Compositions and methods for treating juvenile idiopathic arthritis

Abstract

This disclosure provides compositions and methods for treating and improving symptoms of systemic juvenile primiparous arthritis and polyarticular juvenile primiparous arthritis using antibodies that specifically bind to the human interleukin-6 receptor (hIL-6R).

Description

Technical Field

[0001] This disclosure relates to the field of treatment for juvenile primiparous arthritis, such as systemic juvenile primiparous arthritis and polyarticular-course juvenile primiparous arthritis (which includes polyarticular and extended oligoarticular juvenile primiparous arthritis). Certain aspects of the invention relate to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, for the treatment of systemic juvenile primiparous arthritis and polyarticular-course juvenile primiparous arthritis. Prior Technology

[0002] Juvenile primary arthritis (JIA) is the most common rheumatic disease in children. The International Federation of Rheumatology Societies (ILAR) defines JIA as arthritis of unknown etiology that begins before the age of 16 and lasts for at least 6 weeks after excluding other known conditions (Petty, RE et al., 2001. J Rheumatol. 2004; 31(2): 390-2; Giannini, EH et al., 1997 Arthritis Rheum. 40(7): 1202-9; and Macaubas, C. et al., 2009 Nat Rev Rheumatol. 5(11): 616-26). The condition includes seven subtypes as defined by the ILAR, including polyarticular JIA and systemic JIA. See Petty, RE et al., 2001. J Rheumatol. 2004; 31(2): 390-2, which is incorporated herein by reference in its entirety.

[0003] There is no known cure for JIA. Although conventional treatments can be used to treat affected individuals, more effective treatments are needed for persistent types of JIA. Summary of the Invention

[0004] This disclosure provides, in particular, a method for treating JIA in subjects in need, which includes administering an effective amount of an antibody that specifically binds to IL-6R.

[0005] In one embodiment, JIA is a full-body JIA (sJIA).

[0006] In one embodiment, the antibody that specifically binds to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region of sequence SEQ ID NO:2.

[0007] In various embodiments, the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the three complementarity-determining regions (CDRs) found in the sequence SEQ ID NO:1, and wherein the VL comprises the three CDRs found in the sequence SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three heavy chain complementarity-determining regions (HCDRs; i.e., HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (LCDRs; i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0008] In one embodiment, the antibody is sarilumab.

[0009] In various embodiments, no other disease-modifying antirheumatic drug (DMARD) is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In one embodiment, at least one other DMARD is administered to the subject together with or simultaneously with the antibody.

[0010] In some embodiments, the subject has at least one symptom of sJIA, such as arthritis in at least one joint lasting at least 6 weeks, accompanied by or preceded by fever lasting at least 2 weeks; transient erythematous rash mainly occurring on the trunk and extremities; generalized lymphadenopathy; hepatomegaly and / or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; elevated peripheral blood white blood cell (WBC) count (25,000 to 50,000 / mL3); elevated platelet count (e.g., >1 x 106); significantly elevated erythrocyte sedimentation rate (ESR) of >100 mm / h; anemia; and / or high ferritin levels relative to healthy subjects. In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0011] As used herein, “symptoms” associated with JIA include any clinical or laboratory (e.g., diagnostic) manifestations associated with JIA, and are not limited to those that a subject can feel or observe.

[0012] In various embodiments, the subject had at least one symptom of sJIA, such as limping; stiffness upon waking; reluctance to use the arm or leg; reduced activity level; daily peak fever (e.g., reaching about 40°C or at least 40°C); joint swelling; and / or difficulty with fine motor skills. In one embodiment of the method, at least one symptom of sJIA in the subject improved after administration of the antibody.

[0013] In various embodiments of the method, the antibody improves at least one score or metric, such as JIA ACR (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100), JIA ACR components (e.g., count of joints with active arthritis, count of joints with limited range of motion, comprehensive physician assessment of disease activity, acute-phase reactants such as erythrocyte sedimentation rate or C-reactive protein (CRP), pediatric health assessment questionnaire, comprehensive assessment of the patient's (or parent's) overall health status), and / or fever reduction (e.g., in subjects with fever at the time of initial administration of the antibody), reduction in corticosteroid (e.g., glucocorticoid) usage from baseline, and / or juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score -27). In various embodiments of the method, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and / or JIA ACR100. In various embodiments of the method, the improvement is characterized by at least one score or metric, such as a physician's comprehensive assessment of disease activity score, a patient or parent assessment of overall health status, a child health assessment questionnaire, the number of joints with active arthritis, the number of joints with limited mobility, high-sensitivity C-reactive protein, and / or fever reduction (e.g., in subjects with fever at the time of initial administration of the antibody). In various embodiments, the improvement is characterized by at least one biomarker. In various embodiments of the method, the antibody induces clinically inactive disease, as defined by the Wallace criteria. The Wallace criteria are defined as a physician's comprehensive VAS <1 / 10, no active arthritis, no active uveitis, and CRP <10 mg / L. In various embodiments of the method, the antibody induces clinically inactive disease, such as by a juvenile arthritis disease activity score -27 - CRP. As defined in 1. In various embodiments of the method, the antibody induces clinically inactive or low-disease activity, such as that caused by the disease activity score of juvenile arthritis -27-CRP. As defined in 3.8.

[0014] In one embodiment of the method, the subject did not respond adequately to the current treatment and was considered a candidate for a biological disease-modifying antirheumatic drug.

[0015] In one embodiment of the method, the subject's age is between about 1 year and about 17 years. In other embodiments, the subject's age is between about 4 years and about 6 years, or between about 12 years and about 18 years.

[0016] In one embodiment of the method, the subject has five or more joint mobilities, or two joint mobilities and systemic symptoms (e.g., fever). In one embodiment of the method, although the dose of glucocorticoids has been stabilized for at least 3 days, the subject has five or more joint mobilities or two or more joint mobilities for at least 3 days in any consecutive 7 days, and a fever above about 37.5°C.

[0017] An "active joint" is (i) a joint with swelling within the joint not due to deformity, and / or (ii) a joint with limited range of motion accompanied by pain or tenderness.

[0018] In one embodiment of the method, JIA is polyarticular JIA (pcJIA). In some embodiments, pcJIA is extended oligoarticular JIA. In various embodiments, pcJIA is rheumatoid factor (RF) positive polyarticular JIA. In some embodiments, pcJIA is RF negative polyarticular JIA. In one embodiment of the method, the subject's age is between about 12 and about 14 years, or between about 7 and about 9 years.

[0019] In one embodiment, the antibody that specifically binds to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region of sequence SEQ ID NO:2.

[0020] In various embodiments, the antibody comprises VH and VL, wherein VH comprises the three CDRs found in the sequence SEQ ID NO:1, and wherein VL comprises the three CDRs found in the sequence SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0021] In one embodiment, the antibody is sarriromumab.

[0022] In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In one embodiment, at least one other DMARD is administered to the subject together with or simultaneously with the antibody.

[0023] In some embodiments, the subject has at least one symptom of RF-positive polyarticular arthritis (JIA). In some embodiments, the subject has at least one symptom of RF-positive polyarticular JIA, such as deforming symmetrical polyarthritis that can develop into joint subluxation (e.g., in the wrist and / or thumb); joint contractures (e.g., proximal and distal interphalangeal joints, proximal interphalangeal bone overgrowth, and finger deformities such as swan neck or buttonhole deformity); chronic synovitis; articular cartilage loss and paraarticular bone erosion; orthoglossy chronic anemia; elevated ESR and C-reactive protein; white blood cell count; asymptomatic cervical spondylitis; and / or micrognathia. In various embodiments, the subject has joint subluxation (e.g., in the wrist and / or thumb) and / or joint contractures (e.g., proximal and distal interphalangeal joints, proximal interphalangeal bone overgrowth, and finger deformities such as swan neck or buttonhole deformity). In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms. In one embodiment of the method, the subjects were between approximately 12 and approximately 14 years old.

[0024] In various embodiments, the subject has at least one symptom of RF-negative polyarticular arthritis (JIA). In various embodiments, the subject has at least one symptom of RF-negative polyarticular arthritis, such as symmetrical polyarthritis with reduced movement, muscle weakness, and / or decreased physical function. In one embodiment, treating the subject includes alleviating, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms. In one embodiment of the method, the subject is between approximately 7 and approximately 9 years old.

[0025] In one embodiment, the subject suffers from at least one symptom of extended oligoarticular joint inflammatory lesions (JIA). In various embodiments, the subject suffers from at least one symptom of extended oligoarticular JIA, such as aseptic inflammatory synovitis affecting more than four joints (e.g., in larger joints such as the knee, ankle, and wrist) after the initial 6 months of the disease; limping; chronic anterior uveitis; chronic arthritis of the knee or ankle leading to overgrowth of that limb, resulting in subsequent leg length discrepancies; muscle atrophy (e.g., in extensor muscles such as the vastus lateralis and quadriceps femoris when the knee is affected); and / or flexion contractures of the knee or wrist. In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0026] In various embodiments, the subject had at least one symptom of pcJIA, such as limping; stiffness upon waking; reluctance to use the arm or leg; reduced activity level; joint swelling; and / or difficulty with fine motor activities.

[0027] In one embodiment of the method, at least one symptom of pcJIA in the subject is improved after administration of the antibody. In various embodiments of the method, the improvement is characterized as at least one score or measure, such as defined as one of the following core group variables. 3 / 6 of JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100 showed improvement and no more than 1 / 6 worsened: (i) a comprehensive physician assessment of disease activity (e.g., via the Visual Analogue Scale (VAS)), (ii) a patient or parent assessment of overall health status, (iii) a child health assessment questionnaire (e.g., via the Child Health Assessment Questionnaire Disability Index (CHAQ-DI)), (iv) the number of joints with active arthritis, (v) the number of joints with limited mobility, and (vi) an inflammatory index (e.g., high-sensitivity C-reactive protein). In one embodiment, the JIA ACR30 response is when... 3 / 6 core group variables improved from baseline 30% but no more than 1 / 6 of the deterioration At 30%.

[0028] In various embodiments of the method, improvement in disease activity is characterized by at least one juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score-27, which includes four measurements: a physician’s comprehensive assessment of disease activity, a parent / patient comprehensive assessment of health status, a count of joints with active disease, and an inflammation index (hs-CRP or ESR level)).

[0029] In various embodiments of the method, the improvement is characterized by at least one score or metric, such as a physician’s comprehensive assessment of disease activity, a patient or parent assessment of overall health status, a child health assessment questionnaire, the number of joints with active arthritis, the number of joints with limited mobility, high-sensitivity C-reactive protein, and / or a juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score-27).

[0030] In various embodiments of the method, the antibody induces clinically inactive disease, as defined by the Wallace criteria. The Wallace criteria are defined as a physician-wide VAS <1 / 10, no active arthritis, no active uveitis, and CRP <10 mg / L. In various embodiments of the method, the antibody induces clinically inactive disease, such as juvenile arthritis disease activity score -27 - CRP. As defined in 1. In various embodiments of the method, the antibody induces clinically inactive or low-disease activity, such as that caused by the disease activity score of juvenile arthritis -27-CRP. As defined in 3.8.

[0031] In one embodiment of the method, the subjects were between approximately 2 and approximately 17 years old.

[0032] In various embodiments, the subject had suffered from JIA for at least 6 months. In one embodiment, the subject had arthritis affecting up to 4 joints during at least the first 6 months of the disease, and then progressed to affecting 5 or more joints after at least the first 6 months. In some embodiments, the subject had arthritis affecting up to 4 joints during the first 6 months of the disease, and then progressed to affecting 5 or more joints after the first 6 months.

[0033] In one embodiment of the method, the subject has at least five joints with active arthritis. In one embodiment of the method, the subject has arthritis affecting five or more joints during the first six months of the disease. In one embodiment of the method, the arthritis is rheumatoid factor negative. Alternatively, in one embodiment, the arthritis is rheumatoid factor positive.

[0034] In one embodiment of the method, the antibody is administered subcutaneously. In various embodiments of the method, the antibody is administered weekly or every two weeks.

[0035] In one embodiment of the method, the antibody is administered at a dose of about 2 mg / kg to about 4 mg / kg. In one embodiment, the dose is administered once weekly or once every two weeks. In various embodiments of the method, the antibody is used at doses of about 2 mg / kg weekly, about 2.5 mg / kg weekly, about 2 mg / kg every two weeks, about 2.5 mg / kg every two weeks, about 3 mg / kg every two weeks, and about 4 mg / kg every two weeks. In various embodiments of the method, the antibody is used at the doses listed in Tables 1-5.

[0036] In some embodiments of the method, the subject has a weight of less than 30 kg.

[0037] In some embodiments of the method, the subject has a weight of at least about 30 kg. In some embodiments of the method, the subject has a weight of less than 60 kg.

[0038] In some embodiments of the method, the subjects were aged 1 to 17 years.

[0039] In some embodiments of the method, the subject is a human and the antibody is a human antibody.

[0040] This disclosure further provides a method for treating pcJIA in a subject in need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody specifically binds to IL-6R comprises a heavy chain variable region sequence of SEQ ID NO:1 and a light chain variable region sequence of SEQ ID NO:2, wherein the antibody is administered at a dose of about 2 mg / kg to about 4 mg / kg weekly or every two weeks, wherein the subject weighs ≥10 kg and ≤60 kg.

[0041] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of about 2 mg / kg to about 3 mg / kg every other week or at a dose of about 2 mg / kg per week.

[0042] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg to about 3 mg / kg once every week or at a dose of about 2 mg / kg once a week.

[0043] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg or about 3 mg / kg every other week.

[0044] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg or about 3 mg / kg once every week.

[0045] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of 2 mg / kg or 3 mg / kg every other week or 2 mg / kg per week.

[0046] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of 2 mg / kg or 3 mg / kg once every week or 2 mg / kg once a week.

[0047] In some embodiments of the method, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg to about 4 mg / kg every other week or at a dose of about 2.5 mg / kg per week.

[0048] In some embodiments of the method, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg to about 4 mg / kg every other week or at a dose of about 2.5 mg / kg once a week.

[0049] In some embodiments of the method, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg or about 4 mg / kg every other week.

[0050] In some embodiments of the method, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg or about 4 mg / kg once every week.

[0051] In some embodiments of the method, the subject's weight is greater than or equal to 10 kg and less than 30 kg, and the antibody is administered at a dose of 2.5 mg / kg or 4 mg / kg every other week or 2.5 mg / kg per week.

[0052] In some embodiments of the method, the subject's weight is greater than or equal to 10 kg and less than 30 kg, and the antibody is administered at a dose of 2.5 mg / kg or 4 mg / kg every other week or 2.5 mg / kg once a week.

[0053] This disclosure further provides a method for treating pcJIA in a subject of need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody that specifically binds to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and SEQ ID NO:1. The NO:2 light chain variable region sequence, wherein the subject's weight is greater than or equal to 30 kg and less than 33 kg, and the antibody is administered at a dose of 61.25 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 33 kg and less than 37.5 kg, and the antibody is administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 37.5 kg and less than 42 kg, and the antibody is administered at a dose of 78.75 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 42 kg and less than 46.5 kg, and the antibody is administered at a dose of 87.5 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 46.5 kg and less than 50.5 kg, and the antibody is administered at a dose of 96.25 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 50.5 kg and The subjects weighing less than 55 kg will receive the antibody at a dose of 105 mg every other week or once a week; the subjects weighing 55 kg or more but less than 59.5 kg will receive the antibody at a dose of 113.75 mg every other week or once a week; the subjects weighing 59.5 kg or more but less than 64 kg will receive the antibody at a dose of 122.5 mg every other week or once a week; the subjects weighing 64 kg or more but less than 68 kg will receive the antibody at a dose of 131.25 mg every other week or once a week; the subjects weighing 68 kg or more but less than 72.5 kg will receive the antibody at a dose of 140 mg every other week or once a week; or the subjects weighing 72.5 kg or more will receive the antibody at a dose of 148.75 mg every other week or once a week.

[0054] This disclosure further provides a method for treating pcJIA in subjects in need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region of sequence SEQ ID NO:2, wherein the subject weighs ≥30 kg and <31 kg, and the antibody is administered at a dose of 87.5 mg once every other week or once weekly; wherein the subject weighs ≥31 kg and <34 kg, and the antibody is administered at a dose of 96.25 mg once every other week or once weekly; wherein the subject weighs ≥34 kg and <37 kg, and the antibody is administered at a dose of 105 mg once every other week or once weekly; wherein the subject weighs ≥37 kg and <39.5 kg, and the antibody is administered at a dose of 113.75 mg once every other week or once weekly; wherein the subject weighs ≥39.5 kg and <42.5 kg. The antibody was administered at a dose of 122.5 mg every other week or weekly, for subjects weighing 42.5 kg or more and less than 45 kg; the antibody was administered at a dose of 131.25 mg every other week or weekly, for subjects weighing 45 kg or more and less than 48.5 kg; the antibody was administered at a dose of 140 mg every other week or weekly, for subjects weighing 48.5 kg or more and less than 51.5 kg; and the antibody was administered at a dose of 148.75 mg every other week or weekly, for subjects weighing 42.5 kg or more and less than 45 kg. Subjects weighing 51.5 kg or more and less than 54.5 kg were given the antibody at a dose of 157.5 mg once every other week or once a week; subjects weighing 54.5 kg or more and less than 57 kg were given the antibody at a dose of 166.25 mg once every other week or once a week; subjects weighing 57 kg or more and less than 63 kg were given the antibody at a dose of 175 mg once every other week or once a week; and subjects weighing 63 kg or more were given the antibody at a dose of 192.5 mg once every other week or once a week.

[0055] This disclosure further provides a method for treating pcJIA in a subject in need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises a heavy chain variable region of sequence SEQ ID NO:1 and a light chain variable region of sequence SEQ ID NO:2, wherein the subject weighs ≥10 kg and <12.5 kg, and the antibody is administered at a dose of 26.25 mg once every other week or once weekly; wherein the subject weighs ≥12.5 kg and <16 kg, and the antibody is administered at a dose of 35 mg once every other week or once weekly; wherein the subject weighs ≥16 kg and <19.5 kg, and the antibody is administered at a dose of 43.75 mg once every other week or once weekly; wherein the subject weighs ≥19.5 kg and <23 kg. The antibody was administered at a dose of 52.5 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 61.25 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 26.5 kg and less than 30 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 30 kg and less than 37.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 3 .... Subjects weighing 37.5 kg or more and less than 42 kg were given the antibody at a dose of 78.75 mg every other week or once a week; subjects weighing 42 kg or more and less than 46.5 kg were given the antibody at a dose of 87.5 mg every other week or once a week; subjects weighing 46.5 kg or more and less than 50.5 kg were given the antibody at a dose of 96.25 mg every other week or once a week; subjects weighing 50.5 kg or more and less than 55 kg were given the antibody at a dose of 78.75 mg every other week or once a week. The antibody was administered at a dose of 105 mg once a week; for subjects weighing 55 kg or more and less than 59.5 kg, the antibody was administered at a dose of 113.75 mg once every other week or once a week; for subjects weighing 59.5 kg or more and less than 64 kg, the antibody was administered at a dose of 122.5 mg once every other week or once a week; for subjects weighing 64 kg or more and less than 68 kg, the antibody was administered at a dose of 131.25 mg once every other week or once a week; for subjects weighing 68 kg or more and less than 72 kg...The antibody was administered at a dose of 140 mg every other week or once a week, for subjects weighing 5 kg or more; or the antibody was administered at a dose of 148.75 mg every other week or once a week, for subjects weighing 72.5 kg or more.

[0056] This disclosure further provides a method for treating pcJIA in a subject in need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises a heavy chain variable region of sequence SEQ ID NO:1 and a light chain variable region of sequence SEQ ID NO:2, wherein the subject weighs ≥10 kg and <12.5 kg, and the antibody is administered at a dose of 43.75 mg once every other week or once weekly; wherein the subject weighs ≥12.5 kg and <14.5 kg, and the antibody is administered at a dose of 52.5 mg once every other week or once weekly; wherein the subject weighs ≥14.5 kg and <16.5 kg, and the antibody is administered at a dose of 61.25 mg once every other week or once weekly; wherein the subject weighs ≥16.5 kg and <19 kg, and the antibody is administered at a dose of 43.75 mg once every other week or once weekly. The antibody is administered at a dose of 70 mg once every other week or once a week; wherein the subject weighs ≥19 kg and <21 kg, the antibody is administered at a dose of 78.75 mg once every other week or once a week; wherein the subject weighs ≥21 kg and <23.5 kg, the antibody is administered at a dose of 87.5 mg once every other week or once a week; wherein the subject weighs ≥23.5 kg and <25.5 kg, the antibody is administered at a dose of 96.25 mg once every other week or once a week; wherein the subject weighs ≥25.5 kg and <23.5 kg, the antibody is administered at a dose of 96.25 mg once every other week or once a week. For subjects weighing 27.5 kg or more and less than 30 kg, the antibody is administered at a dose of 105 mg every other week or weekly; for subjects weighing 30 kg or more and less than 39.5 kg, the antibody is administered at a dose of 113.75 mg every other week or weekly; for subjects weighing 39.5 kg or more and less than 42.5 kg, the antibody is administered at a dose of 122.5 mg every other week or weekly. Subjects weighing 42.5 kg or more and less than 45 kg were given the antibody at a dose of 131.25 mg every other week or once a week; subjects weighing 45 kg or more and less than 48.5 kg were given the antibody at a dose of 140 mg every other week or once a week; subjects weighing 48.5 kg or more and less than 51.5 kg were given the antibody at a dose of 148.75 mg every other week or once a week; and subjects weighing 51.5 kg or more and less than 54.5 kg were given the antibody at a dose of 157 mg every other week or once a week.The antibody was administered at a dose of 5 mg; for subjects weighing 54.5 kg or more and less than 57 kg, the antibody was administered at a dose of 166.25 mg once every other week or once a week; for subjects weighing 57 kg or more and less than 60.5 kg, the antibody was administered at a dose of 175 mg once every other week or once a week; for subjects weighing 60.5 kg or more and less than 63 kg, the antibody was administered at a dose of 175 mg once every other week or once a week; for subjects weighing 63 kg or more, the antibody was administered at a dose of 192.5 mg once every other week or once a week.

[0057] This disclosure further provides a method for treating sJIA in a subject in need, comprising administering an effective amount of an antibody that specifically binds to IL-6R, wherein the antibody that specifically binds to IL-6R comprises a heavy chain variable region sequence of SEQ ID NO:1 and a light chain variable region sequence of SEQ ID NO:2, wherein the antibody is administered at a dose of about 2 mg / kg to about 2.5 mg / kg per week or about 3 mg / kg to about 4 mg / kg every two weeks, wherein the subject weighs more than or equal to 30 kg and less than or equal to 210 kg.

[0058] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg per week or about 3 mg / kg every other week.

[0059] In some embodiments of the method, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg once a week or about 3 mg / kg once every other week.

[0060] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of 2 mg / kg per week or 3 mg / kg every other week.

[0061] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of 2 mg / kg once a week or 3 mg / kg once every other week.

[0062] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of about 2.5 mg / kg per week or about 4 mg / kg every other week.

[0063] In some embodiments of the method, the subject weighs 30 kg or more and 210 kg or less, and the antibody is administered at a dose of about 2.5 mg / kg once a week or about 4 mg / kg once every other week.

[0064] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of 2.5 mg / kg per week or 4 mg / kg every other week.

[0065] In some embodiments of the method, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of 2.5 mg / kg once a week or at a dose of 4 mg / kg once every other week.

[0066] This disclosure discloses an antibody for treating JIA in subjects in need, wherein the antibody specifically binds to IL-6R.

[0067] In one embodiment, JIA is sJIA.

[0068] In one embodiment, the antibody that specifically binds to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region of sequence SEQ ID NO:2.

[0069] In various embodiments, the antibody comprises VH and VL, wherein VH comprises the three CDRs found in the sequence SEQ ID NO:1, and wherein VL comprises the three CDRs found in the sequence SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0070] In one embodiment, the antibody is sarriromumab.

[0071] In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In one embodiment, at least one other DMARD is administered to the subject together with or simultaneously with the antibody.

[0072] In some embodiments, the subject has at least one symptom of sJIA, such as arthritis in at least one joint lasting at least 6 weeks, accompanied by or preceded by fever lasting at least 2 weeks; transient erythematous rash mainly occurring on the trunk and extremities; generalized lymphadenopathy; hepatomegaly and / or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; elevated peripheral blood WBC count (25,000 to 50,000 / mL3); elevated platelet count (e.g., >1 x 106); significantly elevated ESR, >100 mm / h; anemia; and / or high ferritin levels relative to healthy subjects. In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0073] In various embodiments, the subject had at least one symptom of sJIA, such as limping; stiffness upon waking; reluctance to use the arm or leg; decreased activity level; daily peak fever (e.g., reaching about 40°C or at least 40°C); joint swelling; and / or difficulty with fine motor skills. In one embodiment of the antibody, at least one symptom of sJIA improved in the subject after administration of the antibody.

[0074] In various embodiments, the antibody improves at least one score or metric, such as JIA ACR (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100), JIA ACR components (e.g., count of joints with active arthritis, count of joints with limited range of motion, comprehensive physician assessment of disease activity, acute-phase reactants such as erythrocyte sedimentation rate or C-reactive protein, pediatric health assessment questionnaire, comprehensive assessment of the patient's (or parent's) overall health status), and / or fever reduction (e.g., in subjects with fever at the time of first administration of the antibody), reduction in corticosteroid (e.g., glucocorticoid) usage from baseline, and / or juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score -27). In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and / or JIA ACR100. In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as a physician's comprehensive assessment of disease activity score, a patient or parent assessment of overall health status, a child health assessment questionnaire, the number of joints with active arthritis, the number of joints with limited mobility, high-sensitivity C-reactive protein, and / or fever reduction (e.g., in subjects with fever at the time of initial administration of the antibody). In various embodiments, the improvement is characterized by at least one biomarker.

[0075] In various embodiments of the method, the antibody induces clinically inactive disease, as defined by the Wallace criteria. The Wallace criteria are defined as a physician-wide VAS <1 / 10, no active arthritis, no active uveitis, and CRP <10 mg / L. In various embodiments of the method, the antibody induces clinically inactive disease, such as juvenile arthritis disease activity score -27 - CRP. As defined in 1. In various embodiments of the method, the antibody induces clinically inactive or low-disease activity, such as that caused by the disease activity score of juvenile arthritis -27-CRP. As defined in 3.8.

[0076] In one embodiment of the intended use, the subject did not respond adequately to the current treatment and was considered a candidate for a biological disease-modifying antirheumatic drug.

[0077] In one embodiment of the described use, the subject's age is between about 1 year and about 17 years. In other embodiments, the subject's age is between about 4 years and about 6 years, or between about 12 years and about 18 years.

[0078] In one embodiment of the described use, the subject has five or more joints, or two joints and systemic symptoms (e.g., fever). In one embodiment of the antibody, the subject has five or more joints or two or more joints for at least three days out of any consecutive seven days, and a fever above about 37.5°C, even though the dose of glucocorticoids has been stable for at least three days.

[0079] In one embodiment of the described use, the JIA is a pcJIA. In some embodiments, the pcJIA is an extended few-joint JIA. In various embodiments, the pcJIA is an RF-positive multi-joint JIA. In some embodiments, the pcJIA is an RF-negative multi-joint JIA.

[0080] In one embodiment, the antibody that specifically binds to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region of sequence SEQ ID NO:2.

[0081] In various embodiments, the antibody comprises VH and VL, wherein VH comprises the three CDRs found in the sequence SEQ ID NO:1, and wherein VL comprises the three CDRs found in the sequence SEQ ID NO:2. In various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0082] In one embodiment, the antibody is sarriromumab.

[0083] In various embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In one embodiment, at least one other DMARD is administered to the subject together with or simultaneously with the antibody.

[0084] In some embodiments, the subject has at least one symptom of RF-positive polyarticular arthritis (JIA). In some embodiments, the subject has at least one symptom of RF-positive polyarticular JIA, such as deforming symmetrical polyarthritis that can develop into joint subluxation (e.g., in the wrist and / or thumb); joint contractures (e.g., proximal and distal interphalangeal joints, proximal interphalangeal bone overgrowth, and finger deformities such as swan neck or buttonhole deformity); chronic synovitis; articular cartilage loss and paraarticular bone erosion; orthoglossy chronic anemia; elevated ESR and C-reactive protein; white blood cell count; asymptomatic cervical spondylitis; and / or micrognathia. In various embodiments, the subject has joint subluxation (e.g., in the wrist and / or thumb) and / or joint contractures (e.g., proximal and distal interphalangeal joints, proximal interphalangeal bone overgrowth, and finger deformities such as swan neck or buttonhole deformity). In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0085] In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular arthritis (JIA). In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular arthritis, such as symmetrical polyarthritis with reduced movement, muscle weakness, and / or decreased physical function. In one embodiment, treating the subject includes alleviating, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0086] In one embodiment, the subject suffers from at least one symptom of expansive oligoarticular arthritis (JIA). In another embodiment, the subject suffers from at least one symptom of expansive oligoarticular arthritis, such as aseptic inflammatory synovitis affecting more than four joints (e.g., in larger joints such as the knee, ankle, and wrist) after the first six months of the disease; limping; chronic anterior uveitis; chronic arthritis of the knee or ankle leading to overgrowth of that limb, resulting in subsequent leg length discrepancies; muscle atrophy (e.g., in extensor muscles such as the vastus lateralis and quadriceps femoris when the knee is affected); and / or flexion contractures of the knee or wrist. In one embodiment, treating the subject includes reducing, slowing, or stopping the progression of these symptoms, or otherwise improving any one (or any combination thereof) of these symptoms.

