptoms. The assessment will be based on the condition of the disease at the time of evaluation and not in relation to the condition at a previous visit. The assessment consists of 3 components: A = extent or affected body surface area, B = severity, and C = subjective symptoms.

[0244] The extent of atopic dermatitis is assessed as area score between 0 to 104 (assigned as “A” in the overall SCORAD calculation). The severity of 6 specific symptoms of atopic dermatitis (redness, swelling, oozing / crusting, excoriation, skin thickening / lichenification,691625938262.3146588-005802dryness) is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation). Subjective assessment of itch and sleeplessness based on the average of the last 3 days / nights is recorded for each symptom by the patient or relative on a 10-cm VAS, where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20. This parameter is assigned as “C” in the overall SCORAD calculation. The SCORAD is calculated as: A / 5 + 7B / 2 + C.Atopic Dermatitis Area Photographs

[0245] All patients will have photographs taken of two representative areas of atopic dermatitis involvement during screening and at specified visits during treatment and follow-up period. The same area(s) selected at screening will be used for subsequent photos to follow outcome overtime.

[0246] In addition, at screening only, take two body photographs each of the front and of back of the body that show the extent of the disease. Each of these pictures will be half body photographs demonstrating the extent of the disease. Instructions for taking the photographs are provided in the photography reference manual.PP-NRS

[0247] PP-NRS is an assessment tool for itching, on which the patient rates the maximum itch intensity from atopic dermatitis on a scale from 0 (no itch) to 10 (worst itch imaginable) over the last 24-hour period. The baseline PP-NRS score is based on the weekly average of the peak pruritus daily PP-NRS scores for the 7 days immediately preceding W0D1.

[0248] Patients will receive eDiary training at the screening visit and start the eDiary, at the screening visit and continue throughout till the last study visit. In order to calculate an average for the weekly average score, the patient must have completed the diary for a minimum of 4 days during the previous 7 days. A minimum of 4 days data is needed before baseline visit (W0D1) before randomization - in order to calculate baseline PP-NRS score.POEM

[0249] The POEM is a validated questionnaire used to assess disease symptoms in atopic eczema patients, consists of 7 items each addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and dryness). The POEM is provided in the study reference manual.701625938262.3146588-005802DLQI

[0250] The DLQI is a validated questionnaire consists of 10 items addressing the patient’s perception of the impact of their skin disease on different aspects of their health-related quality of life over the last week such as dermatology related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment.ADCT

[0251] ADCT is a tool developed to assist patients and the investigators in comprehensively and efficiently understanding their atopic dermatitis. Its six concise questions allow patients and investigations to evaluate the different dimensions of patient-perceived atopic dermatitis control.Safety and Other Assessment and Procedures

[0252] The safety of the anti-TSLP monoclonal antibody will be assessed by the incidence of AEs, anti -the anti-TSLP monoclonal antibody ADA formation, clinical laboratory evaluations, 12-lead ECGs, vital signs, physical examinations, as well as injection site reactions. The relationship between study medication and AEs will be evaluated by the Investigators.

[0253] Safety assessments will typically occur during visits to the study sites or for specific issues (e.g. for follow up of an adverse event) via videoconference or telephone conference. AEs will be collected from screening till the end of the follow-up period to determine whether there are ongoing AEs, S AEs, worsening of AEs or S AEs, or development of new AEs or SAEs. Follow-up of AEs and SAEs will occur during study site visits and whenever abnormal, clinically significant findings are observed. At the Investigator’s discretion, patients may be brought back to the study sites at other times for re-evaluation.Genetic Assessments

[0254] Genetic variation may impact a participant’s response to study intervention, susceptibility to, and severity and progression of disease. Variable response to study intervention may be due to genetic determinants that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the drug; disease etiology; and / or molecular subtype of the disease being treated. Therefore, where local regulations and IRB / EC allow, blood sample will be collected for DNA / RNA analysis from consenting participants.

[0255] A blood sample for DNA / RNA isolation will be collected from patients who have consented to participate in the genetic analysis component of the study at the baseline.711625938262.3146588-005802Participation is optional. Patients who do not wish to participate in the genetic research may still participate in the study.

[0256] DNA / RNA samples will be used for research related to the anti-TSLP monoclonal antibody or atopic dermatitis and related diseases. They may also be used to develop tests / assays, including diagnostic tests related to the anti-TSLP monoclonal antibody and atopic dermatitis. Genetic research may consist of the analysis of one or more candidate genes or the analysis of genetic markers throughout the genome. DNA / RNA samples may be analyzed for genetic analyses if it is determined that this may help further understand the clinical efficacy or safety data. The samples may be analyzed as part of a multistudy assessment of genetic factors involved in the response to the anti-TSLP monoclonal antibody or study interventions of this class to understand the study disease or related conditions.

[0257] The results of genetic analyses may be reported in the clinical study report (CSR) or in a separate study summary. The sponsor will store the genetic samples in a secure storage space with adequate measures to protect confidentiality. The samples may be retained while research on the anti-TSLP monoclonal antibody or atopic dermatitis continues but no longer than 10 years or other period as per local requirements.

