Method for treating moderate and severe psoriasis by using recombinant anti-IL-23p19 antibody

Abstract

Belongs to the field of disease treatment, and relates to application of a recombinant anti-IL-23p19 antibody in treatment of moderate and severe psoriasis and a method for treating moderate and severe psoriasis in a subject, and the method comprises the step of applying an effective amount of the anti-IL-23p19 antibody to the subject.

Description

A method for treating moderate to severe psoriasis with a recombinant anti-IL-23p19 antibody Technical Field

[0001] The present invention relates to the field of disease treatment. More specifically, the present invention relates to the use of a recombinant anti-IL-23p19 antibody in treating moderate to severe psoriasis. The present invention also relates to a method for treating moderate to severe psoriasis in a subject, comprising administering an effective amount of the anti-IL-23p19 antibody to the subject. Background Art

[0002] IL-23 is a heterodimeric cytokine member of the IL-12 family, composed of p40 and p19 subunits. IL-23 activates signaling pathways by binding to the IL-23 receptor (IL-23R) and the β1 subunit of the IL-12 receptor (IL-12Rβ1). Dysregulated IL-23 / Th17 / IL-17 responses leading to chronic inflammation underlie the pathophysiology of multiple autoimmune diseases, including psoriasis, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, and asthma.

[0003] Psoriasis is a chronic, recurrent, inflammatory, systemic disease mediated by the immune system and caused by the combined effects of genetics and the environment. It can occur in all age groups without gender differences. The typical clinical manifestations are scaly erythema or plaques, which are localized or widespread. It is non-contagious, difficult to treat, and often lifelong. Psoriasis can be divided into psoriasis vulgaris (including guttate psoriasis and plaque psoriasis), pustular psoriasis, erythrodermic psoriasis, and arthritis psoriasis. Currently, about 2% of the world's population suffers from psoriasis, 80-90% of patients have plaque psoriasis, and nearly one-third have moderate to severe cases. The prevalence of psoriasis varies significantly around the world. According to a survey conducted in 6 cities in China in 2008, it is estimated that there are more than 6 million psoriasis patients in China.

[0004] Currently, the main systemic drug treatments for psoriasis in China include methotrexate (MTX), cyclosporine A, retinoids, and biologics. In recent years, monoclonal antibody biologics targeting inflammatory cytokines have been used to treat severe psoriasis that is poorly treated with traditional systemic drugs, severely impacts quality of life, and is accompanied by significant joint symptoms. These include tumor necrosis factor α (TNF-α) antagonists (etanercept, infliximab, adalimumab); IL-12 / 23 antagonists (ustekinumab); and IL-17A antagonists (secukinumab). Among them, guselkumab (Johnson & Johnson), risankizumab (AbbVie), and tildrakizumab (Merck) are humanized IgG1 monoclonal antibodies that bind to the IL-23p19 subunit. They have demonstrated significant efficacy in treating plaque psoriasis and are used in several countries to treat moderate to severe plaque psoriasis. Currently, the use of biologics among psoriasis patients in China remains very low, and there remains a significant demand for effective, safe, and cost-effective domestic biologics.

[0005] Guselkumab, a first-in-class IL-23p19 antagonist, was approved in China in December 2019 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Stable guselkumab therapy is administered every eight or four weeks. After drug withdrawal, efficacy and the proportion of patients maintaining efficacy decline over time. Therefore, there remains a need in this field for products that can maintain efficacy longer after drug withdrawal, thereby reducing the burden on patients and improving their quality of life.

[0006] This application satisfies these urgent needs to a certain extent.

[0007] SUMMARY OF THE INVENTION

[0008] The inventors of the present invention unexpectedly discovered that the long half-life of the anti-IL-23p19 antibody of the present invention allows for long-interval dosing, allowing for dosing every 12 weeks after stable treatment. The inventors also discovered that the long half-life of the antibody of the present invention allows for a longer duration of therapeutic efficacy after drug withdrawal, and that a greater number of patients maintain therapeutic efficacy over the same period after drug withdrawal.

[0009] It can be seen that the administration of the anti-IL-23p19 antibody of the present invention, especially according to the dosage regimen of the present invention, has achieved encouraging therapeutic effects in patients with moderate to severe psoriasis, significantly improved the patients' skin lesions, and had overall safety and tolerability. It also provided a longer dosing interval and maintained the therapeutic effect for a longer time after drug withdrawal, thereby reducing the burden on patients and / or improving their quality of life.

[0010] The inventors of the present application also unexpectedly discovered that administration of the anti-IL-23p19 antibody according to the dosage regimen of the present invention can produce beneficial effects in treating moderate to severe psoriasis, and the safety profile is acceptable and controllable.

[0011] therefore,

[0012] In a first aspect, the present invention provides a method for treating moderate to severe psoriasis in a subject, the method comprising administering to the subject in need thereof an effective amount of an anti-IL-23p19 antibody.

[0013] In a second aspect, the present invention provides an anti-IL-23p19 antibody for use in treating moderate to severe psoriasis.

[0014] In a third aspect, the present invention provides use of the anti-IL-23p19 antibody of the present invention in the preparation of a medicament for treating moderate to severe psoriasis.

[0015] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention and one or more pharmaceutically acceptable excipients.

[0016] In a fifth aspect, the present invention provides a single pharmaceutical dosage unit comprising an anti-IL23p19 antibody of the present invention.

[0017] In a sixth aspect, the present invention relates to a pharmaceutical kit comprising the anti-IL23p19 antibody of the present invention or a single pharmaceutical dosage unit of the fifth aspect.

[0018] In a seventh aspect, the present invention relates to use of the single drug dosage unit of the fifth aspect or the complete drug kit of the sixth aspect in preparing a drug for treating moderate to severe psoriasis.

[0019] It should be understood that the technical solutions obtained by any combination of any technical features recorded in the first to seventh aspects above are also included in the present invention.

[0020] Other embodiments of the present invention will become apparent by reference to the detailed description which follows.

[0021] Detailed Description of the Invention

[0022] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terminology used herein is only for describing specific embodiments and is not intended to be limiting.

[0023] definition

[0024] 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. For the purposes of the present invention, the following terms are defined below.

[0025] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0026] The term "and / or" when used to link two or more alternatives should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0027] As used herein, the terms "comprising" or "including" are intended to include the recited elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms "comprising" or "including" are used, unless otherwise indicated, the context of consisting of the recited elements, integers, or steps is also encompassed. For example, when reference is made to an antibody variable region "comprising" a specific sequence, it is intended to encompass an antibody variable region consisting of that specific sequence.

[0028] The p19 subunit of IL-23 (also referred to herein as "IL-23p19" and "p19 subunit") is a 189 amino acid polypeptide containing a 21-amino acid leader sequence (Oppmann et al., Immunity 13:715 (2000), SEQ ID NO:181) and comprises four packed α-helices, designated A, B, C, and D, with an up-up-down-down topology. The four helices are connected by three polypeptide loops. The AB and CD loops are made relatively long because they connect the parallel helices. The short BC loop connects the antiparallel B and C helices. The p19 subunit of IL-23 is a member of the IL-6 family of helical cytokines. This family of cytokines binds to its cognate receptor via three conserved epitopes (sites I, II, and III; Bravo and Heath (2000) EMBO J. 19:2399-2411). The p19 subunit interacts with three cytokine receptor subunits to form a competent signaling complex. When expressed in cells, the p19 subunit initially forms a complex with the p40 subunit, which it shares with IL-12. The p19p40 complex is secreted from cells as a heterodimeric protein and is referred to as IL-23. In one embodiment, the IL-23p19 of the present invention is derived from humans (NCBI: AAG37232) or cynomolgus monkeys (NCBI: AEY84629).

[0029] As used herein, the terms "anti-IL-23p19 antibody," "anti-IL-23p19," "recombinant anti-IL-23p19 antibody," "IL-23p19 antibody," or "antibody that binds to IL-23p19" refer to an antibody that is capable of binding to a (human or cynomolgus monkey) IL-23p19 subunit or fragment thereof with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent in targeting (human or cynomolgus monkey) IL-23p19.

[0030] As used herein, the term "antibody" is used in the broadest sense to refer to a protein that contains an antigen binding site, encompassing natural antibodies and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies.

[0031] The terms "whole antibody," "full-length antibody," "complete antibody," and "intact antibody" are used interchangeably herein to refer to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, which are complementarity determining regions (CDRs), interspersed with more conserved regions, which are framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant region is not directly involved in binding the antibody to the antigen, but exhibits various effector functions.

[0032] The term "complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms a structurally determined loop ("hypervariable loop") and / or contains antigen contact residues ("antigen contact points"). CDR is primarily responsible for binding to the antigen epitope. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3.

[0033] In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment schemes, including, for example, Chothia based on the three-dimensional structure of antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0034] An exemplary AbM rule is as follows:

[0035] Unless otherwise indicated, in the present invention, when referring to residue positions in the variable region of an antibody (including heavy chain variable region residues and light chain variable region residues), the numbering refers to the position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0036] In one embodiment, the CDRs of an antibody of the invention have boundaries defined by the AbM rule.

[0037] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent or bispecific antibodies or fragments thereof; camelid antibodies; and bispecific or multispecific antibodies formed from antibody fragments.

[0038] The term "psoriasis" as used herein is a non-communicable disease with an unknown etiology, and it is generally believed that the immune system plays a role in its onset. Psoriasis has a genetic predisposition and can be induced by external factors such as infection. Psoriasis includes, but is not limited to, psoriasis vulgaris (including guttate psoriasis and plaque psoriasis), pustular psoriasis, erythrodermic psoriasis, and arthritis psoriasis (e.g., psoriatic arthritis). The psoriasis described herein can be any degree of psoriasis, such as mild, moderate, or severe psoriasis, wherein moderate and severe psoriasis ("moderate to severe psoriasis") have a higher risk of complications, such as ischemic heart disease, stroke, hypertension, dyslipidemia, diabetes, and Crohn's disease. The moderate standard in clinical guidelines is more than 3% of the cumulative body surface area of ​​lesions, and severe is more than 10%. The "moderate to severe psoriasis" of the clinical trial enrollment population is actually more than 10%, and the enrollment conditions of this study also follow this standard. Preferably, the psoriasis described herein is moderate to severe psoriasis, such as moderate to severe plaque psoriasis. Psoriasis often manifests as one or more red, silvery, shiny plaques on the scalp, elbows, knees, back, or buttocks. The eyebrows, underarms, navel, skin around the anus, and the junction of the buttocks and lower back may also be affected. It may also manifest as deformed, thickened, or concave nails. Depending on the affected area, psoriasis can be categorized as, for example, scalp psoriasis, nail psoriasis, palmoplantar psoriasis, and perineal psoriasis.

[0039] As used herein, the term "week 0" refers to the time point at which the IL-23p19 antibody is first administered. The term "week 4" as used herein refers to the fourth week from the time point at which the IL-23p19 antibody is first administered. The term "week 8" as used herein refers to the eighth week from the time point at which the IL-23p19 antibody is first administered. Other similar terms should be understood accordingly.

[0040] The terms "treat," ...

[0041] The term "effective amount" refers to the amount or dosage of a formulation or antibody of the present invention that, when administered to a patient in single or multiple doses, produces the desired effect in the treated patient. An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering a variety of factors, such as the species of mammal; its size, age, and general health; the specific disease involved; the extent or severity of the disease; the response of the subject patient; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; and the use of any concomitant therapy.

[0042] The term "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the required dosage and for the required period of time. A therapeutically effective amount of an agent, antibody or antibody fragment, or conjugate or composition of the invention can vary depending on a variety of factors, such as the disease state, age, sex, and weight of the subject, and the ability of the antibody or antibody portion to elicit a desired response in the subject. A therapeutically effective amount is also one in which any toxic or deleterious effects of the agent, antibody or antibody fragment, or conjugate or composition are outweighed by the therapeutically beneficial effects.

[0043] The term "formulation" or "pharmaceutical composition" refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to an animal, preferably a mammal (including a human). "Liquid formulation" or "liquid composition" refers to a formulation in liquid form. The liquid composition of the present invention comprises (i) an antibody according to the present invention; (ii) a buffer; and (iii) a solvent. The composition of the formulation of the present invention may be as shown in the embodiments of the present application relating to liquid pharmaceutical compositions. The liquid formulation of the present invention is preferably an injectable.

