Method for treating subject diagnosed with psoriatic arthritis

Abstract

To provide a method for treating psoriatic arthritis.SOLUTION: Provided is a method for treating psoriatic arthritis which includes administering an anti IL-23p19 antibody hum13B8-b to a patient who needs it. Further, a method for determining effectiveness of an anti IL-23p19 antibody for treating psoriatic arthritis which includes administering an anti IL-23p19 antibody hum13B8-b to a patient is also provided.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to an anti-IL-23p19 antibody hum13B8-b or an antigen-binding fragment thereof, and In some embodiments, the present disclosure relates to a method for treating psoriasis, and its use in the treatment of psoriatic arthritis. The present invention relates to a method for treating chronic arthritis, wherein the treatment is based on both tender and swollen joint counts. In some embodiments, the present disclosure provides a method for treating psoriatic arthritis. The present invention relates to a method for determining the efficacy of an anti-IL-23p19 antibody for treatment of a patient with a disease characterized by a cytotoxic T-cell syndrome. [Background technology]

[0002] Psoriasis (PsO) is a chronic inflammatory skin disorder that affects approximately 1%-2% of the world's population. Psoriatic arthritis (PsA) is defined as a specific inflammatory arthritis associated with PsO. The exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population, P The observed prevalence of inflammatory arthritis among sO patients varies from 6% to 42%. The disease is typically characterized as oligoarticular and mild. However, over time, PsA is polyarticular and severe in at least 20% of patients. et al., Ann. Rheum. Dis. 64(Suppl II): ii14-ii17 (2005). Symptoms include tenderness, pain and stiffness in and around the joints. Nail pain, dactylitis, spondylitis, heel pain and swelling, nail deformity (discoloration, splitting, or pitting) These symptoms include fatigue, dizziness, and general fatigue. PsA patients with polyarticular disease are at risk for disease progression. In addition to the progression of clinical and radiological damage, patients with PsA experience a decline in health-related quality of life. Quality also declines. Gladman et al. (2005).

[0003] Current treatment options for PsA include nonsteroidal anti-inflammatory drugs (NSAIDs), adrenal Corticosteroids, topical treatments (for the skin), phototherapy (for the skin), physical therapy, and disease-modifying These include antirheumatic drugs (DMARDs). There are two approved for use in treating PsA: There are two types of biologics, more recently interleukin-12 (IL-12) and IL- There are also drugs that target 23. Methotrexate (MTX) is approved in the United States for the skin condition PsO. Although approved by the Food and Drug Administration (FDA), it is frequently used off-label for PsA. Methotrexate has been shown to provide relief in some patients with PsO involving multiple joints. Although it has been reported that rituximab may be effective in treating PsA, there is no scientific evidence to support its use as a disease-modifying agent in PsA. There is little evidence. Summary of the Invention

[0004] As used herein, the anti-IL-23p19 antibody hum13B8-b is administered to a patient in need thereof. The present invention provides a method for treating psoriatic arthritis comprising administering to a patient The first dose of antibody was administered subcutaneously at week 0, followed by subsequent doses every 12 weeks. The antibody hum13B8-b also comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:1. and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2.

[0005] Also provided herein is a therapeutically effective amount of the anti-IL-23p19 antibody hum13B8-b, and administering to a patient in need thereof a compound comprising the steps of: Treatment was associated with at least a 20% improvement in tender and swollen joint counts from baseline. and the antibody hum13B8-b (i) comprises the amino acid sequence of SEQ ID NO:1. and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2. nothing.

[0006] Further, a therapeutically effective amount of the anti-IL-23p19 antibody hum13B8-b is provided herein: A method of treating psoriatic arthritis is provided, comprising administering to a patient in need thereof where treatment results in at least a 50% improvement in tender and swollen joint counts from baseline. and the antibody hum13B8-b (i) comprises the amino acid sequence of SEQ ID NO:1. and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2. include.

[0007] Further, a therapeutically effective amount of the anti-IL-23p19 antibody hum13B8-b is provided herein: A method of treating psoriatic arthritis is provided, comprising administering to a patient in need thereof where treatment results in at least a 70% improvement in tender and swollen joint counts from baseline. and the antibody hum13B8-b (i) comprises the amino acid sequence of SEQ ID NO:1. and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2. include.

[0008] Further provided herein is the administration of the anti-IL-23p19 antibody hum13B8-b to a patient. A method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: The method provides a method for administering a first dose of an antibody to a patient subcutaneously at week 0, followed by Subsequent doses are administered subcutaneously every 12 weeks, and antibody hum13B8-b is (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:2; and a heavy chain polypeptide containing 1,2-diaminobenzidine and 1,2-diaminobenzidine. A response rate of at least about 40% indicates the effectiveness of the antibody.

[0009] Further provided herein is the administration of the anti-IL-23p19 antibody hum13B8-b to a patient. A method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: The method includes administering a first dose of the antibody subcutaneously to a patient at week 0, and (b) administering to the patient a dose of hum13B8-b subcutaneously every 12 weeks after the dose, and (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising a 5'-aminobutyric acid sequence, and A response rate of at least about 20% indicates efficacy of the antibody.

[0010] Further provided herein is the administration of the anti-IL-23p19 antibody hum13B8-b to a patient. A method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: The method includes administering a first dose of the antibody subcutaneously to a patient at week 0, and (b) administering to the patient a dose of hum13B8-b subcutaneously every 12 weeks after the dose, and (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising a 5'-aminobutyric acid sequence, and A % of at least about 10% indicates efficacy of the antibody.