[0087] In various embodiments, the subject had at least one symptom of pcJIA, such as limping; stiffness upon waking; reluctance to use the arm or leg; reduced activity level; joint swelling; and / or difficulty with fine motor activities.

[0088] In one embodiment of the antibody, at least one symptom of pcJIA in the subject improved after administration of the antibody. In various embodiments of the antibody, the improvement is characterized as at least one score or measure, such as defined as one of the following core group variables. 3 / 6 of JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100 showed improvement and no more than 1 / 6 worsened: (i) a comprehensive physician assessment of disease activity (e.g., via the Visual Analogue Scale (VAS)), (ii) a patient or parent assessment of overall health status, (iii) a child health assessment questionnaire (e.g., via CHAQ-DI), (iv) the number of joints with active arthritis, (v) the number of joints with limited mobility, and (vi) an inflammatory index (e.g., high-sensitivity C-reactive protein). In one embodiment, the JIA ACR30 response is when... 3 / 6 core group variables improved from baseline 30% but no more than 1 / 6 of the deterioration At 30%.

[0089] In various embodiments of the antibody, improvement in disease activity is characterized by at least one juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score-27, which includes four measurements: a physician’s comprehensive assessment of disease activity, a parent / patient comprehensive assessment of health status, a count of joints with active disease, and an inflammation index (hs-CRP or ESR level)).

[0090] In various embodiments of the antibody, the improvement is characterized by at least one score or metric, such as a physician’s comprehensive assessment of disease activity, a patient or parent assessment of overall health status, a child health assessment questionnaire, the number of joints with active arthritis, the number of joints with limited mobility, high-sensitivity C-reactive protein, and / or juvenile arthritis disease activity score (e.g., juvenile arthritis disease activity score-27).

[0091] In one embodiment of the antibody, the subjects were between approximately 2 and approximately 17 years old.

[0092] In various embodiments, the subject has had JIA for at least 6 months. In one embodiment, the subject has arthritis affecting up to 4 joints during at least the first 6 months of the disease, and then progressing to affecting 5 or more joints after at least the first 6 months. In some embodiments, the subject has arthritis affecting up to 4 joints during the first 6 months of the disease, and then progressing to affecting 5 or more joints after the first 6 months.

[0093] In one embodiment of the antibody, the subject has at least five joints with active arthritis. In another embodiment of the antibody, the subject has arthritis affecting five or more joints during the first six months of the disease. In one embodiment of the antibody, the arthritis is rheumatoid factor negative. Alternatively, in one embodiment, the arthritis is rheumatoid factor positive.

[0094] In one embodiment, the antibody is administered subcutaneously. In various embodiments, the antibody is administered weekly or every two weeks.

[0095] In one embodiment, the antibody is administered at a dose of about 2 mg / kg to about 4 mg / kg. In one embodiment, the dose is administered once weekly or once every two weeks. In various embodiments, the antibody is used at doses of about 2 mg / kg weekly, about 2.5 mg / kg weekly, about 2 mg / kg every two weeks, about 2.5 mg / kg every two weeks, about 3 mg / kg every two weeks, and about 4 mg / kg every two weeks. In various embodiments, the antibody is used at the doses listed in Tables 1-5.

[0096] In some embodiments, the subject has a weight of at least about 10 kg. In some embodiments, the subject has a weight of less than 30 kg.

[0097] In some embodiments, the subject has a weight of at least about 30 kg.

[0098] In some embodiments, the subject has a weight of less than 60 kg.

[0099] In various embodiments, the subjects were aged 1 to 17 years.

[0100] In some embodiments, the subject is a human and the antibody is a human antibody.

[0101] This disclosure further provides an antibody for treating pcJIA in subjects in need, wherein the antibody specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises a heavy chain variable region sequence of SEQ ID NO:1 and a light chain variable region sequence of SEQ ID NO:2, wherein the antibody is administered at a dose of about 2 mg / kg to about 4 mg / kg weekly or every two weeks, wherein the subject weighs ≥10 kg and ≤60 kg.

[0102] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg to about 3 mg / kg every other week or at a dose of about 2 mg / kg per week.

[0103] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg to about 3 mg / kg once every other week or at a dose of about 2 mg / kg once a week.

[0104] In various embodiments, the subject's weight was greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody was administered at a dose of about 2 mg / kg or about 3 mg / kg every other week.

[0105] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg or about 3 mg / kg once every week.

[0106] In various embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of 2 mg / kg or 3 mg / kg every other week or 2 mg / kg per week.

[0107] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of 2 mg / kg or 3 mg / kg every other week or 2 mg / kg once a week.

[0108] In some embodiments, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg to about 4 mg / kg every other week or at a dose of about 2.5 mg / kg per week.

[0109] In various embodiments, the subject's weight is greater than or equal to 10 kg and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg to about 4 mg / kg every other week or at a dose of about 2.5 mg / kg once a week.

[0110] In some embodiments, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg or about 4 mg / kg every other week.

[0111] In some embodiments, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of about 2.5 mg / kg or about 4 mg / kg once every week.

[0112] In various embodiments, the subject's weight is greater than or equal to 10 kg and less than 30 kg, and the antibody is administered at a dose of 2.5 mg / kg or 4 mg / kg every other week or 2.5 mg / kg per week.

[0113] In some embodiments, the subject weighs 10 kg or more and less than 30 kg, and the antibody is administered at a dose of 2.5 mg / kg or 4 mg / kg every other week or 2.5 mg / kg once a week.

[0114] This disclosure further provides an antibody for treating pcJIA in subjects of need, wherein the antibody specifically binds to IL-6R, wherein the IL-6R-specific antibody comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2, wherein the subject's weight is greater than or equal to 30 kg and less than 33 kg, and the antibody is administered at a dose of 61.25 mg once every other week or once weekly; wherein the subject's weight is greater than or equal to 33 kg and less than 37.5 kg. The antibody was administered at a dose of 70 mg every other week or weekly; wherein the subject's weight was greater than or equal to 37.5 kg and less than 42 kg, the antibody was administered at a dose of 78.75 mg every other week or weekly; wherein the subject's weight was greater than or equal to 42 kg and less than 46.5 kg, the antibody was administered at a dose of 87.5 mg every other week or weekly; wherein the subject's weight was greater than or equal to 46.5 kg and less than 50.5 kg, the antibody was administered at a dose of 96.25 mg every other week or weekly; wherein the subject's weight was greater than or equal to 50.5 kg and less than 55 kg, the antibody was administered at a dose of 105 mg every other week or weekly; wherein the subject's weight was greater than... The subjects weighing 55 kg or less than 59.5 kg will receive the antibody at a dose of 113.75 mg once every other week or once a week; the subjects weighing 59.5 kg or less than 64 kg will receive the antibody at a dose of 122.5 mg once every other week or once a week; the subjects weighing 64 kg or less than 68 kg will receive the antibody at a dose of 131.25 mg once every other week or once a week; the subjects weighing 68 kg or less than 72.5 kg will receive the antibody at a dose of 140 mg once every other week or once a week; or the subjects weighing 72.5 kg or more will receive the antibody at a dose of 148.75 mg once every other week or once a week.

[0115] This disclosure further provides an antibody for treating pcJIA in subjects of need, wherein the antibody specifically binds to IL-6R, and wherein the antibody specifically binding to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and SEQ ID NO:1. The NO:2 light chain variable region sequence, wherein the subject's weight is greater than or equal to 30 kg and less than 31 kg, and the antibody is administered at a dose of 87.5 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 31 kg and less than 34 kg, and the antibody is administered at a dose of 96.25 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 34 kg and less than 37 kg, and the antibody is administered at a dose of 105 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 37 kg and less than 39.5 kg, and the antibody is administered at a dose of 113.75 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 39.5 kg and less than 42.5 kg, and the antibody is administered at a dose of 122.5 mg once every other week or once a week; wherein the subject's weight is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131 mg once every other week or once a week. The antibody was administered at a dose of 25 mg; for subjects weighing 45 kg or more and less than 48.5 kg, the antibody was administered at a dose of 140 mg once every other week or once a week; for subjects weighing 48.5 kg or more and less than 51.5 kg, the antibody was administered at a dose of 148.75 mg once every other week or once a week; for subjects weighing 51.5 kg or more and less than 54.5 kg, the antibody was administered at a dose of 157.5 mg once every other week or once a week; for subjects weighing 54.5 kg or more and less than 57 kg, the antibody was administered at a dose of 166.25 mg once every other week or once a week; for subjects weighing 57 kg or more and less than 63 kg, the antibody was administered at a dose of 175 mg once every other week or once a week; and for subjects weighing 63 kg or more, the antibody was administered at a dose of 192.5 mg once every other week or once a week.

[0116] This disclosure further provides an antibody for treating pcJIA in subjects of need, wherein the antibody specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2, wherein the subject weighs ≥10 kg and <12.5 kg, and the antibody is administered at a dose of 26.25 mg once every other week or once weekly; wherein the subject weighs ≥12.5 kg and <16 kg, and the antibody is administered at a dose of 35 mg once every other week or once weekly; wherein the subject weighs ≥16 kg and <19.5 kg, and the antibody is administered at a dose of 43.75 mg once every other week or once weekly; wherein the subject weighs ≥19.5 kg and <23 kg. The antibody was administered at a dose of 52.5 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 61.25 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 26.5 kg and less than 30 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 30 kg and less than 37.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 26.5 kg, the antibody was administered at a dose of 70 mg once every other week or once a week; wherein the subject's weight was greater than or equal to 23 kg and less than 3 .... Subjects weighing 37.5 kg or more and less than 42 kg were given the antibody at a dose of 78.75 mg every other week or once a week; subjects weighing 42 kg or more and less than 46.5 kg were given the antibody at a dose of 87.5 mg every other week or once a week; subjects weighing 46.5 kg or more and less than 50.5 kg were given the antibody at a dose of 96.25 mg every other week or once a week; subjects weighing 50.5 kg or more and less than 55 kg were given the antibody at a dose of 78.75 mg every other week or once a week. The antibody was administered at a dose of 105 mg once a week; for subjects weighing 55 kg or more and less than 59.5 kg, the antibody was administered at a dose of 113.75 mg once every other week or once a week; for subjects weighing 59.5 kg or more and less than 64 kg, the antibody was administered at a dose of 122.5 mg once every other week or once a week; for subjects weighing 64 kg or more and less than 68 kg, the antibody was administered at a dose of 131.25 mg once every other week or once a week; for subjects weighing 68 kg or more and less than 72 kg...The antibody was administered at a dose of 140 mg every other week or once a week, for subjects weighing 5 kg or more; or the antibody was administered at a dose of 148.75 mg every other week or once a week, for subjects weighing 72.5 kg or more.

[0117] This disclosure further provides an antibody for treating pcJIA in subjects in need, wherein the antibody specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises the heavy chain variable region of sequence SEQ ID NO:1 and the light chain variable region sequence of SEQ ID NO:2, wherein the subject weighs ≥10 kg and <12.5 kg, and the antibody is administered at a dose of 43.75 mg every other week or weekly; wherein the subject weighs ≥12.5 kg and <14.5 kg, and the antibody is administered at a dose of 52.5 mg every other week or weekly; wherein the subject weighs ≥14.5 kg and <16.5 kg, and the antibody is administered at a dose of 61.25 mg every other week or weekly; wherein the subject weighs ≥16.5 kg and <19 kg, and the antibody is administered at a dose of 43.75 mg every other week or weekly. The antibody is administered at a dose of 70 mg once every other week or once a week; wherein the subject weighs ≥19 kg and <21 kg, the antibody is administered at a dose of 78.75 mg once every other week or once a week; wherein the subject weighs ≥21 kg and <23.5 kg, the antibody is administered at a dose of 87.5 mg once every other week or once a week; wherein the subject weighs ≥23.5 kg and <25.5 kg, the antibody is administered at a dose of 96.25 mg once every other week or once a week; wherein the subject weighs ≥25.5 kg and <23.5 kg, the antibody is administered at a dose of 96.25 mg once every other week or once a week. For subjects weighing 27.5 kg or more and less than 30 kg, the antibody is administered at a dose of 105 mg every other week or weekly; for subjects weighing 30 kg or more and less than 39.5 kg, the antibody is administered at a dose of 113.75 mg every other week or weekly; for subjects weighing 39.5 kg or more and less than 42.5 kg, the antibody is administered at a dose of 122.5 mg every other week or weekly. Subjects weighing 42.5 kg or more and less than 45 kg were given the antibody at a dose of 131.25 mg every other week or once a week; subjects weighing 45 kg or more and less than 48.5 kg were given the antibody at a dose of 140 mg every other week or once a week; subjects weighing 48.5 kg or more and less than 51.5 kg were given the antibody at a dose of 148.75 mg every other week or once a week; and subjects weighing 51.5 kg or more and less than 54.5 kg were given the antibody at a dose of 157 mg every other week or once a week.The antibody was administered at a dose of 5 mg; for subjects weighing 54.5 kg or more and less than 57 kg, the antibody was administered at a dose of 166.25 mg once every other week or once a week; for subjects weighing 57 kg or more and less than 60.5 kg, the antibody was administered at a dose of 175 mg once every other week or once a week; for subjects weighing 60.5 kg or more and less than 63 kg, the antibody was administered at a dose of 175 mg once every other week or once a week; for subjects weighing 63 kg or more, the antibody was administered at a dose of 192.5 mg once every other week or once a week.

[0118] This disclosure further provides an antibody for treating sJIA in subjects in need, wherein the antibody specifically binds to IL-6R, wherein the antibody specifically binding to IL-6R comprises a heavy chain variable region sequence of SEQ ID NO:1 and a light chain variable region sequence of SEQ ID NO:2, wherein the antibody is administered at a dose of about 2 mg / kg to about 2.5 mg / kg per week or about 3 mg / kg to about 4 mg / kg every two weeks, wherein the subject weighs more than or equal to 30 kg and less than or equal to 210 kg.

[0119] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of about 2 mg / kg per week or about 3 mg / kg every other week.

[0120] In various embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of about 2 mg / kg once a week or at a dose of about 3 mg / kg once every other week.

[0121] In some embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 60 kg, and the antibody is administered at a dose of 2 mg / kg per week or 3 mg / kg every other week.

[0122] In some embodiments, the subject weighs 30 kg or more and 60 kg or less, and the antibody is administered at a dose of 2 mg / kg once a week or 3 mg / kg once every other week.

[0123] In various embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of about 2.5 mg / kg per week or about 4 mg / kg every other week.

[0124] In some embodiments, the subject weighs 30 kg or more and 210 kg or less, and the antibody is administered at a dose of about 2.5 mg / kg once a week or about 4 mg / kg once every other week.

[0125] In some embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of 2.5 mg / kg per week or 4 mg / kg every other week. In various embodiments, the subject's weight is greater than or equal to 30 kg and less than or equal to 210 kg, and the antibody is administered at a dose of 2.5 mg / kg once a week or at a dose of 4 mg / kg once every other week. In some embodiments, the antibody is a pharmaceutical composition. In some embodiments, it is an aqueous solution with a volume of less than about 1 mL. In various embodiments, it is an aqueous solution with a volume of about 0.5 to 1 mL. In some embodiments, it is an aqueous solution with a volume of about 0.75 to 1 mL. In some embodiments, it is an aqueous solution with a volume of about 0.5 to 0.75 mL. In various embodiments, it is an aqueous solution with a volume of about 0.15 to 0.25 mL. In some embodiments, it is an aqueous solution with a volume of about 0.25 to 0.5 mL. Simple Explanation of the Diagram

[0126] [Figure 1] is a flowchart of a multinational, multicenter, open-label, phase 2, two-part study of children and adolescents aged 2 to 17 years with pcJIA who have an inadequate response to or intolerance to current therapies or are considered candidates for biological DMARDs. The two phases of the study consist of an initial 12-week core treatment phase followed by a 144-week extension phase. Abbreviations: EOS = End of Study, EOT = End of Treatment, FDA = Food and Drug Administration, f / u = Follow-up, IMP = Investigational Drug Product, PK = Pharmacokinetics, sIL-6Rα = Soluble Interleukin-6 Receptor α Subunit, V = Visit, Wk = Week.

[0127] Note: All patients must complete the End of Treatment (EOT) visit (V27, week 156) at the completion of treatment (dose groups 1 and 2 at week 154 for the last IMP injection, and dose group 3 at week 155 for the last IMP injection) or at the time of early permanent treatment interruption (regardless of the stage of treatment).

[0128] For a patient who prematurely discontinues study treatment during the 12-week core treatment phase, an additional PK visit is required 2 weeks after the EOT visit to collect blood samples (V88) and measure IL-6 and total sIL-6Rα at the EOT visit.

[0129] All patients must complete post-treatment follow-up (V28) 6 weeks after the EOT visit (i.e., week 162 for patients who have completed treatment and week EOT+6 for patients who prematurely discontinued treatment). However, patients who prematurely discontinued treatment during the core treatment phase should return to the study visit according to the protocol scheduled for 12 weeks without treatment (in accordance with FDA guidance on missing data).

[0130] [Figure 2] is The graphical study design of the 12-week core treatment phase is described in [Figure 1].

[0131] [Figure 3] is a graph showing the mean (with standard deviation; SD) functional salperumab concentration in serum over a period of time following the first subcutaneous administration of salperumab in patients with pcJIA. Abbreviations in the figure include: q2w = every other week, qw = once a week, SC = subcutaneous, SD = standard deviation. Post-treatment concentrations below LLOQ are replaced by LLOQ / 2.

[0132] [Figure 4] is a graph showing the mean trough concentration of salrumab in serum (with standard deviation; SD) over a period of time after the first subcutaneous administration of salrumab in pcJIA patients.

[0133] [Figure 5] is a graph showing the incidence of JIA ACR30 (hs-CRP) response (as observed during treatment) during the 12-week core treatment phase.

[0134] [Figure 6] is a graph showing the incidence of JIA ACR30 (hs-CRP) response (non-responder imputation method) during the 12-week core treatment phase.

[0135] [Figure 7] is a flowchart of a multinational, multicenter, open-label, sequential, phase 2 study of two dose groups in children and adolescents aged 1 to 17 years (or the nationally mandated age requirement) with sJIA who have an inadequate response to or intolerance to standard therapy and will receive q2w or qw SC injections of sarrelusumab.

[0136] [Figure 8] is a flowchart illustrating the study process for patient management. ALT = alanine transaminase; QW = weekly; Q2W = every 2 weeks.

[0137] [Figures 9A-9D] are graphs showing the proportion of patients achieving the JIA ACR response threshold in JADAS-27-CRP as observed during treatment and the mean change from baseline to week 12. CRP = C-reactive protein; JADAS-27-CRP = Juvenile arthritis disease activity score using 27-joint count and CRP; JIA ACR30 / 70 / 90 = American College of Rheumatology 30 / 70 / 90% response in juvenile primary arthritis; SE = standard error.

[0138] [Figures 10A-10B] are graphs showing the mean CRP concentration and the proportion of patients with undetectable CRP (<0.2 mg / L) during the core treatment phase, as observed during treatment. BL = baseline; CRP = C-reactive protein; SE = standard error.

[0139] [Figures 11A-11C] are graphs showing the proportion of patients achieving JIA ACR response calculated using non-response attribution. CRP = C-reactive protein. JIA ACR 30 / 70 / 90 = American College of Rheumatology 30 / 70 / 90% response in juvenile essential arthritis. Implementation [Cross-references to related applications]

[0140] This application claims the benefits of U.S. Provisional Application No. 62 / 799,698, filed January 31, 2019; U.S. Provisional Application No. 62 / 851,474, filed May 22, 2019; U.S. Provisional Application No. 62 / 935,395, filed November 14, 2019; and European Application No. 19306553.9, filed December 3, 2019; each of which is incorporated herein by reference in its entirety.

[0141] This disclosure provides pharmaceutical compositions and methods of using these compositions to treat JIA (e.g., sJIA and pcJIA) and to improve at least one symptom of said disorder. These compositions include at least one antibody that specifically binds to the human interleukin-6 receptor (hIL-6R).

[0142] The efficacy of the antibody therapy for JIA is typically measured using standard methods in the field commonly used by clinicians and rheumatologists, such as the ACR 30 / 50 / 70 / 90 / 100 for juvenile idiopathic arthritis, ACR components, changes in glucocorticoid use (for sJIA), and the juvenile arthritis disease activity score-27 (JADAS) (see Consolaro et al., Development and Validation of a Composite Disease Activity Score for Juvenile Idiopathic Arthritis. Arthritis & Rheumatism. 2009 May;61(5):658-666), which is incorporated herein by reference in its entirety. The JIA ACR is well known to clinicians and can be readily determined by general technicians in the field of JIA diagnosis and treatment. The JIA ACR is also known as the pediatric ACR (and is synonymous with it). The non-restrictive description of JIA ACR is provided in Giannini et al. (1994), “Preliminary core of set of outcome variables for use in JRA clinical trials”, Arthritis Rheum. 37, Supplement 9: S428, which is incorporated herein by reference for all purposes.

[0143] As used in the claims, description, and specific embodiments herein, the term “about” in quantitative terms refers to the value it modifies plus or minus 10% (rounded to the nearest integer if the value is indivisible, such as the number of molecules or nucleotides). For example, the phrase “about 100 mg” would cover 90 mg to 110 mg, including the end value; the phrase “about 2500 mg” would cover 2250 mg to 2750 mg. When applied to percentages, the term “about” refers to the percentage plus or minus 10%. For example, the phrase “about 20%” would cover 18% to 22%, and “about 80%” would cover 72% to 88%, including the end value. Furthermore, when “about” is used in conjunction with quantitative terms herein, it should be understood that, in addition to adding or subtracting 10%, the precise value of the quantitative term is also covered and described. For example, the term “about 23%” explicitly considers, describes, and includes the precise 23%.

[0144] It should be noted that the terms “a” or “an” refer to one or more of the aforementioned entities; for example, “a symptom” should be understood to represent one or more symptoms. Therefore, the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably herein.

[0145] Furthermore, when used herein, “and / or” is considered as a specific disclosure of each of the two specified features or components, whether or not they are together with the other. Therefore, the term “and / or” as used herein in phrases such as “A and / or B” is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used herein in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0146] It should be understood that, regardless of the circumstances in which the multifaceted aspects are described in this document using the language “comprising”, other similar aspects described in terms of “consisting of” and / or “essentially composed of” are also provided. [JIA]

[0147] Arthritis is defined as swelling within the joint or limited range of motion observed by a physician, accompanied by joint pain or tenderness, lasting for at least 6 weeks, and not primarily due to mechanical impairment. (Petty RE et al., International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. 2004 Feb; 31(2):390-2), which is incorporated herein by reference in its entirety.

[0148] JIA is an autoimmune disorder involving joint inflammation. This disorder typically appears before the age of 16 and may persist into adulthood. JIA affects approximately 1 in 1000 children. Typical symptoms include limping, stiffness upon waking, reluctance to use arms or legs in children, reduced activity levels, persistent fever, joint swelling, and difficulty with fine motor skills. JIA is classified into seven subtypes based on age of onset, extent, and disease characteristics within the first six months after onset (e.g., systemic JIA, RF-positive polyarticular JIA, and RF-negative polyarticular JIA), as defined by ILAR in 2001.

[0149] In sJIA, joint inflammation may not occur during a flare-up, with prominent signs being extra-articular, thus delaying diagnosis, but ultimately developing into a polyarticular form in most patients. Clinical features (defined by the ILAR classification) include arthritis, accompanied by / previously a daily fever lasting at least 2 weeks and one or more of the following: transient salmon-colored rash, generalized lymphadenopathy, hepatomegaly / splenomegaly, and serositis. In some embodiments, exclusion criteria for sJIA include psoriasis or a first-degree relative with psoriasis; the presence of human leukocyte antigen-B27 (HLA-B27); ankylosing spondylitis, tendonitis-related arthritis, sacroiliitis with chronic inflammatory bowel disease, a first-degree relative with Leter's disease; and at least two occurrences of rheumatoid factor (RF) at least 3 months apart. sJIA accounts for 10% of JIA cases and is known to occur at any age during childhood and adolescence. In terms of results, patients known to have sJIA showed: 50% reduced severity in the first year; 25% suffered from severe destructive joint disease; general growth abnormalities; and macrophage activation syndrome.

[0150] SJIA is typically characterized by a daily peak-shaped fever and may be accompanied by one or more of the following: transient (non-fixed) erythematous rash, generalized lymphadenopathy, hepatomegaly and / or splenomegaly, and serositis. (Petty RE et al., International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. Feb. 2004; 31(2):390-2). The incidence of sJIA peaks in patients aged 4 to 6 years and occasionally occurs during puberty in patients aged 12 to 18 years.

[0151] As used in this article, the term “polyarticular juvenile primary arthritis” or “pcJIA” includes RF-positive polyarticular JIA, RF-negative polyarticular JIA, and extended oligoarticular JIA.

[0152] Polyarticular arthritis (JIA) is a subtype of pcJIA that affects at least five joints. Both large and small joints can be involved, often in a symmetrical bilateral distribution, and frequently affects weight-bearing joints and small joints of the hands. Mild fever may accompany arthritis. The presence of rheumatoid factor (RF) distinguishes two forms of polyarticular JIA: RF-positive and RF-negative polyarticular JIA.

[0153] Rheumatoid factor (RF)-positive polyarticular jIA accounts for a relatively small proportion (3%–5%) of all children and adolescents with jIA, but it is the only subgroup of jIA similar to adult rheumatoid arthritis (RA), a deforming, symmetrical polyarthritis caused by chronic synovial inflammation, articular cartilage loss, and periarticular bone erosion. RF-positive pcJIA is characterized by a mean age of onset of 12–14 years, a marked female sex predominance (13:1 female / male ratio), symmetrical involvement of small and large joints, production of polyclonal IgM RF or anti-CCP antibodies, genetic susceptibility (associated with the HLA-DR4 allele), a clinical course characterized by orthospheric chronic anemia (reticuloendothelial block), and rarely spontaneously diminishing acute-phase proteins (elevated ESR and C-reactive protein), as well as elevated white blood cell counts. Association with the formation of firm, mobile, and painless rheumatoid nodules is possible, but rare. Laboratory findings are expected to be more severe than those associated with oligoarthritis. Long-term sequelae include joint subluxation (wrist and thumb), joint contractures (proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth), and finger deformities (e.g., swan neck or buttonhole deformity). Asymptomatic cervical spondylitis with decreased flexion can lead to subluxation (typically subluxation of the C2 vertebra above C3) and fusion of posterior vertebral bone elements. Temporomandibular joint arthritis can also be asymptomatic and lead to micrognathia (Petty, RE et al., 2004. J Rheumatol. 31(2):390-2).

[0154] Radiographic changes in RF-negative polyarticular joint iatrogenic lesions (JIAs) occur at a younger age (late childhood, 7 to 9 years) than in RF-positive JIAs, and account for 11% to 28% of all children and adolescents with JIAs. It may not be as devastating or persistent as RF-positive JIAs, but by definition, it does affect five or more joints. Radiographic changes in RF-negative JIAs occur later than in RF-positive JIAs. Severe motor limitation is often accompanied by muscle weakness and decreased physical function.

[0155] Oligoarthritis-associated juvenile arthritis (oJIA), another subtype of pcJIA, is the most common subtype of juvenile arthritis, accounting for approximately 50% of all JIA cases in the United States and Western Europe. The onset ranges from 1 to 5 years, peaking at 2 to 3 years. It is defined as aseptic inflammatory synovitis that typically affects up to four joints (usually larger joints such as the knee, ankle, and wrist) and is not associated with physical examination findings such as fever, weight loss, fatigue, or systemic signs of inflammation. However, if more than four joints are affected after the first 6 months of the disease, it is called extended oligoarthritis, contrasting with persistent oJIA, which is characterized by only a maximum of four joints throughout the course of the disease. Children often appear well despite limping. oJIA carries a risk of developing chronic anterior uveitis, especially when antinuclear antibodies (ANA) are present and the disease has onset in early childhood. It is often asymptomatic at onset and requires screening via slit-lamp examination in the eye. Chronic arthritis of the knee or ankle can lead to overgrowth of that limb, resulting in subsequent leg length discrepancies. Muscle atrophy (usually extensor muscles such as the vastus lateralis, or quadriceps when the knee is affected), and / or knee flexion contractures, and less commonly the wrist.

[0156] Current treatments for JIA include steroids, such as conventional synthetic DMARDs and biological DMARDs. The development of new drugs that can selectively inhibit individual molecules and pathways offers hope for improving remission rates while minimizing disease damage and treatment-related side effects (Giancane et al. Juvenile Idiopathic Arthritis: Diagnosis and Treatment. Rheumatology and Therapy. 2016;3(2):187-207).

[0157] One candidate treatment for JIA is interleukin-6 (IL-6) inhibition. IL-6 is an important cytokine with broad biological activities, including regulating immune reactivity, acute-phase responses, inflammation, tumorigenesis, and hematopoiesis (Kishimoto et al., The Cytokine Handbook (London: Academic Press). 2003, pp. 281-304). Excessive production of IL-6 has been found to play a pathological role in chronic inflammatory diseases.

[0158] IL-6 interacts directly with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit. IL-6Rα also exists in a soluble form, which participates in trans signaling and enables IL-6R to affect cells that do not express IL-6Rα, including synovial cells (Rose-John et al., J Leukoc Biol. 2006;80(2),227-36).