[0044] The term "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0045] As used herein, the term "buffer" refers to a pH buffer. For example, the buffer is selected from histidine, glutamate, phosphate, acetate, citrate, and tris.

[0046] As used herein, the term "solvent" refers to a liquid used to dissolve or suspend active ingredients and inactive ingredients to form a liquid formulation. The solvents that can be used in the present invention include, but are not limited to, water for injection, organic solvents for injection, but are not limited to, oil for injection, ethanol, propylene glycol, etc., or a combination thereof.

[0047] As used herein, the term "single pharmaceutical dosage unit" refers to a single pharmaceutical dosage form comprising an antibody of the present invention to be administered to a subject at the time of administration, such as an injection vial, ampoule, prefilled needle or prefilled syringe containing a solution or lyophilized powder of the drug.

[0048] The term "static Physician Global Assessment (sPGA)" records a physician's assessment of a subject's psoriasis status, including the following aspects: induration, scaling, and erythema. The sPGA is used to assess a subject's psoriasis lesions at a given time point. All lesions are graded based on the following scales: induration, erythema, and scaling. The sPGA score is calculated by dividing the total score of these three items by 3, as shown below.

[0049] Induration (I) (average of all lesions; measured using the National Psoriasis Foundation Reference card)

[0050] 0 = No evidence of raised plaques

[0051] 1 = small raised plaque, 0.25 mm

[0052] 2 = mild plaque elevation, 0.5 mm

[0053] 3 = Moderately raised plaque, 0.75 mm

[0054] 4 = obvious raised plaque, 1 mm

[0055] 5 = Severely raised plaque, ≥1.25 mm

[0056] Erythema (E) (average of all lesions)

[0057] 0 = No evidence of erythema, hyperpigmentation may be present

[0058] 1 = Faint erythema

[0059] 2 = Mild red

[0060] 3 = Medium red

[0061] 4 = Bright red

[0062] 5 = dark red to deep red

[0063] Scaling (S) (average of all lesions)

[0064] 0 = No evidence of scaling

[0065] 1 = Microscaly; occasional scaling in < 5% of total lesions

[0066] 2 = Mild; mainly fine scales

[0067] 3 = Moderate; mainly coarse scales

[0068] 4 = obvious; mainly thick, non-stubborn scales

[0069] 5 = Severe; predominantly very thick, stubborn scales

[0070] sPGA score = (I + E + S) / 3 (total average)

[0071] sPGA (static Physician Global Assessment) is evaluated based on the total average score:

[0072] 0 = Clear, removes some residual discoloration

[0073] 1 = Minimal; most lesions are scored as 1 point individually

[0074] 2 = Mild, most lesions are scored as 2 points individually

[0075] 3 = Moderate, most lesions are scored as 3 points individually

[0076] 4 = obvious, most lesions are scored as 4 points individually

[0077] 5 = severe, most lesions scored individually as 5 points

[0078] Note: Scores should be rounded to the nearest integer. If the total score is <1.50, score = 1; if the total score is ≥1.50, score = 2.

[0079] sPGA-G uses the sPGA evaluation criteria to perform local evaluation of perineal psoriasis, with a score of 0-5.

[0080] The term "Palmoplantar Psoriasis Severity Index" (PPASI) is a scoring system specifically used to assess the severity of palmoplantar psoriasis (i.e., psoriasis on the palms and soles). If the subject has palmoplantar psoriasis at baseline, the physician will assess it at the visit point specified in the protocol. The palm of each hand and the sole of each foot are individually assessed for erythema, induration and scaling, and the area of ​​involvement. Calculation is as follows:

[0081] Based on the proportion of the palms or soles affected by the lesions, the score is as follows:

[0082] 0 = Not involved

[0083] 1=<10%

[0084] 2=10%≤Range<30%

[0085] 3=30%≤Range<50%

[0086] 4=50%≤Range<70%

[0087] 5=70%≤Range<90%

[0088] 6=90%≤range≤100%

[0089] The lesions were then evaluated for erythema, induration, and scaling, with scores of 0-4 for each.

[0090] 0 = Clean

[0091] 1 = Light

[0092] 2 = Medium

[0093] 3 = Heavy

[0094] 4 = Very severe

[0095] The PPASI is a composite score calculated for each palm and sole, and is derived by multiplying the sum of the scores for erythema, induration, and scaling by the scores for the affected area of ​​the palms and soles, multiplied by a weighting factor (0.2 for each palm and 0.3 for each sole).

[0096] The PPASI calculation formula is as follows:

[0097] (Sum of the scores for erythema, induration, and scaling) × lesion involvement score × 0.2 (right palm) + (Sum of the scores for erythema, induration, and scaling) × lesion involvement score × 0.2 (left palm) + (Sum of the scores for erythema, induration, and scaling) × lesion involvement score × 0.3 (right sole) + (Sum of the scores for erythema, induration, and scaling) × lesion involvement score × 0.3 (left sole)

[0098] The value range is 0-72.

[0099] The term "Psoriasis Area and Severity Index (PASI)" is a systematic tool used to assess and grade the severity of psoriasis lesions and their response to treatment. PASI scores range from 0 to 72. It linearly combines the percentage of body surface area affected with the severity of erythema, induration, and scaling in four body regions. This endpoint is based on the percentage reduction from baseline and is usually summarized as a binomial distribution based on achieving X% reduction (or PSAIx), where X can be 50, 75, 90, and 100. To calculate PASI, the areas of four major body regions are assessed: head (h), trunk (t), upper extremities (u), and lower extremities (l), representing 10%, 30%, 20%, and 40% of the same body area, respectively.

[0100] The area of ​​psoriasis affecting these four parts is expressed numerically:

[0101] 0 = not involved;

[0102] 1 = <10%;

[0103] 2 = 10% - < 30%;

[0104] 3 = 30% - < 50%;

[0105] 4 = 50% - < 70%;

[0106] 5 = 70% - < 90%;

[0107] 6 = 90% - 100%

[0108] The severity of the lesions was assessed using a scale of 0 to 4, with 0 representing no skin involvement, 1 being mild, 2 being moderate, 3 being severe, and 4 being very severe. The scores for the four sites were presented separately.

[0109] To assist with area estimation, note the following:

[0110] a. The neck belongs to the head

[0111] b. The armpits and groin belong to the trunk

[0112] c. Buttocks belong to the lower limbs

[0113] PASI=0.1*(Eh+Ih+Sh)Ah+0.3*(Et+It+St)At+0.2*(Eu+Iu+Su)Au+0.4*(El+Il+Sl)Al

[0114] The Dermatology Life Quality Index (DLQI) is a patient-administered, 10-question quality of life questionnaire covering six domains: symptoms and feelings, daily activities, leisure, work and school, relationships, and treatment. The DLQI has a one-week recall period. Response categories include no problem (0), not at all (0), a little (1), a lot (2), and very much (3). Question 7 requires a "yes" / "no" answer, with a "yes" response scored as 3.

[0115] The DLQI was completed by the subjects themselves at the visits indicated in the flow chart.

[0116] DLQI is analyzed through the following six aspects:

[0117] Score corresponding to the option

[0118] For question 7, if you choose “Yes”, you will get the highest score of 3 points. If you choose “No”, you will get the score in the table based on the options.

[0119] The DLQI total score is calculated by summing the scores of each question, with the result ranging from 0 to 30. The higher the score, the more impaired the quality of life.

[0120] 0-1 points = no impact on the patient's life,

[0121] 2-5 points = small impact,

[0122] 6-10 = medium impact,

[0123] 11-20 = Very large impact,

[0124] 21-30 has a great impact on the patient's life.

[0125] If one answer to a question in a dimension is missing, the dimension is considered missing. If two or more questions are missing, the total DLQI score is considered missing. A change of 5 points from baseline is considered a clinically important difference.

[0126] The Psoriasis Scalp Severity Index (PSSI) is a system used to assess and grade scalp psoriasis lesions and their response to treatment. The PSSI is a scaled score ranging from 0 to 72. Disease severity is calculated as follows:

[0127] The scalp is evaluated based on the cumulative extent (measured at the hairline circumference) and the scores are as follows:

[0128] 0 = Not involved

[0129] 1=<10%

[0130] 2=10%≤Range<30%

[0131] 3=30%≤Range<50%

[0132] 4=50%≤Range<70%

[0133] 5=70%≤Range<90%

[0134] 6=90%≤range≤100%

[0135] The scalp lesions were then evaluated for erythema, induration, and scaling, with each scored 0-4 points.

[0136] 0 = Clean

[0137] 1 = Light

[0138] 2 = Medium

[0139] 3 = Heavy

[0140] 4 = Very severe

[0141] PSSI = (sum of erythema, induration, and scaling scores) × (score of cumulative scalp area)

[0142] The term "Nail Psoriasis Severity Index (NAPSI)" is a tool used to assess the severity of nail lesions in patients with psoriasis. It scores each nail based on the characteristics of the lesions on the nail (such as pitting, discoloration, nail plate shedding, etc.), and then summarizes the total score. If the subject has nail psoriasis, the doctor will assess the nail psoriasis at the visit point specified in the protocol. Two independent assessments are performed on each hand's five fingers, and the grading is as follows:

[0143] Nail quality assessment

[0144] 0 = None

[0145] 1 = 1 quadrant of the nail

[0146] 2 = Cumulative 2 quadrants of the nail

[0147] 3 = Cumulative 3 quadrants of the nail

[0148] 4 = 4 quadrants of the nail

[0149] Nail bed assessment

[0150] 0 = None

[0151] 1 = 1 quadrant of the nail

[0152] 2 = Cumulative 2 quadrants of the nail

[0153] 3 = Cumulative 3 quadrants of the nail

[0154] 4 = 4 quadrants of the nail

[0155] The sum of the scores ranges from 0 to 80. If a finger is not evaluated, the final score is calculated by adding the average of the remaining fingers to the total. If < 50% of the fingers are not evaluated, the score is imputed in this way; if > 50% of the fingers are not evaluated, the total score is considered missing.

[0156] The Global Assessment of Disease Activity for PsA (GADA) score is a tool used to assess psoriatic arthritis (PsA). It typically includes an assessment of arthritis symptoms, joint swelling, pain, and functional impairment, helping doctors determine disease severity and treatment effectiveness.

[0157] Diagnostic and treatment standards for psoriatic arthritis

[0158] Patients with inflammatory arthritis of the joints, spine, or tendons are diagnosed with psoriatic arthritis if their combined score is ≥ 3 points on the following five items:

[0159] 1. Evidence of psoriasis (not counted repeatedly)

[0160] - Current history of psoriasis skin lesions noted by a dermatologist or rheumatologist (2 points)

[0161] - Personal history of psoriasis confirmed by the patient, dermatologist, rheumatologist, or other qualified healthcare professional: 1 point

[0162] - Patient reports of a family history of psoriasis in a first- or second-degree relative (1 point)

[0163] 2. Physical examination reveals typical psoriatic nail changes (1 point)

[0164] 3. Rheumatoid factor negative 1 point

[0165] Detection using any method other than gel-based assay, preferably enzyme-linked immunosorbent assay or turbidimetric assay

[0166] 4. Dactylitis (not counted repeatedly)

[0167] - History of present illness with swelling of the entire finger (toe) 1 point

[0168] - History of dactylitis documented by a rheumatologist or dermatologist: 1 point

[0169] 5. Radiographic evidence of new bone formation near the joint: 1 point

[0170] X-rays of the hands and feet may show ossification with unclear boundaries at the joint edges (osteophytes need to be excluded).

[0171] Treatment

[0172] The present inventors conducted carefully designed clinical trials, comprehensively considering preclinical efficacy results as well as pharmacokinetics, pharmacodynamics, immunogenicity and toxicology in human subjects, and determined the use of the anti-IL-23p19 antibody of the present invention for the treatment of moderate to severe psoriasis and a suitable optimized dosing regimen.

[0173] In a first aspect, the present invention relates to a method for treating moderate to severe psoriasis, comprising administering an effective amount of an anti-IL-23p19 antibody to a subject in need thereof.