[0011] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide having the sequence, and An improvement of at least 75% from the baseline score indicates efficacy of the antibody. will achieve at least a 90% improvement from baseline in Psoriasis Area and Severity Index at Week 52 In some embodiments, a Psoriasis Area-Severity Index at Week 52 is indicative of efficacy of the antibody. A 100% improvement from baseline indicates efficacy of the antibody.

[0012] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A decrease in CRP score indicates efficacy of the antibody. In some embodiments, the patient is Experience a decrease of 1, 2, 3, 4, 5, 6, 7, 8, or 9 units in AS28 score It is possible.

[0013] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A statistically significant improvement in disease activity, as determined by, indicates efficacy of the antibody. [Brief description of the drawings]

[0014] [Figure 1] Figure 1 is a schematic diagram showing the study design. Abbreviations: B / l = baseline; LTE = long-term extension; mg = milligrams; PtGA = Patient Global Assessment; q = weekly; Tildra = tildrakizumab; Wk = weekly. [Diagram 2] Figure 2 shows the ACR20 / 50 / 70 of patients throughout the treatment period and at each time point up to week 52. Abbreviations: Q4W: every 4 weeks, Q12W: every 12 weeks, TIL: tildrakizumab. [Diagram 3] Figure 3 shows the ACR20 / 50 / 70 of patients throughout the treatment period and at each time point through week 24. Abbreviations: PBO: placebo, Q4W: every 4 weeks, Q12W: every 12 weeks, TIL: tildrakizumab. *P < 0.05; †P < 0.001; P < 0.0001 vs. placebo. [Figure 4] Figure 4 shows the response rate of minimal disease activity across the entire treatment period and at each time point from baseline to week 52 in patients with PsA. Error bars represent 95% confidence intervals. Abbreviations: PsA: psoriatic arthritis, Q4W: every 4 weeks, Q12W: every 12 weeks, TIL: tildrakizumab. [Diagram 5]Figure 5 shows the PASI 75 / 90 / 100 response rates throughout the treatment period and at each time point through week 52. Patient response rates were calculated as baseline BSA ≥ 3%. Black symbols corresponding to p-values ​​were analyzed using missing value imputation methods for missing responses. P-values ​​are based on the Cochran-Mantel-Haenszel test for missing value imputation datasets (past anti-TNF use and baseline weights as stratification factors). *P < 0.05; †P < 0.001; P < 0.0001 vs placebo. Abbreviations: BSA: body surface area; PASI: Psoriasis Area and Severity Index; Q4W: every 4 weeks; Q12W: every 12 weeks; TIL: tildrakizumab. [Figure 6] Figure 6 shows the DAS28-CRP response rate over the entire treatment period and at each time point. Error bars represent 95% confidence intervals. Abbreviations: Q4W: every 4 weeks, Q12W: every 12 weeks, TIL: tildrakizumab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present disclosure relates to an anti-IL-23p19 antibody hum13B8-b or an antigen-binding fragment thereof, and In some embodiments, the present invention relates to an anti-IL-23p antibody and its use in the treatment of psoriatic arthritis. 19. A method for treating psoriasis-related disorders, comprising administering the antibody hum13B8-b to a patient in need thereof. Provided herein is a method of treating arthritis, wherein a patient receives a first dose of an antibody at week 0. The patient received a subcutaneous dose of antibody hum1 3B8-b is a polypeptide comprising (i) a light chain having the amino acid sequence of SEQ ID NO:1; and (ii) a light chain having the sequence of SEQ ID NO:2. and a heavy chain polypeptide comprising the amino acid sequence of sequence number 2.

[0016] As used in accordance with this disclosure, all technical and scientific terms, unless otherwise indicated, shall be understood to have the same meaning as that term is commonly understood by those skilled in the art. Unless the context otherwise requires, singular terms shall include the plural and plural terms shall refer to the singular. This includes:

[0017] As used herein, the term "antibody" refers to an antibody that has the ability to recognize and specifically bind to an antigen. A normal or conventional mammalian antibody comprises a tetramer, which typically Generally, it consists of two identical pairs of polypeptide chains, each pair consisting of one "light chain" (typically about 2 5 kDa) and one "heavy chain" (typically about 50-70 kDa in molecular weight As used herein, the terms "heavy chain" and "light chain" refer to a target antigen. Any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity to the antigen. The amino-terminal portion of each light and heavy chain is typically responsible for antigen recognition. The carboxyl-terminal portion of each chain contains a variable domain of about 100 to 110 amino acids. Typically, the constant domains define the effector functions. In an antibody, a full-length heavy chain immunoglobulin polypeptide comprises a variable domain (V H ) and three The constant domain (C H1 , C H2 , and C H3 ), and C H1 and C. H2 Between and a range region, where V H The domain is located at the amino terminus of the polypeptide and is C H3 D The main chain is at the carboxyl terminus, and the full-length light chain immunoglobulin polypeptide is A variable domain (VL) and a constant domain (CL), L The domain is Polype At the amino terminus of the peptide, C L The domain is at the carboxyl terminus.