[0159] Sarrelumarab, also known as SAR153191 or REGN88, is a recombinant IgG1κ monoclonal antibody targeting the fully human sequence of the α subunit of the IL-6 receptor complex (IL-6Rα). Sarrelumarab is a potent and specific inhibitor of IL-6 signaling. By binding to IL-6Rα with high affinity, sarrelumarab blocks IL-6 binding and disrupts the cytokine-mediated signaling cascade. In some embodiments, interleukin-6 is a key element in the etiology of rheumatic diseases, and inhibiting its signaling is a crucial part of the mechanism of action of sarrelumarab. In in vitro assays, sarilumab did not exhibit antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in the relevant cell types, with sarilumab binding validated by fluorescence-activated cell sorting (FACS) analysis (Committee on Medicinal Products for Human Use, Assessment Report, April 27, 2017 EMA / 292840 / 2017, available at https: / / www.ema.europa.eu / documents / assessment-report / kevzara-epar-public-assessment-report_en.pdf). [Antibody]

[0160] This disclosure includes methods for administering to a subject an antibody that specifically binds to hIL-6R or an antigen-binding fragment thereof. As used herein, the term "hIL-6R" refers to a human cytokine receptor that specifically binds to human IL-6. In some embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

[0161] As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains, and two light (L) chains interconnected by disulfide bonds, as well as its multimers (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into highly denatured regions, called CDRs, and more conserved regions, called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FR of the antibody (or its antigen-binding portion) may be identical to the human germline sequence, or it may be natural or artificially modified. The common amino acid sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0162] As used herein, the term "antibody" also includes the antigen-binding fragment of a complete antibody molecule. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived from any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable and optional constant domains of the antibody, for example, derived from a complete antibody molecule. This DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0163] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) the smallest recognition unit consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., isolated CDRs, such as CDR3 peptides), or restricted FR3-CDR3-FR4 peptides. As used herein, other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-grafted antibodies, biantibodies, triantibodies, tetraantibodies, microantibodies, nanoantibodies (e.g., monovalent and bivalent nanoantibodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also included in the description “antigen-binding fragments”.

[0164] Antigen-binding fragments of antibodies typically contain at least one variable domain. Variable domains can have any size or amino acid composition and typically contain at least one CDR adjacent to or in frame with one or more structural sequences. In antigen-binding fragments in which the VH and VL domains associate, the VH and VL domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain VH-VH, VH-VL, or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric VH or VL domain.

[0165] In some embodiments, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly connected to each other or may be connected via full or partial hinge or connector regions. In various embodiments, the hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, in various embodiments, the antigen-binding fragment of the antibody may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above, non-covalently associated with each other and / or non-covalently associated with one or more monomeric VH or VL domains (e.g., via disulfide bonds).

[0166] In specific embodiments, the antibody or antibody fragment used in the method of the present invention may be a multispecific antibody, which may be specific to different antigenic determinants of a target polypeptide, or may contain antigen-binding domains specific to antigenic determinants of more than one target polypeptide. An exemplary form of bispecific antibody that may be used in the context of the present invention involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first Ig CH3 domain and the second Ig CH3 domain differ from each other by at least one amino acid, and wherein the at least one amino acid difference reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking said amino acid difference. In one embodiment, the first Ig CH3 domain binds to protein A and the second Ig CH3 domain contains a mutation that reduces or eliminates protein A binding, such as H95R modification (according to IMGT exon number; according to EU number H435R). The second CH3 may further contain Y96F modification (according to IMGT; according to EU Y436F). In the case of IgG1 antibodies, other modifications that can be found in the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (according to IMGT; according to EU, D356E, L358M, N384S, K392N, V397M, and V422I); in the case of IgG2 antibodies, N44S, K52N, and V82I (according to IMGT; according to EU, N384S, K392N, and V422I); and in the case of IgG4 antibodies, Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (according to IMGT; according to EU, Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I). Variations of the above-described bispecific antibody forms are covered within the scope of this invention. In various embodiments, any multispecific antibody form, including the exemplary bispecific antibody forms disclosed herein, can be adapted using conventional techniques available in the art to suit the antigen-binding fragment case of the anti-IL-6R antibody.

[0167] Compared to corresponding germline sequences, the fully human anti-IL-6R antibody disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the architecture and / or CDR regions of the heavy and light chain variable domains. Such mutations can be readily identified by comparing the disclosed amino acid sequences with germline sequences available from, for example, public antibody sequence libraries. This invention includes antibodies and antigen-binding fragments derived from any amino acid sequence disclosed herein, wherein one or more amino acids in one or more architecture and / or CDR regions are reverted to one or more corresponding germline residues or to conserved amino acid substitutions (natural or non-natural) of one or more corresponding germline residues (such sequence changes are referred to herein as "germline reversion mutations"). Those skilled in the art can readily generate numerous antibody and antigen-binding fragments comprising one or more individual germline reversion mutations or combinations thereof, starting from the disclosed heavy and light chain variable region sequences. In some embodiments, all architecture residues and / or CDR residues within the VH and / or VL domains are reverted to the germline sequence. In other embodiments, only certain residues are reverted to the germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3. Furthermore, the antibodies of the present invention may contain any combination of two or more germline reversion mutations within the architecture and / or CDR regions, i.e., certain individual residues are reverted to the germline sequence while retaining certain other residues different from the germline sequence. Once obtained, the antibody and antigen-binding fragment containing one or more germline reversion mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as applicable), reduced immunogenicity, etc. Antibody and antigen-binding fragments obtained in this general manner are covered within the scope of the present invention.

[0168] The constant region of an antibody is important in its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether mediating cytotoxicity is desirable for the antibody.

[0169] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, in various embodiments, the human antibodies characterized in this disclosure (e.g., in CDRs, and in some embodiments, in CDR3) include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which a germline CDR sequence derived from another mammalian species (e.g., mouse) has been grafted onto a human structural sequence.

[0170] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (described further below), antibodies isolated from a recombinant combined human antibody library (described further below), antibodies isolated from transgenic animals (e.g., mice) targeting human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295, which is incorporated herein by reference in its entirety), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing a human immunoglobulin gene sequence into another DNA sequence. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some instances, such recombinant human antibodies are mutagenized in vitro (or, when using animals transgenic to target human Ig sequences, in vivo somatic mutagenization) so that, although the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and associated with human germline VH and VL sequences, the amino acid sequences of the VH and VL regions of the recombinant antibody may not be sequences naturally present in the in vivo human antibody germline library.

[0171] Human antibodies can exist in two forms related to hinge heterogeneity. In one embodiment, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, wherein the dimers are held together by interchain heavy chain disulfide bonds. In another embodiment, the dimers are not linked via interchain disulfide bonds and form a molecule of approximately 75-80 kDa, consisting of covalently coupled light and heavy chains (half-antibodies). These embodiments / forms are extremely difficult to isolate, even after affinity purification.

[0172] The frequency of the second form in each intact IgG isotype is attributable to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence rate of the second form (Angal et al., (1993) Molecular Immunology 30:105, which is incorporated herein by reference in its entirety) to levels typically observed with the human IgG1 hinge. In various embodiments, this disclosure covers antibodies having one or more mutations in the hinge region, CH2 region, or CH3 region, which may be desirable, for example, in manufacturing to improve the yield of the desired antibody form.

[0173] As used herein, "isolated antibody" means an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism or from tissues or cells in which antibodies are naturally present or naturally produced is an "isolated antibody." In various embodiments, isolated antibodies also include in situ antibodies within recombinant cells. In other embodiments, isolated antibodies are antibodies that have undergone at least one purification or isolation step. In various embodiments, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0174] The term "specific binding" refers to the formation of a relatively stable complex between an antibody or its antigen-binding fragment and an antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, as used herein, antibodies that "specifically bind" IL-6R include antibodies or portions thereof that bind IL-6R and have a KD less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or about 0.5 nM, as measured in a surface plasmon resonance assay. Specific binding can also be characterized by a dissociation constant of at least about 1 x 10⁻⁶ M or less. In other embodiments, the dissociation constant is at least about 1 x 10⁻⁷ M, 1 x 10⁻⁸ M, or 1 x 10⁻⁹ M. However, isolated antibodies that specifically bind to human IL-6R may exhibit cross-reactivity with other antigens, such as IL-6R molecules from other (non-human) species.

[0175] As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentrations within a biosensor matrix, for example, using the BIACORE system (Biacore Life Sciences division of GE Healthcare, Piscataway, New Jersey).

[0176] As used in this article, the term "KD" is intended to refer to the equilibrium dissociation constant of antibody-antigen interactions.

[0177] The term "antigenic determinant" refers to an antigenic determinant cluster that interacts with a specific antigen-binding site called a paratope in the variable region of an antibody molecule. A single antigen can have more than one antigenic determinant. Therefore, different antibodies can bind to different regions of the antigen and can have different biological effects. Antigenic determinants can be conformational or linear. Conformational antigenic determinants are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear antigenic determinants are antigenic determinants generated from adjacent amino acid residues in the polypeptide chain. In some cases, antigenic determinants may include portions of sugar, phosphoyl, or sulfonylurea groups on the antigen.

[0178] In various embodiments, anti-IL-6R antibodies usable in the methods described herein may contain one or more amino acid substitutions, insertions, and / or deletions in the architecture and / or CDR regions of the variable domains of the heavy and light chains, compared to the corresponding germline sequences from which the antibodies are derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. In various embodiments, this disclosure includes methods relating to the use of antibodies and antigen-binding fragments derived from any amino acid sequence disclosed herein, wherein one or more amino acids within one or more architecture and / or CDR regions are mutated to one or more corresponding residues of the germline sequence from which the antibody is derived, or one or more corresponding residues of another human germline sequence, or conserved amino acid substitutions of the one or more corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). Numerous antibodies and antigen-binding fragments can be constructed containing one or more individual germline mutations or combinations thereof. In some embodiments, all architecture residues and / or CDR residues within the VH and / or VL domains are reverted to residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues are reverted to the original germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3. In other embodiments, one or more of the structural and / or CDR residues are mutated to one or more corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Furthermore, the antibody may contain any combination of two or more germline mutations within the structural and / or CDR regions, for example, where certain individual residues are mutated to corresponding residues of certain germline sequences, while retaining or mutating certain other residues different from the original germline sequence to corresponding residues of a different germline sequence. Once obtained, the antibody and antigen-binding fragment containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as applicable), reduced immunogenicity, etc. This disclosure covers the use of antibody and antigen-binding fragments obtained in this general manner.

[0179] This disclosure also includes methods relating to the use of anti-IL-6R antibodies comprising variants of any HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conserved substitutions. For example, this disclosure includes the use of anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer conserved amino acid substitutions relative to any HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0180] According to this disclosure, in various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCVR, an LCVR, and / or a CDR, said HCVR, LCVR, and / or CDR comprising any amino acid sequence of the anti-IL-6R antibody described in U.S. Patent No. 7,582,298 (which is incorporated herein by reference in its entirety). In some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCDR of an HCVR containing the amino acid sequence of SEQ ID NO:1 and an LCDR of an LCVR containing the amino acid sequence of SEQ ID NO:2. According to some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8. In yet other embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO:1 and an LCVR containing the amino acid sequence of SEQ ID NO:2.

[0181] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO:9 and a light chain containing the amino acid sequence of SEQ ID NO:10. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO:11. According to certain exemplary embodiments, the methods of this disclosure include using an anti-IL-6R antibody, known in the art as sarirodulan, or a bioequivalence thereof.

[0182] The amino acid sequence of SEQ ID NO:1 is

[0183]

[0184] The amino acid sequence of SEQ ID NO:2 is

[0185]

[0186] The amino acid sequence of SEQ ID NO:3 is RFTFDDYA.

[0187] The amino acid sequence of SEQ ID NO:4 is ISWNSGRI.

[0188] The amino acid sequence of SEQ ID NO:5 is AKGRDSFDI.

[0189] The amino acid sequence of SEQ ID NO:6 is QGISSW.

[0190] The amino acid sequence of SEQ ID NO:7 is GAS.

[0191] The amino acid sequence of SEQ ID NO:8 is QQANSFPYT.

[0192] The amino acid sequence of SEQ ID NO:9 is

[0193]

[0194] The amino acid sequence of SEQ ID NO:10 is

[0195]

[0196]

[0197] The sequence of SEQ ID NO:11 is

[0198]

[0199] As used herein, a "bioequivalent" is a molecule that, when administered at the same molar dose and under similar conditions (e.g., the same route of administration), has similar bioavailability (rate and extent of utilization), such that its efficacy and safety can be expected to be substantially the same as that of the comparative molecule. Two pharmaceutical components containing an anti-IL-6R antibody are pharmaceutically equivalent; this means they contain the same amount of the active ingredient (e.g., the IL-6R antibody), in the same dosage form, via the same route of administration, and meet the same or equivalent criteria. Bioequivalence can be determined, for example, by comparing the pharmacokinetic parameters of the two components in an in vivo study. Commonly used parameters in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration-time curve (AUC).

[0200] In some embodiments, this disclosure relates to a method of administering an antibody to a subject, said antibody comprising a heavy chain variable region containing sequence SEQ ID NO:1 and a light chain variable region containing sequence SEQ ID NO:2.

[0201] This disclosure provides pharmaceutical compositions containing such antibodies, as well as methods of using these compositions.

[0202] In various embodiments, the antibody comprises a heavy chain variable region containing sequence SEQ ID NO:1 and a light chain variable region containing sequence SEQ ID NO:2, and is an antibody that specifically binds to hIL-6R. See International Publication No. WO 2007 / 143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region containing sequence SEQ ID NO:9 and a light chain variable region containing sequence SEQ ID NO:10. In various embodiments, the antibody is sareruciclovir. [DMARD]

[0203] DMARDs are defined by their use in rheumatoid arthritis and JIA to slow disease progression.

[0204] DMARDs have been classified into synthetic (sDMARDs) and biological (bDMARDs). sDMARDs are not limited to methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. bDMARDs are not limited to adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, and tocilizumab.

[0205] In some embodiments, no other DMARD is administered with the antibody. In some embodiments, at least one other DMARD is administered to the subject. In one embodiment, at least one other DMARD is administered to the subject with or simultaneously with the antibody.

[0206] In some embodiments, the subject has not responded adequately to current JIA treatment. In some embodiments, the subject has not responded adequately to current JIA treatment and is considered a candidate for bDMARD. In some embodiments, the subject's current treatment is a corticosteroid, sDMARD, and / or bDMARD. For example, but not as a limitation, in some embodiments, the corticosteroid is selected from prednisone, prednisolone, and methyl-prednisolone. [Administration method and preparation]

[0207] The methods described herein include administering a therapeutically effective dose of anti-IL-6R antibody to a subject. As used herein, "effective dose" or "therapeutically effective dose" is the dose of a therapeutic agent that results in treatment of sJIA and / or pcJIA. As used herein, "treatment" means causing a detectable improvement in one or more symptoms associated with sJIA and / or pcJIA, or causing a biological effect (e.g., a decrease in the level of a specific biomarker) associated with one or more underlying pathological mechanisms that produce the condition or one or more symptoms. For example, an IL-6R antibody dose that causes improvement in any of the following symptoms or conditions associated with juvenile primary arthritis is considered a "therapeuticly effective dose": limping, stiffness upon waking, reluctance of the subject to use their arm or leg, decreased activity level, persistent fever, joint swelling, and difficulty with fine motor skills.

[0208] In various embodiments, “improvement” in JIA-related symptoms refers to a reduction in the incidence of JIA symptoms, which may be associated with improvement in one or more JIA-related tests, scores, or measures (as described herein). For example, the improvement may be associated with an increase from baseline in one or more of the JIA ACR criteria, and / or a decrease from baseline in one or more of corticosteroid use, juvenile arthritis disease activity score, or fever. In one embodiment, improvement may include a decrease from baseline in stiffness (e.g., limited joint mobility). As used herein, the term “baseline,” in relation to JIA-related parameters, means the value of a patient’s JIA-related parameter before or at the time of administration of the antibody of the present invention. Detectable “improvement” may also be detected using at least one of the tests, scores, or measures described herein. In various embodiments, the improvement is detected using at least one of the following: Juvenile Primary Arthritis American College of Rheumatology (ACR) (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100). In various embodiments, the improvement is characterized by at least one score or metric, such as a physician's comprehensive assessment of disease activity score, a patient or parent assessment of overall health status, a child health assessment questionnaire, the number of joints with active arthritis, the number of joints with limited mobility, and / or high-sensitivity C-reactive protein. In some embodiments, improvement in sJIA symptoms is fever reduction (e.g., in subjects with fever at the time of initial antibody administration). In various embodiments, the improvement is characterized by at least one biomarker. In some embodiments, the improvement is characterized by an increase in at least one biomarker. In some embodiments, the improvement is characterized by a decrease in at least one biomarker.

[0209] In another example, treatment is ineffective when a dose of anti-IL-6R antibody does not cause a detectable improvement in one or more parameters or symptoms associated with JIA, or does not cause a biological effect associated with one or more underlying pathological mechanisms that produce JIA or one or more symptoms.

[0210] According to some of these embodiments, the IL-6R antibody is administered subcutaneously. According to some of these embodiments, the IL-6R antibody is salperumab.

[0211] According to the method of the present invention, the therapeutically effective amount of anti-IL-6R antibody administered to the subject will vary depending on the subject's age and size (e.g., weight or body surface area), as well as the route of administration and other factors known to the general artisan.

[0212] In some embodiments, the dosage of the antibody varies according to the subject's weight. In various embodiments, if the subject weighs at least 30 kg (e.g., up to 60 kg, 70 kg, 80 kg, 90 kg, or 100 kg), a dose of 2.0 mg / kg is administered every 2 weeks. In other embodiments, if the subject weighs at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, a dose of 2.0 mg / kg is administered every 2 weeks. In some embodiments, if the subject weighs at least 30 kg, a dose of 3.0 mg / kg is administered every 2 weeks. In some embodiments, if the subject weighs at least 30 kg, a dose of 4-6 mg / kg is administered every 2 weeks. In other embodiments, if the subject weighs at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, a dose of 3.0 mg / kg is administered every 2 weeks. In some embodiments, if the subject weighs at least 30 kg, a dose of 2.0 mg / kg is administered once weekly. In other embodiments, if the subject weighs at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, a dose of 2.0 mg / kg is administered once weekly. In various embodiments, if the subject weighs 10-<30 kg, a dose of 2.5 mg / kg is administered every 2 weeks. In some embodiments, if the subject weighs 10-<30 kg, a dose of 4 mg / kg is administered every 2 weeks. In some embodiments, if the subject weighs 10-<30 kg, a dose of 2.5 mg / kg is administered weekly. In various embodiments, if the subject weighs 10-<30 kg, a dose of 5-7 mg / kg is administered every 2 weeks. In various embodiments, if the subject has a weight of 10-<30 kg, the subject is given a dose of 4 mg / kg every 2 weeks.

[0213] In some embodiments, the dose of the anti-IL-6R antibody administered to the subject is from about 10 mg to about 600 mg. In some embodiments, the dose of the antibody administered to the subject is from about 25 mg to about 200 mg. In various embodiments, the dose of the antibody administered to the subject is from about 60 mg to about 200 mg. For example, the present invention includes (but is not limited to) administering to a patient once weekly or every two weeks the following amounts: about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg. mg, approximately 160mg, approximately 165mg, approximately 170mg, approximately 175mg, approximately 180mg, approximately 185mg, approximately 190mg, approximately 195mg, approximately 200mg, approximately 205mg, approximately 210mg, approximately 215mg, approximately 220mg, approximately 225mg, approximately 230mg, approximately 235mg, approximately 240mg, approximately 245mg, approximately 250mg, approximately 255mg, approximately 260mg, approximately 265mg, approximately 270mg, approximately 275mg, approximately 280mg, approximately 285mg, approximately 290mg, approximately 295mg, approximately 300mg, approximately 325mg, approximately 350mg, approximately 375mg Methods involving anti-IL-6R antibodies in mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, approximately 500 mg, approximately 525 mg, approximately 550 mg, approximately 575 mg, approximately 600 mg, or more.

[0214] As used herein, "administered at a dose of about 2.0 to about 4.0 mg / kg" means administering the substance at any value within the range (including the endpoints of the range). For example, "the dose of anti-IL-6R antibody administered to a patient is from 2.0 mg / kg to 4.0 mg / kg" includes administering 2.0 mg / kg of anti-IL-6R antibody, 4.0 mg / kg of anti-IL-6R antibody, and all doses in between.

[0215] In various embodiments, the IL-6R antibody is administered at a dose of about 25 to 150 mg once weekly or 40 to 200 mg every other week. In one embodiment, the IL-6R antibody is administered at a dose of 25 to 50 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 50 to 75 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 75 to 100 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 100 to 125 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 125 to 150 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 150 to 175 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 175 to 200 mg once weekly or every other week. In one embodiment, the IL-6R antibody is administered at a dose of 100 mg once weekly. In one embodiment, the IL-6R antibody is administered at a dose of 150 mg once weekly. In one embodiment, the IL-6R antibody is administered at a dose of 200 mg once weekly. In one embodiment, the IL-6R antibody is administered at a dose of 100 to 150 mg once weekly. In one embodiment, the IL-6R antibody is administered at a dose of 100 to 200 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of 150 to 200 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of about 100 or about 150 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of about 100, 150, or 200 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of 100 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of 150 mg every two weeks. In one embodiment, the IL-6R antibody is administered at a dose of 200 mg every two weeks.

[0216] In various embodiments of the method, the antibody is used at the doses listed in Tables 2-5.

[0217] The amount of anti-IL-6R antibody administered to a patient can be expressed in milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the method of the present invention includes administering anti-IL-6R antibody to a patient at a daily dose of about 0.01 to about 100 mg / kg, about 0.1 to about 50 mg / kg, or about 1 to about 10 mg / kg of patient body weight. In some embodiments, the anti-hIL6R antibody is salperumab and is administered at about 2 mg / kg to about 4 mg / kg. In various embodiments, the anti-hIL6R antibody is salperumab and is administered at about 2 mg / kg to about 3 mg / kg. In some embodiments, the anti-hIL6R antibody is salperumab and is administered at about 2.5 mg / kg to about 4 mg / kg. In various embodiments, the anti-hIL6R antibody is salperumab and is administered at a frequency of once weekly (qw) or once every two weeks (q2w) from about 2 mg / kg to about 3 mg / kg. In some embodiments, the anti-hIL6R antibody is administered at a dose of about 2 mg / kg to 4 mg / kg at a frequency of once weekly (qw) or once every two weeks (q2w). In some embodiments, the anti-hIL6R antibody is administered at a dose of about 2.5 mg / kg to 4 mg / kg at a frequency of once weekly (qw) or once every two weeks (q2w). In various embodiments, the anti-hIL6R antibody is administered at a dose of about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg. In some embodiments, the anti-hIL6R antibody comprises VH and VL, wherein VH comprises the three CDRs found in the sequence SEQ ID NO:1, and wherein VL comprises the three CDRs found in the sequence SEQ ID NO:2. In other embodiments, the anti-hIL6R antibody is salperamide.

[0218] The method of the present invention includes administering multiple doses of anti-IL-6R antibody to a patient over a specific time period. For example, the anti-IL-6R antibody may be administered about 1 to 5 times daily, about 1 to 5 times weekly, about 1 to 5 times monthly, or about 1 to 5 times annually. In some embodiments, the method of the present invention includes administering a first dose of anti-IL-6R antibody to the patient at a first time point, followed by administering at least a second dose of anti-IL-6R antibody to the patient at a second time point. In some embodiments, the first and second doses may contain the same amount of anti-IL-6R antibody. For example, the first and second doses may each contain about 10 mg to about 500 mg, about 20 mg to about 300 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg of the antibody. The time between the first and second doses may be from about several hours to several weeks. For example, the second time point (i.e., the time when the second dose is administered) may be from about 1 hour to about 7 weeks after the first time point (i.e., the time when the first dose is administered). According to certain exemplary embodiments of the invention, the second time point may be approximately 1 hour, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, or longer after the first time point. In some embodiments, the second time point is approximately 1 week or 2 weeks. A third dose and subsequent doses may be administered similarly throughout the patient's treatment. The invention provides a method of using a therapeutic composition comprising an anti-IL-6R antibody or an antigen-binding fragment thereof, and optionally one or more additional therapeutic agents. The therapeutic composition of the invention will be administered together with suitable carriers, excipients, and other agents incorporated into the formulation to provide improved delivery, administration, tolerability, etc. Many suitable formulations can be found in formulations known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference in its entirety. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing vesicles (such as LIPOFECTIN), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycol with different molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.See also Powell et al., “Compendium of excipients for parenteral formulations”, PDA (1998), J Pharm Sci Technol 52:238-311, which is incorporated herein by reference in its entirety.

[0219] Various delivery systems are known and can be used to administer the pharmaceutical composition of the present invention, such as encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol. Chem. 262:4429-4432, which is incorporated herein by reference in its entirety). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered via any convenient route, such as by infusion or bolus, absorption through the epithelial or mucosal lining of the skin (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents. Administration can be systemic or local. IL-6R antibodies can be administered subcutaneously.

[0220] Pharmaceutical components can also be delivered in vesicles such as liposomes (see Langer (1990) Science 249:1527-1533, which is incorporated herein by reference in its entirety). In some cases, pharmaceutical components can be delivered in controlled-release systems, for example, using pumps or polymeric materials. In another embodiment, the controlled-release system can be positioned close to the target of the component, so that only a portion of the systemic dose is required.

[0221] Injectable formulations can include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, local injection, intravenous infusion, etc. These injectable formulations can be prepared using publicly known methods. For example, they can be prepared by dissolving, suspending, or emulsifying, for instance, the aforementioned antibodies or their salts in a sterile aqueous or oily medium known for injection. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose, and other adjuvants, which can be used in combination with: suitable solubilizers, such as alcohols (e.g., ethanol); polyols (e.g., propylene glycol, polyethylene glycol); nonionic surfactants [e.g., polysorbate 80, HCO-50 (a polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. Oily media include, for example, sesame oil, soybean oil, etc., which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The resulting injectable formulation can be filled into suitable ampoules.

[0222] The antibodies are typically formulated as described in this paper and International Publication No. WO 2011 / 085158 (which is incorporated herein by reference in its entirety).

[0223] In various embodiments, the antibody was administered as an aqueous buffer solution of approximately pH 6.0, containing...

[0224] - Approximately 21 mM histidine,

[0225] - Approximately 45 mM arginine,

[0226] - Approximately 0.2% (w / v) polysorbate 20,

[0227] - Approximately 5% (w / v) sucrose, and

[0228] - The antibody concentration is between approximately 100 mg / mL and approximately 200 mg / mL.

[0229] In another embodiment, the antibody is administered as an aqueous buffer solution at approximately pH 6.0, which contains

[0230] - Approximately 21 mM histidine,

[0231] - Approximately 45 mM arginine,

[0232] - Approximately 0.2% (w / v) polysorbate 20,

[0233] - Approximately 5% (w / v) sucrose, and

[0234] - At least approximately 130 mg / mL of the antibody.

[0235] In another embodiment, the antibody is administered as an aqueous buffer solution at approximately pH 6.0, which contains

[0236] - Approximately 21 mM histidine,

[0237] - Approximately 45 mM arginine,

[0238] - Approximately 0.2% (w / v) polysorbate 20,

[0239] - Approximately 5% (w / v) sucrose, and

[0240] - The antibody at approximately 131.6 mg / mL.

[0241] In another embodiment, the antibody is administered as an aqueous buffer solution at approximately pH 6.0, which contains

[0242] - Approximately 21 mM histidine,

[0243] - Approximately 45 mM arginine,

[0244] - Approximately 0.2% (w / v) polysorbate 20,

[0245] - Approximately 5% (w / v) sucrose; and

[0246] - The antibody at approximately 175 mg / mL.

[0247] In other embodiments, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains

[0248] - 21mM histidine,

[0249] - 45mM arginine,

[0250] - 0.2% (w / v) polysorbate 20,

[0251] - 5% (w / v) sucrose, and

[0252] - The antibody concentration is between 100 mg / mL and 200 mg / mL.

[0253] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains

[0254] - 21mM histidine,

[0255] - 45mM arginine,

[0256] - 0.2% (w / v) polysorbate 20,

[0257] - 5% (w / v) sucrose, and

[0258] - At least 130 mg / mL of the antibody.

[0259] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains

[0260] - 21mM histidine,

[0261] - 45mM arginine,

[0262] - 0.2% (w / v) polysorbate 20,

[0263] - 5% (w / v) sucrose, and

[0264] - The antibody at a concentration of 131.6 mg / mL.

[0265] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains

[0266] - 21mM histidine,

[0267] - 45mM arginine,

[0268] - 0.2% (w / v) polysorbate 20,

[0269] - 5% (w / v) sucrose; and

[0270] - 175 mg / mL of the antibody.

[0271] Advantageously, the above-described pharmaceutical ingredients for oral or parenteral use are formulated into dosage forms suitable for matching the dosage of the active ingredient. Such dosage forms for unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0272] According to the methods disclosed herein, anti-IL-6R antibodies (or pharmaceutical formulations containing said antibodies) can be administered to a patient using any acceptable device or structure. For example, the administration can be performed using a syringe and needle or a reusable pen and / or auto-injector delivery device. The method of the present invention includes administering anti-IL-6R antibodies (or pharmaceutical formulations containing said antibodies) using a number of reusable pen and / or auto-injector delivery devices. Examples of such devices include, but are not limited to, AUTOPEN (Owen Mumford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Bodolf, Switzerland), HUMALOG MIX 75 / 25 pen, HUMALOG pen, HUMALIN 70 / 30 pen (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD pen (Becton Dickinson, Franklin Lake, New Jersey), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET, and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or auto-injector delivery devices for subcutaneous delivery of the pharmaceutical components of the present invention include, but are not limited to, the SOLOSTAR pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk) and KWIKPEN (Eli Lilly), SURECLICK auto-injector (Amgen, Thousand Oaks, California), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA pen (AbbVie Inc., North Chicago, Illinois), to name just a few.