[0174] In some embodiments, the present invention provides a method for treating moderate to severe psoriasis in a subject using an anti-IL-23p19 antibody, comprising administering to the subject an effective amount of the anti-IL-23p19 antibody.

[0175] For the first aspect, further implementation plans are as follows:

[0176] In some embodiments, the anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region comprises GYTFTSYLMH (SEQ ID NO: 1) or consists thereof, the amino acid sequence of CDR2 of the heavy chain variable region comprises YINPYNEGTN (SEQ ID NO: 2) or consists thereof, and the amino acid sequence of CDR3 of the heavy chain variable region comprises NWDLPY (SEQ ID NO: 3) or consists thereof; the amino acid sequence of CDR1 of the light chain variable region of the antibody comprises RASQSISDYLH (SEQ ID NO: 4) or consists thereof, the amino acid sequence of CDR2 of the light chain variable region comprises YASQSMS (SEQ ID NO: 5) or consists thereof, and the amino acid sequence of the light chain CDR3 variable region comprises QQGHSFPFT (SEQ ID NO: 6) or consists thereof. In some embodiments, the boundaries of the CDRs are determined by the AbM rule.

[0177] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region, VH, and a light chain variable region, VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence at least 90%, 95%, 98% or 99% identical thereto:

[0178] Sequence (SEQ ID NO:7)

[0179] Sequence (SEQ ID NO:8)

[0180] In some embodiments, the recombinant anti-IL-23p19 antibody is an IgG1 antibody, preferably comprising SEQ ID NO: 9 or a heavy chain sequence at least 90%, 95%, 98% or 99% identical thereto and SEQ ID NO: 10 or a light chain sequence at least 90%, 95%, 98% or 99% identical thereto.

[0181] Sequence (SEQ ID NO:9)

[0182] Sequence (SEQ ID NO:10)

[0183] In some embodiments, the recombinant anti-IL-23p19 antibody comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In some embodiments, the recombinant anti-IL-23p19 antibody consists of the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0184] In some embodiments, the dose of the anti-IL-23p19 antibody administered per dose is 50 mg-500 mg, preferably 50 mg-300 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg. In some embodiments, the dose of anti-IL-23p19 antibody administered at each dose is 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg. In a preferred embodiment, the dose administered at each dose is the same or different during the dosing regimen.

[0185] In some embodiments, the above-mentioned method of treating moderate to severe psoriasis of the present invention comprises administering an anti-IL-23p19 antibody to a subject in need thereof, wherein 50 mg to 500 mg of the anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and once every 12 weeks thereafter. In some preferred embodiments, 100 to 200 mg of the anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and once every 12 weeks thereafter. In some more preferred embodiments, 200 mg of the anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and once every 12 weeks thereafter.

[0186] In some embodiments, the above methods of the present invention comprise administering 200 mg of an anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, followed by administering 50 mg to 300 mg of the anti-IL-23p19 antibody at week 20 and / or week 32 and / or week 44. In further embodiments, 50 mg to 250 mg of the anti-IL-23p19 antibody is administered at week 20 and / or week 32 and / or week 44; and in even more specific embodiments, 100 mg to 200 mg of the anti-IL-23p19 antibody is administered to a subject in need thereof at week 20 and / or week 32 and / or week 44. For example, 100 mg, 120 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg of the anti-IL-23p19 antibody is administered to a subject in need thereof. Specifically, 100 mg or 200 mg of the anti-IL-23p19 antibody is administered to a subject in need thereof at week 20 and / or week 32 and / or week 44.

[0187] In some embodiments, the above methods of the present invention comprise administering 200 mg of an anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, administering 50 mg-300 mg of an anti-IL-23p19 antibody at week 20, and then suspending administration of the anti-IL-23p19 antibody or continuing to administer a dose of 50 mg-300 mg at weeks 32 and 44, preferably, administering 50 mg-250 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44, more preferably, administering 100 mg-200 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44, and more preferably, administering 100 mg or 200 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44.

[0188] In some embodiments, the above method of the present invention comprises administering an anti-IL-23p19 antibody to a subject in need thereof according to the following regimen:

[0189] 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody is administered at week 20; or,

[0190] 2) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and administer 100 mg of anti-IL-23p19 antibody at week 20.

[0191] In some embodiments, the above method of the present invention further comprises detecting whether the subject has responded to treatment at week 32. In some preferred embodiments, the subject's response is defined as an improvement of at least 90% in PASI score relative to baseline PASI, i.e., PASI 90.

[0192] In some embodiments, the above methods of the present invention comprise administering an anti-IL-23p19 antibody to a subject who has responded at week 32 according to the following regimen:

[0193] 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody is administered at week 20, and 100 mg of anti-IL-23p19 antibody is administered at weeks 32 and 44; or

[0194] 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody at week 20, followed by withholding of anti-IL-23p19 antibody administration; or

[0195] 3) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0196] 4) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, administering 200 mg of anti-IL-23p19 antibody at week 20, and then suspending administration of anti-IL-23p19 antibody. In some embodiments, the above method of the present invention further comprises administering anti-IL-23p19 antibody to subjects who did not respond at week 32 according to the following regimen:

[0197] 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0198] 2) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44.

[0199] In some embodiments, the method comprises administering 200 mg of an anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, and further administering 100 mg or 200 mg of an anti-IL-23p19 antibody at week 20, and assessing the subject for a response at week 32, and

[0200] Subjects who responded at week 32 were given 100 mg or 200 mg of anti-IL-23p19 antibody at weeks 32 and 44, respectively;

[0201] Subjects who did not respond at week 32 were administered 200 mg of anti-IL-23p19 antibody at weeks 32 and 44, respectively.

[0202] For the purposes of this invention, "response" is defined as an improvement of at least 90% in the PASI score relative to baseline, or PASI 90. PASI 90 refers to a ≥90% improvement in the PASI score relative to baseline. The Psoriasis Area and Severity Index (PASI) is a systematic tool used to assess and grade the severity of psoriasis lesions and response to treatment.

[0203] In some embodiments, the method comprises:

[0204] 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and, if the subject is found to have a response at week 32, 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0205] 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody at week 20, with no further suspension of anti-IL-23p19 antibody administration if the subject is found to have a response at week 32; or

[0206] 3) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44 if the subject is found to be non-responsive at week 32; or

[0207] 4) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and, if the subject is found to have a response at week 32, 100 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0208] 5) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, administer 100 mg of anti-IL-23p19 antibody at week 20, and withhold administration of anti-IL-23p19 antibody when the subject is tested as having a response at week 32; or

[0209] 6) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44 if the subject is found to be non-responsive at week 32.

[0210] In some embodiments, the above method of the present invention further comprises detecting whether the subject has relapsed at week 36. In some preferred embodiments, if the subject's PASI response between weeks 36 and 44 loses more than 50% relative to the response at week 32, the subject is defined as having relapsed.

[0211] In some embodiments, for subjects who responded at week 32, the above method of the present invention further comprises detecting whether they relapse starting at week 36. In some preferred embodiments, if a subject loses more than 50% of the PASI response between week 36 and week 44 relative to the response at week 32, the subject is defined as having relapsed.

[0212] In some embodiments, for subjects who have responded at week 32 and continue to receive anti-IL-23p19 antibody administration, the above method of the present invention further comprises detecting whether they have relapsed starting at week 36. In some preferred embodiments, if the subject loses more than 50% of the PASI response between week 36 and week 44 relative to the response at week 32, the subject is defined as having relapsed.

[0213] In some embodiments, for subjects who responded at week 32 but suspended administration of the anti-IL-23p19 antibody after week 20, the above method of the present invention further comprises detecting whether they relapse starting at week 36. In some preferred embodiments, if the subject loses more than 50% of the PASI response between week 36 and week 44 relative to the response at week 32, the subject is defined as having relapsed.

[0214] In some embodiments, the above methods of the present invention further comprise administering 200 mg of the anti-IL-23p19 antibody to a subject who has relapsed, starting from the time of determination of relapse, once every four weeks until the final dose at the end of week 44. In other embodiments, for a subject who has responded at week 32, if the PASI response has lost more than 50% between weeks 36 and 44 relative to the response at week 32 (relapse), the subject is administered 200 mg of the anti-IL-23p19 antibody at intervals consistent with the dosing interval starting at week 0 (administering 200 mg of the anti-IL-23p19 antibody at weeks 0, 4, and 8, and every 12 weeks thereafter) until the final dose at the end of week 44.

[0215] In some embodiments, the method comprises:

[0216] 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and, if the subject is found to have a response at week 32, 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0217] 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody at week 20, withholding administration of anti-IL-23p19 antibody when the subject is tested as having a response at week 32; or

[0218] 3) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44 if the subject is found to be non-responsive at week 32; or

[0219] 4) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and, if the subject is found to have a response at week 32, 100 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0220] 5) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody at week 20, withholding administration of anti-IL-23p19 antibody when the subject is tested as having a response at week 32; or

[0221] 6) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44 if the subject is found to be non-responsive at week 32.

[0222] In a further embodiment, the above method further comprises:

[0223] For subjects receiving the administration regimen defined in 1), the subjects are tested for relapse starting at week 36. If the subject's PASI response loses more than 50% between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed. For relapsed subjects, 200 mg of the anti-IL-23p19 antibody is administered once every four weeks starting from the time of relapse until the final dose at the end of week 44.

[0224] For subjects receiving the administration regimen defined in 2), the subjects are tested for relapse starting at week 36. If the subject's PASI response loses more than 50% between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed. For relapsed subjects, 200 mg of the anti-IL-23p19 antibody is administered once every four weeks starting from the time of relapse until the final dose at the end of week 44.

[0225] For subjects receiving the administration regimen defined in 4), the subjects are tested for relapse starting at week 36. If the subject's PASI response loses 50% or more between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed. For relapsed subjects, 200 mg of the anti-IL-23p19 antibody is administered once every four weeks starting from the time of relapse until the final dose at the end of week 44; or

[0226] For subjects receiving the administration regimen defined in 5), the subjects are monitored for relapse starting at week 36. If the subject's PASI response loses 50% or more between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed. For relapsed subjects, 200 mg of the anti-IL-23p19 antibody is administered once every four weeks starting from the time of relapse determination until the final dose at the end of week 44.

[0227] In some embodiments, the anti-IL-23p19 antibodies of the present invention are formulated and administered as liquid pharmaceutical compositions. Suitable carriers and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils may be used as solvents or suspending media, where appropriate. For this purpose, any mixture of non-volatile mineral or non-mineral oils, including synthetic mono- or diglycerides, may be utilized. Furthermore, fatty acids such as oleic acid may also be used to prepare injectables.

[0228] In some embodiments, the pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention is a solution or dry powder formulation for injection. For example, the composition is a lyophilized powder, which can be reconstituted in a pharmaceutically acceptable liquid carrier to form an injection. The pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution.

[0229] In some embodiments, the pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention is a solution for injection, comprising 100.0 mg / mL of anti-IL23p19 antibody, 0.76 mg / mL of histidine, 1.08 mg / mL of histidine hydrochloride, 50.00 mg / mL of sorbitol, 0.5 mg / mL of polysorbate 80, pH 6.0, or consisting of said ingredients.

[0230] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the invention is administered topically.

[0231] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the invention is administered by subcutaneous injection.

[0232] In some embodiments, the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

[0233] The formulation of the anti-IL-23p19 antibody of the present invention comprises 100.0 mg / mL of anti-IL23p19 antibody, 0.76 mg / mL of histidine, 1.08 mg / mL of histidine hydrochloride, 50.00 mg / mL of sorbitol, and 0.5 mg / ml of polysorbate 80, with a pH of 6.0.

[0234] Preferably, the formulation of the IL-23p19 antibody can be prepared according to the method disclosed in PCT application number PCT / CN2021 / 093219 (international application date: May 12, 2021).

[0235] In some embodiments, the moderate to severe psoriasis is moderate to severe plaque psoriasis.

[0236] In some embodiments, the subject has moderate to severe plaque psoriasis for ≥ 6 months, with or without psoriatic arthritis.