[0018] Within full-length light and heavy chains, the variable and constant domains typically span approximately 1 The heavy chains are joined by a "J" region of two or more amino acids, and The variable region of each light / heavy chain pair typically contains an antigen-binding site. The variable domains of naturally occurring antibodies are formed by the following sequences: The three hypervariable regions share the same general structure of relatively conserved framework regions (FRs) linked together. The CDRs in the two chains of each pair are typically bounded by framework regions. The amino terminus of the sequence may be aligned to allow binding to a specific epitope. To the carboxyl terminus, both the light chain variable domain and the heavy chain variable domain typically Includes main FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0019] As used herein, the term "antigen-binding fragment" refers to a portion of an intact antibody, and The antigen-binding function of an antibody is determined by the full-length, nucleotide sequence and / or the antigen-determining variable domains of an intact antibody. It is known that this can be achieved by using antibody fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments formed from antibody fragments, linear antibodies, single chain These include, but are not limited to, antibodies, diabodies, and multispecific antibodies.

[0020] In certain embodiments, the anti-IL-23p19 antibody hum13B8-b is tildrachizumab. As used herein, the term "tildrakizumab" refers to SCH 9002. Humanized anti-IL-23p19 monoclonal antibody, also known as 22 or MK-3222 Tildrakizumab is an antibody specific to the p19 protein of the IL-23 heterodimer. It binds to human IL-12 (IL-12 / 23p40 and IL12p35 heterodimers). High affinity (297 picomolar [ [pM] humanized immunoglobulin G1 / kappa (IgG1 / n) antibody.

[0021] In certain embodiments, tildrakizumab comprises a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:1. and a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2, which is disclosed in the U.S. Nos. 8,404,813 and 8,293,883, respectively. The disclosure of which is incorporated herein by reference in its entirety. Rakizumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain. The heavy chain variable domain comprises CDR1, CDR2, and The light chain variable domain comprises CDR1 having the amino acid sequence of SEQ ID NO:6 to 8, CDR3, Includes CDR2 and CDR3 sequences.

[0022] As used herein, the terms "subject" and "patient" are interchangeable. In some embodiments, the subject and / or patient is a mammal.

[0023] A "disorder" is any condition that would benefit from treatment with an antibody of the present disclosure. The terms "injury" and "condition" are used interchangeably herein and refer to the condition in which a patient is suffering from the disorder at issue. This includes chronic and acute disorders or diseases, including pathological conditions that predispose a person to such disorders or diseases.

[0024] As used herein, the term "treatment" or "treating" refers to therapeutic treatment, It refers to both preventative or preventative measures. Patients who require treatment include those with psoriatic joint disease. Patients with psoriatic arthritis, as well as patients who are predisposed to psoriatic arthritis or in whom psoriatic arthritis should be prevented This includes patients with

[0025] As used herein, the terms "administration" or "administering" refer to a desired effect. providing, contacting, and / or administering the antibody or fragment thereof by any suitable route to achieve the desired effect; Administration includes, but is not limited to, oral administration, sublingual administration, non-oral administration, and intravenous administration. Oral administration (e.g., intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, intraarticular injection, intra-arterial injection) injection, intrasynovial injection, intrasternal injection, intrathecal injection, intralesional injection, or intracranial injection), percutaneous injection administration, topical administration, buccal administration, rectal administration, vaginal administration, nasal administration, eye drops, inhalation, and implantation. This may include

[0026] In some embodiments, the anti-IL-23p19 antibody hum13B8-b or its antigen-binding Fragments are administered every 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks. It is given.

[0027] As used herein, the term "week 0" refers to the administration of the anti-IL-23p19 antibody hum13B This refers to the first day that 8-b or an antigen-binding fragment thereof is administered.

[0028] In some embodiments, the anti-IL-23p19 antibody hum13B8-b or its antigen-binding Fragments were taken over a 2-week treatment period, over a 4-week treatment period, and over a 6-week treatment period. over an 8-week treatment period, over a 12-week treatment period, over a 24-week Over the treatment period, Over the 36-week treatment period, Over the 48-week treatment period, Over a 60-week treatment period, over a 72-week treatment period, or over 1 year of treatment It is administered over a period of time.

[0029] The therapeutic dose of the anti-IL-23p19 antibody hum13B8-b or an antigen-binding fragment thereof is Generally, the patient's body size (weight, body surface, or organ size) and condition (age and In some embodiments, the patient will: One or more doses of the anti-IL-23p19 antibody hum13B8-b or an antigen-binding fragment thereof where the doses are 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 20 mg, 140 mg, 160 mg, 180 mg, or 200 mg. In one embodiment, the anti-IL-23p19 antibody hum13B8-b or an antigen-binding fragment thereof is used for the first time. The amount and subsequent doses are the same. In some embodiments, the anti-IL-23p19 antibody hum1 The initial dose and subsequent doses of 3B8-b or an antigen-binding fragment thereof are different. In some embodiments, the initial dose is 100 mg. In some embodiments, the initial dose is 200 mg. In some embodiments, the subsequent dose is 100 mg. In some embodiments, the initial dose and subsequent doses are 100 mg. In some embodiments, the initial dose and subsequent doses are 200 mg.

[0030] In some embodiments, a therapeutically effective amount of the anti-IL-23p19 antibody hum13B8-b is administered. Provided herein are methods for treating psoriatic arthritis, comprising administering to a patient in need thereof wherein the treatment results in an increase of at least 2% from baseline in tender and swollen joint counts. 0%, at least 50%, or at least 70% improvement, and 13B8-b comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO:1; and (ii) and a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:2.