[0273] In one embodiment, the antibody is administered using a pre-filled syringe. In another embodiment, the antibody is administered using a pre-filled syringe containing a safety system. For example, the safety system prevents accidental needlestick injuries. In various embodiments, the antibody is administered using a pre-filled syringe containing the ÈRIS safety system (West Pharmaceutical Services Inc.). See also U.S. Patent Nos. 5,215,534 and 9,248,242, which are incorporated herein by reference in their entirety.

[0274] In another embodiment, the antibody is administered using an autoinjector. In various embodiments, the antibody is administered using an autoinjector (SHL Group) characterized by PUSHCLICK technology. In various embodiments, the autoinjector is a device including a syringe that allows the administration of a dose of the composition and / or antibody to a subject. See also U.S. Patent Nos. 9,427,531 and 9,566,395, which are incorporated herein by reference in their entirety.

[0275] This article also considers the use of microinfusion devices to deliver anti-IL-6R antibodies (or pharmaceutical formulations containing said antibodies) to patients. As used herein, the term "microinfusion device" means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of therapeutic formulations over an extended period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, for example, US 6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46:107-116 (1996), which are incorporated herein by reference in their entirety. Microinfusion devices are particularly suitable for delivering large doses of therapeutic proteins contained in high concentrations (e.g., about 100, 125, 150, 175, 200 mg / mL or higher) and / or viscous solutions.

[0276] In various embodiments, the antibody according to this disclosure is administered to a subject suffering from a type of JIA (e.g., systemic juvenile idiopathic arthritis). In some embodiments, the method disclosed herein includes the step of selecting a subject suffering from a type of JIA (e.g., systemic juvenile idiopathic arthritis). The diagnosis of systemic juvenile idiopathic arthritis is based on the ILAR 2001 JIA classification criteria (Petty RE et al., International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. Feb. 2004; 31(2):390-2). In some embodiments, the patient's age is between about 1 year and about 17 years. In various embodiments, the patient's age is between about 4 years and about 6 years, between about 12 years and about 18 years, between about 12 years and about 14 years, or between about 7 years and about 9 years. In various embodiments, the subject exhibits arthritis in 5 mobile joints. In some embodiments, despite using glucocorticoids at a stable dose for at least 3 days, the subject exhibited arthritis in two mobile joints accompanied by systemic juvenile primary arthritis and fever (temperature above 37.5°C) for at least 3 out of any consecutive 7 days. In various embodiments, the subject did not respond adequately to the current treatment and was considered a candidate for bDMARD.

[0277] In various embodiments, the antibody according to this disclosure is administered to a subject suffering from pcJIA. In some embodiments, the method disclosed herein includes the step of selecting a subject suffering from a type of JIA (e.g., pcJIA). The diagnosis of rheumatoid factor negative or RF positive polyarticular juvenile idiopathic arthritis subtype or oligoarticular extended juvenile idiopathic arthritis subtype is based on the ILAR 2001 JIA classification criteria (Petty RE et al., International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. Feb. 2004; 31(2):390-2). In some embodiments, the patient's age is between about 2 years and about 17 years. In various embodiments, the patient's age is between about 4 years and about 6 years, between about 12 years and about 18 years, between about 12 years and about 14 years, or between about 7 years and about 9 years. In various embodiments, the subject exhibited arthritis in at least five active joints, according to the American College of Rheumatology definition of active arthritis. In various embodiments, the subject did not respond adequately to current treatment and was considered a candidate for bDMARD.

[0278] In some embodiments, an inadequate response to prior treatment refers to a subject whose jIA is not well controlled after receiving prior treatment (e.g., glucocorticoid joint injections and / or methotrexate) at the maximum tolerated typical dose. In one embodiment, an inadequate response to prior treatment refers to a subject who, despite prior treatment, still has moderate or high disease activity and poor prognostic characteristics. In various embodiments, an inadequate response to prior treatment refers to a subject who, despite prior treatment, has unimproved or worsened jIA symptoms (e.g., any of the symptoms listed herein).

[0279] The effectiveness of various treatments for sJIA and pcJIA can be assessed using any of the methods described herein, such as the Juvenile Idiopathic Arthritis Activity Score-27 (JADAS). (Consolaro et al. Development and Validation of a Composite Disease Activity Score for Juvenile Idiopathic Arthritis. Arthritis & Rheumatism. May 2009;61(5):658-666).

[0280] All publications mentioned in this article are incorporated herein in their entirety by reference for all purposes. [List of Abbreviations]

[0281] ACR: American College of Rheumatology

[0282] ADA: Anti-drug antibody

[0283] AE: Negative Events

[0284] AESI: One or more negative events of particular concern

[0285] ALP: Alkaline phosphatase

[0286] ALT: Alanine transaminase

[0287] ANA: Antinuclear antibody

[0288] ANC: Absolute neutrophil count

[0289] Anti-dsDNA: Anti-double-stranded DNA

[0290] AST: Aspartate transaminase

[0291] BP: Blood Pressure

[0292] BUN: Blood urea nitrogen

[0293] CHAQ: Child Health Assessment Questionnaire

[0294] COX-2: Cyclooxygenase-2 inhibitor

[0295] CRF: Medical Record Report Form

[0296] CRP: C-reactive protein

[0297] CSR: Clinical Research Report

[0298] CYP: Cytochrome

[0299] DEC: Dose Elevation Committee

[0300] DMARDs: Disease-modifying antirheumatic drugs

[0301] DMC: Data Monitoring Committee

[0302] DNA: deoxyribonucleic acid

[0303] EBV: Epstein-Barr virus

[0304] e-CRF: Electronic Medical Record Report Form

[0305] EOS: Research Completed

[0306] EOT: Treatment complete

[0307] Erythrocyte sedimentation rate (ESR)

[0308] GCP: Good Clinical Practice

[0309] HAQ-DI: Health Assessment Questionnaire Disability Index

[0310] HBc-Ab: Hepatitis B core antibody

[0311] HIV: Human Immunodeficiency Virus

[0312] HLGT: High-level group terminology

[0313] HR: Heart Rate

[0314] hs-CRP: High-sensitivity C-reactive protein

[0315] ICF: Informed Consent Form

[0316] ICH: International Coordination Council

[0317] IEC: Independent Ethics Committee

[0318] IgG: Immunoglobulin G

[0319] IL-6: Interleukin-6

[0320] IL-6R: IL-6 receptor

[0321] ILAR: International Federation of Rheumatology Societies

[0322] IMP: Research Drug Products

[0323] IRB: Institutional Review Board

[0324] IVRS: Interactive Voice Response System

[0325] IWRS: Interactive Network Response System

[0326] JADAS: Juvenile Arthritis Disease Activity Score

[0327] JAK: Janus kinase

[0328] JIA: Juvenile Primary Arthritis

[0329] JIA ACR: Juvenile Essential Arthritis, American College of Rheumatology

[0330] LDH: lactate dehydrogenase

[0331] LDL: Low-density lipoprotein

[0332] LFT: Liver function test, liver function test

[0333] LLOQ: Lower limit of quantitation

[0334] mAB: Monoclonal antibody

[0335] MAS: Macrophage activation syndrome

[0336] mTSS: Corrected Total Sharp Score

[0337] MTX: Methotrexate

[0338] NIMP: Non-investigational drug products

[0339] NSAIDs: Nonsteroidal anti-inflammatory drugs

[0340] oJIA: Juvenile primary arthritis

[0341] pcJIA: Polyarticular Course of Juvenile Primary Arthritis

[0342] PCSA: Potentially Significant Clinical Abnormality

[0343] PD: Pharmacodynamics

[0344] PK: Pharmacokinetics

[0345] PopPK: Population Pharmacokinetics

[0346] PPD: Purified protein derivative

[0347] PT: Preferred term

[0348] q2w: Once every other week

[0349] qw: Once a week

[0350] RA: Rheumatoid Arthritis

[0351] RF: Rheumatoid factor

[0352] SAE: Serious Negative Event

[0353] SC: Subcutaneous

[0354] SD: Standard Deviation

[0355] sJIA: Systemic juvenile primary arthritis

[0356] SOC: Systemic Organ Classification

[0357] SUSAR: Suspected serious adverse reaction

[0358] TB: Tuberculosis

[0359] TEAE: Treatment for sudden negative events

[0360] ULN: Normal upper limit

[0361] VAS: Visual Analog Scale

[0362] WBC: White blood cells [Example]

[0363] The following examples are provided to give those skilled in the art a complete disclosure and description of how to prepare and use the methods and compositions characterized in this invention, and are not intended to limit the scope of what the inventors consider their invention. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account. [Example 1: An open-label, sequential, escalation, repeated-dose exploratory study of subcutaneous (SC) administration of sarrelumab (followed by an extension phase) in children and adolescents aged 2 to 17 years with pcJIA. (Study ID: DRI13925, Study Title: In Children and Adolescents with pcJIA)] [An open-label, escalation, and repeated-dose exploratory study of sarrelumab is underway.]

[0364] A phase 2 controlled trial (NCT02776735) has been initiated to test the subcutaneous administration of the human IgG1 anti-IL-6Rα monoclonal antibody salirumab in the treatment of pcJIA. This study is a multinational, multicenter, open-label, phase 2, 2-part study of children and adolescents aged 2 to 17 years (or the nationally mandated age requirement) with pcJIA who have an inadequate response to or are intolerant of current therapies or who are considered candidates for biological disease-modifying antirheumatic drugs (DMARDs). The two phases of the study consist of an initial 12-week core treatment phase followed by a 144-week extension phase (for participants). [Figure 1] and [Figure 2]). [Overall Study Design and Planning:] 12-Week Core Treatment Phase

[0365] This multinational, multicenter, open-label study included patients aged 2–17 years diagnosed with RF-positive or RF-negative pJIA or eoJIA according to the ILAR 2001 JIA classification criteria (1). Five active joints, and based on the researchers' judgment, they must be considered as candidates for bDMARD.

[0366] Patients received sareruzumab via subcutaneous (SC) injection, provided by professional caregivers at the investigation site. In two recombinant groups (Group A, ... Dosing regimens were tested using a stepwise approach in groups 30–60 kg and B (10–<30 kg), starting with the lowest sarerudumab dose regimen in the higher weight group (Group A) (Figure 2). For dose regimens 1, 2, and 3, the dose regimens in Groups A and B were 2.0 / 2.5 mg / kg Q2W, 3.0 / 4.0 mg / kg Q2W, and 2.0 / 2.5 mg / kg QW, respectively. After at least 4 weeks of treatment, dose regimen 1 was permitted to be started in Group B after reviewing the data of the first 3 patients enrolled in the same dose regimen in Group A. Once the first 3 patients enrolled in the current weight and dose group had completed 6 weeks of treatment, escalation to higher dose regimens was permitted within each weight group after reviewing safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data. Dose 3, Group B, was permitted to be enrolled after reviewing data from all other weight and dose groups. The dose escalation decision was made by the Dose Escalation Committee (DEC). If the first three patients in the dose and weight groups enrolled do not achieve a JIA ACR30 response by week 6, the DEC may declare the dose ineffective, discontinue enrollment in the dose and weight groups, and interrupt investigator-approved standards of care for patients in the protocol. Throughout the study, the safety of sarrerucitabine was formally monitored by an independent data monitoring committee comprising three pediatric rheumatologists.

[0367] The primary objective of this study was to investigate the pharmacokinetic characteristics of three dosing regimens of sarrerucizumab administered for 12 weeks in order to select one regimen for further investigation. Dosing regimens were selected based on modeling and simulation to provide exposure similar to that evaluated in adult RA. Dosing regimen 1 corresponds to 150 mg every 2 weeks (Q2W), the lowest approved adult dose; dosing regimen 2 corresponds to 200 mg Q2W, the recommended approved adult dose; and dosing regimen 3 corresponds to 150 mg weekly (QW), the highest dose tested in adults, which demonstrated greater efficacy than placebo with acceptable safety (20).

[0368] 12-week core treatment phase (e.g.) [Figure 2] shows that the study was divided into three parts. The first part was a sequential escalation dose exploration, in which, starting with Group A and dose group 1, three dose regimens were studied in each of the following two individual recombinations in 6 evaluable patients (approximately 36 patients in total) at each dose and weight group (Table 1): patients 30kg and 60kg (Group A) and patients <30kg and 10kg (Group B). The next part will involve approximately 24 additional patients (12 from each weight group). 30kg (Group A) and <30kg and The 10kg group was directly included in the selected dosage regimen, resulting in a total of 18 evaluable patients per group under this selected dosage regimen. Part III included approximately 28 additional patients (up to 70% of the total patient population). 30kg [Group A] and patients <30kg and Patients receiving 10 kg (Group B) will be directly enrolled in the selected dosage regimen to reach a total of approximately 100 patients treated throughout the study. During the 12-week core treatment phase, these patients will undergo the same field visit as those recruited in the dose exploration and Part II; however, patients in Part III will not undergo a sarrelumbab PK sampling visit between baseline and week 2.

[0369] The 12-week core treatment phase was the period from the second visit (baseline - week 0) to the 12th visit during which the investigational drug product (IMP) was administered. During the 12-week core treatment phase, the lower weight group (Group B: <30kg and...) was... Patients weighing 10 kg or less were randomly assigned to either the following sarrizumab PK sampling schedule 1 or 2 to minimize blood draws and visit frequency while maintaining assessment of the primary endpoint:

[0370] ￭Schedule 1: Baseline, Day 3, Day 8, Week 2, Week 4, Week 8, and Week 12

[0371] ￭ Schedule 2: Baseline, Day 5, Day 12, Week 2, Week 4, Week 8, and Week 12.

[0372] Assessment. Data for all three dosage regimens in both weight groups were available and reported from study baseline to week 12.

[0373] The primary endpoint was PK exposure, including maximum serum concentration, area under the curve of serum concentration versus time calculated using the trapezoidal method during dosing intervals, and serum concentration observed prior to treatment dosing during repeated dosing. Secondary endpoints were PD, including high-sensitivity C-reactive protein (CRP) concentration, safety, and clinical efficacy. Efficacy was determined by the proportion of patients achieving a JIA ACR 30 / 70 / 90 response at week 12, changes in JIA ACR response components from baseline, and the mean change in the juvenile arthritis disease activity score (JADAS-27-CRP) assessed using the 27-joint count and CRP evaluation.

[0374] In addition, following the completion of the dose exploration and Part 2 enrollments, approximately 28 additional patients will be directly enrolled in Part 3, as advised by health authorities, to bring the total number of treated patients to approximately 100 throughout the study. During the 12-week core treatment phase, these patients will undergo the same field visits as those recruited in the dose exploration and Part 2; however, patients in Part 3 will not undergo sarrenzumab PK sampling visits between baseline and Week 2.

[0375] The additional treatment period within the extension phase will allow for the collection of long-term safety and clinical response data for salperumab in pcJIA patients. This extension phase is up to 144 weeks for patients included in the dose exploration and Part II, and up to 84 weeks for patients included in Part III. Patients included in the dose exploration portion (those already in the extension phase at the time of dose selection, and those not receiving the selected dose regimen) will have their dose regimen adjusted to the selected dose regimen.

[0376] To minimize the amount of blood collected, dose exploration and the second part of the B group of patients (<30kg and Patients (10 kg) will be randomly assigned to one of two different sarerutumab PK sample collection schedules. PK analysis will integrate these sampling schedules to characterize the PK profile of sarerutumab. No PK sample collection is planned for patients included in Part 3 between baseline and week 2. The total blood volume drawn for the study over the 4 weeks will not exceed 3% of the total blood volume, and at any single time, it will not exceed 1% of the total blood volume (39). Furthermore, planned frequent assessments control for the risk to study participants.

[0377] Finally, given the PK characteristics observed in adult RA procedures, a post-treatment follow-up period of 6 weeks following the last treatment visit for TEAE, sarerutumab PK and PD assessment is appropriate.

[0378] Statistical analysis.

[0379] A population pharmacokinetic (PK) model of mixed data was established using nonlinear mixed-effects modeling to describe the PK characteristics of salperumab. Descriptive statistics were used only for PD, safety, and efficacy data. Efficacy endpoints were analyzed based on data obtained as observed during treatment (method) (without attribution for missing data). Furthermore, the JIA ACR30 / 70 / 90 results were obtained using a nonresponder imputation method (nonresponder status was automatically assigned to patients with insufficient data or after treatment interruption). 144-week / 84-week extended phase:

[0380] The IMP at the 12th visit is considered the first IMP of the extended phase. Patients who achieved a JIA ACR30 response only at the 12th visit (week 12) were allowed to continue into the extended phase. Patients continued to receive the same dose regimen of salperumab they were assigned to during the 12-week core treatment phase of this study until a selected dose regimen was determined. Once a dose regimen was selected, patients who were not yet using this regimen were adjusted to the selected dose regimen and followed a new visit schedule with more frequent monitoring (PK, safety, and efficacy) during the first 12 weeks compared to patients who were not adjusted.

[0381] At the 27th visit, patients who prematurely discontinued study treatment were evaluated using the EOT procedure. These patients were required to return for an end-of-study (EOS) assessment 6 weeks after the EOT visit (EOT+6 weeks). For patients who discontinued study treatment during the 12-week core treatment phase, an additional sarerutumab PK assessment was performed 2 weeks after the EOT visit (EOT+2), and IL-6 and sIL6R were measured at the EOT visit. These patients were required to undergo all scheduled visits and assessments except for sarerutumab administration until the 12th visit.

[0382] An 84-week extension phase was arranged for patients included in Part III. The IMP at the 12th visit was considered the first IMP of the extension phase. As shown in Table 32, patients included in Part III using the selected dosing regimen will be followed up.

[0383] Tested dosing regimen

[0384] For each body group, the three sequentially escalating dosing regimens to be tested are defined based on PK modeling, and the basic principle is as follows:

[0385] • Dosage group 1: A dose similar to salperumab 150 mg q2w targeting PK exposure, representing the lowest effective dose regimen in adult patients with RA.

[0386] • Dosage group 2: A dose similar to 200 mg q2w for targeting PK exposure, which is the recommended dosing regimen in adult patients with RA.

[0387] • Dosage group 3: A dose similar to salperumab 150 mg qw targeting PK exposure, which produced the highest exposure in long-term administration studies in adult patients with RA.

[0388]

[0389]

[0390] Abbreviations: qw = once a week, q2w = every other week

[0391] The dose (mg) to be administered to the patient was calculated at baseline. Regardless of changes in patient weight, the dose and corresponding volume of the drug product remained constant throughout the 12-week core treatment phase of the trial. During the extension phase, patient weight was measured at each visit, and the dose was adjusted only based on weight gain if calculations indicated a need for an increased dose. Specifically, the upper limit dose was 150 mg for dose groups 1 and 3, and 200 mg for dose group 2. The volumes of salperumab to be injected for dose groups 1 through 3 are presented in Tables 2-5 below.

[0392] Tables 2 and 3 show the dosage information for patients in the high-weight group (Group A). ​​High-weight patients were those for whom dosage exploration was conducted on a portion of body weight. 30kg and Those patients weighing 60kg, and the weight in Part Two Another patient weighing 30kg. Tables 4 and 5 show the low weight group (Group B): <30kg and Dosage information for patients weighing 10 kg.

[0393]

[0394]

[0395]

[0396] Tables 3 and 4 show the low body weight group (Group B): <30kg and Dosage information for patients weighing 10 kg.

[0397]

[0398] [Table 5. Dosage information for low-body weight group (Group B) 2]

[0399] During the 12-week core treatment phase, the volume to be administered at each injection was calculated based on baseline (second visit) weight and remained constant throughout all 12-week core treatment phases. If weight gain occurred and calculations indicated a need for increased dose, the volume to be administered during the extended treatment phase could be adjusted using weight measured at each visit. If the selected dosing regimen was one of three predefined dosing groups, patients subsequently enrolled or switched to the selected dosing regimen used the corresponding doses listed in Tables 2–5. Duration of study participation for each patient.

[0400] The total duration of the study (per patient) was up to 166 weeks for patients included in the dose exploration and Part 2, and up to 106 weeks for patients included in Part 3.

[0401] ￭A screening process lasting 4 weeks + 3 days (up to 31 days)

[0402] ￭12-week core treatment phase

[0403] For patients included in the dose exploration and Part 2, there was an extended phase of up to 144 weeks, and for patients included in Part 3, there was an extended phase of up to 84 weeks.

[0404] Follow-up 6 weeks after treatment.

[0405] For all visits, using day 1 as a reference, a timeframe of ±3 days for dose groups 1 and 2 and ±1 day for dose group 3 is acceptable, except...

[0406] ￭ For the 3rd visit (day 3), 4th visit (day 5), and 5th visit (day 8), no visit window is allowed during PK sampling. For patients included in Part 3, PK sampling visits, i.e., visits 3, 4, 5, and 6, are not applicable during the core treatment phase.

[0407] ￭For all three dose groups, the 6th visit (day 12) ± 1 day

[0408] ￭For all three dose groups, the 7th visit (week 2) ± 1 day

[0409] ￭For dose groups 1 and 2, the 8th visit (week 4) was ±2 days, and for dose group 3, it was ±1 day.

[0410] [Inclusion Criteria]

[0411] The inclusion criteria for this study are as follows:

[0412] 1. Age at the time of screening and home visit 2 and Male and female patients aged 17 or older (or the age requirement stipulated by the state)

[0413] 2. According to the ILAR 2001 JIA classification criteria (2), diagnosed as RF-negative or RF-positive polyarticular JIA subtype or oJIA subtype, with at least 5 active joints as defined by ACR at the time of screening (Table 6).

[0414] 3. Patients who, according to the researchers' judgment, do not respond adequately to current treatments and are considered candidates for bDMARDs.

[0415] 4. For patients who have reached the legal age of consent, or whose parents or one or more legal guardians have signed and dated a written informed consent form approved by the ethics committee. The patient's consent should be obtained based on local guidelines and the patient's maturity and intellectual capacity to understand the information relevant to the research. In cases involving independent or mature minors with full decision-making capacity, or in other circumstances permitted by law, informed consent will be obtained directly from one or both parents or one or more legal guardians. Exclusion Criteria

[0416] Patients were excluded from this study for the following reasons: weight <10 kg or >60 kg; JIA subtype other than RF positive, RF negative, or eoJIA; prior treatment with anti-IL-6 or IL-6R antagonists; treatment with any other biologic within 5 half-lives of the first salperumab dose; use of parenteral or intra-articular glucocorticoid injections within 4 weeks prior to baseline; active or past history of opportunistic infections (including tuberculosis); vaccination with a live attenuated vaccine within 4 weeks prior to baseline; or any condition that would adversely affect the patient's participation in this study. Patients receiving NSAID, oral corticosteroid, or csDMARD treatment are excluded if the dose of a nonsteroidal anti-inflammatory drug (NSAID) or oral corticosteroid is unstable within 2 weeks prior to baseline, or if the oral corticosteroid dose exceeds the equivalent prednisone dose of 0.5 mg / kg / day (or 30 mg / day); or if the dose of a conventional synthetic disease-modifying antirheumatic drug (csDMARD) is unstable within 6 weeks prior to baseline, or if the csDMARD dose exceeds the locally labeled recommended dose. Written informed consent from all patients / guardians is required based on local regulatory guidelines.

[0417]

[0418]

[0419] a. The patient or a first-degree relative has psoriasis or a history of psoriasis.

[0420] b. HLA B27-positive males begin to develop arthritis after age 6;

[0421] c. A history of ankylosing spondylitis, tendonitis-related arthritis, sacroiliitis with inflammatory bowel disease, Leter syndrome, acute anterior uveitis, or a first-degree relative with one of these disorders;

[0422] d. IgM rheumatoid factor appears at least twice, with an interval of at least 3 months;

[0423] e. The patient has systemic JIA. [, Research on treatment Research Drug Product (IMP)

[0424] Salirumab is an anti-IL-6R mAb (anti-interleukin-6 receptor α subunit monoclonal antibody). Preparations

[0425] Salirumab product was administered at a concentration of 175 mg / mL in an aqueous buffer at pH 6.0. It was dispensed into 5 mL vials containing 2.7 mL of sarrurimab, with a drawable volume of 2.0 mL. One or more routes of administration:

[0426] For self-injection, sarerumab is administered subcutaneously on the abdomen or thigh, or by a professional or non-professional caregiver on the upper arm (lateral side). Preferably, SC injection sites alternate between the four quadrants of the abdomen (excluding the navel or lumbar region) or thigh (anterior and lateral).

[0427] For patients receiving dosing regimen 1 or 2 (q2w), injections were administered at the study site by a professional caregiver during the 12-week core treatment phase of this study. For patients receiving dosing regimen 3 (weekly injections), a qualified field person or family nurse was arranged to administer the IMP for doses not planned to be given at the study site. For the extension phase of this study, home injections are permitted if the patient, one or both parents, one or more legal guardians, or one or more caregivers are willing and able to administer the injection. In these cases, training to prepare and administer the IMP is required and provided during the core treatment phase, starting from the 10th visit (week 8). This training is documented in the patient's study file. Prior to permitting home injections during the extension treatment phase, patients, one or both parents, one or more legal guardians, or one or more caregivers are permitted to administer the injection at the 10th visit (week 8), 11th visit (week 10), and 12th visit (week 12) under the observation / supervision of one or more investigators or one or more representatives.

[0428] During patient study visits, IMP is administered following clinical procedures and blood collection. A diary is provided to record information related to these injections; this diary is retained as source data in the patient's study file. If a caregiver is unable or unwilling to administer IMP, a qualified field personnel will administer the dose not planned for on-site administration. Dosing regimen

[0429] Salrelumab was administered q2w or qw. However, according to the protocol, a salrelumab administration window of ±3 days was permitted for dose groups 1 and 2 and ±1 day for dose group 3 to accommodate special circumstances, such as pending laboratory test results, persistent adverse events (AEs), or scheduling difficulties for patients other than at the 5th visit (day 8). There was no administration window at the 5th visit (day 8). At the 7th visit (week 2), patients in dose groups 1, 2, and 3 had only a ±1 day administration window, and at the 8th visit (week 4), dose group 3 had only a ±1 day administration window or dose groups 1 and 2 had only a ±2 day administration window.

[0430] Please note that for q2w administration over intervals of less than 11 days and for weekly administration over intervals of less than 6 days, an overdose of IMP (accidental or intentional) is defined as at least twice the stated dose.

[0431] Administer the following dose of sarrizumab at q2w or qw intervals: [Dosage Group 1:]

[0432] Group A ( 30kg and 60kg): 2mg / kg q2w

[0433] Group B (<30kg and 10kg): 2.5mg / kg q2w. [Dose Group 2:]

[0434] Group A ( 30kg and 60kg): 3mg / kg q2w

[0435] Group B (<30kg and) 10kg): 4mg / kg q2w. [Dosage group 3:]

[0436] Group A ( 30kg and 60kg): 2mg / kg qw

[0437] Group B (<30kg and) 10kg): 2.5mg / kg qw. Dosage modification.

[0438] The dose (mg) administered to patients was calculated at baseline. Regardless of changes in patient weight, the dose and corresponding volume of the drug product remained constant throughout the 12-week core treatment phase of the trial. During the extension phase, patient weight was measured at each visit, and the dose was adjusted only based on weight gain if calculations indicated a need for an increased dose. Specifically, the upper limit dose was 150 mg for dose groups 1 and 3, and 200 mg for dose group 2. Tables 2-5 further detail the injection volumes based on patient weight. Methods for patient allocation to treatment groups...

[0439] A list of randomly assigned treatment kit numbers is generated centrally. IMPs are packaged according to this list. Treatment kits are assigned to patients via an Interactive Voice Response System (IVRS) or an Interactive Web Response System (IWRS).

[0440] Patients meeting the inclusion criteria will be included and will be divided into two groups (Group A: for patients enrolled during the dose exploration phase). 30kg and 60kg, and for patients enrolled during the second and third parts, Group B: For all three parts, <30kg and Treatment kits are distributed within 10kg.

[0441] • For dose exploration and Part 2, the planned inclusion ratio for 2-individual recombinant therapy is 1:1.

[0442] For Part III, there is no pre-defined inclusion ratio for the 2-individual reassortment, but the upper limit for each weight group is 70% (i.e., 20 patients). Therefore, the most unbalanced inclusion by weight grouping would likely be 20 patients to 8 patients in Part III. Packaging and labeling.

[0443] IMP is provided in patient treatment kits containing labeled vials. Storage conditions.

[0444] The research drug will be kept refrigerated between 2°C and 8°C, either on-site or at home. [Pharmacokinetics, Efficacy, and Safety Assessment]

[0445] According to the following flowchart, the patient is scheduled to undergo a 12-week core treatment phase assessment (Table 7). Pharmacokinetic measurements and time points.

[0446] The blood collection schedule during the 12-week core treatment phase is shown in Table 7. If a patient experiences a sarerutumab (SAE), blood samples should be collected at or near the start and end of the event, if possible, to determine sarerutumab concentrations. For patients who prematurely discontinue study treatment during the core treatment phase (at or before the 12th visit), an additional sarerutumab PK assessment should be collected 2 weeks after the planned EOT assessment (3 weeks after the last IMP injection for dose group 3 patients, or 4 weeks after the last IMP injection [for dose groups 1 and 2 patients]). These patients are required to return 6 weeks after the EOT assessment for the study end (EOS) assessment. The date of sample collection should be recorded. For patients who prematurely discontinue treatment, blood samples should have been collected at the EOS visit, if possible. Serum samples should be analyzed for functional sarerutumab concentrations using a validated enzyme-linked immunosorbent assay (ELISA).