[0237] In some embodiments, the subject has moderate to severe plaque psoriasis involving ≥10% of body surface area (BSA), a Psoriasis Area and Severity Index (PASI) ≥12 points, and a static Physician Global Assessment (sPGA) ≥3 points.

[0238] In some embodiments of the aforementioned methods, following administration, the subject does not experience a serious adverse event.

[0239] In some embodiments of the above methods, following administration, the subject experiences an adverse event at a rate comparable to that of subjects receiving a placebo.

[0240] In some embodiments of the above methods, the subject is a human.

[0241] use

[0242] In a second aspect, the present invention relates to use of a recombinant anti-IL-23p19 antibody in the preparation of a medicament for treating moderate to severe psoriasis in a subject.

[0243] In a third aspect, the present invention relates to a recombinant anti-IL-23p19 antibody for treating moderate to severe psoriasis.

[0244] For the second and third aspects, further embodiments are as follows:

[0245] In some embodiments, the anti-IL23p19 antibody of the present invention comprises a heavy chain variable region and a light chain variable region, which further comprise the following six CDRs:

[0246] - heavy chain VH CDR1 of GYTFTSYLMH (SEQ ID NO: 1);

[0247] - Heavy chain VH CDR2 of YINPYNEGTN (SEQ ID NO: 2);

[0248] - heavy chain VH CDR3 of NWDLPY (SEQ ID NO: 3);

[0249] - light chain VLCDR1 of RASQSISDYLH (SEQ ID NO: 4);

[0250] - light chain VL CDR2 of YASQSMS (SEQ ID NO: 5); and

[0251] -Light chain VL CDR3 of QQGHSFPFT (SEQ ID NO: 6).

[0252] In some embodiments, the recombinant anti-IL-23p19 antibody comprises a heavy chain variable region, VH, and a light chain variable region, VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0253] In some embodiments, the recombinant anti-IL-23p19 antibody is an IgG1 antibody, preferably comprising SEQ ID NO: 9 or a heavy chain sequence at least 90%, 95%, 98% or 99% identical thereto and SEQ ID NO: 10 or a light chain sequence at least 90%, 95%, 98% or 99% identical thereto.

[0254] In some embodiments, the recombinant anti-IL-23p19 antibody comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10. In some embodiments, the recombinant anti-IL-23p19 antibody consists of the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0255] In some embodiments, the dose of the anti-IL-23p19 antibody administered per dose is 50 mg-500 mg, preferably 50 mg-300 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg. In some embodiments, the dose of anti-IL-23p19 antibody administered at each dose is 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg. In a preferred embodiment, the dose administered at each dose is the same or different during the dosing regimen.

[0256] In some embodiments, the above-mentioned use of the present invention comprises administering 50 mg to 500 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and once every 12 weeks thereafter. In some preferred embodiments, 100 to 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and once every 12 weeks thereafter. In some more preferred embodiments, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and once every 12 weeks thereafter.

[0257] In some embodiments, the above-mentioned use of the present invention comprises administering 200 mg of anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, and administering 50 mg to 300 mg of anti-IL-23p19 antibody at week 20 and / or week 32 and / or week 44. In a further embodiment, 50 mg to 250 mg of anti-IL-23p19 antibody is administered at week 20 and / or week 32 and / or week 44; in an even more specific embodiment, 100 mg to 200 mg of anti-IL-23p19 antibody is administered to a subject in need thereof at week 20 and / or week 32 and / or week 44. For example, 100 mg, 120 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg of anti-IL-23p19 antibody is administered to a patient in need thereof. Specifically, 100 mg or 200 mg of the anti-IL-23p19 antibody is administered to a subject in need thereof at week 20 and / or week 32 and / or week 44.

[0258] In some embodiments, the above methods of the present invention comprise administering 200 mg of anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, administering 50 mg-300 mg of anti-IL-23p19 antibody at week 20, and then suspending administration of anti-IL-23p19 antibody or continuing to administer 50 mg-300 mg of anti-IL-23p19 antibody at weeks 32 and 44, preferably, administering 50 mg-250 mg of anti-IL-23p19 antibody at weeks 20, 32, and 44, more preferably, administering 100 mg-200 mg of anti-IL-23p19 antibody at weeks 20, 32, and 44, and more preferably, administering 100 mg or 200 mg of anti-IL-23p19 antibody at weeks 20, 32, and 44.

[0259] In some embodiments, the above-mentioned use of the present invention comprises administering an anti-IL-23p19 antibody to a subject in need thereof according to the following regimen:

[0260] 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody is administered at week 20; or,

[0261] 2) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and administer 100 mg of anti-IL-23p19 antibody at week 20.

[0262] In some embodiments, the use of the present invention further comprises detecting whether the subject has responded to the treatment at week 32. In some preferred embodiments, the subject's response is defined as an improvement of at least 90% in PASI score relative to baseline PASI, i.e., PASI 90.

[0263] In some embodiments, the above use of the present invention comprises administering an anti-IL-23p19 antibody to a subject who has responded at week 32 according to the following regimen:

[0264] 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody is administered at week 20, and 100 mg of anti-IL-23p19 antibody is administered at weeks 32 and 44; or

[0265] 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody at week 20, followed by withholding of anti-IL-23p19 antibody administration; or

[0266] 3) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0267] 4) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, administer 200 mg of anti-IL-23p19 antibody at week 20, and then suspend administration of anti-IL-23p19 antibody.

[0268] In some embodiments, the above use of the present invention further comprises detecting whether the subject has relapsed at week 36. In some preferred embodiments, if the PASI response of the subject loses more than 50% between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed.

[0269] In some embodiments, for subjects who responded at week 32, the above-mentioned use of the present invention further comprises detecting whether they relapse starting at week 36. In some preferred embodiments, if a subject loses more than 50% of its PASI response between week 36 and week 44 relative to its response at week 32, the subject is defined as having relapsed.

[0270] In some embodiments, for subjects who have responded at week 32 and continue to receive anti-IL-23p19 antibody administration, the above-mentioned use of the present invention further comprises detecting whether they have relapsed starting at week 36. In some preferred embodiments, if the subject loses more than 50% of the PASI response between week 36 and week 44 relative to the response at week 32, the subject is defined as having relapsed.

[0271] In some embodiments, for subjects who responded at week 32 but suspended administration of the anti-IL-23p19 antibody after week 20, the above-mentioned use of the present invention further comprises detecting whether they relapse starting at week 36. In some preferred embodiments, if the PASI response of a subject loses more than 50% between weeks 36 and 44 relative to the response at week 32, the subject is defined as having relapsed.

[0272] In some embodiments, the use of the present invention further comprises administering 200 mg of the anti-IL-23p19 antibody to the relapsed subject once every four weeks starting from the time of relapse, until the first administration at the end of the 44th week.

[0273] In some embodiments, the use of the present invention further comprises administering an anti-IL-23p19 antibody to a subject who has no response at week 32 according to the following regimen:

[0274] 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or

[0275] 2) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44.

[0276] In some embodiments, the use comprises administering 200 mg of the anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, 100 mg or 200 mg of the anti-IL-23p19 antibody at week 20, and to a subject who responds at week 32, 100 mg or 200 mg of the anti-IL-23p19 antibody at weeks 32 and 44, respectively.

[0277] Among them, the use includes administering 200 mg of anti-IL-23p19 antibody to subjects in need at weeks 0, 4 and 8, administering 100 mg or 200 mg of anti-IL-23p19 antibody at week 20, and administering 200 mg of anti-IL-23p19 antibody to subjects who have no response at week 32, respectively, at weeks 32 and 44.

[0278] Single dose unit

[0279] In a fourth aspect, the present invention relates to a single pharmaceutical dosage unit, characterized in that it comprises the anti-IL23p19 antibody of the present invention.

[0280] In some embodiments, the single pharmaceutical dosage unit comprises the anti-IL-23p19 antibody at a dose comprising a fixed dose of 50 mg to 500 mg; more preferably, comprising 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg of anti-IL-23p19 antibody.

[0281] In some embodiments, the single-dose unit is a single-dose unit packaged in a prefilled autoinjector pen.

[0282] Complete set of medicine boxes

[0283] The present invention also provides a kit comprising an effective amount of the anti-IL-23p19 antibody; preferably, comprising a fixed dose of 50 mg to 500 mg; more preferably, comprising 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg of the anti-IL-23p19 antibody;

[0284] Specifically, a package insert containing instructions for using the anti-IL-23p19 antibody to treat moderate to severe psoriasis in a subject is also included.

[0285] In some embodiments, the kit comprises the anti-IL-23p19 antibody in the form of a single-dose unit. In other embodiments, the single-dose unit is packaged in a prefilled autoinjector pen.

[0286] application

[0287] The present invention also provides use of the anti-IL-23p19 antibody, single-dose unit, and complete drug kit of the present invention in preparing a medicament for treating moderate to severe psoriasis.

[0288] The method of treating moderate to severe psoriasis with the anti-IL-23p19 antibody of the present invention has the characteristics of a long half-life and a long interval of administration. After stable treatment, the antibody is administered once every 12 weeks, which has the potential to maintain therapeutic effects for a longer period of time after drug withdrawal, and a larger number of patients can maintain therapeutic effects within the same period of time after drug withdrawal. Example

[0289] Example 1. Preparation and purification of IL-23p19 antibody

[0290] The antibody 17D1-YTE, which specifically binds to IL-23p19, was obtained according to PCT application number PCT / CN2019 / 121261. The antibody has a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. PCT application number PCT / CN2019 / 121261 is hereby incorporated by reference in its entirety.

[0291] Briefly, the antibody was recombinantly expressed in CHO cells and purified by affinity chromatography to obtain the IL-23p19 antibody sample used in the pH screening experiment of the present invention, and by cation exchange chromatography to obtain the IL-23p19 antibody sample used in the formulation screening experiment of the present invention.

[0292] Example 2. Clinical study

[0293] Preclinical pharmacokinetic (PK), pharmacodynamic (PD), and toxicology studies demonstrate that the anti-IL-23p19 antibody has a clear target, a well-defined mechanism of action, and significant anti-inflammatory effects. It is expected to reduce or even clear skin lesions, improve the severity of lesions, and reduce the cumulative body surface area of ​​lesions in subjects with plaque psoriasis. The anti-IL-23p19 antibody exhibits linear PK characteristics in cynomolgus monkeys, a long half-life, and high bioavailability. It demonstrates high safety in cynomolgus monkeys after repeated short-term and long-term dosing, and demonstrates no risk of hemolysis or cytokine release in vitro.

[0294] The anti-IL-23p19 antibody of this application has completed a Phase I randomized, double-blind, placebo-controlled safety and tolerability clinical study in healthy subjects with single-dose escalation. The results showed that the anti-IL-23p19 antibody is safe and well tolerated in healthy people.

[0295] The anti-IL-23p19 antibody of this application has completed a Phase II multicenter, randomized, double-blind, placebo-controlled clinical study across a range of doses in moderate to severe plaque psoriasis and has achieved the primary efficacy endpoint. The Phase II study results showed that the anti-IL-23p19 monoclonal antibody can significantly improve the skin lesions of subjects in the treatment of moderate to severe plaque psoriasis and has good overall safety and tolerability. In addition, the 52-week data demonstrated the advantages of the anti-IL-23p19 antibody in long-term efficacy and significantly improved the quality of life of subjects compared with the placebo group.

[0296] The above results support further clinical research of anti-IL-23P19 antibodies.

[0297] This multicenter, randomized, double-blind, placebo-controlled Phase III study of an anti-IL-23p19 antibody, with randomized withdrawal and retreatment, aims to evaluate the efficacy of maintenance therapy with the anti-IL-23p19 antibody relative to withdrawal and to determine the duration of efficacy after withdrawal. This is also the first randomized withdrawal and retreatment Phase III study of a drug with the same target in China, aiming to provide more extensive confirmatory data supporting the efficacy and safety of the anti-IL-23p19 antibody in subjects with moderate-to-severe plaque psoriasis.

[0298] 3.1 Research Objectives

[0299] Main purpose:

[0300] To evaluate the maintenance of efficacy of an anti-IL-23p19 antibody in the treatment of moderate to severe plaque psoriasis after randomized withdrawal of treatment.