[0031] Regarding joint count, five clinical patterns were observed in PsA patients: distal interphalangeal joints (DIP); Asymmetric oligoarticular, symmetric polyarticular, spondylitis, and destructive arthritis have been described. The joints are assessed for tenderness and swelling. There are no validated scales, and the scale used was initially developed for the assessment of patients with rheumatoid arthritis (RA). The ACR joint count was developed in 2011. The ACR joint counts for tenderness were 28, 44, and 68, respectively. and 78, and for swelling the range was 28, 44, 66, and 76 ( Swelling cannot be felt at the hip joint, and the hip joint is excluded from the assessment of swelling. The ACR joint count, consisting of the number of painful joints and the number of 66 swollen joints, was used to estimate the proportion of joints affected by PsA. This includes the temporomandibular joint, sternoclavicular joint, and acromioclavicular joint, which can be easily performed during a clinic visit. , shoulder joint, elbow joint, wrist joint (including carpometacarpal joint and intercarpal joint as one unit), metacarpophalangeal joint Interphalangeal joint (MCP), proximal interphalangeal joint (PIP), DIP, hip joint, knee joint, ankle joint, transverse foot The joints of the toes (including the subtalar joint), metatarsophalangeal joints, and interphalangeal joints of the toes (each (The proximal and distal joints are counted as one unit.)

[0032] The American College of Rheumatology 20 / 50 / 70 response criteria (ACR20 / 50 / 70) are (68) and swollen joints (66) with at least 20%, 50%, or The proportion of subjects who showed 70% or greater improvement and the associated PGA (VAS) score for disease activity 2) PtGA of disease activity (measured using a VAS); 3) Patient pain assessment (measured using a VAS), and 4) patient self-rated disability (measured using the HAQ-DI). and 5) improvement in three of the other five parameters, such as acute phase C-reactive protein (CRP). Evaluate the success rate.

[0033] C-reactive protein (CRP) or high-sensitivity C-reactive protein (hsCRP) is a It is a cellular reaction product produced by the liver and is involved in the prevention and treatment of tissue injury, infection, or autoimmune disease. It is a protein that is released into the blood within hours after the onset of other causes of inflammation. Increased levels of psoriatic arthritis were observed in patients with active psoriatic arthritis, suggesting a role for the biomarker of psoriatic arthritis pathology. It serves as one of the car

[0034] Physician Global Assessment (PGA) of disease activity was assessed by a physician using a visual analogue scale (VAS). This refers to an assessment of the subject's PsA status using a schizophrenia test. The VAS is a verbal rating scale ranging from "very good" to "very bad." It is set by the predicate.

[0035] Patient Global Assessment of Disease Activity (PtGA) was conducted by participants using a visual analog scale (VAS) to assess the current status of their PsA. Overall condition ("Taking into account all the ways that arthritis affects the subject, how is he or she feeling today, on average?") The scale ranges from "very good" to "very bad." It is set by the descriptor.

[0036] Patient pain assessment was conducted by asking subjects to rate their current pain level using a VAS ("I'm currently suffering from arthritis"). The subject was asked to evaluate the degree of pain he or she felt at that time. Pain was assessed on a scale set out with verbal descriptors ranging from "no pain" to "worst pain." do.

[0037] Patient self-rated disability was defined as the number of times participants completed the HAQ-DI questionnaire over the past week. This refers to someone who uses a scale to evaluate their own overall disability.

[0038] In some embodiments, the methods disclosed herein include (i) a physician global assessment of disease activity. (ii) patient global assessment of disease activity; (iii) patient pain assessment; and (iv) patient self-assessment. and (v) acute phase CRP. At least three of them had an improvement of at least 20% and at least 50% from baseline , or at least a 70% improvement.

[0039] The Health Assessment Questionnaire Disability Index (HAQ-DI) is a standardized instrument used to measure the It is designed to assess normal abilities. For patients, the HAQ-DI is usually self-explanatory. There are eight categories assessed by the HAQ-DI that require little explanation. The activities are: 1) dressing and grooming, 2) rising, 3) eating, 4) walking, and 5) hygiene. These categories were: 1) ability to read, 2) ability to reach, 3) ability to hold the hand, 4) ability to reach, 5) ability to grasp, and 6) ability to reach out. For each of the goals, patients were asked to rate how easy it was to perform two or three specific activities. The time frame for the questions on obstacles was the past week, and each question was scored 0 (no difficulties 1 (no difficulty), 1 (some difficulty), 2 (great difficulty), or 3 (unable to function) The use of aids and devices for these activities can also be recorded. If a device or assistive device is used, the minimum score for that category is 2. The index score is the average of the eight category scores. If there are no categories, the scale is not scored. If there are no categories, the The sum of the scores is divided by the number of categories answered. The higher the score, the greater the disability.

[0040] The Disease Activity Score 28-item C-reactive protein (DAS28-CRP) is used to evaluate the shoulder, elbow, and 28 joints including the right knee, wrist, MCP (1-5), PIP (1-5), and knee This refers to a measure of disease activity assessed across all 14 joints in each aspect of the body. This involves the examination of 28 joints for swelling and tenderness, pain and tenderness using a visual analog scale (VAS), and The results were derived from a global assessment of overall condition and blood marker of inflammation (hsCRP). This is the overall score.