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] Abbreviations: ADA = Anti-drug antibody, ANA = Antinuclear antibody, BP = Blood pressure, DNA = Deoxyribonucleic acid, D = Day, EBV = Epstein-Barr virus, EC = Ethics Committee, EOT = End of treatment, ESR = Erythrocyte sedimentation rate, HbA1c = Glycated hemoglobin, HIV = Human immunodeficiency virus, hs-CRP = High-sensitivity C-reactive protein, Ig = Immunoglobulin, IVRS = Interactive voice response system, IL = Interleukin, IMP = Investigational drug product, JADAS = Juvenile arthritis disease activity score, JIA ACR = Juvenile primary arthritis American College of Rheumatology, PK = Pharmacokinetics, PPD = Purified protein derivative, SAE = Serious adverse events, sIL-6R = Soluble interleukin-6 receptor, TB = Tuberculosis, V = Visit, Wk = Week, yrs = Year.

[0454] a. For patients who discontinued treatment during the 12-week core treatment phase (at or before the 12th visit), an additional sarritubamab PK assessment will be performed 2 weeks after the EOT visit (2 weeks after EOT++). The 88th visit is not applicable for patients included in Part III.

[0455] b. Saliruzumab PK sampling between the 2nd and 7th visits differed among patients: for group A ( For group B (<30kg), the visits and days for the 3rd visit (day 3), 4th visit (day 5), 5th visit (day 8), and 6th visit (day 12) are as follows: For group B (<30kg), Schedule 1, the visits and days for the 3rd visit (day 3) and 5th visit (day 8) are as follows; For group B (<30kg), Schedule 2, the visits and days for the 4th visit (day 5) and 6th visit (day 12) are as follows. Saliruzumab PK sampling can be performed at home. A PK diary will be provided to record the date and time of sample collection. No sample collection window is allowed for the 3rd visit (day 3), 4th visit (day 5), and 5th visit (day 8). A window of ±1 day is allowed for the 6th visit (day 12). For patients included in Part III, visits 3, 4, 5, and 6 are not applicable. However, additional hematological tests must be performed before the second administration of sarruzumab (see footnote "o" for details).

[0456] c. Based on the investigator's determination, the laboratory tests mentioned in exclusion criterion E24 can be repeated via central laboratory retesting between the screening visit and the first IMP administration to ensure the patient meets the eligibility criteria for exclusion criterion E24. Patients requiring Gilbert's syndrome genetic testing will sign a locally approved specific consent form (a consent form / permission must be obtained prior to this assessment and local regulations must be followed).

[0457] d. Prior to all screening assessments, the patient (if he / she has reached the legal age of consent based on local regulations), one or both parents, or one or more legal guardians must sign and date an EC-approved written informed consent form. The patient, one or both parents, and one or more legal guardians will receive information from the investigator regarding one or more study objectives and procedures. Separate written consent should be obtained from one or both parents or one or more legal guardians allowing their child to participate in optional saliva sample collection for pharmacogenomics research and allowing the organizer to retain any remaining / unused blood samples for future research.

[0458] e. In accordance with local regulations, a separate (locally approved) informed consent form will be completed by any patient requiring Gilbert's genetic disease testing. A signed consent form should be obtained from the patient based on local regulations and the patient's understanding and maturity of the research information.

[0459] f. The family journal regarding the IMP should be kept at home in relation to the IMP.

[0460] g. A complete physical examination will be conducted at the first visit (day -28 to day -1, up to 31 days), the second visit (day 1, week 0), the eighth visit (week 4), the ninth visit (week 6), and the twelfth visit (week 12), including the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, gastrointestinal system, nervous system, lymphatic system, and musculoskeletal system.

[0461] h. [Optional]: Based on the investigator's judgment, Epstein-Barr virus (EBV) titer testing (including IgG and IgM) may be performed at screening; based on the patient's family and medical history and the investigator's judgment, hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), total hepatitis B core antibody (HBc-Ab), and hepatitis C antibody (HCV-Ab) testing may be performed at screening. HIV serological testing will only be performed based on the investigator's assessment of suspected HIV patients. For Argentina and Germany only: Serological testing for hepatitis B and C and HIV must be performed on all patients at screening visits to screen for the corresponding exclusion criterion E14.

[0462] i. The second visit should be conducted before the baseline visit (day 1, week 0). Patients aged 5 years underwent a purified protein derivative (PPD) skin test. Patients should be evaluated within 48 to 72 hours after the PPD skin test. For patients not evaluated within 72 hours, the skin test should be repeated. When determining the skin test result, an assessment of the level of risk (TB exposure and / or recent migration from a TB-prone country) vaccination history should be considered. For all details, refer to exclusion criterion E13. Patients >5 years of age will undergo an interferon-γ (IFN-γ) release assay, i.e., the QuantiFERON-TB test. (1) If, after the initial TB screening, the PPD or QuantiFERON result is negative but the clinical suspicion of TB is above moderate, patients should be retested for TB at any time during the study period based on the investigator's assessment. [Based on local PPD availability, local regulations for TB screening, and investigator judgment, the younger patient group will be included in the study.] Consider QuantiFERON-TB testing for children aged 5 years and older.

[0463] j. For JIA patients who have not had a chest X-ray within 3 months prior to the second baseline visit (day 1, week 0), a chest X-ray may be performed only if deemed necessary based on the investigator's judgment or according to local TB screening guidelines before initiating biotherapy.

[0464] k. Patients in dosage regimens 1 and 2 will receive the study drug product every other week, and patients in dosage regimen 3 will receive it weekly. A home nurse will be scheduled to administer the IMP to patients in dosage regimen 3 at the mid-term visit (home administration if possible). Patients should be monitored for at least 30 minutes after IMP administration to detect any signs or symptoms of an allergic reaction. For Germany only: Patients must be monitored for at least 1 hour after the first IMP administration to assess local tolerability. In the dose exploration and Part II, patients who do not achieve JIA ACR 30 by the end of the 12-week core treatment period will discontinue study treatment to receive care based on investigator clinical judgment. Only after the 12th visit will the organizers provide investigators with ACR responses in juvenile primary arthritis (including JIA ACR 30 responses) to evaluate this criterion. For patients who completed the core treatment phase at the 12th visit (week 12) but did not continue to the extended phase for reasons other than lack of JIA ACR30 response, IMP injections will not be administered at the 12th visit.

[0465] 1. During the core treatment phase, the investigational drug product will be allocated to patients in dose regimen group 3.

[0466] m. During the study, a rangefinder will be used to measure height on-site.

[0467] The core set of the Juvenile Primary Arthritis (ACR) includes: a physician's comprehensive assessment of disease severity, a comprehensive assessment of overall health status by the patient or one or both parents / one or more guardians, the number of joints with active arthritis (defined as swelling not due to deformity or accompanied by pain or tenderness or both with limited mobility), the number of joints with limited mobility, the Child Health Assessment Questionnaire (CHAQ), and hs-CRP (2,3,4). At screening, only the number of joints with active arthritis and the number of joints with limited mobility will be assessed.

[0468] o. This article explains the activity score for juvenile arthritis.

[0469] p. Hematology (blood should be drawn before drug administration): hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). Additional hematological tests must be performed on dose regimens 1 and 2 at the 6th visit (day 12±1) to obtain results before the second dose of sarerutumab (7th visit: week 2, day 15), or on dose regimen 3 (not before the 4th visit [day 5]) before or at the 5th visit (day 8) to obtain results before the second dose of sarerutumab. For patients included in the dose exploration and Part II, additional hematological tests to confirm neutrophil and platelet counts may be performed at a central or local laboratory prior to administration of the second dose of sarelumab. For patients included in Part III but not at the sixth field visit, additional hematological tests will be performed at a local laboratory prior to administration of the second dose of sarelumab, but no earlier than day 12. If a local laboratory is used, central laboratory samples for hematological testing should still be drawn prior to administration of IMP at the seventh visit (day 15, week 2) as scheduled for dose regimens 1 and 2, and at the fifth visit (day 8) for dose regimen 3. For all patients, the second visit (day 1) and additional hematological laboratory assessments must be reviewed prior to administration of the second dose of sarelumab at the fifth visit (day 8) for dose regimen 3 patients or the seventh visit (week 2, day 15) for dose regimens 1 and 2 patients.

[0470] q. Chemistry (blood should be drawn before medication administration): The entire chemistry testing process will be performed only at the screening visit, the second visit at baseline (day 1, week 0), and the 12th visit (week 12) or at EOT: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine and creatinine clearance, glomerular filtration rate (using the modified Schwartz formula), calcium, phosphate, total protein, albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, and unconjugated bilirubin. At all other visits: only ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested.

[0471] r. Fasting blood lipids (blood should be drawn before medication administration): triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Patients need to fast for at least 8 hours before the test.

[0472] s. [Optional]: HbA1c levels will be measured solely based on the patient’s medical history and the researcher’s judgment.

[0473] t. Urine analysis strips: specific gravity, pH, glucose, blood, protein, nitrate, leukocyte esterase, bilirubin. If any parameter on the strip is abnormal, the urine sample should be sent to the central laboratory for testing. If protein is positive, it will be analyzed under a microscope by the central laboratory.

[0474] u. For women who have started menstruating, a serum pregnancy test must be performed during the screening visit.

[0475] v. For women who have started menstruating, local urine pregnancy tests should be performed at the 2nd visit (week 0, day 1), 8th visit (week 4), 10th visit (week 8), and 12th visit (week 12). Urine pregnancy tests can be performed locally. Pregnancy status should be checked by urine pregnancy tests before exposure to IMP and EOT.

[0476] w. On the day of administration during the treatment period, blood samples will be collected prior to IMP administration. If the patient develops SAE, blood samples should be collected, where possible, at or near the start and end of the event to determine salperumab concentration and assess antidrug antibody (ADA). In dose exploration and Part II, if the patient prematurely discontinues study treatment during the 12-week core treatment phase, an additional PK visit (88th visit) will be required 2 weeks after the EOT visit for blood sampling.

[0477] x. For patients who prematurely discontinue study treatment during the core treatment phase, IL-6 and total sIL-6R will be measured during EOT assessment.

[0478] y. One or both parents or one or more legal guardians must sign a separate informed consent form prior to the optional saliva sample collection for pharmacogenomics studies. Samples are preferably collected at the second visit at baseline (Day 1, Week 0), but may be collected at any visit. Patients may also sign informed consent based on their age, local regulations, and their maturity to understand the study information. Patients are still eligible for inclusion in the study if they or their parents or one or more legal guardians do not wish them to participate in saliva sample collection. Pharmacokinetic Variables

[0479] Saliruzumab PK variables include the maximum serum concentration (Cmax) observed after the first dose and the area under the serum concentration versus time curve (AUC) calculated using the trapezoidal method during the dose interval (AUC0-τ), as well as the concentration observed before treatment administration from baseline to the 12-week repeat administration period (Cval).

[0480] A population PK (PopPK) model of mixed data was established using nonlinear mixed-effects modeling to describe the PK characteristics of sarerutumab. The following PK parameters were calculated using the PopPK model of functional sarerutumab in serum (PopPK analysis will be reported in a separate letter). PK parameters include, but are not limited to, those listed in Table 8.

[0481] [Efficacy Assessment] JIA ACR Response

[0482] In this study, the JIA ACR response level was used to assess signs and symptoms (see Table 7). The JIA ACR 30 / 50 / 70 / 90 / 100 (JIA ACR30 / 50 / 70 / 90 / 100) response was defined as a patient in whom three of the six core variables improved by at least 30% / 50% / 70% / 90% / 100% from baseline, while no more than one of the remaining variables worsened by more than 30%.

[0483] The JIA ACR core set includes 6 variables:

[0484] 1. Comprehensive physician assessment of disease activity

[0485] 2. Patient / Parent Assessment of Overall Health Status

[0486] 3. Functional abilities as determined by the Child Health Assessment Questionnaire (CHAQ)

[0487] 4. Number of joints with active arthritis (0 to 71 joints)

[0488] 5. Number of joints with limited mobility (0 to 67 joints)

[0489] 6. High-sensitivity C-reactive protein.

[0490] During the 12-week core treatment phase, the JIA ACR disease core set will be assessed at each field visit, except for the 3rd visit (day 3), 4th visit (day 5), 5th visit (day 8), and 6th visit (day 12). During the extension phase (for patients maintaining the current dose (selected dosing regimen), the JIA ACR core set will be assessed periodically at weeks 24, 48, 72, 96 (EOT for Part III), 120 (not applicable to Part III), 144 (not applicable to Part III), and EOT (week 156 for dose exploration and Part II / week 96 for Part III). For patients switching to the selected dosing regimen during the extension phase, a comprehensive physician assessment of disease activity is required.

[0491] Researchers were asked to rate patients’ disease activity on an anchored 100 mm level Visual Analogue Scale (VAS), where 0 was considered the best disease activity and 100 the worst. Patient / parent assessment of overall health status.

[0492] Patient / parent assessment of overall health status measured on a 100mm horizontal VAS. The form should be completed by the patient or the same parent or guardian to ensure consistency. Child Health Assessment Questionnaire (CHAQ)

[0493] CHAQ is a type of... Interviews or self-management tools were used to assess the health status of children aged 8 years and their parents / agents managing children under 8 years. The CHAQ is a general measure of health status for children aged 1 to 19 years. The assessment consists of 43 items and takes approximately 10 minutes to complete. The CHAQ questionnaire was completed before and after IMP administration (according to guidance provided by the Department of Health Economics and Outcomes Research). The recall period was 1 week (Singh, G. et al. 1994 Arthritis Rheum. Dec. 1994;37(12):1761-9).

[0494] The median CHAQ scores reported in the development of the CHAQ for mild, mild to moderate, and moderate disability were 0.13, 0.63, and 1.75, respectively (Dempster, H. et al., 2001 Arthritis Rheum. 44(8): 1768-74).

[0495] In order to eliminate differences that may be caused by growth and development,

[0496] Parents were instructed to only pay attention to difficulties caused by the illness (e.g., if a child was too young to do an activity, the response was marked "not applicable"). The response options for assessing difficulty were based on... On a 5-point Likert scale

[0497] (0 = no difficulty, 1 = some difficulty, 2 = many difficulties, 3 = cannot be done, and 4 = not applicable).

[0498] CHAQ is divided into 3 parts:

[0499] 1. Disability Index: 41 items assessing daily living abilities, further divided into 8 subscales / domains: dressing and grooming; getting up; eating; walking; hygiene; reaching; grasping; and activity. For each domain, the following were assessed: the degree of difficulty in performing daily functions, the need for special assistive tools or devices, and the need for assistance from others.

[0500] To calculate CHAQ-DI, first calculate the score for each domain:

[0501] The score for the functional area is determined by the question with the highest response rate.

[0502] If assistive tools or devices are used or assistance is required to complete a task in a certain area, the minimum score for that functional area will be recorded as 2.

[0503] ￭Average the 8 subscales / domains to calculate the average score, or disability index (ranging from 0 to 3).

[0504] A lower disability index score indicates a better / healthier quality of life / fewer signs and symptoms than the health status, while a higher disability index score indicates a poorer health status / poorer HRQL / more signs and symptoms (Singh, G. et al. 1994 Arthritis Rheum. Dec. 1994; 37(12):1761-90; Klepper S. 2003 Arthritis Rheum. 49(3):435-43). The smallest clinically significant improvement in the CHAQ disability index was a score reduction of 0.13. The smallest clinically significant deterioration in the CHAQ disability index was a median change in score of 0.75 (Dempster, H. et al. 2001 Arthritis Rheum. 44(8):1768-74).

[0505] 2. Discomfort Index: Determined by the severity of pain over the past week, rated on the VAS (anchored at "0" for "no pain" and "100" for "very severe pain"). To calculate the CHAQ Discomfort Index, the distance from the left end of the VAS in item 67 to the responder's marker is measured and multiplied by 0.2. The range is 0 to 3.

[0506] 3. Health status: A measure of comprehensive assessment by the patient or their parents.

[0507] To calculate the CHAQ health status score, the distance from the left end of the VAS in item 69 to the responder's marker was measured and multiplied by 0.2. The range is 0 to 3. The number of joints with active arthritis and the number of joints with limited mobility were also considered.

[0508] Active joints were defined as joints with intra-articular swelling not due to deformity, or joints with limited range of motion accompanied by pain or tenderness. Seventy-one joints were assessed for active disease by counting the number of active joints (Bazso, A. et al., 2009 J Rheumatol. 36(1): 183-90; Beukelman, T. et al., 2011 Arthritis Care Res (Hoboken). 63(4): 465-82).

[0509] The 71 joints include the cervical spine (counted as 1 joint), temporomandibular joint (2 joints, right and left), sternoclavicular joint (2 joints), acromioclavicular joint (2 joints), shoulder (2 joints), elbow (2 joints), wrist (2 joints), metacarpophalangeal joint (10 joints in total, 5 on each side), proximal interphalangeal joint (10 joints in total, 5 on each side), distal interphalangeal joint (8 joints in total, 4 on each side), hip (2 joints), knee (2 joints), ankle (2 joints), subtalar joint (2 joints), tarsometatarsal joint (2 joints), metatarsophalangeal joint (10 joints, 5 on each side), and interphalangeal joint (10 joints, 5 on each side).

[0510] Except for the sternoclavicular and acromioclavicular joints (n=2), the 67 joints used for the examination of limited mobility were the same as those used for the examination of active disease. Formal joint counting was performed by trained assessors. Joint tenderness was defined as pain induced by joint pressure applied by the assessor's thumb and forefinger. High-sensitivity C-reactive protein (hs-CRP) was measured.

[0511] hs-CRP was assessed at each visit. See Table 7. High-sensitivity C-reactive protein levels are directly correlated with IL-6R activity. An active dosing regimen is expected to significantly reduce C-reactive protein (CRP) levels.

[0512] Juvenile arthritis disease activity score

[0513] This study used the JADAS score (see Table 7) to assess disease activity. The JADAS includes four measurements:

[0514] 1. A comprehensive physician assessment of disease activity, measured on a 10 cm VAS, where 0 = no activity and 10 = maximum activity.

[0515] 2. Comprehensive assessment of the health status of parents / patients, measured on a 10cm VAS, where 0 = very good and 10 = very poor.

[0516] 3. Joint count with active disease

[0517] 4. Inflammation index: hs-CRP or ESR level:

[0518] The erythrocyte sedimentation rate is normalized to grades 0 to 10 according to the following formula: (ESR [mm / hour] - 20) / 10, where ESR values ​​<20 mm / hour are converted to 0 and ESR values ​​>120 mm / hour are converted to 120 before calculation.

[0519] Alternatively, hs-CRP can be normalized to levels 0 to 10 using the following formula: (CRP[mg / L]-10) / 10, where CRP values ​​<10 mg / L are converted to 0 and CRP values ​​>110 mg / L are converted to 110 before calculation.

[0520] JADAS is calculated as a simple linear sum of its four component scores. See Consolaro, A. et al. 2009 Arthritis Rheum. 61(5):658-66. JADAS-27 includes the following joints: cervical spine, elbow, wrist, metacarpophalangeal joints (from the first to the third), proximal interphalangeal joints, hip, knee, and ankle. JADAS is considered an effective tool for assessing disease activity in JIA and has the potential to be applied in standard clinical care, observational studies, and clinical trials (ibid.). [Pharmacokinetic Measurements and Time Points]

[0521] The efficacy of sarrucumab was evaluated by measuring the following biomarkers: hs-CRP, IL-6, and total sIL-6Rα.

[0522] The concentration of high-sensitivity N-CRP was measured by Covance CLS using a turbidimetric method (HS) with an LLOQ of 0.20 mg / L.

[0523] Serum IL-6 concentrations were determined by Covance CLS using an empirically validated quantitative sandwich enzyme immunoassay with an LLOQ of 3.12 pg / mL.

[0524] Serum total sIL-6Rα concentration was measured by Covance using an empirically validated ELISA method (DOH1163) with an LLOQ of 15 ng / mL.

[0525] The blood collection schedule is shown in the study chart in Table 7. Clinical Laboratory Evaluation

[0526] Summary statistics (including quantity, mean, median, SD, minimum, and maximum) for all laboratory variables (central laboratory values ​​and changes from baseline) were calculated by dose cohort and organized by biological function for each visit or study assessment (baseline, each post-baseline time point, endpoint). The incidence of PCSA and abnormal laboratory values ​​at any time during the TEAE period were summarized by biological function and dose cohort. For lipids, baseline was classified using the NCEP APTIII classification. The incidence of neutropenia, thrombocytopenia, and lymphopenia was summarized by the highest level. Pharmacokinetic data analysis

[0527] Serum concentrations of functional sarrelumarab were summarized using descriptive statistics. All PK analyses were performed using a PK cohort. This consisted of all patients in the safety cohort with at least one post-dose non-missing sarrelumarab concentration value. Trough serum concentrations of functional sarrelumarab at each visit were summarized using descriptive statistics (including count, arithmetic and geometric mean, SD, SE of mean (SEM), CV, minimum, median, and maximum) by dose, population, and body weight. Samples were considered ineligible for these analyses if the previous administration was <11 days or >17 days prior to the sampling time for the bi-weekly protocol, or <5 days or >9 days prior to the sampling time for the weekly protocol. Before administration (week 0), concentrations below LLOQ were set to zero. Other concentrations below LLOQ were replaced with LLOQ / 2. A PopPK model was established using nonlinear mixed-effects modeling to characterize the PK properties of sarrelumarab. The PopPK model is presented in a CSR-independent file. Pharmacokinetic Data Analysis

[0528] From baseline to week 12, serum concentrations of IL-6, total sIL-6Rα, and hs-CRP were summarized by dose and body weight using descriptive statistics (including quantity, arithmetic and geometric mean, SD, SEM, CV, minimum, median, and maximum). Pharmacokinetic-pharmacological data analysis.

[0529] Exploratory analyses were conducted to elucidate exposure-response relationships with key efficacy endpoints and / or biomarkers. Results regarding exposure-response relationships with key efficacy endpoints were presented in a document independent of the CSR. Demographic and other baseline characteristics were also included.

[0530] The results of this article relate to the dose-finding phase of the core 12-week study. Demographics

[0531] Demographic and patient characteristics for all treatment groups are described in Table 9 by treatment group. Overall, patients were predominantly female (64.3%) and Caucasian (78.6%), with similar distributions across weight and dose groups. Specifically, mean weight and age were 45.0 kg and 13.0 years in group A and 19.7 kg and 5.2 years in group B, respectively. Nine patients (21.4%) were recruited from South American countries, and 33 patients (78.6%) were enrolled from the Western Region and other parts of the world. These demographic characteristics were comparable across the three dose groups within each weight group. Detailed baseline characteristics are presented in Table 9. Medical History

[0532] A total of 9 [69.2%], 11 [78.6%], and 9 [60.0%] patients in dose groups 1, 2, and 3 had any medical history. The most common primary SOC was infection and invasiveness found in a total of 11 patients, with more than half of them in dose group 2 (6 patients [42.9%]). One patient from dose group 2 in group A had a history of bowel problems due to surgery within 3.5 years prior to enrollment in this study, which met exclusion criterion 21 and subsequently led to permanent discontinuation of treatment.

[0533] At baseline, patients had high disease activity, with a mean JADAS-27-CRP of 20.6, a mean active joint count of 13.9, and a mean CRP of 9.5 mg / L. Concomitant medications and prior medication use were balanced across weight groups (Table 21).

[0534]

[0535]

[0536]

[0537]

[0538] Abbreviation: BMI = Body Mass Index.

[0539] Region 1 (Western countries): Czech Republic, Germany, Spain, Netherlands, United Kingdom, Finland, France and Italy.

[0540] Region 2 (South America): Argentina, Chile, and Mexico

[0541] Region 3 (Other parts of the world): Poland and Russia

[0542] The percentage is calculated using the number of patients assessed as the denominator. [, Disease characteristics at baseline , ]

[0543] Baseline disease characteristics for all treatment groups are described in Table 10 by treatment group. Baseline disease characteristics were comparable across the three dose groups within each weight group. The distribution of patients with RF-negative pcJIA, RF-positive pcJIA, and e-oJIA subtypes was 64.3%, 21.4%, and 14.3%, respectively. The distribution of RF-negative pcJIA was similar in both weight groups; however, compared to group B, group A had approximately twice as many patients with RF-positive pcJIA and half the number with e-oJIA.

[0544] As expected and due to age in the dose cohorts, the median duration of JIA since diagnosis was higher in group A (2.6 years [range: 0.3 to 15.1 years]) than in group B (1.1 years [range: 0.1 to 7.2 years]). The median number of mobile joints and limited joints were 10.0 (range: 5.0 to 45.0) and 8.0 (range: 1.0 to 46.0), respectively, broken down into subcategories: 15.5 (range: 5.0 to 45.0) and 8.5 (range: 1.0 to 46.0) in group A and 8.5 (5.0 to 32.0) and 7.0 (range: 1.0 to 34.0) in group B. The median baseline JADAS-27-CRP was 19.3 (range: 8.5 to 35.5) (23.2 [range: 9.2 to 33.8] in group A and 16.8 [range: 8.5 to 35.5] in group B), reflecting a population with highly active disease. The median baseline hs-CRP in group A and group B was 1.1 mg / L (range: 0.1 to 86.5) (1.0 mg / L [range: 0.1 to 45.9] and 1.6 mg / L [range: 0.1 to 86.5], respectively. ANC distribution was similar across weight and dosage groups.

[0545] Overall, 76.2% of patients enrolled in this study received concomitant csDMARD treatment and 31.0% received concomitant oral glucocorticoids; 28.6% of patients received One instance of bDMARD treatment discontinued prior to this study. Other patient and disease characteristics were comparable between the groups.

[0546]

[0547]

[0548]

[0549]

[0550] Abbreviations: CHAO-DI = Child Health Assessment Questionnaire - Disability Index, hs-CRP = High-sensitivity C-reactive protein, JADAS = Juvenile arthritis disease activity score, JIA = Juvenile primary arthritis, ESR = Erythrocyte sedimentation rate, RF = Rheumatoid factor, SD = Standard deviation. Measurement of treatment adherence.

[0551] If a patient does not receive the planned dose of IMP as required by the protocol, the given administration is considered non-compliance. The patient compliance percentage is defined as the number of administrations the patient complied with divided by the total number of administrations the patient was scheduled to receive on or before the last administration date.

[0552] Overall adherence was 97.6%. Adherence to IMP intake was 96.4%. Adherence rates were similar across dose groups. One patient in dose group 2 of group B had adherence <80% due to dose interruption caused by neutropenia. No patients received incorrect doses or overdoses.

[0553] Of the 42 patients included (Group A=20, Group B=22), 34 completed the 12-week core treatment phase (Group A=17; Group B=17), and 8 patients discontinued treatment: 5 due to adverse events (AEs), 2 due to investigator's judgment of lack of efficacy, and 1 due to poor adherence (Figure 8). [, Pharmacokinetic and pharmacodynamic evaluation Concentration of functional sarrelumab in serum

[0554] All pre-administration serum functional sarerutumab concentrations were below LLOQ (0.3125 mg / L). Individual functional serum concentrations during the 12-week core treatment phase were analyzed using descriptive statistics for each treatment group. The mean (SD) concentration of sarerutumab observed after the first SC administration was [missing value]. As shown in [Figure 3], the mean (SD) trough concentration of sarruzanol observed on the time curve is... The pharmacokinetic parameters are shown in Figure 4.

[0555] Descriptive statistics of sarrelumab PK parameters estimated from the population PK model (POH0516) after the first dose are shown in Table 11A, and descriptive statistics after repeated administration are shown in Table 11B. In patients with pcJIA, sarrelumab exhibits nonlinear PK with target-mediated drug disposition. [Figure 3]). AUC0-τ is the AUC for the q2w regimen with a 2-week dose interval or the qw regimen with a 1-week dose interval. After repeating the SC dose of sarerutumab from week 10 to week 12, the exposure of different q2w and qw regimens was compared using AUC0-14 days (for the qw regimen, AUC0-14 days = 2 × AUC0-τ, and for the q2w regimen, AUC0-14 days = AUC0-τ).

[0556] [Table 11A. - Mean (CV%) of salperumab exposure after first SC administration [median] in pediatric patients with pcJIA]

[0557]

[0558] Abbreviation: AUC0 τ: Area under the curve of serum concentration versus time during a 2-week (q2w) or 1-week (qw) dose interval τ, Cmax = maximum observed serum concentration, Cvalence = concentration observed before treatment administration during repeated administration, CV = coefficient of variation, pcJIA = polyarticular juvenile primary arthritis, q2w = once every week, qw = once a week, SC = subcutaneous.

[0559] Bayesian Exposure Derived from Group PK Model

[0560] Following repeated q2w SC and qw administrations at weeks 10–12, sarerutumab exposure increased in a greater-than-dose proportionate manner, with a 1.5–1.6-fold increase in AUC0–14 days from dose group 1 to dose group 2, and a 2.4–2.6-fold increase from dose group 1 to dose group 3, with a 3.4–4.4-fold increase from AUC0–14 days. At week 12, the cumulative increases in dose groups 1 and 2 were 1.9–2.2-fold compared to the initial dose, and the cumulative increase in dose group 3 was 4.1–4.5-fold. (Table 22) The dosing regimens tested in the two-individual recombinant achieved similar exposures in each dose group. In patients with pcJIA, the variability of Cmax and AUC0–τ after repeated SC doses ranged from 13.6% to 36.6%.

[0561] Data from the 12-week dose-exploration study were analyzed. Data from patients randomly assigned to two groups based on weight were analyzed: Group A (30–60 kg) and Group B (10–<30 kg). As described above, patients received sequentially escalating doses of sarrelumab: Dose 1 (Groups A / B): 2.0 / 2.5 mg / kg q2w; Dose 2 (Groups A / B): 3 / 4 mg / kg q2w; Dose 3 (Groups A / B): 2.0 / 2.5 mg / kg qw. The pcJIA dose target was to achieve exposures in adults similar to approximately 150 mg q2w, 200 mg q2w, and 150 mg qw. As described above, the primary outcome was pharmacokinetics (PK), and secondary outcomes included the safety, drug reaction (PD), and efficacy of sarrelumab.