[0301] Secondary purpose:

[0302] To evaluate the efficacy of anti-IL-23p19 antibodies in retreatment of moderate-to-severe plaque psoriasis in participants who relapsed after randomized withdrawal of treatment.

[0303] To evaluate the safety of anti-IL-23p19 antibodies in the treatment of moderate to severe plaque psoriasis;

[0304] To evaluate the immunogenicity of anti-IL-23p19 antibodies in patients with moderate to severe plaque psoriasis;

[0305] To evaluate the effects of anti-IL-23p19 antibody therapy on health-related quality of life in patients with moderate-to-severe plaque psoriasis.

[0306] Other purposes:

[0307] To evaluate the effectiveness of anti-IL-23p19 antibodies for the treatment of scalp psoriasis in patients with pre-existing scalp psoriasis;

[0308] To evaluate the effectiveness of anti-IL-23p19 antibodies for the treatment of nail psoriasis in patients with pre-existing nail psoriasis;

[0309] To evaluate the effectiveness of anti-IL-23p19 antibodies for the treatment of palmoplantar psoriasis in patients with pre-existing palmoplantar psoriasis;

[0310] To evaluate the effectiveness of anti-IL-23p19 antibodies in treating perineal psoriasis in patients with pre-existing perineal psoriasis;

[0311] To investigate the effectiveness of anti-IL-23p19 antibodies on baseline PsA activity scores in patients with psoriatic arthritis (PsA).

[0312] 3.2 Study Endpoints

[0313] Primary endpoint:

[0314] - The proportion of subjects achieving a ≥90% improvement in the Psoriasis Area and Severity Index (PASI) at Week 56 (PASI 90).

[0315] Secondary endpoints:

[0316] Secondary efficacy endpoints

[0317] - the proportion of subjects achieving a PASI improvement of ≥75% (PASI 75) at Week 56;

[0318] - the proportion of subjects achieving 100% improvement in PASI (PASI 100) at Week 56;

[0319] - Proportion of subjects achieving sPGA clear (score of 0) or nearly clear (score of 1) at Week 56.

[0320] - Proportion of subjects achieving sPGA clearance (score 0) at Week 56;

[0321] - the proportion of subjects with a DLQI score of 0 / 1 at Week 56;

[0322] - Time to subject's loss of PASI 90;

[0323] - Changes in PASI and sPGA in relapsed and re-treated subjects

[0324] Safety endpoints

[0325] All adverse events, including serious adverse events, etc. Changes in vital signs, physical examinations, laboratory tests, electrocardiograms, etc. before and after drug administration.

[0326] Immunogenicity evaluation

[0327] The production of anti-drug antibodies (ADA) and neutralizing antibodies (NAb).

[0328] Other endpoints:

[0329] - Changes from baseline in DLQI at different time points;

[0330] - Proportion of participants achieving PASI 90, PASI 75, PASI 100, sPGA 0, or sPGA 0 / 1 at different time points, and proportion of participants achieving DLQI 0 / 1 at different time points;

[0331] - Change in PSSI from baseline at different time points (limited to participants with scalp psoriasis at baseline);

[0332] - Change in NAPSI from baseline at different time points (limited to participants with concurrent nail psoriasis at baseline);

[0333] - Change in PPASI from baseline at different time points (limited to participants with palmoplantar psoriasis at baseline);

[0334] - Change from baseline in sPGA-G at different time points (limited to participants with perineal psoriasis at baseline);

[0335] - Changes from baseline in the Psoriatic Arthritis Disease Activity Score at different time points (limited to subjects with baseline psoriatic arthritis).

[0336] 3.3 Research Design

[0337] This multicenter, randomized, double-blind, placebo-controlled study, with a randomized withdrawal and retreatment design, primarily evaluated the maintenance of efficacy of subcutaneous anti-IL-23p19 antibody in the treatment of moderate-to-severe plaque psoriasis after randomized withdrawal. The target population was men and women aged 18 to 75 years who had been diagnosed with plaque psoriasis for at least 6 months prior to the first dose of study drug, with or without psoriatic arthritis. Participants diagnosed with plaque psoriasis had to have an sPGA ≥ 3, a PASI ≥ 12, and ≥ 10% body surface area (BSA) involvement.

[0338] The study plans to enroll approximately 550 patients with moderate to severe plaque psoriasis.

[0339] After 4 weeks of screening, subjects who met the inclusion criteria received subcutaneous injections of 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively. At week 20, they were randomly divided into two groups in a 1:1 ratio to receive 200 mg or 100 mg of anti-IL-23p19 antibody, respectively. Previous use of biologics was used as a stratification factor.

[0340] At week 32, all subjects in each group were assessed for response to treatment (defined as an improvement in PASI score of at least 90% from baseline (ASI90). Responding subjects in each group were then re-randomized. Responding subjects in the group that had previously received 200 mg of anti-IL-23p19 antibody were re-randomized in a 1:1 ratio into two groups: one group continued to receive 200 mg of anti-IL-23p19 antibody treatment (i.e., the 200 mg maintenance treatment group) and the other group received placebo (i.e., the 200 mg withdrawal treatment group). Responding subjects in the group that had previously received 100 mg of anti-IL-23p19 antibody were re-randomized in a 1:1 ratio into two groups: one group continued to receive 100 mg of anti-IL-23p19 antibody treatment (i.e., the 100 mg maintenance treatment group) and the other group received placebo (i.e., the 100 mg withdrawal treatment group). All groups received the corresponding drug every 12 weeks starting at week 32, with the last dose at week 44. Subjects who did not respond at week 32 in the groups that received either 200 mg or 100 mg of anti-IL-23p19 antibody at week 20 received 200 mg of anti-IL-23p19 antibody at weeks 32 and 44, respectively.

[0341] For subjects who were assessed as responding to treatment at week 32 and were re-randomized, they were considered relapsers if their PASI response decreased by more than 50% between weeks 36 and 44 compared with the PASI response at week 32. For relapsers, 200 mg of anti-IL-23p19 antibody was administered every four weeks starting from the time of relapse confirmation until the last dose at the end of week 44; if the PASI response decreased by more than 50% from week 48 compared with the PASI response at week 32, the subject was withdrawn from the study.

[0342] The subjects received their last dose at week 44 and were followed up until week 56. Subjects who completed the week 56 visit were considered to have completed the study.

[0343] 3.4 Inclusion Criteria

[0344] Eligible subjects must meet all of the following inclusion criteria:

[0345] (1) Male or female aged 18 years or younger than 75 years;

[0346] (2) diagnosed with plaque psoriasis for ≥6 months, with or without psoriatic arthritis;

[0347] (3) body surface area (BSA) involved by plaque psoriasis ≥10% at screening and baseline, Psoriasis Area and Severity Index (PASI) ≥12 points, and static physician global assessment (sPGA) ≥3 points;

[0348] (4) The subjects are suitable for phototherapy and / or systemic treatment of psoriasis;

[0349] (5) Have a full understanding of the purpose of the trial, and a basic understanding of the pharmacological effects of the trial drugs and possible adverse reactions; voluntarily sign the informed consent form in accordance with the spirit of the Declaration of Helsinki.

[0350] 3.5 Exclusion criteria

[0351] Eligible subjects must not meet any of the following exclusion criteria:

[0352] (1) diagnosed with other types of psoriasis other than plaque psoriasis (guttate psoriasis, pustular psoriasis, or erythrodermic psoriasis);

[0353] (2) diagnosed with drug-induced psoriasis (e.g., psoriasis caused by β-blockers, calcium channel inhibitors, etc.);

[0354] (3) Patients who had previously used anti-IL23P19 antibodies or IL-23 target therapy;

[0355] (4) Receiving topical treatment drugs that may affect the evaluation of psoriasis within 2 weeks before the first use of the study drug (including but not limited to glucocorticoids, vitamin D3 derivatives, retinoic acid drugs, calcineurin inhibitors, keratinogens and compound preparations, etc.);

[0356] (5) Received systemic drug treatment that may affect the evaluation of psoriasis within 4 weeks before the first use of study drug (including but not limited to methotrexate, cyclosporine, tretinoin, azathioprine, leflunomide, mycophenolate mofetil, sulfasalazine, glucocorticoids, JAK inhibitors such as tofacitinib, baricitinib, or traditional Chinese medicine or Chinese patent medicine for the treatment of psoriasis);

[0357] (6) Received tumor necrosis factor-α (TNF-α) antagonists (including but not limited to etanercept, infliximab, and adalimumab) within 3 months before the first use of study drug (or within 5 half-lives of the drug);

[0358] (7) Received IL-17 target treatment (including but not limited to secukinumab, ixekizumab, etc.) within 6 months before the first use of the study drug (or within 5 half-lives of the drug);

[0359] (8) Use of Natalizumab, or B cell or T cell regulators (such as rituximab, abatacept, or visilizumab) within 12 months before the first medication;

[0360] (9) Used psoriasis phototherapy within 1 month before the first medication, and / or was unwilling to avoid continuous sun exposure and other ultraviolet light sources during the study period;

[0361] (10) There is evidence that the subject has serious, progressive, uncontrolled (including but not limited to) cardiovascular disease, neuromuscular disease, blood disease, respiratory disease, liver or digestive disease, urinary disease, neurological or psychiatric disease;

[0362] (11) had opportunistic infections within 6 months before screening [such as herpes zoster (severe or recurrent), active cytomegalovirus, Pneumocystis carinii, Histoplasma, Aspergillus, Mycobacterium, etc.];

[0363] (12) Known history of recurrent or chronic infection, including but not limited to chronic kidney infection, chronic chest infection (such as bronchiectasis), recurrent urinary tract infection, open, draining or infected wounds on the skin;

[0364] (13) A history of severe infection (e.g., sepsis, pneumonia, pyelonephritis), or hospitalization or intravenous antibiotic treatment due to infection within 2 months before screening;

[0365] (14) having a malignant tumor or a history of malignant tumor (except for skin squamous cell carcinoma, basal cell carcinoma, or localized cervical carcinoma in situ that has been successfully removed and has no evidence of recurrence or metastasis within 5 years);

[0366] (15) have or have had a lymphoproliferative disease, or have symptoms or signs suggestive of a lymphoproliferative disease within 5 years prior to screening, such as lymphadenopathy and / or splenomegaly;

[0367] (16) Patients with a history of active tuberculosis or clinical manifestations suspected of tuberculosis (including but not limited to pulmonary tuberculosis, lymphadenopathy, tuberculous pleurisy, etc.); Screen the subjects' tuberculosis status through interferon gamma release assay (IGRA) and chest X-ray. For subjects without active tuberculosis symptoms and imaging evidence of tuberculosis, if:

[0368] - Negative IGRA test result, eligible for enrollment;

[0369] - Inconclusive IGRA test results can be retested. Those with inconclusive results after retesting are not eligible for enrollment;

[0370] - Patients with positive IGRA test results can be re-screened and evaluated after receiving preventive anti-tuberculosis treatment for at least 1 month. Patients who have no tuberculosis symptoms, tolerate tuberculosis drugs well, and are willing to receive complete preventive anti-tuberculosis treatment during the study period can be included in the study group after evaluation by the researchers.

[0371] (17) BCG vaccination within 12 months before the first use of study drug, or plan to receive BCG vaccination during the study or within 12 months after the last study treatment;

[0372] (18) Received a live vaccine or bacterial vaccine within 3 months before the first use of the study drug, or planned to receive a live vaccine or bacterial vaccine during the study or within 3 months after the last study treatment;

[0373] (19) Received treatment with an investigational biologic within 6 months before the first use of the study drug, or received any investigational treatment within 30 days, or within 5 half-lives of the study drug, or is currently participating in a clinical study;

[0374] (20) The results of routine blood tests and blood biochemistry tests during the screening and baseline periods meet the following conditions:

[0375] - Any index of hemoglobin, red blood cells, white blood cells, neutrophils, or platelets is less than the lower limit of normal value (LLN), and the abnormality is judged by the investigator to be clinically significant;

[0376] - Alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), or direct bilirubin (DBIL) > 2 times the upper limit of normal value (ULN);

[0377] - Creatinine (Cr) > ULN;

[0378] If the patient meets the requirements of the plan after review, he or she may be included in the group.