[0041] The Leeds dactylometer is used to assess dactylitis. The dactylometer is a validated tool used to measure the circumference of the base of the affected finger. The LDI is a measure of this comparison and is used to assess the effect of dactylitis on the Tenderness score for the joint considered to be affected (0=not tender, 1=tender, 2=painful) dactylitis is accompanied by 1 = tenderness on the contralateral side, and 2 = intolerable tenderness on the contralateral side. (defined as a 10% difference in circumference of the affected finger compared to the control finger). , the lateral epicondyle of the humerus, the medial condyle of the femur, and the Achilles tendon insertion site. Tenderness is examined at six sites (left and right) for each enthesitis site. Then, adjacent joints are assessed for tenderness and soft tissue swelling, with a score of 1 if present. The LEI score ranges from 0 to 6.

[0042] Psoriasis Area and Severity Index (PASI) is a measure of the average redness, thickness, and scalyness of lesions. It is a measure of the severity of the disease (each rated on a scale of 0 to 4) and is weighted according to the area of ​​involvement. A 75% reduction in the Patients with Mycosis Area and Severity Index (PASI 75) score was observed in It is the current benchmark primary endpoint for most clinical trials in psoriasis.

[0043] Minimal Disease Activity (MDA) is a measure of disease remission. Tender joint count ≤1, swollen joint count ≤1 Psoriasis Activity and Severity Index ≤1 or body surface area ≤3, Patient Pain Visual Analyser Log scale (VAS) score ≤ 15, patient global disease activity VAS score ≤ 20 , Health Assessment Questionnaire (HAQ) score ≤0.5, and enthesitis score ≤1. Patients were classified as having achieved MDA if they met five of the seven criteria listed above.

[0044] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a composition suitable for use in a patient. It refers to a compound or composition that is capable of inducing a desired therapeutic effect when administered appropriately. One embodiment of the present disclosure comprises a pharma- ceutical carrier and at least one of the compositions of the present disclosure. and a therapeutically effective amount of the antibody.

[0045] As used herein, a "pharmaceutical acceptable carrier" or a "physiologically acceptable carrier" refers to a " refers to an antibody or antibody combination suitable for achieving or enhancing delivery of one or more antibodies of the present disclosure. Refers to one or more formulation ingredients.

[0046] Tildrakizumab alone or in combination with prophylactic, therapeutic, and / or pharmaceutical agents In yet another aspect, a pharmaceutical composition is provided comprising the compound provided herein in combination with a suitable carrier. Pharmaceutical compositions comprising rudrakizumab may be used to diagnose, detect, or monitor a disorder or disorder. in the prevention, treatment, management, or amelioration of one or more symptoms of These drugs are intended for use in, but not limited to, the treatment of cancer, including as a preventative or therapeutic agent alone. The formulation of a pharmaceutical composition in combination with a therapeutic agent and / or a pharma- ceutical acceptable carrier is carried out by It is well known to those skilled in the art.

[0047] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A value of at least about 40% indicates efficacy of the antibody. An ACR20 response rate of at least approximately 50% at week 1 or 52 was considered to demonstrate efficacy of the antibody. In some embodiments, the ACR20 response value is at least about A response rate of 60% indicates efficacy of the antibody.

[0048] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A value of at least about 20% indicates efficacy of the antibody. An ACR50 response rate of at least approximately 25% at week 1 or 52 was considered to demonstrate efficacy of the antibody. In some embodiments, the ACR50 response value is at least about A response rate of 30% indicates efficacy of the antibody.

[0049] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A value of at least about 10% indicates efficacy of the antibody. An ACR70 response rate of at least about 12% indicates efficacy of the antibody. In some embodiments, the ACR70 response rate is at least about 15% at week 24 or week 52. indicates the effectiveness of the antibody.

[0050] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide having the sequence, and An improvement of at least 75% from the baseline score indicates efficacy of the antibody. will achieve at least a 90% improvement from baseline in Psoriasis Area and Severity Index at Week 52 In some embodiments, a Psoriasis Area-Severity Index at Week 52 is indicative of efficacy of the antibody. A 100% improvement from baseline indicates efficacy of the antibody.

[0051] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A decrease in CRP score indicates efficacy of the antibody. In some embodiments, the patient is Experience a decrease of 1, 2, 3, 4, 5, 6, 7, 8, or 9 units in AS28 score It is possible.

[0052] In some embodiments, administering the anti-IL-23p19 antibody hum13B8-b to a patient and a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, comprising: Provided herein is a method for treating a patient's pulmonary disease, wherein the patient receives a first dose of the antibody subcutaneously at week 0. and then every 12 weeks, with subsequent doses administered subcutaneously. (ii) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain polypeptide comprising the sequence, and A statistically significant improvement in disease activity, as determined by, indicates efficacy of the antibody. EXAMPLES

[0053] The following examples are illustrative of particular embodiments of the disclosure and various uses thereof. They are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. should not be construed as [Example 1]

[0054] Administration of Tildrakizumab in Subjects with Active Psoriatic Arthritis