[0562] Data showed that 42 patients were included (20 / 22 in groups A and B), with a mean age of 13.0 / 5.2 years. At baseline, the mean duration of pcJIA, number of active joints, and JADAS27-CRP were 4.6 / 1.7 years, 17.2 / 11.0 years, and 22.2 / 19.1 years, respectively, in groups A and B. As in adult patients, sarrerutumab exhibited non-linear pharmacokinetic behavior with target-mediated drug disposition. Following repeated SC administration, exposure increased in a greater-than-dose proportionate manner, accumulating 1.9–4.5-fold over 12 weeks. In both weight groups, sarrerutumab exposure was similar for each dose (Table 12) and comparable to the corresponding adult doses. Treatment-emergent adverse events were reported in 36 / 42 (85.7%) patients (comparable between dose and weight groups); infection (28 / 42, 66.7%) was the most frequently reported AE. Twelve cases of grade 3 / 4 neutropenia were identified, primarily in dose 3 (n=6) and group B (n=8). None were infection-related; all resolved within days. Overall, four patients discontinued treatment due to neutropenia, and one patient discontinued treatment due to elevated alanine transaminase. There were no serious adverse events, no cases of gastrointestinal perforation, and no deaths. By week 12, as observed during treatment: all patients achieved JIA ACR30; 50%, 62%, and 100% of patients achieved JIA ACR70 at doses 1, 2, and 3, respectively; and the mean changes from baseline in JADAS27-CRP were -74.6%, -73.1%, and -87.9% at doses 1, 2, and 3, respectively.

[0563]

[0564] AUC, area under the curve of serum concentration versus time calculated using the trapezoidal method during the dose interval; C-valence, serum concentration observed before treatment administration during repeated administration; CV, coefficient of variation; N, number of patients; pcJIA, polyarticular juvenile idiopathic arthritis; qw, weekly; q2w, every two weeks; SC, subcutaneous. Pharmacokinetic conclusions

[0565] In patients with pcJIA, sarrerutumab exhibited non-linear pharmacokinetic (PK) with target-mediated drug action. Following repeated SC administration, sarrerutumab exposure increased proportionally to the dose, accumulating 1.9 to 4.5-fold over 12 weeks. For each dose group, dosing regimens tested in two individual recombinants achieved similar exposures. Further analysis of data from patient group A (30–60 kg) and patient group B (10–<30 kg) revealed that sarrerutumab exhibited non-linear PK with target-mediated drug action. Furthermore, all dosing regimens demonstrated efficacy in reducing disease activity. Safety was consistent with class effects; a higher incidence of neutropenia was observed at dose 3 and in patients weighing 10–<30 kg. CRP, ESR, IL-6, and sIL-6R concentrations were also assessed.

[0566] From baseline to week 12, descriptive statistics of hs-CRP, ESR, IL-6, and total sIL-6Rα concentrations were analyzed for each treatment group. Mean (SE)CRP, ESR, IL-6, and sIL-6Rα concentrations were obtained over time profiles for each group. Following administration of salperumab to the SC, the mean inhibition of CRP and the increase in sIL-6Rα were greater in dose groups 2 and 3 compared to dose group 1. In dose groups 2 and 3, mean CRP concentrations decreased over 2 to 4 weeks, with the decreases observed being greater and faster in dose groups 2 and 3 compared to dose group 1 (Figure 10A). From baseline to week 12, the changes in mean CRP concentrations using doses 1, 2, and 3 were 7.4 to 5.8 mg / L, 14.6 to 0.5 mg / L, and 6.5 to 0.1 mg / L, respectively. Between week 2 and week 6, all patients achieved normal CRP concentrations using doses 2 and 3. At week 4, the majority of patients using doses 2 and 3 achieved CRP levels below the detection limit (<0.2 mg / L), compared to 25.0% using dose 1 (71.4% and 83.3%, respectively, as observed during treatment). This effect persisted for some time, with 66.7% and 90.9% of patients using doses 2 and 3 achieving CRP <0.2 mg / L at week 12, compared to 30.0% using dose 1 (Figure 10B).

[0567] The high mean CRP value in dose group 1 of group A was primarily driven by one patient whose CRP remained elevated (between 40 and 110 mg / L) during the 12-week core treatment phase.

[0568] The erythrocyte sedimentation rate at week 12 was consistent with that observed for CRP. Generally, at week 12, mean erythrocyte sedimentation rate (ESR) concentration decreased, while mean IL-6 and sIL-6Rα concentrations increased. Similar to CRP levels, greater decreases were observed in dose groups 2 and 3, with mean changes from baseline to week 12 of 22.2 to 18.2 mm / h, 21.4 to 6.9 mm / h, and 21.9 to 4.4 mm / h for dose groups 1, 2, and 3, respectively. Biomarker pharmacokinetic relationships

[0569] Exploratory analyses were performed to elucidate the exposure-response relationship with PD biomarkers. At week 12, individual CRP, ESR, IL-6, and sIL-6Rα concentrations were plotted against serum trough concentrations. No significant relationship was found between individual IL-6 levels and sarrelumab trough concentrations. Data showed that in isolated patients with pcJIA, total sIL-6Rα increased with increasing sarrelumab trough concentrations following repeated dosing. (The last sentence appears to be incomplete and possibly refers to a different topic.) Compared to patients with a 1 mg / L trough concentration, individual patients with sarrizumab trough concentrations >1 mg / L had lower C-reactive protein levels. (1 mg / L). Compared with patients in dose group 1, dose groups 2 and 3 showed greater inhibition of CRP. (Compared to sarrelumab trough concentration) Compared to patients with a trough concentration of >1 mg / L, patients with sarrizumab had a lower erythrocyte sedimentation rate. (10 mm / hour). Compared with patients in dose group 1, patients in dose groups 2 and 3 showed greater ESR inhibition.

[0570] Following administration of sarerutumab to SCs, the inhibition of CRP and the increase in sIL-6Rα were greater in dose groups 2 and 3 compared to dose group 1. Generally, at week 12, the mean ESR concentration decreased and the mean IL-6 and sIL-6Rα concentrations increased relative to baseline.

[0571] Safety was assessed during the 2-week core treatment phase. Total exposure (patient-to-treatment years) was similar between the dose and weight groups, with 4.6 years in group A and 5.0 patient-years in group B.

[0572] No serious adverse events (AEs) or deaths were reported (Table 23). The most frequently observed AEs were infection and neutropenia (n=28 [66.7%] and n=11 [26.2%], respectively). Infection rates were similar across dose and body weight groups and were primarily caused by upper respiratory tract infections (n=9 [21.4%]; Table 25). No serious infections were reported. No cases of pneumonia or tuberculosis were identified. One case of oral candidiasis occurred (dose group 3, group A), which resolved spontaneously without corrective treatment and without interruption of salperumab treatment. No patients discontinued treatment due to any infection.

[0573] Pre-specified laboratory monitoring identified 12 patients (28.6%) with transient grade 3 / 4 neutropenia. Of these patients, 3 received dose 1 (2 in group A, 1 in group B), 3 received dose 2 (1 in group A, 2 in group B), and 6 received dose 3 (1 in group A, 5 in group B; Table 24). All patients were asymptomatic, but 3 patients required protocol-specified treatment interruption (1 each of the following: dose 2, group B; dose 3, groups A and B). No neutropenia events were infection-related and all resolved within a few days. Laboratory monitoring, including red blood cell count, platelet count, lipid levels, and liver function assessment, did not reveal any other potentially clinically significant abnormalities. Specifically, there were no cases of drug-induced liver injury as defined by Hy's law (21).

[0574] Five patients (11.9%) permanently discontinued treatment as per protocol guidelines due to adverse events (AEs). Among them, one patient had grade 3 neutropenia in dose 1, group A at week 2; three patients had grade 4 neutropenia in dose 3, group B; and one patient had elevated alanine transaminase (ALT) in dose 1, group A (>5 × upper limit of normal [ULN] at week 4).

[0575] Seven patients reported local reactions following injection (4 in group A and 3 in group B). These reactions were primarily erythema and pain; all were mild to moderate in intensity and did not lead to treatment discontinuation. At week 12, two patients tested positive for anti-drug antibodies: one in group A at dose 1 (positive neutralizing antibody; treatment was discontinued due to ALT > 5 × ULN at week 4); and one in group B at dose 3 (non-positive neutralizing antibody; treatment was discontinued due to grade 4 neutropenia following the first injection). [Efficacy Evaluation] JIA ACR Response Rate

[0576] In this study, JIA ACR response levels were used to assess signs and symptoms. A JIA ACR 30 / 50 / 70 / 90 / 100 response was defined as a patient in whom three of the six core variables improved by at least 30% / 50% / 70% / 90% / 100% from baseline, while no more than one of the remaining variables worsened by more than 30%.

[0577] JIA ACR response rates were calculated for patients receiving treatment by direct observation ("as observed during treatment") and for patients who discontinued treatment by attribution ("non-respondent imputation approach", where patients who discontinued treatment were automatically considered non-responders in follow-up after treatment discontinuation). JIA ACR response rates for all doses and weight groups at week 12 are summarized in Table 13. Precision estimates of JIA ACR response rates are shown in Table 33.

[0578] As observed during treatment, at week 12, the JIA ACR30 response rate was 100% across all dose groups and weight sets. The JIA ACR70 response rates were 50.0%, 61.5%, and 100% in dose groups 1, 2, and 3, respectively. As calculated using the non-responder imputation method, at week 12, the JIA ACR30 rates were 76.9%, 92.9%, and 73.3% in dose groups 1, 2, and 3, respectively. The JIA ACR70 response rates were 38.5%, 57.1%, and 73.3% in dose groups 1, 2, and 3, respectively.

[0579] Overall, using the same methods observed during treatment, JIA ACR30 responses were observed in all dose groups and weight groups at the initial assessment at week 2. For dose groups 2 (groups A and B), a steady-state response approaching 100% was achieved at weeks 4 and 8, respectively, and for dose groups 3 (groups A and B), a steady-state response approaching 100% was achieved at weeks 6 and 8, respectively, while response rates in dose group 1 fluctuated until week 12. [Figure 5]). Results of the non-reactor interpolation method in [Figure 6] shows the JIA ACR components.

[0580] Data on JIA ACR components were compiled during the 12-week core treatment phase. A summary of the JIA ACR components at week 12 is shown in Table 14. At week 12, all JIA ACR components in all dose groups and weight classes showed a decrease from baseline, which was generally more pronounced in dose groups 2 and 3 compared to dose group 1. Throughout the 12-week core treatment phase, the number of joints with active arthritis decreased in all dose groups across both weight classes. At week 12, the largest mean decrease (-16.5) was observed in patients in dose group 3, group A. Throughout the 12-week core treatment phase, the number of joints with limited mobility decreased in all dose groups across both weight classes. At week 12, the largest mean decrease (-11.3) was observed in patients in dose group 3, group B. Throughout the 12-week core treatment phase, physician-wide VAS decreased in all dose groups across both weight classes. At week 12, the largest mean decrease (-5.0) was observed in patients in dose group 3, group B. Throughout the 12-week core treatment phase, the overall VAS of patients in all dose groups of both body weight groups decreased. At week 12, the largest mean decrease (-5.7) was observed in patients in dose group 3, group B. Overall, the CHAQ-DI scores of patients in all dose groups of both body weight groups decreased throughout the 12-week core treatment phase. At week 12, the largest mean decrease (-1.0) was observed in patients in group B, dose group 2. At week 12, the mean hs-CRP concentration decreased in all dose groups of both body weight groups. The mean CRP concentration decreased over 2 to 4 weeks in dose groups 2 and 3. The high mean CRP value in dose group 1, group A was primarily caused by one patient whose CRP remained elevated (between 40 and 110 mg / L) during the 12-week core treatment phase. At week 12, the largest mean decrease (-15.2) was observed in patients in group B, dose group 2. Juvenile arthritis disease activity score`

[0581] Disease activity was assessed using JADAS-27 CRP scores. JADAS-27 CRP scores over time were analyzed for each dose group and body weight group. A summary of JADAS-27 (ESR) scores during the 12-week core treatment phase is provided in Table 15. Investigator-reported TEAEs are shown in Table 30. Data showed that, starting from week 2, all dose groups and body weight groups exhibited a decrease in JADAS-27 CRP scores compared to baseline. At week 12, the mean percentage changes from baseline for dose groups 1, 2, and 3 were -74.6%, -73.1%, and -87.9%, respectively.

[0582]

[0583] Patients who have interrupted treatment are automatically considered non-responsive during their post-interruption visits.

[0584]

[0585]

[0586]

[0587] Abbreviations: CHAQ-D1 = Child Health Assessment Questionnaire Disability Index, hs-CRP = High Sensitive C-Reactive Protein, VAS = Visual Analogue Scale.

[0588]

[0589]

[0590] Efficacy conclusion

[0591] From week 2 onwards, improvements in signs and symptoms as assessed by JIA ACR response were observed in all dose groups and weight sets, whether observed during treatment or by non-responder imputation. No dose groups were prematurely discontinued due to lack of efficacy. As judged by the investigators, two patients discontinued treatment due to insufficient efficacy: one in dose group 1, B at week 10; and another in dose group 3, B at week 4. Using the method observed during treatment, the JIA ACR30 response rate was 100% (34 / 34) in all dose groups and weight sets at week 12, with dose groups 2 and 3 producing a faster and more sustained JIA ACR30 response compared to dose group 1 (Figure 9A). At week 12, as calculated by non-responder imputation, 77%, 93%, and 73% of patients achieved JIA ACR30 (dose groups 1, 2, and 3, respectively; Figure 11). Most patients also achieved high response thresholds, with 50%, 62%, and 100% of patients in dose groups 1, 2, and 3 achieving JIA ACR70 at week 12, as observed during treatment, and 40%, 31%, and 64% achieving JIA ACR90, respectively (Figures 9B and 9C; results based on the non-responder imputation method shown in Figures 11B and 11C). Each of the three sarrelumab dosing regimens reduced all JIA ACR components (Table 26).

[0592] Compared to dose group 1, dose groups 2 and 3 showed a trend toward faster JIA ACR response. Using the same methods observed during treatment, dose groups 2 and 3 (groups A and B) achieved a stable JIA ACR30 response rate approaching 100% within the first 2 months of salperumab treatment, while the response rate in dose group 1 fluctuated until week 12.

[0593] At week 12, reduced disease activity as assessed by JADAS-27 CRP was observed in all dose groups and weight groups, with mean percentage changes from baseline also observed from week 2 in dose groups 1, 2, and 3 of -74.6%, -73.1%, and -87.9%, respectively (Figure 9D). In a post-hoc analysis, 20 patients achieved low disease activity (LDA; JADAS-27-CRP) at week 12. 3.8): Dose groups 1, 2, and 3 had 6, 5, and 9 patients, respectively. (As indicated by JADAS-27-CRP) Clinical inactive disease (CID) as defined in dose group 1 was achieved by 3 patients (1 in dose group 2 and 2 in dose group 3). CID as defined by the Wallace criteria was achieved by 9 patients (3, 2, and 4 patients in dose groups 1, 2, and 3, respectively) (22). Thirteen patients had no active joints at week 12, including 4 in dose groups 1 and 2 and 5 in dose group 3 (Table 27). [discuss]

[0594] The experimental dosing regimen of sarrelumbab tested in this study was selected based on modeling and simulation of sarrelumbab PK data from adult RA patients. Pediatric patients differ from adults in weight range, body composition, and drug metabolism, and responses to treatment and side effects may vary with age. Therefore, it is not advisable to extrapolate pediatric doses directly from adult doses in pediatric clinical trials without prior testing (23,24). The clearance of monoclonal antibodies often increases non-linearly relative to progressive weight gain (25), therefore, considering the range of weight and age in the pcJIA population, weight-adjusted dosing was considered appropriate for this study. Based on population PK simulations, a dosing regimen tested in patients with pcJIA was selected to achieve similar exposures in both weight groups, comparable to the exposures achieved with the dosing regimen studied in adult RA patients. The results support the accuracy of the original weight-based model design. Sarrelumbab exhibits non-linear PK with target-mediated drug disposition. The weight-adjusted dosing regimen produced comparable exposures in both weight groups, where the achieved exposures were comparable to those achieved with the fixed-dose regimen tested in adults with RA.

[0595] In this study, sarrelusumab treatment was associated with a decrease in mean CRP and a decrease in ESR, demonstrating functional inhibition of IL-6 in patients with pcJIA (20). Specifically, a decrease in CRP levels is known to be a direct result of IL-6 neutralization, and this study demonstrates the effectiveness of IL-6 neutralization in patients with RA (26-28). The decrease in mean CRP was more pronounced in dose groups 2 and 3, with a greater number of these patients achieving and maintaining CRP levels below the detection limit (<0.2 mg / L) of the highly sensitive method used in this study.

[0596] Starting from week 2, JIA ACR responses were observed in all dose regimens of sarrerucizumab. Based on JIA ACR70, the reduction in disease signs and symptoms was more significant and sustained in dose groups 2 and 3 compared to dose group 1. As assessed by JADAS-27-CRP, more patients in dose group 3 achieved CID or LDA compared to dose groups 1 or 2. These efficacy results paralleled the clear trend (i.e., CRP concentration) observed in PD outcomes, further supporting the relationship between IL-6 neutralization and treatment response (20, 29). Overall, the sustained effect on CRP was smaller in dose group 1, and these results support the exclusion of dose group 1 from further studies.

[0597] The treatment response rate observed in this study was favorable compared to published data from a larger cohort of patients with pcJIA treated with the IL-6R blocker tocilizumab (18). Current results suggest that treatment with sarrerucizumab aligns with the goals of the recently published guidelines from the International Working Group, which establish disease remission as the ultimate treatment objective and recommend achieving improvement in disease activity within 3 months. A 50% improvement was expected, and once achieved, the treatment goal should be maintained (11). The study described in this article included patients with established disease, one-third of whom had failed biologic therapy. One dose was administered. However, among the 24 patients receiving dose groups 2 or 3, at 3 months, 23 and 19 achieved JIA ACR50 and JIA ACR70, respectively, 14 achieved JADAS-27-CRP LDA, and 9 had no active joints. Long-term follow-up during the extension phase of the study will provide a deeper understanding of sarelucumab's ability to meet long-term treatment goals and, once achieved, maintain durable clinical remission.

[0598] The types of adverse events (AEs) observed with sarrerutumab in this study were consistent with those observed in adult patients treated with sarrerutumab and with those observed in pediatric patients with anti-IL-6 class 6 effects (18, 30–32). Few injection site reactions were reported, and those that did were mild to moderate in intensity, demonstrating good local tolerability; this is important in pediatric patients, as fear of pain from syringe injection is common. The most frequently reported AEs were infection and neutropenia. Infection rates were primarily due to upper respiratory tract infections, which are common in the pediatric population and were balanced between weight and dose groups. No serious infections, infections leading to treatment interruption, or opportunistic infections were reported.

[0599] According to the study protocol, absolute neutrophil counts (ANCs) were assessed periodically throughout the treatment period (including after the first salerilumab administration and before the second administration). This thorough hematological monitoring, with post-dose assessments performed on day 12 of the Q2W regimen and days 5–8 of the QW regimen, resulted in the detection of 12 cases of grade 3 / 4 neutropenia. In adult patients treated with salerilumab or tocilizumab, the ANC nadir occurred several days after the first treatment administration (before day 7), after which the ANC value recovered, consistent with class effects (33). Based on these data from adult studies, the timing of assessments in this study helps explain the imbalance in the number of events in dose cohort 3 (n=6, including 4 cases found on day 5) compared to the other two dose regimens (n=3, in doses 1 and 2).

[0600] Of the 12 cases of grade 3 / 4 neutropenia, 8 occurred in group B. A marked trend toward increased neutropenia has also been observed in pcJIA patients treated with tocilizumab, particularly in younger, lower-weight patients (34, 35). No clear mechanism explains why younger patients are more likely to develop neutropenia than older pediatric patients or adults, but overall, a higher prevalence of neutropenia has been reported in children (36). In this study, neutropenia was the cause of most treatment interruptions due to adverse events (AEs) (n=4 / 5): 3 cases were grade 4 neutropenia leading to treatment interruption according to protocol-defined criteria, and 1 case was a patient with grade 3 neutropenia and a baseline ANC below 2,000 / mm3. Importantly, none of the grade 3 / 4 neutropenia cases identified during this study were infection-related, and most resolved within days. This observation is consistent with data from children and adults treated with tocilizumab or salperumab, adding further data to support the conclusion that neutropenia caused by IL-6 inhibition does not increase the risk of infection (18, 32-34, 37). Although all available data support the conclusion that neutropenia caused by IL-6 inhibition is not associated with an increased risk of infection, the neutropenia data obtained in the study, and the dynamic changes in ANC in adults after tocilizumab or salperumab administration, oppose the choice of dose group 3 (32, 33, 37). This cautious choice reduces the risk of neutropenia, especially in high-risk young children. Furthermore, the 2-week administration regimen at dose 2 allows for a longer ANC recovery time.

[0601] Following a review of all data from the 12-week dose-exploration phase of this study, dose cohort 2 was selected as the optimal salperumab regimen for enrolling additional patients in the second part of the core treatment phase of this study, and was used for patients already enrolled in dose cohort 1 or 3 and continuing into the second part. Compared to cohorts 1 and 3, dose cohort 2 demonstrated a favorable balance between efficacy and safety. This dosage regimen achieved similar exposures to the equivalent adult dose of 200 mg Q2W (the recommended approved dose in adults with RA) and reflected its efficacy characteristics (20, 30, 31). Dose cohort 2 also followed a 2-week dosing regimen (compared to the weekly regimen of dose cohort 3), which reduced injection pressure, particularly significant in children, and, as noted above, increased ANC recovery time.

[0602] Additional data on the safety and efficacy of sarrelusumab over time in patients with pcJIA will be provided in a larger patient cohort by including additional patients who will receive the selected dosing regimen and will be followed during the extended phase of the study. As noted, this study is not blinded and does not include placebo or active controls. This is due to the potentially chronic and severe nature of the disease, and the ethical concerns of exposing children to ineffective treatment given the availability of data on IL-6 inhibition in both adults and children with arthritis (18, 38). These concerns are reflected in the following: study design (using a sequential approach to test doses and frequent monitoring), the use of an independent data monitoring committee to formally assess the safety of sarrelusumab throughout the study, the use of a DEC to monitor patient response to treatment, and the ability of the DEC to discontinue any doses deemed ineffective and return patients to investigator-approved standard of care.

[0603] In summary, in patients with pcJIA, sarrelumab exhibited non-linear pharmacokinetic (PK) with target-mediated drug disposition, demonstrating a safety profile consistent with anti-IL-6 class 6 effects and reducing disease activity. This 12-week dose-finding phase of the core treatment phase of this study showed that dose group 2 (3.0 mg / kg Q2W in patients weighing 30–60 kg and 4.0 mg / kg Q2W in patients weighing 10–<30 kg) achieved exposures similar to the approved dose of 200 mg Q2W in adults with RA. Dose group 2 provided a good balance between safety / tolerability and efficacy in patients with pcJIA and will be further investigated as the optimal sarrelumab dosing regimen in pcJIA. [Example 2: An open-label, sequential, escalating repeated-dose exploration of sarreluzumab administered subcutaneously (SC) followed by an extension phase in children and adolescents aged 1 to 17 years with systemic juvenile arthritis (sJIA). (Study ID: DRI13926, Study Title: Repeated-dose exploration of sarreluzumab in children and adolescents with systemic juvenile arthritis)]

[0604] A phase 2 controlled trial [NCT02991469] was planned to test subcutaneous administration of salperumab, a human IgG1 anti-IL-6Rα monoclonal antibody, for the treatment of sJIA. This study targeted children and adolescents aged 1 to 17 years with sJIA, a subset of JIA resembling adult-onset Still's disease, a relatively rare inflammatory disease (estimated global incidence of 0.22 and 0.34 per 100,000 men and women, respectively; Bennett, AN et al., Adult onset Still's disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil. Rheumatology (Oxford). 2004;43(6):795-9). Three dosage regimens of salperumab were planned to be tested in this pediatric population. [Research Design] Description of the Plan

[0605] Study DRI 13926 was a multinational, multicenter, open-label, sequential, phase 2 study of children and adolescents aged 1 to 17 years (or the nationally mandated age requirement) with sJIA who had an inadequate response to or intolerance to standard therapy and were to receive q2w or qw injections of sarreluzumab SC. The two phases are as follows:

[0606] 1. The 12-week core treatment phase is divided into two parts:

[0607] The first sequence, the escalating dose group, and the dose exploration section will investigate at least two dose regimens in two individual recombinants: 30kg and Patients weighing 60kg (Group A) and <30kg and Patients weighing 10 kg (Group B) will be included, with 6 evaluable patients per dose regimen (at least 24 patients in total). Patient inclusion will be staggered by weight group and dose regimen, starting from Group A ( 30kg and 60kg) and start with dose group 2.

[0608] The subsequent group included approximately 24 additional patients (12 in each weight group). 30kg [Group A] and <30kg and Patients weighing 10 kg (Group B) will be directly included in the selected dosing regimen (identified based on aggregate data from patients included in Part I) to achieve a total of 18 evaluable patients per body weight group under this selected dosing regimen.

[0609] The 12-week core treatment phase is the period from the second visit (baseline - week 0) to the 12th visit (week 12) during which the investigational drug product (IMP) is administered. During the 12-week core treatment phase, to minimize blood draws and visit frequency while maintaining assessment of the primary endpoint, patients in group B (<30 kg and 210 kg) will be randomly assigned to either of the following sarrizumab PK sampling schedules 1 or 2:

[0610] • Schedule 1: Baseline, Day 3, Day 8, Week 2, Week 4, Week 8, and Week 12

[0611] • Schedule 2: Baseline, Day 5, Day 12, Week 2, Week 4, Week 8, and Week 12

[0612] [, 2. , ] 144-week extension phase:

[0613] The IMP at the 12th visit was considered the first IMP in the extended phase.

[0614] Patients who achieve a JIA ACR30 response (in the absence of fever) only at the 12th visit (week 12) will be allowed to continue to the extension phase. Patients will continue to receive the same dose regimen of sarrenzumab they were assigned to receive during the 12-week core treatment phase of this study until a selected dose regimen is determined. Once a dose regimen has been selected, patients who have not yet adopted this dose regimen will have their dose adjusted to the selected dose regimen and will follow a new visit schedule in which more frequent monitoring (PK, safety, and efficacy) will be performed in the first 12 weeks compared to patients who have not had their dose regimen adjusted.

[0615] At the 27th visit, patients who prematurely discontinued study treatment will be evaluated using the EOT procedure. These patients will be required to return 6 weeks after the EOT visit (EOT+6 weeks) for a study completion (EOS) assessment. For patients who discontinued study treatment during the 12-week core treatment phase, an additional sarerudumab PK assessment will be performed 2 weeks after the EOT visit (EOT+2), and IL-6 and sIL-6R will be measured at the EOT visit. These patients will be required to undergo all scheduled visits and assessments except for sarerudumab administration until the 12th visit. The dosage regimen being tested...

[0616] For each body group, the three initially planned sequential escalation dosing regimens were defined based on PK modeling, and the basic principle is as follows:

[0617] ￭ Dosage Group 1: A dose similar to sarrelumab 150 mg q2w targeting PK exposure, representing the lowest effective dose in adult patients with RA.

[0618] ￭ Dosage Group 2: A dose similar to salperumab 200 mg q2w targeting PK exposure, which is the recommended dosing regimen in adult patients with RA.

[0619] ￭ Dosage group 3: A dose similar to salperumab 150 mg qw targeting PK exposure, which produced the highest exposure in long-term administration studies in adult patients with RA. See Table 1 for information on the dosage groups by weight and dosage group to be used in this study. See also Figure 7.

[0620] The dose (mg) to be administered to the patient will be calculated at baseline. Regardless of changes in patient weight, the dose and corresponding volume of the drug product will remain constant throughout the 12-week core treatment phase of the trial. During the extension phase, patient weight will be measured at each visit, and the dose will be adjusted only based on weight gain if calculations indicate a need for an increased dose. Specifically, the upper limit dose will be 200 mg for dose group 2 and 150 mg for dose group 3. The volumes of salperumab to be injected for each dose group are presented in Tables 2–5.

[0621] Even though the 12-week core treatment phase begins at the second visit (baseline - week 0) and continues until the 12th visit (week 12) (inclusive), the IMP at the 12th visit is only administered to patients about to enter the extension phase of treatment who have completed the evaluation (including efficacy, safety, and PK / PD) after the 12th visit. Duration of each patient's participation in the study.

[0622] The total duration of the study (per patient) is expected to be up to 166 weeks.

[0623] ￭A screening process lasting 4 weeks + 3 days (up to 31 days)

[0624] ￭12-week core treatment period

[0625] ￭Extended phase lasting 144 weeks

[0626] Follow-up 6 weeks after treatment

[0627] For all visits, using day 1 as a reference, ±3 days for dose group 2 (including any potential q2w intermediate doses) and ±1 day for dose group 3 (including any potential qw intermediate doses) are acceptable timeframes, except...

[0628] During the 3rd visit (day 3), 4th visit (day 5), and 5th visit (day 8), no visit window is allowed when conducting PK sampling.

[0629] ￭For all dose groups, 6th visit (day 12) ± 1 day

[0630] ￭For all dose groups, 7th visit (week 2) ± 1 day

[0631] ￭ For dose group 2, the discontinuation rule for grade 3 / 4 neutropenia of sJIA is ±2 days at the 8th visit (week 4) and for dose group 3, it is ±1 day.