[0379] (21) Virus test results during screening meet any of the following conditions:

[0380] - Positive for human immunodeficiency virus (HIV) antibodies;

[0381] - Hepatitis C virus (HCV) antibody positive with no history of successful treatment, where successful treatment is defined as completion of antiviral therapy for at least 24 weeks with negative HCV RNA status;

[0382] - Hepatitis B virus (HBV) screening should include at least hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb). If the test results of the above three indicators are: HBsAg positive; or if only HBcAb is positive when HBsAg is negative, HBV DNA testing is required and the test result is positive;

[0383] - Positive syphilis-specific antibodies (except for those whose non-specific syphilis antibodies titer turns negative after regular syphilis treatment).

[0384] (22) The following clinically significant 12-lead electrocardiogram (ECG) abnormalities at screening: QTcF>450ms, shortened or delayed PR interval, second-degree or third-degree atrioventricular block, preexcitation syndrome, long QT syndrome; or severe arrhythmia requiring treatment;

[0385] (23) Those who have had severe drug or food allergic reactions in the past, and / or those who are allergic to the experimental drugs or their ingredients;

[0386] (24) history of alcohol and drug abuse within 12 months before screening;

[0387] (25) Female subjects are pregnant or lactating, or female subjects of childbearing age have a positive pregnancy test before screening and administration;

[0388] (26) Those who have plans to have children during the study period and within 6 months after the administration of the study drug, or those who are unwilling to take contraceptive measures (such as condoms, etc.) deemed appropriate by the doctor during the trial;

[0389] (27) Those who the researcher considers are not suitable to participate in this clinical trial due to various reasons.

[0390] 3.6 Study Drug Dosage and Administration

[0391] Participants received a subcutaneous injection of 200 mg of anti-IL23p19 antibody at weeks 0, 4, and 8. At week 20, participants were randomized in a 1:1 ratio to receive either 200 mg or 100 mg of anti-IL23p19 antibody. At week 32, responding participants (achieving PASI 90) in each group underwent a second randomization (re-randomization).

[0392] Responding subjects who received 200 mg of anti-IL23p19 antibody at week 20 were divided into a 200 mg maintenance treatment group and a 200 mg withdrawal group. Subjects in the 200 mg maintenance treatment group received 200 mg of anti-IL23p19 antibody at weeks 32 and 44, respectively, with the last dose at week 44. Subjects in the 200 mg withdrawal group received the corresponding placebo at weeks 32 and 44, respectively, with the last dose at week 44.

[0393] Responding subjects who received 100 mg of anti-IL23p19 antibody at week 20 were divided into a 100 mg maintenance treatment group and a 100 mg withdrawal group. Subjects in the 100 mg maintenance treatment group received 100 mg of anti-IL23p19 antibody at weeks 32 and 44, respectively, with the last dose at week 44; subjects in the 100 mg withdrawal group received the corresponding placebo at weeks 32 and 44, respectively, with the last dose at week 44.

[0394] All subjects who did not respond at week 32 received 200 mg of anti-IL23p19 antibody at weeks 32 and 44.

[0395] Participants who responded at week 32 but relapsed between weeks 36 and 44 received three subcutaneous injections of 200 mg of anti-IL23p19 antibody every four weeks upon relapse.

[0396] Specifically:

[0397] 100 mg-maintenance treatment group: 200 mg of anti-IL-23p19 antibody subcutaneously at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody subcutaneously at week 20, and every 12 weeks thereafter until week 44 (last dose);

[0398] 100 mg-withdrawal / placebo group: 200 mg of anti-IL-23p19 antibody subcutaneously at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody subcutaneously at week 20, and placebo every 12 weeks thereafter until week 44 (last dose);

[0399] 200 mg-maintenance treatment group: 200 mg of anti-IL-23p19 antibody was administered subcutaneously at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody was administered subcutaneously at week 20, and then every 12 weeks until week 44 (last dose);

[0400] 200 mg-withdrawal / placebo group: 200 mg anti-IL-23p19 antibody was administered subcutaneously at weeks 0, 4, and 8, and 200 mg anti-IL-23p19 antibody was administered subcutaneously at week 20, followed by placebo every 12 weeks thereafter until week 44 (last dose).

[0401] For subjects who were tested as responders at Week 32 and did not receive anti-IL-23p19 antibody after Week 20, if their PASI response between Weeks 36 and 44 decreased by 50% or more compared to the PASI response at Week 32, they were considered relapsers. These relapsers were given 200 mg of anti-IL-23p19 antibody once every four weeks for three doses at the time of relapse, until the final dose at Week 44. If, starting from Week 48, the subject's PASI response decreased by 50% or more compared to the response at Week 32, they were withdrawn from the study.

[0402] For subjects who did not respond at week 32, 200 mg of anti-IL23p19 antibody was administered at weeks 32 and 44.

[0403] 3.7 Treatment compliance

[0404] Patients received study treatment at the study center, and treatment compliance was monitored using medication delivery and receipt records, subject medical records, and eCRFs.

[0405] 3.8 Indicators related to efficacy evaluation

[0406] 3.8.1.PASI

[0407] The Psoriasis Area and Severity Index (PASI) is a systematic tool used to grade the severity of psoriasis lesions and their response to treatment. PASI scores range from 0 to 72.

[0408] Whenever possible, the physician who performed the PASI assessment on the subject at screening / baseline should also perform the PASI assessment on the subject at subsequent follow-up visits.

[0409] PASI 90 refers to a ≥90% improvement in PASI score relative to baseline; PASI 75 refers to a ≥75% improvement in score relative to baseline; and PASI 100 refers to a 100% improvement in score relative to baseline.

[0410] Response was defined as an improvement of at least 90% in PASI score relative to baseline (PASI 90).

[0411] Relapse was defined as a loss of PASI response of more than 50% relative to the week 32 response.

[0412] 3.8.2.sPGA

[0413] The static Physician Global Assessment (sPGA) records the physician's assessment of the subject's psoriasis status and includes the following aspects: induration, scaling, and erythema. Whenever possible, the physician who performed the sPGA assessment on the subject at screening / baseline should also perform the sPGA assessment on the subject at subsequent follow-up visits.

[0414] 3.8.3.DLQI

[0415] The Dermatology Life Quality Index (DLQI) is a dermatology-related quality of life tool that assesses the impact of the disease on a participant's quality of life (AY Finlay and GK Khan). It is a 10-question questionnaire that assesses six different aspects of quality of life: symptoms and feelings, usual activities, leisure activities, standards of work or school, personal relationships, and treatment.

[0416] For visits involving DLQI assessment, DLQI assessment was performed before all other visit contents (examination, procedure, psoriasis assessment, adverse events and concomitant medication collection, etc.) during the study.

[0417] 3.8.4.PSSI

[0418] The Psoriasis Scalp Severity Index (PSSI) is only used for subjects with scalp psoriasis at baseline. The PSSI records the extent of scalp psoriasis and the presence of induration, scaling, and erythema on the scalp lesions. Similar to the PASI, the numerical score ranges from 0 to 72. Whenever possible, the same physician who performed the PSSI assessment at screening / baseline should also perform the PSSI assessment on the subject at subsequent follow-up visits.

[0419] 3.8.5.NAPSI

[0420] The Nail Psoriasis Severity Index (NAPSI) should only be used for subjects with concurrent nail psoriasis at baseline. The NAPSI assesses nail texture and nail bed damage, with a total score ranging from 0 to 80. Whenever possible, the physician who performed the NAPSI assessment at screening / baseline should also perform the NASPI assessment on the subject at subsequent follow-up visits.

[0421] 3.8.6.PPASI

[0422] The Palmoplantar Psoriasis Severity Index (PPASI) should only be used for subjects with concurrent palmoplantar psoriasis at baseline. The PPASI assesses psoriasis on both the palms and soles, with a total score ranging from 0 to 72. Whenever possible, the physician who performed the PPASI assessment at screening / baseline should also perform the PPASI assessment on the subject at the subsequent follow-up visit.

[0423] 3.8.7.sPGA-G

[0424] The sPGA-G assessment is only for subjects with perineal psoriasis at baseline. The sPGA-G is a localized assessment of perineal psoriasis using the sPGA assessment criteria. Whenever possible, the physician who performed the sPGA-G assessment on the subject at screening / baseline should also perform the sPGA-G assessment on the subject at subsequent follow-up visits.

[0425] PsA disease activity

[0426] Psoriatic arthritis disease activity assessments should only be performed for subjects with concurrent psoriatic arthritis at baseline. Physicians and subjects must independently complete this assessment. Whenever possible, the same physician who performed the baseline PsA disease activity assessment should also perform the PsA disease activity assessment at the subsequent follow-up visit.

[0427] The Visual Analogue Scale (VAS) was used to record the assessment of psoriatic arthritis disease activity by both the participants and the physicians. The VAS ranged from "very good (0 cm)" to "very poor (10 cm)" for the participants, and from "no arthritis activity (0 cm)" to "some arthritis activity (10 cm)" for the physicians.

[0428] 3.8.9. Photographing the skin lesions

[0429] In order to obtain more data for efficacy evaluation, each time the efficacy evaluation is conducted, the subject's skin condition (except the perineum) is photographed.

[0430] 3.9 Safety Assessment

[0431] I. Laboratory tests

[0432] Routine laboratory safety assessments include the laboratory tests listed in the table below.

[0433] Routine laboratory examination contents

[0434] HBcAb: hepatitis B core antibody; HBeAb: hepatitis B E antibody; HBeAg: hepatitis B E antigen; HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus.

[0435] Laboratory-related examinations were performed in the fasting state.

[0436] II. Clinical Examination

[0437] Clinical examinations include general physical examination, vital signs examination (including temperature, pulse and blood pressure), 12-lead electrocardiogram (12-lead ECG), chest X-ray, severe allergic reactions, injection site reactions, cardiovascular events (including major cardiovascular events known in the art (such as cardiovascular and cerebrovascular-related death, non-fatal myocardial infarction and non-fatal stroke) and other cardiovascular events), and psychiatric events.

[0438] 3.10 Immunogenicity

[0439] About 5 mL of whole blood was collected, serum was separated, and aliquots were frozen for ADA and NAb analysis.

[0440] Statistical analysis methods

[0441] 3.11.1 Hypothesis Testing

[0442] The primary endpoint of this trial was a dual-endpoint design: the proportion of subjects in the 100 mg and 200 mg groups who maintained treatment and then received placebo at week 56, with a PASI improvement of ≥90%. Statistical significance was considered only if both endpoints were achieved simultaneously, so no alpha adjustment was performed.

[0443] Primary endpoint:

[0444] Proportion of subjects in the 100 mg maintenance group (p11) and the 100 mg withdrawal / placebo group (p10):

[0445] H0:p11=p10 H1:p11≠p10

[0446] Proportion of subjects in the 200 mg maintenance group (p21) and the 200 mg withdrawal / placebo group (p20):

[0447] H0:p21=p20 H1:p21≠p20

[0448] When both primary endpoints achieved positive results, ordinal tests were performed for the secondary efficacy endpoints at the α = 0.05 (two-sided) level in the following order: When both primary endpoints achieved positive results, ordinal tests were performed for the secondary efficacy endpoints at the α = 0.05 (two-sided) level in the following order:

[0449] ① The proportion of subjects with a PASI improvement of ≥75 at week 56 did not differ between the maintenance treatment group and the withdrawal / placebo group;

[0450] ② The proportion of subjects achieving PASI 100 at week 56 did not differ between the maintenance treatment group and the withdrawal / placebo group;

[0451] ③ The proportion of subjects achieving a static Physician Global Assessment (sPGA) score of clear (0) or nearly clear (1) at week 56 showed no difference between the maintenance treatment group and the withdrawal / placebo group;

[0452] ④ The proportion of subjects achieving a clear static Physician Global Assessment (sPGA) score of 0 at week 56 showed no difference between the maintenance treatment group and the withdrawal / placebo group;

[0453] ⑤ The proportion of subjects achieving a DLQI score of 0 or 1 at week 56 did not differ between the maintenance treatment group and the withdrawal / placebo group;

[0454] ⑥ During weeks 32 to 56, there was no difference in the time it took for subjects to lose PASI90 between the maintenance treatment group and the withdrawal / placebo group (null hypothesis H0: HR = 1, alternative hypothesis: H1: HR1 ≠ 1).