[0055] 1. Study Design Administered by subcutaneous injection in subjects with active PsA (NCT02980692) A randomized, double-blind, placebo-controlled study evaluating the efficacy of four doses of tildrakizumab administered A placebo-controlled, multiple-dose, phase 2b study was conducted. Rudrakizumab 200 milligrams (mg) subcutaneously (SC) every 4 weeks (q) until week 52 injection and tildrakizumab 200 mg administered every 12 weeks until week 52. C and tildrakizumab 100mg administered SC every 12 weeks until week 52. and tildrakizumab 20 mg administered SC at weeks 0 and 12 followed by tildrakizumab Patients were randomly assigned to receive 200 mg of izumab every 12 weeks for 24 weeks and then 52 weeks. Sebo was administered SC at weeks 0, 4, 8, 12, 16, 20, and 24. followed by tildrakizumab 200 mg every 12 weeks until week 52. All subjects received injections every 4 weeks. Subjects randomized to the active treatment group received 12-week follow-up at weeks 4, 8, 16, They received placebo injections at weeks 20, 28, 32, 40, and 44.

[0056] The study consisted of a screening period (days -28 to 0) and part 1, a double-blind placebo-controlled trial. Part 1, double-blind follow-up period (weeks 25 to 52) Part 1 consisted of one treatment group, and part 2 consisted of a 20-week washout period (weeks 53 to 72). During the treatment period, subjects did not receive tildrakizumab. Subjects who responded (≥2 increase from baseline in both swollen and tender joint counts) 0% improvement from baseline in Patient Global Assessment of Disease Activity [PtGA] ≥ Patients who underwent CT scans during part 1 (defined as a 20% improvement) were enrolled in part 2 of the study. Rudrakizumab (100 mg q12 weeks or 200 mg [q4 and q12 weeks] dose) Subjects who received the treatment but did not demonstrate a clinical response to treatment at 24 weeks were included in the study. Patients who received placebo or 20 mg tildrakizumab during part 1 were Participants who did not demonstrate a clinical response to treatment at week 24 were entered into part 2, Part 2 participants received tildrakizumab 200 mg every 12 weeks until the first week of Treatment was discontinued because no sufficient clinical benefit was achieved at any time point after week 24. Cancelled.

[0057] The primary endpoint was American College of Rheumatology response criteria (ACR20) at weeks 24 and 52. Response rate was measured by the proportion of subjects achieving a 20% improvement from baseline. Secondary efficacy outcomes included ACR50, ACR70 response rates, and ACR response rates. The components of and the proportion of subjects requiring adjustment of background therapy and DAS28- The proportion of subjects who achieved CRP < 3.2 and those who achieved minimal disease activity (MDA) criteria The proportion of subjects and the Leeds Dactylitis Index (LDI) and Leeds Enthesitis Index (LEI) were ) from baseline, change from baseline in HAQ-DI, and area of ​​psoriasis -Improvement of 75% / 90% / 100% in Patient Severity Index (PASI). The PK and immunogenicity of zumab and treatment-emergent adverse events (TEAEs) were also evaluated.

[0058] 2. Selection of study population The study population was comprised of subjects aged 18 years or older who had at least 6 Ps with symptoms of 3 or more tender joints and 3 or more swollen joints for 3 months Subjects diagnosed with psoriatic arthritis type A (according to the Classification of Psoriatic Arthritis [CASPAR] criteria) were included.

[0059] Aspartate aminotransferase (AST) or alanine aminotransferase If ALT is more than twice the upper limit of normal (ULN), creatinine is greater than the ULN. If serum direct bilirubin is 1.5 mg / dL or more, white blood cell ( If the WBC count is less than 3.0 × 103 / μL or if the rheumatoid factor test result is positive If any of these conditions were present, the subject was excluded from participating in the study.

[0060] Table 1 provides an overview of the demographic characteristics by treatment for selected subjects. Table 2 provides a summary of the baseline disease characteristics of the selected subjects. N is the number of subjects in the treatment group analysis is the number of subjects in the population, and n is the number of subjects in the specified category with no missing values. The baseline is defined as the last available value prior to the first dose of investigational drug. [Table 1] Summary of demographic characteristics by treatment full analysis set TIFF2025069284000001.tif228159

[0061] TIFF2025069284000002.tif232159[Table 2] Full analysis set of baseline disease characteristics TIFF2025069284000003.tif241158

[0062] TIFF2025069284000004.tif228158

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[0064] 3.Statistical analysis The primary efficacy analysis population was all randomized patients who received at least one dose of the investigational medicinal product (IMP). The full analysis set (FAS) was defined as subjects who completed the primary evaluation. Response rates for efficacy endpoints (ACR20 at 24 and 52 weeks) were compared between placebo and each active dose. To compare between groups, previous anti-TNF use and baseline weight were used as stratification factors. Based on the Cochran-Mantel-Haenszel test, In addition, the differences in response rates between placebo and each active dose group and the corresponding confidence intervals were (CI) was estimated for participants who discontinued early and for other randomized controlled trials with incomplete data at 24 weeks. were classified as non-responders for the primary endpoint (ACR20). Minimal response to treatment (either in swollen or tender joint counts) at week 1 For subjects who demonstrated only a <10% improvement from baseline in Patients may have received background medications adjusted according to daily doses and may have been discriminated against for participating in the study. Any subjects requiring these adjustments were included as non-responders for the primary analysis. was counted as.