[0258] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.721625938262.3

Claims

146588-005802CLAIMS WHAT IS CLAIMED IS:

1. A method of treating atopic dermatitis in a subject comprising administering to the subject a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) antibody, or an antigen-binding portion thereof, the anti-TSLP antibody comprises:(a) a heavy chain variable region comprising a VH CDR1, a VH CDR2 and a VH CDR3 comprising amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 1, 2 and 3, respectively; and(b) a light chain variable region comprising a VL CDR1, a VL CDR2 and a VL CDR3 comprising amino acid sequences of SEQ ID NOs: 5, 6 and 7, respectively, or amino acid sequences having at least 95% sequence identity to SEQ ID NOs: 5, 6 and 7, respectively.

2. The method of claim 1, wherein the anti-TSLP antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 95% sequence identity to SEQ ID NO:4.

3. The method of claim 1, wherein the anti-TSLP antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8.

4. The method of claim 1, wherein the administration comprises subcutaneous administration, intravenous administration, intramuscular administration, or intradermal administration.

5. The method of claim 1 , wherein the administration comprises administration of the anti-TSLP antibody once every week, once every month, or once every three months.

6. The method of claim 1, wherein the administration comprises administration of the anti-TSLP antibody once every calendar week or 7 days, once every two weeks or 14 days, once every four weeks or 28 days, once every eight weeks or 56 days, or once every 12 weeks or 84 days.

7. The method of claim 6, wherein the administration comprises administration of the anti-TSLP antibody once every 2 weeks or 14 days.731625938262.3146588-0058028. The method of claim 1, wherein the administration comprises administering 120 mg, 240 mg, 300 mg, 480 mg, 600 mg or 720 mg of the anti-TSLP antibody.

9. The method of claim 1, wherein the administration comprises:(a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every two weeks thereafter as maintenance doses; or(a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every four weeks thereafter as maintenance doses; or(a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every eight weeks thereafter as maintenance doses; or(a) administering 300 mg of the anti-TSLP antibody weekly for 4 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every 12 weeks thereafter as maintenance doses; or(a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every 2 weeks thereafter as maintenance doses; or(a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every four weeks thereafter as maintenance doses; or(a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and(b) administering 300 mg of the anti-TSLP antibody every eight weeks thereafter as maintenance doses; or(a) administering 600 mg of the anti-TSLP antibody every 2 weeks as loading doses; and741625938262.3146588-005802(b) administering 300 mg of the anti-TSLP antibody every 12 weeks thereafter as maintenance doses.

10. The method of claim 1, wherein the treatment comprises at least one of:(a) an improved Eczema Area and Severity Index (EASI) score;(b) an improved Investigator Global Assessment (IGA) score; or(c) an improved Peak Pruritus Numerical Rating Scale (PP-NRS) score;(d) an improved Body Surface Estimate (BSA) score;(e) an improved Scoring Atopic Dermatitis (SCORAD) score;(f) an improved Patient- Oriented Eczema Measure (POEM) score;(g) an improved Dermatology Life Quality Index (DLQI) score;(h) an improved Atopic Dermatitis Control Tool (ADCT).

11. The method of claim 10, wherein the treatment comprises an improvement of the EASI, IGA, PP-NRS, BSA, SCORAD, POEM, DLQI and / or ADCT score of about 30-100%.

12. The method of claim 1, wherein the treatment comprises:(a) an about >50% improvement in EASI score (EASI50);(b) an about >75% improvement in EASI score (EASI75);(c) an about >90% improvement in EASI score (EASI90);(d) an about >95% improvement in EASI score (EASI95);(e) an IGA score of 0 or 1 ; or(f) a Facial IGA score of 0 or 1.

13. The method of claim 12, wherein the treatment comprises:(a) an about >50% improvement in EASI score (EASI50);(b) an about >75% improvement in EASI score (EASI75);(c) an about >90% improvement in EASI score (EASI90);(d) an about >95% improvement in EASI score (EASI95);(e) an IGA score of 0 or 1 ; or(f) a Facial IGA score of 0 or 1,by about two weeks after a final administration of the anti-TSLP antibody.

14. The method of claim 1, wherein the anti-TSLP antibody blocks human TSLP-TSLPR / IL7R interaction.751625938262.3146588-00580215. The method of claim 1, wherein the anti-TSLP antibody comprises a humanized antibody.

16. The method of claim 1, further comprising administration of therapeutic agent.

17. The method of claim 16, wherein the therapeutic agent comprises an anti-atopic dermatitis agent.

18. The method of claim 17, wherein the anti-atopic dermatitis agent comprises an anti-IL4 antibody, an anti-IL4R antibody, an anti-IL-13 antibody, an anti-IL13R antibody, an IL-5 antibody, and IL-5R antibody, an, IL- 17 antibody, an IL-17R antibody, an IL-25 antibody, an IL-25R antibody, an IL-31 antibody, an IL-31R antibody, an IL-33 antibody, an IL-33R antibody, or combinations thereof.761625938262.3

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