[0455] For the 100 mg and 200 mg groups, sequential comparisons of secondary efficacy endpoints were performed between the maintenance treatment group and the withdrawal / placebo group. If p < 0.05 was achieved for both groups for this endpoint, a statistically significant difference between the maintenance treatment group and the withdrawal / placebo group was considered for that endpoint, and the next endpoint comparison could be performed. If a statistically significant difference was not established for this endpoint, only nominal p-values ​​were calculated for the subsequent endpoints.

[0456] 3.11.2 Statistical Analysis Population

[0457] This trial will be summarized by treatment group and treatment period. The treatment period includes the open-label treatment period, the randomized double-blind treatment period, and the randomized double-blind withdrawal period. The analysis population will be defined for each period and for the entire trial (if necessary).

[0458] Intent-to-treat (ITT) open-label treatment phase: This population consists of all subjects who received at least one anti-IL-23p19 antibody treatment before randomization from week 0 to week 20. This population was used for efficacy analysis during the open-label treatment phase.

[0459] Intent-to-Treat (ITT) - Randomized Double-Blind Treatment Period: This population consists of all subjects who underwent the first randomization at Week 20. The analysis of this population will be based on the treatment group to which the subject was randomly assigned at the first randomization, for efficacy analysis during the randomized double-blind treatment period.

[0460] Intent-to-Treat (ITT) - Randomized Double-Blind Withdrawal Period Responders: This population consists of subjects who have a PASI 90 response and are randomized for the second time at Week 32. This population will be analyzed based on the treatment group to which the subject was randomly assigned at the second time for efficacy analysis during the randomized double-blind withdrawal period.

[0461] Per-Protocol Set (PPS) - Randomized Double-Blind Withdrawal Period: The Intention-to-Treat Set (ITT) is a subset of the randomized double-blind withdrawal period, consisting of subjects without major protocol deviations that would affect efficacy evaluation (e.g., use of concomitant medications prohibited by the protocol, failure to meet the second randomization criteria, and no erroneous receipt of study drug). The analysis of this population will be based on the treatment group actually received by the subjects after Week 32, and will be used for supplemental analysis of efficacy indicators during the randomized double-blind withdrawal period.

[0462] Intention-to-treat (ITT) randomized double-blind withdrawal non-responders consisted of subjects without a PASI 90 response at Week 32. This population was used for efficacy analysis of non-responders after Week 32.

[0463] Intention-to-Treat (ITT)-Randomized Double-Blind Withdrawal Period Re-treatment Subjects: This population consists of ITT-Randomized Double-Blind Withdrawal Period responders who relapsed and received retreatment. This population is used for efficacy analysis of retreatment subjects who relapsed and received retreatment during the randomized double-blind withdrawal period.

[0464] Safety Analysis Set (SS) - Open-label Treatment Period: This refers to the population of subjects who have signed informed consent and received at least one dose of the study drug between Week 0 and Week 20. This population is used to assess safety indicators during the open-label treatment period.

[0465] Safety Analysis Set (SS) - Randomized Double-Blind Treatment Period: This population consists of subjects who received at least one dose of study drug between Weeks 20 and 32. The analysis of this population will be based on the treatment group the subjects actually received between Weeks 20 and 32, and will be used to assess safety indicators during the randomized double-blind treatment period.

[0466] Safety Analysis Set (SS) - Randomized Double-Blind Withdrawal Period: This population includes subjects who received at least one dose of study drug at or after Week 32. The analysis of this population will be based on the treatment group the subjects actually received from Week 32 to Week 56, and will be used to assess safety indicators during the randomized double-blind withdrawal period.

[0467] Safety Analysis Set (SS) - Entire Trial: All subjects who received at least one dose of study drug. Analyses of this population will be based on the treatment groups actually received throughout the trial and will be used to assess safety indicators throughout the trial.

[0468] 3.11.3 Statistical analysis methods

[0469] A. General Methods of Statistical Analysis

[0470] Unless otherwise specified, this trial will be summarized by treatment group and treatment period. The treatment period includes the open-label treatment period (weeks 0-20), the randomized double-blind treatment period (weeks 20-32), the double-blind withdrawal period (weeks 32-56), and the entire trial (and, if necessary, safety assessments throughout the trial). Overlapping periods (weeks 20 and 32) will be included in the corresponding period based on the assessments / tests performed before and after randomization.

[0471] For continuous variables, descriptive statistics (including number of cases, mean, standard deviation, median, Q1, Q3, minimum and maximum) were used for summary, and for discrete variables, frequencies and percentages were used for summary.

[0472] All statistical analyses were performed using SAS v 9.4 (or higher).

[0473] B. Subject Distribution

[0474] The number of subjects entering each treatment period, randomized, receiving treatment, discontinuing study treatment, and discontinuing the study will be summarized separately. The main reasons for discontinuing study drug treatment and / or discontinuing the study will be summarized according to the category of the eCRF.

[0475] Significant protocol deviations will be summarized and tabulated within each category.

[0476] C. Baseline characteristics of subjects

[0477] Descriptive statistics were used to summarize the demographic and baseline characteristics of the subjects, diagnosis and treatment information of the study disease, medical history, and previous concomitant treatment.

[0478] D. Efficacy Analysis

[0479] Efficacy measures were analyzed by treatment period in the corresponding intention-to-treat set. Between-group comparisons of efficacy measures between the maintenance treatment group and the withdrawal / placebo group were conducted only during the double-blind withdrawal period. Descriptive statistics were summarized for efficacy measures during the open-label and randomized double-blind treatment periods.

[0480] ①Analysis of primary endpoints

[0481] The primary endpoint of this study was a dual endpoint: the proportion of subjects in the 100 mg and 200 mg groups who maintained treatment versus the withdrawal / placebo group who achieved a ≥90% improvement in PASI at week 56 compared to before the first dose of study medication.

[0482] Analysis of primary endpoints under the main estimated target

[0483] Descriptive statistics will be summarized for the primary endpoint, including the number of cases, percentages, and corresponding 95% confidence intervals (CIs) for each treatment group. For dichotomous outcomes, the chi-square test will be used to compare PASI-90 statistical differences between the maintenance treatment group and the withdrawal / placebo group, with p-values ​​calculated. The between-group rate difference and 95% CI for the proportion of subjects treated with anti-IL-23p19 antibodies compared with those in the placebo group will be calculated using the Wald method.

[0484] Management of Concomitant Events: Premature discontinuation of treatment will be treated with a treatment strategy, with subsequent data collection continuing. Use of contraindicated medications that affect efficacy assessment will be treated with a composite variable strategy, with use of other psoriasis treatments considered ineffective. Relapse after Week 32 will be treated with a composite variable strategy, regardless of retreatment and / or study withdrawal, and relapse will be considered ineffective.

[0485] Missing value imputation: imputation was performed based on non-response (NRI).

[0486] Sensitivity analysis: Missing values ​​due to premature termination of treatment were imputed using the predicted values ​​in the MMRM model of the corresponding continuous variables and the LOCF method. Missing values ​​of categorical variables due to the use of other psoriasis treatments or relapses were imputed using the NRI method. The statistical analysis method was the same as the main analysis method.

[0487] Supplementary analysis of the primary endpoint:

[0488] Different analysis populations: The primary endpoint was analyzed in the PPS using the same primary estimation objective analysis method as described above.

[0489] Different strategies were used for handling concurrent events: Premature discontinuation of treatment was treated with an ongoing strategy, using only efficacy data before premature discontinuation. Categorical variables after discontinuation were imputed using the predicted values ​​from the MMRM model for the corresponding continuous variables. A composite variable strategy was used for other psoriasis treatments or relapses; patients who used other psoriasis treatments or had relapses were considered to have no response.

[0490] ②Analysis of secondary efficacy endpoints

[0491] Binary variable analysis

[0492] Secondary efficacy endpoints of dichotomous variables included the proportion of subjects with PASI75, PASI100, sPGA0 or sPGA 0 / 1 scores, and DLQI 0 / 1 scores at week 56, and their analysis was the same as the primary endpoint analysis.

[0493] Event time variable analysis

[0494] The event variable was the time for subjects to lose PASI90 during the randomized double-blind withdrawal period, which was defined as the time from randomization to loss of PASI90 at week 32.

[0495] Statistical analysis of the main estimation objectives:

[0496] The number and percentage of subjects who lost PASI 90 and those who were censored were summarized by treatment group. The median time to loss of PASI 90 and its 95% confidence interval (CI) were estimated using the Kaplan-Meier method, and KM curves were plotted. P values ​​were calculated for intergroup comparisons using the log-rank test, and the Cox model was used to calculate the between-group hazard ratios (HRs) and their 95% CIs.

[0497] Management of Concomitant Events: Premature discontinuation of treatment will be treated using a therapeutic strategy, with subsequent data collection continuing. Use of other psoriasis treatments will be treated using a composite variable strategy, with use of other psoriasis treatments considered a PASI 90 loss event. Relapse after Week 32 will be treated using a composite variable strategy, with relapse considered a PASI 90 loss event, regardless of retreatment and / or study withdrawal.

[0498] If no event was observed, it was censored at the last efficacy assessment, without imputation of missing values.

[0499] Supplementary analysis: Statistical analysis methods with the same primary estimation objective were performed for loss of PASI 90 in PPS.

[0500] ③Analysis of other efficacy endpoints

[0501] Other efficacy endpoints included the change in DLQI from baseline at each time point, the proportion of subjects with PASI90, PASI75, PASI100, sPGA 0 score, sPGA 0 / 1 score, and DLQI 0 / 1 score at each time point, and the change in specific scores for specific psoriasis from baseline.

[0502] Descriptive statistics were summarized for the other efficacy endpoints mentioned above according to the treatment period: for continuous variables, descriptive statistics were summarized, including the number of cases, mean, standard deviation, median, Q1, Q3, minimum value, and maximum value; for categorical variables, frequencies and percentages were summarized.

[0503] The MMRM will also be used to evaluate the change in DLQI from baseline in responders during the randomized double-blind withdrawal period. In the model, treatment group, visit, and the interaction between visit and treatment group will be used as fixed effects, within-subject error will be used as a random effect, and baseline value and its interaction with visit will be used as covariates. The mean change in DLQI from baseline and its 95% CI will be calculated for the maintenance treatment group and the withdrawal / placebo group. The between-group difference and its 95% CI, as well as the p-value for the between-group comparison, will be provided.

[0504] E. Security Analysis

[0505] Safety indicators were analyzed by treatment period in the corresponding safety analysis set. Overall safety during the entire trial was also analyzed in the safety analysis set - the entire trial.

[0506] ①Drug exposure

[0507] Summarize the subjects' exposure to study drugs, medication duration, compliance, etc. during each treatment period and the entire study period.

[0508] ② Adverse events

[0509] Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects experiencing each category of AE (including treatment-emergent adverse events, drug-related adverse events, AESIs, and SAEs) were summarized. The occurrence of each AE was further summarized according to the MedDRA system organ class and preferred terminology. The relationship between each adverse event and the study drug and the severity of each adverse event were also analyzed.

[0510] ③ Laboratory examination

[0511] The number of cases, mean, standard deviation, median, Q1, Q3, minimum and maximum values ​​of the blood routine and blood biochemistry indicators were used to descriptively summarize the measurement values ​​of each visit and the change values ​​compared with the baseline. The cross-classification table was used to summarize the normal and abnormal changes before and after the drug treatment.

[0512] Urinalysis will use a cross-classification table to describe the normal and abnormal changes before and after treatment.

[0513] ④12-lead electrocardiogram

[0514] Descriptive statistics were used to summarize the measured values ​​and changes from baseline of the ECG quantitative indices. Cross-classification tables were used to summarize the changes in normal and abnormal parameters before and after drug treatment.

[0515] ⑤ Vital signs, physical examination, and other safety-related examinations

[0516] Descriptive statistics were presented for the examination results of vital signs and the changes compared with baseline.

[0517] In the form of a list, describe the conditions of the subjects who have abnormal changes in physical examination and other safety examinations compared with baseline.