[0065] The analysis of the primary outcome was based on the FAS. Sensitivity analyses were performed based on the PPAS. [Example 4]

[0066] Results up to 24 weeks

[0067] A summary of the subject status at week 24 is shown in Table 3. The safety analysis population consisted of 10 subjects with IMP. The full analysis set consisted of all randomized subjects who received at least one dose of study drug. The study consisted of all randomized subjects who received at least one dose of IMP. The analysis set conforming to the specifications may affect the validity of the data for the primary efficacy variable. The study consisted of all subjects in the full analysis set without any major deviations from the study protocol. Percentages are based on the number of subjects in the safety analysis set. Part 1 was based on the number of subjects randomized, except for those listed below. Part 1 is a double-blind, placebo-controlled period from week 25 to week 52. The double-blind follow-up period is until the end of the study. [Table 3] Summary of subject status at 24 weeks TIFF2025069284000006.tif205158

[0068] Cochran-Mantel Haenszel study of ACR20 response rate by week 24 The (CMH) analysis is shown in Table 4. ACR20 was significantly higher than baseline for tender and swollen joint counts. ≥20% improvement from baseline and the remaining five ACR Core Set measures: patient and physician 20% improvement from baseline in three of the following: nurse global assessment, pain, disability, and acute CRP The improvement was calculated as an improvement of ≥ 100 mg q12 weeks during part 1. or 200 mg [q4 and q12 weeks], but discontinued treatment at 24 weeks Subjects who did not demonstrate a clinical response to the study drug were discontinued and placed on a drug hold as per the study protocol. Week 24 assessments for subjects who discontinued study drug were recorded at Week 52 / EOT. Two-sided 95% CIs and p values ​​were calculated for anti-TNF use and baseline weight as stratification factors. Based on the CMH test with the Mantel-Fleiss criterion of <5. Pairwise comparisons , were based on Fisher's exact test after collapsing across levels of the stratification factors. This is noted with an "*" for the p-value. Baseline is the most recent baseline data prior to the first dose of study drug. It is defined as the next available value. [Table 4] CMH analysis of ACR20 response rate up to 24 weeks (no response = non-response) - Maximum solution Analysis target population TIFF2025069284000007.tif227159

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[0073] Table 5 shows the CMH analysis of ACR50 response rates through 24 weeks. ≥ 50% improvement from baseline in joint and swollen joint counts and remaining five ACR core scores Among the five scales, namely patient and physician global assessment, pain, disability, and acute CRP, ACR50 was calculated as ≥50% improvement from baseline in three trials. The R20 analysis was performed in the same manner as described above.

[0074] Tildrakizumab (100 mg q12 weeks or 200 mg q4 and q12 weeks) but showed no clinical response to treatment at 24 weeks. Subjects who fail the study will be discontinued and will enter a washout period as per the study protocol. Week 24 assessments for subjects who discontinued the drug will be recorded at Week 52 / EOT. Titers will be reported as part of the 24-week visit. Two-sided 95% CIs and p values ​​are Based on the CMH test with stratification factors of F and baseline weights. Mantel-F If the Leiss criterion is less than 5, pairwise comparisons are based on fits after collapsing across levels of the stratification factors. The results are based on the Shah exact test, which is indicated by a "*" next to the p-value. The baseline is defined as the last available value prior to the first dose of investigational drug. [Table 5] CMH analysis of ACR50 response rate up to 24 weeks (no response = non-response) - Maximum solution Analysis target population TIFF2025069284000012.tif227158

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[0079] Table 6 shows the CMH analysis of ACR70 response rates through 24 weeks. ≥70% improvement from baseline in joint and swollen joint counts and the remaining five ACR core scores Among the five scales, namely patient and physician global assessment, pain, disability, and acute CRP, ACR70 was calculated as ≥70% improvement from baseline in three trials. The R20 analysis was performed in the same manner as described above. [Table 6] CMH analysis of ACR70 response rate up to 24 weeks (no response = non-response) - Maximum solution Analysis target population TIFF2025069284000017.tif223158

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[0084] 4. Results up to 52 weeks Of 500 patients screened, 391 were randomized to receive at least one dose of the drug. The proportion of ACR20 / 50 / 70 responders was significantly higher than placebo by week 24. After week 24, responders were Tildrakizumab 20 → 200 mg Q12W and placebo → 200 mg Q12 There was a further increase with W (Figures 2 and 3). Additional efficacy results are shown in Table 7.

[0085] MDA was assessed throughout the study, and a response was determined if 5 of 7 criteria were met. Baseline disease characteristics related to MDA varied little between study arms. By week 24, MDA status was significantly higher in the tildrakisma group compared with placebo. This was achieved in significantly more patients receiving cyclophosphamide (0% to 24% vs. 0% to 7%). %-39%, p<0.02 for all groups). This rate was The incidence rate further increased with continued tildrakizumab treatment through week 52, including in patients who switched to tildrakizumab (47%). The percentage of patients with pulmonary circulation disorders increased (45%–64%) (Figure 4).

[0086] Treatment with tildrakizumab resulted in PASI 75 / 90 / 100 responders at 24 weeks. The proportion of patients with schizophrenia who had a history of schizophrenia was significantly increased compared to placebo. This proportion continued to increase, reaching 5 The effect remained stable until the second week (Figure 5). Similarly, placebo → tildrakizumab 200 mg Q Patients who switched from 12 weeks or after 24 weeks switched to tildrakizumab 20→200mg Q PASI 75 / 90 / 100 response rates were up to 36 weeks in patients who were titrated from 12 weeks The PASI score increased and remained stable through week 52. The improvement in 75 skin reactions was significant compared with placebo as early as the fourth week. Rudrakizumab had a tolerable safety profile through 52 weeks.