[0632] In grade 4 neutropenia without signs of infection, temporary discontinuation of sarreluzumab treatment is recommended. Once the ANC is greater than 1000 / mm3, the investigator can resume the treatment based on a comprehensive assessment of the benefits and risks. ANC reduction is a pharmacodynamic anti-interleukin-6 (IL-6) effect observed in adult and pediatric patients treated with anti-IL-6 antibodies. In long-term studies in adults with rheumatoid arthritis (RA), ANC reductions following repeated sarreluzumab administration are typically transient and not associated with an increased risk of infection. In pediatric patients, although currently available data are limited, anti-IL-6 use is not associated with an increased risk of infection in those with grade 3 / 4 neutropenia. Table 31 shows the incidence of grade 3 and 4 neutropenia based on the lowest neutrophil count recorded in the studies. [, Patient choice Inclusion criteria

[0633] 1. Age at the time of screening and home visit 1 and 17-year-old male and female patients

[0634] 2. Diagnose sJIA subtypes according to the ILAR 2001 JIA classification criteria (Petty, RE et al. 2001. J Rheumatol. 2004;31(2):390-2), among which the following characteristics are present during screening.

[0635] ￭ 5 movable joints or

[0636] ￭ During screening Two active joints, with a generalized JIA fever >37.5°C lasting for at least 3 days within 3 days prior to baseline or within any consecutive 7 days during the screening period (even though glucocorticoids were administered at a stable dose for at least 3 days).

[0637] 3. Patients who, according to the researchers' judgment, do not respond adequately to current treatments and are considered candidates for bDMARDs.

[0638] 4. For patients who have reached the legal age of consent, or whose parents or one or more legal guardians have signed and dated a written informed consent form approved by the ethics committee (EC). The patient's consent should be obtained based on local guidelines and the patient's maturity and intellectual capacity to understand the information relevant to the study. In cases involving independent or mature minors with full decision-making capacity, or in other circumstances permitted by law, informed consent will be obtained directly from one or both parents or one or more legal guardians. [Research Treatment] Research Drug Products

[0639] Sarilumab, an anti-IL-6R mAb. Preparation

[0640] The sarruzumab product will be administered at a concentration of 175 mg / mL in an aqueous buffer at pH 6.0. The product will be supplied in 5 mL vials filled with 2.7 mL of sarruzumab, with a drawable volume of 2.0 mL. One or more routes of administration:

[0641] For self-injection, sarerumab is administered subcutaneously in the abdomen or thigh, or by a professional or non-professional caregiver in the upper arm (outer side). Preferably, SC injection sites alternate between the four quadrants of the abdomen (excluding the navel or lumbar region) or thigh (anterior and lateral).

[0642] For patients receiving dosing regimen 2 (q2w), injections will be administered at the study site by a professional caregiver during the 12-week core treatment phase of this study. See Figure 1. For patients receiving dosing regimen 3 (weekly injections), a qualified field person or family nurse must be arranged to administer the IMP for doses not planned to be given at the study site. For the extension phase of this study, home injections will be permitted if the patient, one or both parents, one or more legal guardians, or one or more caregivers are willing and able to administer the injection. In these cases, training will be required and provided during the core treatment phase, starting from the 10th visit (week 8). This training must be documented in the patient's study file. Prior to permitting home injections during the extension treatment phase, patients, one or both parents, one or more legal guardians, or one or more caregivers will be permitted to administer the injection at the 10th visit (week 8), 11th visit (week 10), and 12th visit (week 12) under the observation / supervision of one or more investigators or one or more representatives.

[0643] During the patient's study visit, IMP will be administered following clinical procedures and blood collection. A diary will be provided to record information related to these injections; this diary will be retained as source data in the patient's study file. If the caregiver is unable or unwilling to administer IMP, a qualified field personnel must be arranged to administer the dose not planned for on-site administration. Dosing regimen

[0644] Salrelumab should be administered q2w or qw. However, according to the protocol, a salrelumab administration window of ±3 days is permitted for dose group 2 (including any potential q2w intermediate doses) and ±1 day for dose group 3 (including any potential qw intermediate doses) to accommodate special circumstances such as pending laboratory test results, persistent adverse events (AEs), or scheduling difficulties for patients other than at the 5th visit (day 8). There is no administration window at the 5th visit (day 8). At the 7th visit (week 2), patients in dose groups 2 and 3 will have only a ±1 day administration window, and at the 8th visit (week 4), dose group 3 will have only a ±1 day administration window or dose group 2 will have only a ±2 day administration window. Note that for q2w administrations within a time interval of less than 11 days and for weekly administrations within a time interval of less than 6 days, an overdose of IMP (accidental or intentional) is defined as at least twice the stated dose.

[0645] The dose of sarrirodus will be administered q2w or qw. [Dose Group 2]:

[0646] Group A (>30kg and) 60kg): 3mg / kg q2w

[0647] Group B (<30kg and 210kg): 4mg / kg q2w. [Dosage Group 3]:

[0648] Group A (>30kg and) 60kg): 2mg / kg qw

[0649] Group B (<30kg and 210kg): 2.5mg / kg qw.

[0650] Dose group 3 was also tested as a bi-weekly regimen, but with the same PK exposure. Therefore, the ranges are as follows:

[0651] - For patients weighing less than 30 kg: 5 to 7 mg / kg q2w (dose 2 is 4 mg / kg q2w)

[0652] - For patients weighing 30 kg or more: 4 to 6 mg / kg q2w (Dose 2 is 3 mg / kg q2w) Dosage modification

[0653] The dose (mg) to be administered to the patient will be calculated at baseline. Regardless of changes in patient weight, the dose and corresponding volume of the drug product will remain the same throughout the 12-week core treatment phase of the trial. During the extension phase, patient weight will be measured at each visit, and the dose will be adjusted only based on weight gain if calculations indicate a need for an increased dose. Specifically, the upper limit dose will be 200 mg for dose group 2 and 150 mg for dose group 3. The volumes to be injected for dose groups 2 through 3 based on patient weight are described herein. See Tables 2–5. Packaging and Labelling

[0654] IMP will be provided in patient treatment kits containing labeled vials. The labeled contents comply with local regulatory guidelines and requirements. One kit contains one vial. Storage conditions and shelf life.

[0655] The research drug should be kept refrigerated between 2°C and 8°C at the site or at home.

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663] Abbreviations: ALP = Alkaline phosphatase, ANA = Antinuclear antibody, ANC = Absolute neutrophil count, BP = Blood pressure, DNA = Deoxyribonucleic acid, D = Day, EBV = Epstein-Barr virus, EOT = End of treatment, ESR = Erythrocyte sedimentation rate, HIV = Human immunodeficiency virus, hs-CRP = High-sensitivity C-reactive protein, Ig = Immunoglobulin, IVRS = Interactive voice response system, IL = Interleukin, IMP = Investigational drug product, JADAS = Juvenile arthritis disease activity score, JIA ACR = Juvenile primary arthritis (American College of Rheumatology), PK = Pharmacokinetics, PPD = Purified protein derivative, q2w = Every other week, SAE = Serious adverse event, sIL-6R = Soluble interleukin-6 receptor, sJIA = Systemic juvenile primary arthritis, TB = Tuberculosis, V = Visit, Wk = Week.

[0664] For patients who interrupted their study treatment during the 12-week core treatment phase (at or before the 12th visit), an additional PK assessment will be conducted 2 weeks after the EOT visit (EOT+2 weeks).

[0665] b. Pharmacokinetic sampling: For group A ( For Group B (<30kg), the visits and number of days for the 3rd (D3), 4th (D5), 5th (D8), and 6th (D12) visits are as follows: For Group B (<30kg), Schedule 1, the visits and number of days for the 3rd (D3) and 5th (D8) visits are as follows: For Group B (<30kg), Schedule 2, the visits and number of days for the 4th (D5) and 6th (D12) visits are as follows: PK sampling can be performed at home. No sample collection window is allowed for the 3rd (D3), 4th (D5), and 5th (D8) visits. A window of ±1 day is allowed for the 6th (D12) visit. Please refer to the additional hematological tests during the PK sampling period.

[0666] c. Based on the investigator's determination, the laboratory tests mentioned in exclusion criterion 27 can be repeated by retesting at a central laboratory between the screening visit and the first IMP administration to ensure that the patient meets the eligibility requirements for exclusion criterion 27. Patients requiring Gilbert's syndrome genetic testing will sign a locally approved specific consent form (a consent form / permission must be obtained before this assessment and local regulations must be followed).

[0667] d. Prior to all screening assessments, the patient (if he / she has reached the legal age of consent according to local regulations), one or both parents, or one or more legal guardians must sign and date an EC-approved written informed consent form. The patient, one or both parents, and one or more legal guardians will receive information from the investigator regarding one or more study objectives and procedures. A separate written consent should be obtained from one or both parents or one or more legal guardians allowing their child to participate in optional saliva sample collection for pharmacogenomics research and allowing the organizer to retain any remaining / unused blood samples for future research. A separate (locally approved) informed consent form will be completed by any patient requiring Gilbert's genetic disease testing, in accordance with local regulations. A signed consent form should be obtained from the patient based on local regulations and the patient's maturity of understanding of the study information.

[0668] e. Patient diaries regarding IMP administration should be kept at home regarding IMP administration.

[0669] A complete physical examination will be conducted at the first visit (D-28 to D-1, up to 31 days), the second visit (D1, week 0), the eighth visit (week 4), the ninth visit (week 6), and the twelfth visit (week 12), including the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, gastrointestinal system, nervous system, lymphatic system, and musculoskeletal system.

[0670] g. Optional: Based on the investigator's judgment, Epstein-Barr virus (EBV) titer testing (including IgG and IgM) may be performed at screening; based on the patient's family and medical history and the investigator's judgment, hepatitis B surface antigen (HBs-Ag), hepatitis B surface antibody (HBs-Ab), total hepatitis B core antibody (HBc-Ab), and hepatitis C antibody (HCV-Ab) testing may be performed at screening. HIV serological testing will be performed only based on the investigator's assessment of suspected HIV patients.

[0671] For Germany only: serological testing for hepatitis B and C, and HIV must be performed on all patients during screening visits in order to identify the corresponding exclusion criteria.18

[0672] h should be performed before the second baseline visit (D1, week 0). Patients aged 5 years underwent a purified protein derivative (PPD) skin test. Patients should be evaluated within 48–72 hours after the PPD skin test. For patients not evaluated within 72 hours, the skin test should be repeated. When determining the skin test result, an assessment of the level of risk (TB exposure and / or recent migration from a TB-prone country) should be considered. For all details, please refer to exclusion criteria 17. Patients >5 years of age will undergo an interferon-γ (IFN-γ) release assay, i.e., the QuantiFERON-TB test (1). Following the initial TB screening, if the PPD or QuantiFERON result is negative but the clinical suspicion of TB is above moderate, patients should be rescreened for TB at any time during the study period based on the investigator's assessment. [Based on local PPD availability, local regulations for TB screening, and investigator judgment, the younger patient group will be included in the study.] Consider the Quantiferon TB test for children aged 5 years and older.

[0673] i. For JIA patients who have not had a chest X-ray within 3 months prior to the second baseline visit (D1, week 0), a chest X-ray may be performed only if it is deemed necessary based on the investigator's judgment or according to local TB screening guidelines before initiating biotherapy.

[0674] Patients in dose group 2 will receive the study drug product once every 2 weeks (q2w), and patients in dose group 3 will receive it weekly. A home nurse will be scheduled to administer the IMP to patients in dose group 3 at the mid-term visit (home administration if possible). Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of an allergic reaction. Patients who do not achieve the American College of Rheumatology (JIA ACR) 30 response by the end of the 12-week core treatment period will discontinue study treatment to receive care based on investigator clinical judgment. Only after V12 will the organizers provide investigators with JIA ACR responses (including JIA ACR 30 responses) to evaluate this criterion. Patients who completed the core treatment phase at V12 but did not continue the extended phase for reasons other than lack of a JIA ACR 30 response will not receive an IMP injection at the 12th visit. For Germany only: Patients must be monitored for at least 1 hour after the first IMP administration to assess local tolerability.

[0675] During the core treatment phase, the investigational drug product will be allocated to patients in dose group 3.

[0676] The patient's temperature / rash diary will include assessment using the ACR JIA efficacy core set, recording tympanic membrane temperature and reporting rash (if any) at home every day between screening and baseline visits and for at least 7 days before each subsequent scheduled visit. Temperature should be measured at least twice daily at fixed times (upon waking and before bedtime) and whenever fever is suspected.

[0677] m. Additional height measurements taken within the most recent year prior to baseline will be collected. During the study, heights will be measured in the field using a rangefinder.

[0678] The core set of the Juvenile Primary Arthritis (ACR) includes: a comprehensive assessment of disease severity by a physician; a comprehensive assessment of overall health status by the patient or one or both parents / one or more legal guardians; the number of joints with active arthritis (defined as intra-articular swelling not due to deformity, or accompanied by pain or tenderness or both with limited mobility); the number of joints with limited mobility; the Child Health Assessment Questionnaire (CHAQ); hs-CRP; and fever (Petty, RE et al., International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-2; Giannini, EH et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7):1202-9;4. Beukelman, T. et al., 2011 American College of Rheumatology recommendations for the treatment of juvenile arthritis). Idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011;63(4):465-82. During screening, only fever, the number of joints with active arthritis, and the number of joints with limited mobility will be assessed. The JADAS score is explained in this article.

[0679] Systemic features of o sJIA include fever at screening, baseline, and the 12th visit, transient salmon-colored rash, generalized lymphadenopathy, hepatomegaly, splenomegaly, and serositis, as well as other complications. Fever and transient salmon-colored rash will be evaluated only at weeks 2, 4, 6, 8, and 10.

[0680] p Hematology (blood should be drawn before drug administration): hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC), white blood cell differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC). Additional hematological tests must be performed on patients in group 2 at the 6th visit (day 12±1) to obtain results before the 7th visit (day 15, week 2), i.e., before the second dose of sarerutumab. For patients in dose group 3, additional hematological tests should be performed before or at the 5th visit (day 8), but not earlier than the 4th visit (day 5), and the results need to be reviewed before the second sarerutumab injection at the 5th visit (day 8). Additional hematological tests can be performed at a central or local laboratory to confirm that the ANC and platelet count are within the protocol-defined limits for temporary or permanent interruption of the study drug. If a local laboratory is used, central laboratory samples for hematological testing should still be drawn before administering IMP at the 7th visit (day 15, week 2) for group 2 and the 5th visit (day 8) for group 3. For all patients, the hematological laboratory assessment at the 2nd visit (day 1) must be reviewed before administering the second dose of salperumab at the 5th visit (day 8) for dose group 3 patients or the 7th visit (week 2, day 15) for dose group 2 patients.

[0681] q. Chemistry (blood should be drawn before medication administration): The entire chemistry testing process will only be performed at the screening visit, the second visit at baseline (day 1, week 0), and the 12th visit (week 12) or at the end-of-cycle (EOT): sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine and creatinine clearance, glomerular filtration rate, calcium, phosphate, total protein, albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, conjugated bilirubin, and unconjugated bilirubin. At all other visits: only ALT, AST, ALP, LDH, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested.

[0682] Fasting blood lipids (blood should be drawn before medication administration): triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Patients need to fast for at least 8 hours before the test.

[0683] s [Optional]: HbA1c levels will be measured solely based on the patient’s medical history and the researcher’s judgment.

[0684] t for Patients weighing 30 kg (Group A) will have their hs-CRP measured on days 3 and 8. Patients weighing <30 kg in PK schedule 1 (Group B) will have their hs-CRP measured on days 3 and 8. Patients weighing <30 kg in PK schedule 2 (Group B) will have their hs-CRP measured on days 5 and 12.

[0685] When macrophage activation syndrome (MAS) is suspected, ferritin, blood cell counts (red blood cells, white blood cells, platelets, and hemoglobin), AST / ALT, triglycerides, and fibrinogen tests should be performed, if necessary, based on the investigator's judgment. This article describes the clinical and laboratory features used for the diagnosis of MAS.

[0686] v Urine analysis test strips: specific gravity, pH, glucose, blood, protein, nitrite, leukocyte esterase, bilirubin. If any parameter on the test strip is abnormal, the urine sample should be sent to the central laboratory for testing. If protein is positive, it will be analyzed under a microscope by the central laboratory.

[0687] For women who have started menstruating, a serum pregnancy test must be performed during the screening visit.

[0688] For women who have started menstruating, a serum pregnancy test should be performed at screening, and a urine pregnancy test should be performed at the second visit (week 0, week 1), the eighth visit (week 4), the tenth visit (week 8), and the twelfth visit (week 12). Urine pregnancy testing can be performed locally. Pregnancy status should be checked by urine pregnancy testing prior to exposure to IMP and EOT.

[0689] On the day of administration during the treatment period, blood samples will be collected prior to IMP administration. If the patient develops SAE, blood samples should be collected at or near the start and end of the event, where possible, to determine sarerutumab concentration and assess anti-drug antibody (ADA).

[0690] For patients who prematurely discontinue study treatment during the core treatment phase, IL-6 and total sIL-6R will be measured during EOT assessment.

[0691] One or both parents or one or more legal guardians must sign a separate written participant information (WSI) prior to saliva sample collection for pharmacogenomics studies. Samples are preferably collected at the second visit at baseline (D1, week 0), but can be collected at any visit. Patients may also sign a WSI based on their age, local regulations, and their maturity to understand the study information. Patients are still eligible for inclusion in the study if they, or one or both parents or one or more legal guardians, do not wish for them to participate in saliva sample collection.

[0692]

[0693]

[0694]

[0695] Abbreviations: AE = Negative Event, ALP = Alkaline Phosphatase, ALT = Alanine Transaminase, ANC = Absolute Neutrophil Count, AST = Aspartate Transaminase, ANA = Antinuclear Antibody, BP = Blood Pressure, DNA = Deoxyribonucleic Acid, D = Day, EOS = End of Study, EOT = End of Treatment, ESR = Erythrocyte Sedimentation Rate, EBV = Epstein-Barr Virus, HIV = Human Immunodeficiency Virus, hs-CRP = High Sensitive C-Reactive Protein, IMP = Investigational Drug Product, IVRS = Interactive Voice Response System, IL = Interleukin, JADAS = Juvenile Arthritis Disease Activity Score, JIA ACR = Juvenile Primary Arthritis (American College of Rheumatology), PK = Pharmacokinetics, PPD = Purified Protein Derivative, q2w = Every other week, SAE = Serious Negative Event, sJIA = Systemic Juvenile Primary Arthritis; TB = Tuberculosis, V = Visit, Wk = Week.

[0696] The 27th visit is the End-of-Treatment (EOT) visit of the study program. If a patient prematurely discontinues study treatment, an EOT will occur 1 week after the last IMP injection in dose group 3 and 2 weeks after the last IMP injection in dose group 2.

[0697] b. The 28th visit is the study end-of-study (EOS) visit. If a patient prematurely discontinues study treatment, these patients will be required to return for an EOS assessment 6 weeks after the EOS visit (EOT+6 weeks). This EOS (EOT+6 weeks) visit will apply to all patients in both the core treatment phase and the extension phase.

[0698] c. Patient diaries regarding IMP administration should be kept at home regarding IMP administration.

[0699] d. A complete physical examination will be conducted at the 15th visit (week 24), 18th visit (week 48), 20th visit (week 72), 22nd visit (week 96), 24th visit (week 120), 26th visit (week 144), 27th visit for EOT, and 28th visit for EOS, including the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, gastrointestinal system, nervous system, lymphatic system, and musculoskeletal system.

[0700] IMP will be administered bi-weekly (q2w) for patients in dose group 2 and weekly for patients in dose group 3. For patients completing the extension phase, the last IMP injection will occur at week 154 if the chosen dosing regimen is bi-weekly (q2w) and at week 155 if the chosen dosing regimen is weekly (qw). Patients will undergo EOT assessment at the 27th visit (week 156). For patients who prematurely discontinue study treatment during the extension phase, EOT assessment is preferably performed 2 weeks after the last IMP injection for patients in dose group 2 and 1 week after the last IMP injection for patients in dose group 3. In cases where patients cannot meet the planned schedule, assessment will be performed at the next protocol-defined visit following the last IMP injection. Patients will be required to return for EOS assessment 6 weeks after the EOT visit. Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of allergic reactions. No IMP injection will be given at the 27th visit (week 156).

[0701] f. The patient's temperature / rash diary will include assessment using the ACR JIA efficacy core set, continuing for at least 7 days prior to each subsequent scheduled visit, recording tympanic membrane temperature at home, and reporting rash (if it occurs). Temperature should be measured at least twice daily at fixed times (upon waking and before bedtime) and whenever fever is suspected.

[0702] g. Collect additional height measurements taken within the most recent year prior to baseline. During the study, height will be measured on-site using a rangefinder.

[0703] The core set of the JIA ACR includes: a comprehensive assessment of disease severity by a physician, a comprehensive assessment of overall health status by the patient or parent / legal guardian, the number of joints with active arthritis (defined as intra-articular swelling not due to deformity, or accompanied by pain or tenderness, or both, and limited range of motion), the number of joints with limited range of motion, the Child Health Assessment Questionnaire (CHAQ), hs-CRP, and fever. The JADAS score is explained in this article.

[0704] Systemic features of isJIA include fever, transient salmon-colored rash, generalized lymphadenopathy, hepatomegaly, splenomegaly, serositis, and other complications at week 156 (EOT visit). Fever and transient salmon-colored rash will be evaluated only at weeks 24, 48, 72, 96, 120, 144, and 162 (EOS visit).

[0705] j. Hematology (blood should be drawn before drug administration): hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC).

[0706] k. Chemistry (blood should be drawn before medication administration): ALT, AST, ALP, lactate dehydrogenase (LDH), total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. A complete chemistry test should be performed at the 27th visit to the EOT.

[0707] Blood lipids (blood should be drawn before medication administration): triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Patients need to fast for at least 8 hours before the test.

[0708] When MAS is suspected, ferritin, blood cell counts (red blood cells, white blood cells, platelets, and hemoglobin), AST / ALT, triglycerides, and fibrinogen tests should be performed, if necessary, based on the investigator's judgment. Refer to the clinical and laboratory diagnostic features of MAS described in this article.

[0709] For women who have started menstruating, a urine pregnancy test should be performed before each scheduled visit and before exposure to IMP injection and EOT. Urine pregnancy testing can be performed locally.

[0710] On the day of administration during the treatment period, blood samples will be collected prior to IMP administration. If the patient develops SAE, blood samples should be collected, where possible, at or near the start and end of the event to determine sarrucumab concentration and assess anti-drug antibody (ADA).

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717] Abbreviations: AE = Negative Event, ALP = Alkaline Phosphatase, ANA = Antinuclear Antibody, ANC = Absolute Neutrophil Count, BP = Blood Pressure, DNA = Deoxyribonucleic Acid, D = Day, EOT = End of Treatment, EOS = End of Study, ESR = Erythrocyte Sedimentation Rate, hs-CRP = High-Sensitivity C-Reactive Protein, IMP = Investigational Drug Product, IVRS = Interactive Voice Response System, JADAS = Juvenile Arthritis Disease Activity Score, JIA ACR = Juvenile Primary Arthritis (American College of Rheumatology), PK = Pharmacokinetics, PPD = Purified Protein Derivative, SAE = Serious Negative Event, sJIA = Systemic Juvenile Primary Arthritis; TB = Tuberculosis, V = Visit, Wk = Week.

[0718] The 27th visit is the End-of-Treatment (EOT) visit of the study program. If a patient prematurely discontinues study treatment, an EOT will occur 1 week after the last IMP injection in dose group 3 and 2 weeks after the last IMP injection in dose group 2.

[0719] b. The 28th visit is the study end-of-study (EOS) visit. If a patient prematurely discontinues study treatment, these patients will be required to return for an EOS assessment 6 weeks after the EOS visit (EOT+6 weeks). This EOS (EOT+6 weeks) visit will apply to all patients in both the core treatment phase and the extension phase.

[0720] c. Patient diaries regarding IMP administration should be kept at home regarding IMP administration.

[0721] A complete physical examination will include the skin, nasal cavity, eyes, ears, respiratory system, cardiovascular system, gastrointestinal system, nervous system, lymphatic system, and musculoskeletal system.

[0722] Patients in dose group 2 received the study drug product q2w (twice weekly), while patients in dose group 3 received it weekly. For patients completing the extension phase, if the chosen dosing regimen was bi-weekly (q2w), the last IMP injection would occur 2 weeks prior to the EOT; if the chosen dosing regimen was weekly (qw), the last IMP injection would occur 1 week prior to the EOT. Patients would undergo an EOT assessment at the 27th visit (week 156). For patients who prematurely discontinued the study during the extension phase, an EOT assessment would preferably be performed 2 weeks after the last IMP injection for patients in dose group 2 and 1 week after the last IMP injection for patients in dose group 3. In cases where patients could not meet the planned schedule, an EOT visit would be used for assessment at the next protocol-defined visit following the last IMP injection. Patients would be required to return for an EOS assessment 6 weeks after the EOT visit. Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of an allergic reaction. No IMP injection will be given at the 27th visit (week 156).

[0723] f. The patient's temperature / rash diary will include assessment using the ACR JIA efficacy core set, continuing for at least 7 days prior to each subsequent scheduled visit, recording tympanic membrane temperature at home, and reporting rash (if it occurs). Temperature should be measured at least twice daily at fixed times (upon waking and before bedtime) and whenever fever is suspected.

[0724] g. Collect additional height data from the most recent year prior to baseline. During the study, height will be measured on-site using a rangefinder.

[0725] The core set of the Juvenile Primary Arthritis (ACR) includes: a comprehensive assessment of disease severity by a physician, a comprehensive assessment of overall health by the patient or parent / legal guardian, the number of joints with active arthritis (defined as intra-articular swelling not due to deformity, or accompanied by pain or tenderness, or both, and limited range of motion), the number of joints with limited range of motion, the Child Health Assessment Questionnaire (CHAQ), hs-CRP, and fever. The JADAS score is explained in this article.

[0726] i will only assess fever and transient salmon-colored rash.

[0727] j. Hematology (blood should be drawn before drug administration): hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count, absolute neutrophil count (ANC).

[0728] k. Chemistry (blood should be drawn before medication administration): ALT, AST, ALP, lactate dehydrogenase (LDH), total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. A complete chemistry test should be performed at the 27th visit to the EOT.

[0729] Blood lipids (blood should be drawn before medication administration): triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Patients need to fast for at least 8 hours before the test.

[0730] When MAS is suspected, ferritin, blood cell count (red blood cells, white blood cells, platelets and hemoglobin), AST / ALT, triglycerides and fibrinogen tests should be performed if necessary, based on the researcher's judgment.

[0731] For women who have started menstruating, a urine pregnancy test should be performed at the scheduled visit mentioned in the aforementioned flowchart, prior to exposure to IMP injection. Urine pregnancy testing can be performed locally.

[0732] On the day of administration during the treatment period, blood samples will be collected prior to IMP administration. If the patient develops SAE, blood samples should be collected, if possible, at or near the start and end of the event to determine sarrenumab concentration and assess anti-drug antibody (ADA). Pharmacokinetic Procedures

[0733] It is extremely important to collect all blood samples as close as possible to the dates specified in the protocol (see the study workflow table in Table 17 for the sampling schedule). The reason for any missed or lost blood samples should be documented. Specific procedures described for the collection, storage, and transport of serum may be utilized. See Table 20.

[0734]

[0735] For research visits involving blood collection for PK and anti-sarrelumab antibody samples (e.g., baseline second visit), it is recommended to draw 1 mL of blood. The serum will be divided into two aliquots to obtain one PK serum aliquot and one anti-sarrelumab antibody serum aliquot. Bioanalytical Methods

[0736] Validated bioanalytical methods will be used to determine serum levels of functional sarelumab and anti-sarelumab antibodies. Pharmacokinetic parameters

[0737] A PopPK model will be developed using nonlinear mixed-effects modeling to describe the PK characteristics of sarerutumab. The PopPK model of functional sarerutumab in serum will be used to calculate the following PK parameters, including but not limited to: Cmax, C-valence, tmax, and AUC0-τ.

[0738]

[0739]

[0740]

[0741] *ANC = Absolute Neutrophil Count; bDMARD = Biological DMARD; CHAQ-DI = Child Health Assessment Questionnaire - Disability Index; CRP = C-Reactive Protein; csDMARD = Accustomed Synthetic DMARD; DMARD = Disease-Modifying Antirheumatic Drug; ESR = Erythrocyte Sedimentation Rate; GC = Glucocorticoids; JADAS-27 CRP = Juvenile Arthritis Disease Activity Score = 27-Joint Count Score with C-Reactive Protein Use; JIA = Juvenile Primary Arthritis; n = Total number of patients who meet the criteria at least once during treatment; QW = Weekly; Q2W = Every 2 Weeks; RF = Rheumatoid Factor; SD = Standard Deviation; VAS = Visual Analogue Scale; yrs = Years / Year.

[0742] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0743] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0744] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0745]

[0746]

[0747] *AUC0-τ = Area under the curve of serum concentration versus time during the 2-week (Q2W) or 1-week (QW) dose interval τ; Cmax = Maximum observed serum concentration; Cvalence = Concentration observed before treatment administration during repeated administration; CV% = Coefficient of variation; n = Total number of patients who met the criteria at least once during treatment; QW = Weekly; Q2W = Every 2 weeks; SC = Subcutaneous.

[0748] †Q2W dosing regimen tested at weeks 10–12; QW dosing regimen tested at weeks 11–12.

[0749]

[0750]

[0751] *AE = Treatment-induced adverse events; ALT = Alanine transaminase; n = Total number of patients who met the criteria at least once during treatment; nE = Number of events; PY = Patient-year; QW = Weekly; Q2W = Every 2 weeks; SAE = Serious AE. All terms from MedDRA 21.0.