[0518] F. Immunogenicity

[0519] Descriptive statistics were used to summarize the positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against IL-23P19 antibody during the entire trial period.

[0520] F. Multiple Comparisons and Adjustment for Multiplicity

[0521] Primary endpoint:

[0522] This study has dual endpoints. Only when both primary endpoints are significant will the maintenance treatment group be considered superior to the withdrawal / placebo group. No alpha adjustment will be performed.

[0523] ①The proportion of subjects who achieved PASI 90 at week 56 in the 100mg and 200mg maintenance treatment groups and the withdrawal / placebo group

[0524] When both primary endpoints achieved positive results, the secondary endpoints were tested in the following order at the α = 0.05 (two-sided) level to verify the superiority of the anti-IL-23p19 antibody group over the placebo group. The specific order is as follows:

[0525] Secondary endpoints:

[0526] ②Proportion of subjects achieving PASI 75 at week 56

[0527] ③Proportion of subjects achieving PASI 100 at week 56

[0528] ④The proportion of subjects who achieved a static Physician Global Assessment (PGA) score of clean (0 points) or nearly clean (1 point) at week 56

[0529] ⑤Proportion of subjects achieving a static Physician Global Assessment (PGA) score of 0 at week 56

[0530] ⑥Proportion of subjects achieving DLQI score 0 or 1 at week 56

[0531] ⑦ The time when the subjects lost PASI90 between weeks 32 and 56.

[0532] For the 100 mg and 200 mg groups, sequential comparisons of secondary efficacy endpoints were performed between the maintenance treatment group and the withdrawal / placebo group. If p < 0.05 was achieved for both groups for this endpoint, a statistically significant difference between the maintenance treatment group and the withdrawal / placebo group was considered for that endpoint, and the next endpoint comparison could be performed. If a statistically significant difference was not established for this endpoint, only nominal p-values ​​were calculated for the subsequent endpoints.

[0533] Results

[0534] The above content shows that the anti-IL23p19 antibody of the present invention can effectively treat moderate to severe psoriasis, has excellent efficacy and safety, and continues to maintain treatment after random withdrawal of the product, which has better therapeutic benefits than the withdrawal of the control product.

[0535] In addition, this product has the characteristics of long half-life and long interval dosing. It can be administered once every 12 weeks after stable treatment, which gives it the potential to maintain therapeutic effects for a longer time after withdrawal of the drug, and more patients can maintain therapeutic effects within the same period of time after withdrawal of the drug.

[0536] Specifically, the anti-IL23p19 antibodies of the present invention have a favorable safety profile: in single-dose studies in healthy subjects and multiple-dose studies in psoriasis patients, the overall safety profile of the subjects was favorable, with no significant increase in adverse event rates compared to the placebo group, and no dose-dependent safety events observed. Based on blinded data, with subcutaneous injections of 200 mg of the anti-IL23p19 antibody at weeks 0, 4, and 8, more than 70% of psoriasis patients are expected to achieve PASI 90 at week 16. With 100 mg and 200 mg of 12-week maintenance dosing, the long-term (week 52) PASI 90 compliance rate is expected to reach over 85%. These two long-term maintenance dosing regimens are expected to provide psoriasis patients with optimally convenient treatment options and stable therapeutic efficacy. Furthermore, the anti-IL-23p19 antibody method of the present invention for treating moderate to severe psoriasis features long-interval dosing, with dosing every 12 weeks after stable treatment, and is expected to have the potential to maintain efficacy for longer periods after withdrawal.

[0537] Specifically, a blinded estimate of the proportion of subjects in the different groups who still achieved PASI 90 after Week 32 was performed. Because the data were blinded, no distinction was made between the 100mg and 200mg dose groups after Week 32. The data are as follows:

[0538] The data showed that when the subjects who responded at week 32 continued to receive maintenance treatment with anti-IL23P19 antibodies, 94.0% and 95.7% of the subjects responded at week 36 and week 40, respectively; and when the subjects who responded at week 32 were withdrawn and received placebo, 89.6% and 81.8% of the subjects still responded at week 36 (14 weeks after the last dose at week 20) ​​and week 40, respectively.

[0539] While the exemplary embodiments of the present invention have been described above, it should be understood by those skilled in the art that these disclosures are merely exemplary and that various other substitutions, adaptations, and modifications may be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A method for treating moderate to severe psoriasis in a subject, comprising administering to a subject in need thereof an effective amount of an anti-IL-23p19 antibody, wherein: The anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region comprises SEQ ID NO: 1, the amino acid sequence of CDR2 of the heavy chain variable region comprises SEQ ID NO: 2, and the amino acid sequence of CDR3 of the heavy chain variable region comprises SEQ ID NO: 3; the amino acid sequence of CDR1 of the light chain variable region of the antibody comprises SEQ ID NO: 4, the amino acid sequence of CDR2 of the light chain variable region comprises SEQ ID NO: 5, and the amino acid sequence of CDR3 of the light chain variable region comprises SEQ ID NO:

6.

2. The method of claim 1, wherein the anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence having at least 90% identity thereto.

3. The method according to claim 1 or 2, wherein the anti-IL23p19 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the sequence shown in SEQ ID NO:9 or comprises a sequence having at least 90% identity with SEQ ID NO:9, and the light chain comprises the sequence shown in SEQ ID NO:10 or comprises a sequence having at least 90% identity with SEQ ID NO:

10.

4. The method according to any one of claims 1 to 3, wherein each dose of the anti-IL-23P19 antibody is 50 mg to 500 mg, and optionally, each dose during the dosing regimen is the same or different.

5. The method according to any one of claims 1 to 4, wherein: The method comprises administering 200 mg of an anti-IL-23p19 antibody to a subject in need thereof at weeks 0, 4, and 8, administering 50 mg-300 mg of an anti-IL-23p19 antibody at week 20, and then suspending administration of the anti-IL-23p19 antibody or continuing to administer 50 mg-300 mg of an anti-IL-23p19 antibody at weeks 32 and 44, preferably, administering 50 mg-250 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44, more preferably, administering 100 mg-200 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44, more preferably, administering 100 mg or 200 mg of an anti-IL-23p19 antibody at weeks 20, 32, and 44.

6. The method according to any one of claims 1 to 5, wherein the anti-IL-23p19 antibody is administered to a subject in need thereof according to the following regimen: 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody is administered at week 20; or, 2) 200 mg of anti-IL-23p19 antibody was administered at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody was administered at week 20.

7. The method according to any one of claims 1-6, wherein the method further comprises detecting whether the subject has responded to treatment at week 32.

8. The method according to any one of claims 1-7, wherein the method comprises administering an anti-IL-23p19 antibody to a subject who has responded at week 32 according to the following regimen: 1) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody is administered at week 20, and 100 mg of anti-IL-23p19 antibody is administered at weeks 32 and 44; or, 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody at week 20, followed by suspension of administration of anti-IL-23p19 antibody; or, 3) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, administering 200 mg of anti-IL-23p19 antibody at week 20, and administering 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or, 4) Administer 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and administer 200 mg of anti-IL-23p19 antibody at week 20, after which administration of anti-IL-23p19 antibody is suspended.

9. The method according to any one of claims 1-8, wherein for a subject who has a response at week 32, the method further comprises detecting whether the subject has relapsed starting at week 36.

10. The method according to any one of claims 1 to 9, wherein the method further comprises administering 200 mg of the anti-IL-23p19 antibody once every four weeks starting from the time of determination of relapse until the first administration at the end of week 44 for the relapsed subject.

11. The method according to any one of claims 1-7, wherein the method further comprises administering an anti-IL-23p19 antibody to a subject who has not responded at week 32 according to the following regimen: 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or 2) 200 mg of anti-IL-23p19 antibody was administered at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody was administered at week 20, and 200 mg of anti-IL-23p19 antibody was administered at weeks 32 and 44.

12. The method according to any one of claims 1 to 11, wherein the method further comprises: 1) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at week 20, and when the subject is tested as a responder at week 32, 200 mg of anti-IL-23p19 antibody at weeks 32 and 44; or 2) administering 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, and 200 mg of anti-IL-23p19 antibody at week 20, and suspending administration of anti-IL-23p19 antibody when the subject is tested as having a response at week 32; or 3) 200 mg of anti-IL-23p19 antibody at Weeks 0, 4, and 8, 200 mg of anti-IL-23p19 antibody at Week 20, and when the subject is tested as non-responsive at Week 32, 200 mg of anti-IL-23p19 antibody at Weeks 32 and 44; or 4) 200 mg of anti-IL-23p19 antibody at weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at week 20, and when the subject is tested as a responder at week 32, 100 mg of anti-IL-23p19 antibody is administered at weeks 32 and 44; or 5) 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and 100 mg of anti-IL-23p19 antibody is administered at week 20, and when the subject is tested as having a response at week 32, administration of anti-IL-23p19 antibody is suspended; or 6) Administer 200 mg of anti-IL-23p19 antibody at Weeks 0, 4, and 8, 100 mg of anti-IL-23p19 antibody at Week 20, and when the subject is tested as non-responsive at Week 32, 200 mg of anti-IL-23p19 antibody at Weeks 32 and 44.

13. The method according to claim 12, wherein for a subject detected as having a response at week 32, the method further comprises detecting whether the subject has relapsed starting from week 36, wherein if the subject loses more than 50% of the PASI response between week 36 and week 44 relative to the response at week 32, the subject is considered to have relapsed.

14. The method according to claim 13, wherein for a subject with relapse, 200 mg of the anti-IL-23p19 antibody is administered once every four weeks starting from the time when the relapse is determined until the first administration at the end of the 44th week.

15. The method of any one of claims 1-14, wherein the moderate to severe psoriasis is moderate to severe plaque psoriasis.

16. The method according to any one of claims 1-15, wherein the subject has moderate to severe plaque psoriasis for ≥6 months, the subject's moderate to severe plaque psoriasis involves a body surface area (BSA) of ≥10%, a Psoriasis Area and Severity Index (PASI) of ≥12 points, a static Physician Global Assessment (sPGA) of ≥3 points, optionally with or without psoriatic arthritis.

17. The method of any one of claims 1-16, wherein the anti-IL-23p19 antibody is formulated for administration as a liquid pharmaceutical composition.

18. The method of claim 17, wherein the liquid pharmaceutical composition is an injection.

19. The method of any one of claims 1-18, wherein the anti-IL-23p19 antibody or pharmaceutical composition is administered by subcutaneous injection.

20. Use of an anti-IL-23p19 antibody or a pharmaceutical composition comprising the anti-IL-23p19 antibody in the preparation of a medicament for treating moderate to severe plaque psoriasis, wherein the anti-IL-23p19 antibody is as described in any one of claims 1 to 3.

21. The use of claim 20, wherein the subject is as described in claim 16.

22. The use according to claim 20 or 21, wherein the anti-IL-23p19 antibody or the pharmaceutical composition comprising the anti-IL-23p19 antibody is administered according to the method of claims 1-19.

23. A single pharmaceutical dosage unit comprising the anti-IL-23p19 antibody of any one of claims 1-3.

24. The single pharmaceutical dosage unit according to claim 23, wherein the single pharmaceutical dosage unit comprises the following dosage of the anti-IL-23p19 antibody: 50 mg-500 mg, preferably 50 mg-300 mg, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg of anti-IL-23p19 antibody.

25. The single pharmaceutical dose unit according to claim 23 or 24, wherein the single dose unit is a single dose unit packaged in a prefilled autoinjector pen.

26. A pharmaceutical kit comprising a single pharmaceutical dosage unit according to any one of claims 23 to 25, and optionally, a package insert having instructions for use of an anti-IL-23p19 antibody for preventing or treating plaque psoriasis in a patient.

27. Use of a single pharmaceutical dosage unit according to any one of claims 23 to 25 or a kit of parts according to claim 26 for the preparation of a medicament for treating moderate to severe plaque psoriasis.

28. A single pharmaceutical dosage unit as claimed in any one of claims 23 to 25 or a kit of parts as claimed in claim 26 for use in the treatment of plaque psoriasis.

29. The use according to claim 27, or the single pharmaceutical dosage unit according to any one of claims 23 to 25 or the kit of parts according to claim 26 for use according to claim 28, for use in a subject according to claim 16.