[0087] DAS28-CRP has been shown to be reliable in PsA, with a score of <3.2 being associated with Patients who achieved this were considered responders. At baseline, disease characteristics were similar between treatment arms. Consistently, 1.3% to 7.7% of patients had a DAS28-CRP score of <3.2. At week 24, all tildrakizumab treatment groups had The response rate of DAS28-CRP increased over the course of the study (Figure 6). The response rate increased from week 24 onwards. and persisted through week 52, including in patients who switched from placebo to tildrakizumab .

[0088] Overall, the increase from baseline to weeks 24 / 25 to 52 was 50.4%, respectively. TEAEs and serious AEs were experienced by 39.9% / 2.3% and 1.0% of patients, respectively. The most common TEAE was nasopharyngitis (5.4% / 4.2% in the tildrakizumab group vs. and upper respiratory tract infections (total 3.8% / 4.2% in the tildrakizumab group) % vs placebo 1.3% / 0.0%). One patient (0.3%) died at 24 hours of Participation was discontinued weeks before the trial. From baseline to week 24, TIL 100mg Q12W One case of pyelonephritis and urinary tract infection was reported in the TIL 20mg → 200mg Q12 group. One case of chronic tonsillitis was reported in the W group. One malignancy was reported in the 0 mg Q12W group. No deaths or major adverse cardiac events occurred. It was. [Table 7] Clinical efficacy at week 52 (W52) TIFF2025069284000022.tif106170[Table 8] Baseline disease characteristics associated with minimal disease activity at week 52 TIFF2025069284000023.tif105170[Table 9] Baseline disease characteristics associated with DAS28-CRP TIFF2025069284000024.tif140170

[0089] 5. Conclusion: Tildrakizumab, administered Q12Wk, showed surprisingly high efficacy in this clinical trial. Tildrakizumab demonstrated efficacy against ACR20, ACR50, and ACR70 response criteria. Significantly better than placebo in treating joint symptoms of active psoriatic arthritis as measured by While the present disclosure has been described with reference to various embodiments, those skilled in the art may It is understood that variations and modifications will occur. Therefore, the appended claims are to be construed as though they were merely illustrative. It is intended to cover all such equivalent variations that are within the scope of this disclosure. Additionally, the section headings used herein are for organizational purposes only and are not intended to be limiting. It should not be construed as limiting the subject matter.

[0090] Each embodiment described herein may be combined with any other embodiment unless expressly indicated to the contrary. Any aspect or embodiment that is specifically indicated as being preferred or advantageous may be combined with any aspect or embodiment. Any feature or embodiment is preferred or advantageous unless expressly indicated to the contrary. The above-mentioned features may be combined with any other features or embodiments shown.

Claims

1. A composition for use in a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, wherein the composition comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2, and comprises the anti-IL-23p19 antibody hum13B8-b; wherein the method comprises subcutaneously administering an initial dose of the antibody to a patient in need thereof at week 0, and subsequently administering subsequent doses subcutaneously every 12 weeks; and wherein a DAS28-CRP score reduced by 1 to 9 units from the baseline value at week 52 indicates the efficacy of the antibody, Composition.

2. A composition for use in a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, wherein the composition comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2, and comprises the anti-IL-23p19 antibody hum13B8-b; wherein the method comprises subcutaneously administering an initial dose of the antibody to a patient in need thereof at week 0, and subsequently administering subsequent doses subcutaneously every 12 weeks; and wherein a Leeds enthesitis index (LEI) score reduced from the baseline value at week 52 indicates the efficacy of the antibody, Composition.

3. A composition for use in a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, wherein the composition comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2, and comprises the anti-IL-23p19 antibody hum13B8-b; wherein the method comprises subcutaneously administering an initial dose of the antibody to a patient in need thereof at week 0, and subsequently administering subsequent doses subcutaneously every 12 weeks; and wherein a Leeds dactylitis index (LDI) score reduced from the baseline value at week 52 indicates the efficacy of the antibody, Composition.

4. A composition for use in a method for determining the efficacy of an anti-IL-23p19 antibody for the treatment of psoriatic arthritis, wherein the composition comprises (i) a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and (ii) a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2, and comprises the anti-IL-23p19 antibody hum13B8-b; Here, the method includes subcutaneously administering an initial dose of the antibody to a patient in need thereof at week 0, and then subcutaneously administering subsequent doses every 12 weeks; and here, a functional disability index (HAQ-DI) score using a health assessment questionnaire that has decreased from baseline at week 52 indicates the efficacy of the antibody. Composition. **Claim 5** A pharmaceutical composition comprising the anti-IL-23p19 antibody hum13B8-b for use in a method of treating psoriatic arthritis, wherein the antibody hum13B8-b (i) comprises a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 1, and (ii) comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 2; wherein the method includes administering hum13B8-b to a patient in need thereof; wherein the patient is subcutaneously administered an initial dose of the antibody at week 0, and then subcutaneously administered subsequent doses every 12 weeks; where the initial dose is 20 mg, the subsequent doses are 20 mg until week 24, and then are changed to 200 mg. Pharmaceutical composition.

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