[0752] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0753] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0754] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0755]

[0756] *n = the total number of patients who meet the criteria at least once during the treatment period; QW = weekly; Q2W = every 2 weeks.

[0757] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0758] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0759] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0760]

[0761]

[0762] *nE = Number of events; PY = Patient-year; QW = Weekly; Q2W = Every 2 weeks. All terms from MedDRA 21.0.

[0763] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0764] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0765] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0766]

[0767] *ACR = American College of Rheumatology; BL = Baseline; CHAQ-DI = Child Health Assessment Questionnaire - Disability Index; CRP = C-reactive protein; JIA ACR30 / 70 / 90 = American College of Rheumatology 30 / 70 / 90% response in juvenile primary arthritis; QW = Weekly; Q2W = Every 2 weeks; SE = Standard error; VAS = Visual Analogue Scale.

[0768] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0769] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0770] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0771] ∥Relaxed weight A, 30-60kg, Relaxed weight B, 10-<30kg.

[0772]

[0773]

[0774] *CRP = C-reactive protein; JADAS-27-CRP = Disease activity score of juvenile arthritis using 27-joint count and CRP; LDA = Low disease activity; n = Total number of patients who meet the criteria at least once during treatment; QW = Weekly; Q2W = Every 2 weeks; VAS = Visual Analogue Scale.

[0775] † Dosage 1: 2.0 mg / kg Q2W in patients weighing 30-60 kg and 2.5 mg / kg Q2W in patients weighing 10-<30 kg.

[0776] ‡ Dosage 2: 3.0 mg / kg Q2W in patients weighing 30-60 kg and 4.0 mg / kg Q2W in patients weighing 10-<30 kg.

[0777] § Dosage 3: 2.0 mg / kg QW in patients weighing 30-60 kg and 2.5 mg / kg QW in patients weighing 10-<30 kg.

[0778] ∥Relaxed weight A, 30-60kg, Relaxed weight B, 10-<30kg.

[0779] **One patient did not complete all components of the JADAS-27-CRP assessment at week 12 and was removed.

[0780] ††Wallace's criteria are defined as a physician-reported VAS <1 / 10, no active arthritis, no active uveitis, and CRP <10 mg / L.

[0781] [, Secondary endpoint , ]

[0782] 12-week core treatment phase

[0783] The following parameters will be analyzed during the 12-week open-label core processing phase.

[0784] ￭ Security

[0785] negative events, vital signs, physical examination, laboratory values

[0786] o Acceptability assessment (local tolerability)

[0787] ￭Efficacy

[0788] JIA ACR 30 / 50 / 70 / 90 / 100 (in the absence of fever) response rate at week 12

[0789] o Changes from baseline in the JIA ACR component alone at week 12

[0790] o Change from baseline in Juvenile Arthritis Disease Activity Score-27 (JADAS) at Week 12

[0791] Changes in glucocorticoid use will be descriptively assessed by dose group and body weight, using a linear graph of prednisone dose (the glucocorticoid equivalent) for each individual patient from baseline to the end of the 12-week core treatment period.

[0792] Pharmacodynamics

[0793] Changes in serum levels of IL-6-related biomarkers (e.g., high-sensitivity C-reactive protein [hs-CRP], IL-6, sIL-6R).

[0794] Extended phase

[0795] ￭ Security

[0796] negative events, vital signs, physical examination, laboratory values

[0797] o Acceptability assessment (local tolerability)

[0798] ￭Efficacy

[0799] JIA ACR 30 / 50 / 70 / 90 / 100 (in the absence of fever) response rate at weeks 24, 48, and every 24 weeks until the end of the study; change from baseline in juvenile arthritis disease activity score -27 at weeks 24, 48, and every 24 weeks until the end of the visit.

[0800] o- Variation from baseline in individual JIA ACR components at weeks 24 and 48, and every 24 weeks until the end of the study.

[0801] o- Compared with baseline, the proportion of patients receiving glucocorticoids by dose class (prednisone equivalent doses of 20.5 mg / kg, 20.2 mg / kg and <0.5 mg / kg, <0.2 mg / kg) at weeks 24, 48, and every 24 weeks until the end of the study.

[0802] o- The proportion of patients who did not receive glucocorticoids and did not experience exacerbations of JIA at weeks 24, 48, and every 24 weeks thereafter until the end of the study.

[0803] Changes in o-glucocorticoid use will be descriptively assessed by linear graphs of prednisone dose (glucocorticoid equivalent) used from baseline to the end of treatment for each individual patient, categorized by dose group and body weight.

[0804] [, Exploratory endpoint , ]

[0805] 12-week core treatment period

[0806] ￭ The proportion of patients with baseline fever due to generalized JIA who were fever-free at week 12

[0807] ￭ The proportion of patients with a baseline rash in generalized JIA who were rash-free at week 12

[0808] Extended phase

[0809] Growth assessments at years 1, 2, and 3, including height velocity and height standard deviation (SD) scores, were performed on patients who had never received growth hormone and had not reached stage 5 Donald at the end of the first year of treatment.

[0810] The proportion of patients who had fever at baseline who were fever-free at week 24, week 48, and every 24 weeks until the end of the study.

[0811] The proportion of patients with rash due to generalized JIA at baseline who were rash-free at weeks 24, 48, and every 24 weeks until the end of the study.

[0812] [, efficacy endpoint , ]

[0813] JIA ACR reaction

[0814] In this study, the JIA ACR rating scale will be used to assess signs and symptoms. JIA ACR 30 / 50 / 70 / 90 / 100 will be assessed at weeks 12, 24, 48, 72, 96, 120, 144, and 156 (EOT). A JIA ACR 30 / 50 / 70 / 90 / 100 response (in the absence of fever) is defined as a patient in whom at least 30% / 50% / 70% / 90% / 100% improvement from baseline in three of the six core set variables, while no more than one of the remaining variables worsens by more than 30%.

[0815] JIA ACR core set includes 6 variables plus sJIA's audiophile-grade features:

[0816] ￭Comprehensive physician assessment of disease activity

[0817] ￭ Patient / Parent Assessment of Overall Health Status

[0818] ￭ Functional abilities determined by the Child Health Assessment Questionnaire (CHAQ)

[0819] ￭ Number of joints with active arthritis (0-71 joints)

[0820] ￭ Number of joints with limited mobility (0-67 joints)

[0821] High-sensitivity C-reactive protein

[0822] ￭ Fever (within the first 7 days)

[0823] ￭Except for the 3rd visit (day 3), 4th visit (day 5), 5th visit (day 8), 6th visit (day 12), and EOS visit, the JIA ACR core set will be evaluated at each on-site visit. Body temperature should be measured 7 days prior to the ACR assessment.

[0824] JIA ACR30 core set variable scores and changes from baseline will be summarized for each dose group and body weight using mean, standard error, and corresponding 95% CI via visits. JIA ACR30 / 50 / 70 / 90 / 100 responses using ESR, instead of hs-CRP, will also be summarized using the same methodology. Comprehensive physician assessment of disease activity will be conducted.

[0825] A comprehensive physician assessment of disease activity will be conducted at screening, at baseline prior to IMP administration, and at each field visit prior to the EOT visit. Investigators will be asked to rate patients’ disease activity on an anchored 100mm horizontal visual analog scale (VAS), where 0 is considered the best disease activity and 100 the worst. Patient / parent assessment of overall health status.

[0826] Overall health status assessment for the patient / parent will be measured on a 100mm horizontal VAS at screening, at baseline prior to administration, and at each site visit before the EOT visit. The form should be completed by the patient or the same parent or guardian to ensure consistency. Child Health Assessment Questionnaire (CHAQ)

[0827] CHAQ is for Interviews or self-management tools for children aged 8 and under and parents / agents of children under 8. The CHAQ is a general measure of health status for children aged 1 to 19. The Spearman correlation coefficient between disability index scores of questionnaires given to parents and questionnaires given to other children (>8 years) was 0.84 (n=29; P<0.001), demonstrating that parents can accurately report for their children. The surface validity of the tool was evaluated by a panel of 20 health professionals and parents of 22 healthy children. The assessment consisted of 43 items in total and took approximately 10 minutes to complete. The CHAQ was completed before and after IMP administration. The recall period was 1 week (Klepper, SE et al. 2003 Arthritis Rheum. 49(3):435-43; Singh, G. et al. 1994 Arthritis Rheum. 37(12):1761-9). In this case, the actual date and data of the CHAQ will be recorded in the eCRF.

[0828] The median CHAQ scores reported in the development of the CHAQ for mild, mild to moderate, and moderate disability were 0.13, 0.63, and 1.75, respectively (Dempster, H. et al., 2001 Arthritis Rheum. 44(8): 1768-7).

[0829] To eliminate potential differences due to growth and development, parents were instructed to only notice difficulties caused by the illness (e.g., marking the response as "not applicable" if the child is too small to perform an activity). The response options for assessing difficulty were based on a 5-point Likert scale (0 = no difficulty, 1 = some difficulty, 2 = many difficulties, 3 = cannot do, and 4 = not applicable).

[0830] Part 1 of the CHAQ is the Disability Index, which contains 41 items assessing the ability to perform daily living functions. The following eight subscales / domains are used: 1. Dressing and grooming, 2. Getting out of bed, 3. Eating, 4. Walking, 5. Hygiene, 6. Reaching, 7. Grasping, and 8. Activity. For each domain: (a) the degree of difficulty performing daily functions was assessed (items 6-9, 12-13, 16-18, 21-22, 34-38, 41-44, 47-51, and 54-58); (b) the need for special assistive tools or equipment (items 24-27, 60-62); and (c) the need for assistance from others (items 29-30, 64-65).

[0831] To calculate the Child Health Assessment Questionnaire Disability Index (CHAQ-DI), first calculate the score for each domain:

[0832] The score for the functional area is determined by the question with the highest response rate.

[0833] If assistive tools or devices are used or help is needed to complete a task in a certain area, the minimum score for that functional area is recorded as 2.

[0834] The eight subscales / domains are averaged to calculate the mean score, or Disability Index (range 0-3).

[0835] A lower disability index score indicates a better / healthier quality of life / fewer signs and symptoms than the health status, while a higher disability index score indicates a poorer health status / poorer health-related quality of life (HRQL) / more signs and symptoms. The smallest clinically significant improvement in the CHAQ disability index was a score decrease of 0.13. The smallest clinically significant deterioration in the CHAQ disability index was a median change in score of 0.75 (20, 19).

[0836] Part 2 of the CHAQ is the Discomfort Index, while Part 3 of the CHAQ is the Health Status Measurement; both are measured on separate 15cm scales.

[0837] The CHAQ Discomfort Index is determined by the severity of pain over the past week and is rated on the VAS (anchored to “0 no pain” and “100 very severe pain”).

[0838] Calculate the CHAQ discomfort index (item 67).

[0839] - Measure the distance from the left end of the VAS in item 67 to the responder's marker and multiply by 0.2, ranging from 0 to 3. The discomfort index score can be readjusted to a scale of 0-100.

[0840] Part 3 of the CHAQ Health Status Score measures the patient's or parents' comprehensive assessment.

[0841] Calculate the CHAQ health status score (item 69)

[0842] - Measure the distance from the left end of the VAS in item 69 to the responder marker and multiply by 0.2, ranging from 0 to 3. Health scores can be readjusted to a scale of 0-100.

[0843] The number of joints with active arthritis and the number of joints with limited mobility.

[0844] A mobile joint is defined as a joint with the following characteristics:

[0845] ￭ Swelling within the joint is not due to deformity, or

[0846] ￭Limited mobility accompanied by pain or tenderness

[0847] Seventy-one (71) joints will be assessed for active disease by counting the number of joints with swelling not due to deformity or with pain or tenderness or both that restrict movement (Bazso, A. et al., 2009 J Rheumatol. 36(1): 183-90; National Cholesterol Education Program (NCEP): highlights of the report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics. 1992; 89(3); 495-501).

[0848] There are a total of 71 joints, including the cervical spine (counted as 1 joint), temporomandibular joint (2 joints, right and left), sternoclavicular joint (2 joints), acromioclavicular joint (2 joints), shoulder (2 joints), elbow (2 joints), wrist (2 joints), metacarpophalangeal joint (10 joints in total, 5 on each side), proximal interphalangeal joint (10 joints in total, 5 on each side), distal interphalangeal joint (8 joints in total, 4 on each side), hip (2 joints), knee (2 joints), ankle (2 joints), subtalar joint (2 joints), tarsometatarsal joint (2 joints), metatarsophalangeal joint (10 joints, 5 on each side), and interphalangeal joint (10 joints, 5 on each side).

[0849] Except for the sternoclavicular and acromioclavicular joints (n=2), the sixty-seven (67) joints examined for limited mobility will be the same as those examined for active disease. Formal joint counting will be performed by trained assessors. Joint tenderness is defined as pain induced by joint pressure applied by the assessor's thumb and forefinger. High-sensitivity C-reactive protein

[0850] For patients maintaining the selected dose, high-sensitivity C-reactive protein (HRP) will be evaluated at the following times: first visit (day -28 to day -1, up to 31 days), baseline, second visit (week 0, day 1), seventh visit (week 2), eighth visit (week 4), ninth visit (week 6), tenth visit (week 8), eleventh visit (week 10), twelfth visit (week 12), and extended visits. Each visit during the phase, from the 13th visit (week 16) to the 27th visit (week 156); from the 101st visit (week 0) to the 108th visit (week 12), the 109th visit (week 24), the 112th visit (week 48), the 114th visit (week 72), the 116th visit (week 96), the 118th visit (week 120), and the 27th visit (week 27). For patients <30kg in PK schedule 1 (group B), hs-CRP will be measured on days 3 and 8. For patients <30kg in PK schedule 2 (group B), hs-CRP will be measured on days 5 and 12. High-sensitivity C-reactive protein levels are directly related to IL-6R activity. The active dosing regimen is expected to have a significant reducing effect on CRP levels. Juvenile arthritis disease activity score.

[0851] JADAS includes four measurements:

[0852] 1. A comprehensive physician assessment of disease activity, measured on a 10cm VAS, where 0 = no activity and 10 = maximum activity.

[0853] 2. Comprehensive assessment of the health status of parents / patients, measured on a 10cm VAS, where 0 = very good and 10 = very poor.

[0854] 3. Joint count with active disease

[0855] 4. Normalize the erythrocyte sedimentation rate to a 0-10 scale using the following formula:

[0856] [ESR(mm / hour)-20] / 10

[0857] Before performing the calculations, ESR values ​​<20 mm / h were converted to 0, and ESR values ​​>120 mm / h were converted to 120.

[0858] JADAS will be calculated as a simple linear sum of its four component scores (Consolaro, A. et al., 2009 Arthritis Rheum. 61(5): 658-623). The total score of JADAS-27 and the change from baseline will be summarized for each dose group and body weight group (if possible) by visits (including number, mean, standard error, SD, median, minimum, and maximum).

[0859] JADAS-27 includes the following joints: cervical spine, elbow, wrist, metacarpophalangeal joints (from the first to the third), proximal interphalangeal joints, hip, knee, and ankle. JADAS is considered an effective tool for assessing disease activity in JIA and has the potential to be applied in standard clinical care, observational studies, and clinical trials (23). For patients maintaining the selected dose, JADAS-27 will be calculated at the following times: 12th visit (week 12), 15th visit (week 24), and 18th visit (week 48).

[0860] The 20th visit (week 72), 22nd visit (week 96), 24th visit (week 120), 26th visit (week 144), and 27th visit for EOT (week 156); for patients switching to the selected dose, the following times will be calculated: 101st visit (week 0) to 106th visit (week 12), 109th visit (week 24), 112th visit (week 48), 114th visit (week 72), 116th visit (week 96), 118th visit (week 120), and 27th visit for EOT. Systemic characteristics of sJIA.

[0861] Systemic features of sJIA (including fever, transient salmon-colored rash, generalized lymphadenopathy, hepatomegaly, splenomegaly, serositis, and other complications) will be collected at the first screening visit (day -28 to day -1, up to day 31) (to confirm the diagnosis), the second visit (week 0), the 12th visit (week 12), and the 27th visit (week 156); fever and transient salmon-colored rash will be collected only at the 15th visit (week 24), the 18th visit (week 48), and every 24 weeks until the end of the study.

[0862] When assessing the core components of JIA ACR, common systemic features (including fever and rash associated with sJIA) will be collected at all visits.

[0863] The rash associated with sJIA refers to a transient salmon-colored erythematous rash.

[0864] No rash was defined as no rash associated with sJIA recorded in the patient's diary within 7 days prior to the assessment date.

[0865] No fever was defined as the absence of a measured body temperature within 7 days prior to the visit when assessing the JIA ACR core components. 37.5℃.

[0866] The effects of treatment on fever and rash will be assessed at week 12 compared to baseline.

[0867] The proportion of patients with fever due to systemic JIA who were fever-free at baseline will be summarized by visits (i.e., at weeks 12, 24, 48 and every 24 weeks until the end of the study) for each dose group, overall, and by body group (if sufficient data are available).

[0868] The proportion of patients with rash due to generalized JIA at baseline will be summarized by visits (i.e., at weeks 12, 24, 48, and every 24 weeks until the end of the study) for each dose group, overall, and by body group (if sufficient data). Glucocorticoid use assessment

[0869] The proportion of patients receiving glucocorticoids by dose category (20.5 mg / kg, 20.2 mg / kg, and <0.5 mg / kg, <0.2 mg / kg) and the proportion of patients not receiving glucocorticoids and without JIA exacerbation at weeks 24, 48, 72, and 104 were summarized for each dose group and weight group and compared to the proportion at baseline. The glucocorticoid equivalent prednisone dose (mg / kg / day) at specific time points (i.e., weeks 0, 24, 48, 72, or 104) was calculated based on glucocorticoids received in the two weeks preceding that time point. JIA exacerbation at a specific time point (i.e., weeks 24, 48, 72, or 104) was defined as failure of the JIA ACR50 response between the previous visit and this time point, or fever (any temperature measurement). 37.5℃), or ESR 220mm / h.

[0870] The prednisolone equivalent dose (original value and change from baseline) will be summarized by dose group and body weight based on visits (mean, SD, median, etc.). Furthermore, the prednisolone equivalent dose at each visit during the treatment period (both core and extended) will be plotted for each individual patient by dose group and body weight. Growth assessment

[0871] For patients who have never received growth hormone and have not reached stage 5 Donald at the end of the first year of treatment, the impact on growth will be assessed using height velocity and height SD score.

[0872] Height velocity (cm per year) will be calculated based on the time interval between height change and height measurement. Assuming measurements were obtained between 9 and 24 months prior to baseline, the pre-treatment height velocity will be estimated using the height measured most closely 1 year prior to baseline. Subsequently, height velocities for year 1 and year 2 of treatment will be calculated. Height measurements most closely 1-year and 2-year cutoffs will be used.

[0873] Height will be measured while standing using a wall-mounted distance meter. When obtaining the height measurement, the child will be measured without shoes, hats, or hair accessories, and with their head, shoulders, hips, and heels forming a fixed right angle with the wall and feet together. Because the child's posture may vary slightly with each measurement, three consecutive measurements will be taken for each child. The average of the three measurements will be considered the child's true height, provided the measurement is within 0.3 cm. If the measurements are more than 0.3 cm apart, they will be repeated, and the average will be taken if they are within an acceptable range. Measurements used for growth rate calculations will be performed as indicated in the assessment schedule.

[0874] Height will be measured using a field-verified method. The expected normal height rate for a given patient during the interval will be calculated as the difference between the patient's age and sex and the World Health Organization (WHO) mean height (WHO Anthro (2011 version) and macros. URL: http: / / www.who.int / childgrowth / software / en / ) divided by age variation. Height rates will be compared to the expected normal height rates before treatment and during years 1, 2, and 3 of treatment. The height SD score will be calculated using WHO standards (ibid.) (see below). The mean SD score for the reference population is 0, and values ​​between -2 and +2 are generally considered to be within the normal range: SD score = (observed value - median of the reference population) / SD value of the reference population.

[0875] To assess the impact on growth, changes in height SD scores from baseline at years 1, 2, and 3 of treatment will be descriptively summarized using the mean, SD, and 95% CI. The proportion of patients whose height rate exceeds WHO expectations will be summarized before treatment and during years 1, 2, and 3 of treatment. The mean height rate will be compared to the expected WHO normal height rate before treatment and during years 1, 2, and 3. Physical examination

[0876] For patients maintaining the selected dose, a full physical examination will be conducted at the following times: first screening visit (day -28 to day -1, maximum 31 days), second visit (day 1, week 0), eighth visit (week 4), ninth visit (week 6), twelfth visit (week 12), fifteenth visit (week 24), eighteenth visit (week 48), twentyth visit (week 72), twenty-second visit (week 96), twenty-fourth visit (week 120), and twenty-sixth visit. (Week 144) and 27th visit for EOT (Week 156); for patients switching to the selected dose, visits will be made at the following times: 101st visit (Week 0), 104th visit (Week 6), 106th visit (Week 12), 109th visit (Week 24), 112th visit (Week 48), 114th visit (Week 72), 116th visit (Week 96), 118th visit (Week 120), 27th visit for EOT, and 28th visit for EOS. Any clinically significant abnormalities observed and known at the first visit (day -28 to day -1, up to 31 days) should be reported as a medical history in the patient's eCRF, and if observed at the second visit (day 1, week 0) and during subsequent visits, should be reported as AEs. Any clinically significant physical examination abnormalities known at the screening visit should be reported as medical history, not as adverse events (AEs). Clinically significant abnormalities reported after the screening visit, or deterioration from baseline, should be reported as AEs. Weight

[0877] Weight should be measured with the patient wearing underwear or very light clothing (no outerwear or accessories), unshoes, and with an empty bladder. It is recommended to use the same scale throughout the study. Weight should be accurate to 0.1 kg.

[0878] It is recommended to use the same scale throughout the study. For patients maintaining the selected dose, weight will be collected at the following times: the first screening visit (day -28 to day -1, up to 31 days), the second visit from baseline (day 1, week 0), the 12th visit (week 12), and each visit during the extension phase; for patients switching to the selected dose, weight will be collected at the following times: the 101st visit (week 0) to the 119th visit (week 132), the 27th visit to EOT, and the 28th visit to EOS (except for the 102nd visit (week 2) and the 104th visit (week 6)). Pharmacokinetic parameters

[0879] The pharmacokinetics of sarrizumab will be evaluated by measuring the following biomarkers: hs-CRP, IL-6, and sIL-6R. Evaluation timeline.

[0880] The blood collection schedule is available in the study flowchart (see Tables 17-19). IL-6 and total sIL-6R will be measured at the baseline second visit (week 0) and the 12th visit (week 12). For patients who prematurely discontinue study treatment during the core treatment phase, IL-6 and total sIL-6R will be measured at the EOT assessment. Pharmacogenomics

[0881] One or both parents, or one or more legal guardians, will be required to sign a separate ICF for saliva sample collection. DNA samples used for genomic research will be double-coded according to the d...

Claims

1. A composition for use in the preparation of a medicament for treating juvenile primary arthritis (JIA) in subjects of need, wherein the composition comprises an antibody that specifically binds to a specific-binding interleukin-6 receptor (IL-6R) and three heavy chain complementarity-determining regions (HCDR) sequences comprising a heavy chain variable region and three light chain complementarity-determining regions (LCDR) sequences comprising a light chain variable region, wherein the anti-IL-6R antibody is administered once weekly at a dose of 200 mg; wherein the three HCDRs are HCDR1, HCDR2, and HCDR3 and the three LCDRs are LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

6. The amino acid sequence of number 8.

2. The use as described in claim 1, wherein the JIA is polyarticular JIA (pcJIA) or systemic JIA (sJIA).

3. The use as claimed in claim 1, wherein the JIA is pcJIA, the pcJIA being selected from: rheumatoid factor negative polyarticular juvenile arthritis (RF negative pJIA); rheumatoid factor positive polyarticular juvenile arthritis (RF positive pJIA); and extended oligoarticular juvenile arthritis (oJIA).

4. The use as claimed in any one of claims 1 to 3, wherein the subject's weight is 63 kg or greater.

5. The use as claimed in any one of claims 1 to 3, wherein the subject is 2 to 17 years old.

6. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R anti-system is administered in combination with at least one other disease-modifying antirheumatic drug (DMARD).

7. The use as claimed in claim 6, wherein the at least one other DMARD comprises synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs).

8. The use as described in claim 7, wherein the at least one other DMARD includes sDMARD and the sDMARD includes methotrexate, sulfasalazine, leflunomide or hydroxychloroquine.

9. The use as described in claim 7, wherein the at least one other DMARD includes sDMARD and the sDMARD includes methotrexate.

10. The use as described in claim 7, wherein the at least one other DMARD comprises a bDMARD and the bDMARD comprises adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, or tocilizumab.

11. The use as claimed in any one of claims 1 to 3, wherein during the use of the anti-IL-6R antibody, the IL-6R antibody is used without any DMARD, in addition to the anti-IL-6R antibody.

12. The use as claimed in any one of claims 1 to 3, wherein the IL-6R antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

2.

13. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

14. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R antibody is sarilumab.

15. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R anti-system is formulated for use with a syringe or autoinjector.

16. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R anti-system is present in a prefilled syringe in an amount of 200 mg.

17. The use as claimed in any one of claims 1 to 3, wherein the anti-IL-6R anti-system is formulated for subcutaneous use.

18. A composition for use in the preparation of a medicament for treating juvenile primary arthritis (JIA) in subjects of need, wherein the composition comprises an antibody that specifically binds to an interleukin-6 receptor (IL-6R) and three heavy chain complementarity-determining regions (HCDRs) comprising a heavy chain variable region and three light chain complementarity-determining regions (LCDRs) comprising a light chain variable region, and wherein the anti-IL-6R antibody is used at the following doses: (i) when the subject has a body weight greater than or equal to 10 kg and less than 30 kg, at a dose of 5-7 mg / kg every week; or (ii) when the subject has a body weight of at least 30 kg, at a dose of 4-6 mg / kg every week, wherein the three HCDRs are HCDR1, HCDR2, and HCDR3 and the three LCDRs are LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, and HCDR3 comprises the amino acid sequence of SEQ ID NO:

4. The LCDR1 contains the amino acid sequence of SEQ ID NO: 6, the LCDR2 contains the amino acid sequence of SEQ ID NO: 7, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

8.

19. A composition for use in the preparation of a medicament for treating juvenile primary arthritis (JIA) in subjects of need, wherein the composition comprises an antibody that specifically binds to a specific-binding interleukin-6 receptor (IL-6R) and three heavy chain complementarity-determining regions (HCDRs) comprising a heavy chain variable region and three light chain complementarity-determining regions (LCDRs) comprising a light chain variable region, wherein the anti-IL-6R antibody is administered once weekly at a dose of 2 mg / kg to 4 mg / kg, and wherein the subject's weight is greater than or equal to 10 kg; wherein the three HCDRs are HCDR1, HCDR2, and HCDR3, and the three LCDRs are LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, and LCDR2 comprises the amino acid sequence of SEQ ID NO:

6. The amino acid sequence of SEQ ID NO: 7, and the amino acid sequence of SEQ ID NO: 8 contained in the LCDR3.

20. The use as described in claim 19, wherein: - When the subject's weight is greater than or equal to 10 kg and less than 30 kg, the antibody is administered at a dose of 4 mg / kg once every other week; or - when the subject's weight is greater than or equal to 30 kg and less than or less than 60 kg, the antibody is administered at a dose of 3 mg / kg once every other week.

21. The use as described in claim 20, wherein the maximum dose of the antibody is 200 mg every week.

22. The use as described in claim 18, wherein the JIA is polyarticular JIA (pcJIA) or systemic JIA (sJIA).

23. The use as described in claim 19, wherein the JIA is polyarticular JIA (pcJIA) or systemic JIA (sJIA).

24. The use as described in claim 20, wherein the JIA is polyarticular JIA (pcJIA) or systemic JIA (sJIA).

25. The use as claimed in any one of claims 18 to 24, wherein the subject is a pediatric patient.

26. The use as claimed in any one of claims 18 to 24, wherein the subject is 2 to 17 years old.

27. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R anti-system is administered in combination with at least one other disease-modifying antirheumatic drug (DMARD).

28. The use as claimed in claim 27, wherein the at least one other DMARD comprises synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs).

29. The use as described in claim 27, wherein the at least one other DMARD includes sDMARD and the sDMARD includes methotrexate, sulfasalazine, leflunomide or hydroxychloroquine.

30. The use as described in claim 27, wherein the at least one other DMARD includes sDMARD and the sDMARD includes methotrexate.

31. The use as described in claim 27, wherein the at least one other DMARD comprises a bDMARD and the bDMARD comprises adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab, or tocilizumab.

32. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R antibody is used in the absence of any DMARD, in addition to the anti-IL-6R antibody, during the use of the anti-IL-6R antibody.

33. The use as claimed in any one of claims 18 to 24, wherein the IL-6R antibody comprises a heavy chain variable region sequence containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region sequence containing the amino acid sequence of SEQ ID NO:

2.

34. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

35. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R antibody is sarriromumab.

36. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R anti-system is formulated for subcutaneous use.

37. The use as claimed in any one of claims 18 to 24, wherein the anti-IL-6R anti-system is formulated for use with a syringe or autoinjector.

38. The use as claimed in any one of claims 18 to 24, wherein the JIA is a pcJIA selected from: rheumatoid factor negative polyarticular juvenile arthritis (RF negative pJIA); rheumatoid factor positive polyarticular juvenile arthritis (RF positive pJIA); and extended oligoarticular juvenile arthritis (oJIA).

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