RU2822089C2 - Il-6 receptor antibody for treating juvenile idiopathic arthritis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to methods of treating systemic juvenile idiopathic arthritis with a polyarticular course using an antibody which specifically binds the human interleukin-6 receptor (IL-6R). Antibody is administered subcutaneously in dose of 2 to 4 mg/kg once a week or once every two weeks. Subject may be between 2 and 17 years old.

EFFECT: invention provides effective and safe methods of treating persistent types of JIA.

16 cl, 11 tbl, 33 dwg, 2 ex

Description

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application No. 62/799698, filed Jan. 31, 2019, U.S. Provisional Patent Application No. 62/851474, filed May 22, 2019, U.S. Provisional Patent Application No. 62/935395, filed 14 November 2019, and European Patent Application No. 19306553.9, filed December 3, 2019; each of which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the field of therapeutic treatment of juvenile idiopathic arthritis, such as systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis (which includes polyarticular and widespread oligoarticular juvenile idiopathic arthritis). Certain aspects of the present invention relate to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, for the treatment of systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis.

BACKGROUND OF THE INVENTION

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. JIA is defined by the International League of Associations of Rheumatology (ILAR) as arthritis of unknown etiology with onset before age 16 years that persists for at least 6 weeks when other known conditions have been excluded (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. 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.

There is no known cure for JIA. While traditional treatments can be used to treat affected individuals, more effective treatments for persistent types of JIA are needed.

SHORT DESCRIPTION

The present invention provides, inter alia, methods for treating JIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R.

In an embodiment, the JIA is a system JIA (sJIA).

In an embodiment, an 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.

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

In an embodiment, the antibody is sarilumab.

In various embodiments, no other disease-modifying antirheumatic drug (DMARD) is administered with the antibody. In some embodiments, the subject is administered at least one other DMARD. In an embodiment, at least one other DMARD is administered to a subject in parallel with or simultaneously with the antibody.

In some embodiments, the subject suffers from at least one symptom of sJIA, such as arthritis in at least 1 joint for at least 6 weeks with concomitant or preceding fever lasting at least 2 weeks; transient erythematous rash mainly on the trunk and limbs; generalized lymphadenopathy; hepatomegaly and/or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; increased number of leukocytes in peripheral blood (WBC) (from 25,000 to 50,000/ml ³ ); elevated platelet count (eg, >1x10 ⁶ ), markedly elevated erythrocyte sedimentation rate (ESR) >100 mm/h; anemia and/or high ferritin levels compared to a healthy subject. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

As used herein, a “symptom” associated with JIA includes any clinical or laboratory finding (eg, diagnostic) manifestation associated with JIA and is not limited to what the subject can feel or observe.

In various embodiments, the subject suffers from at least one symptom of sJIA, such as lameness; stiffness upon awakening; subject's reluctance to use an arm or leg; decreased activity level; daily fever with high peaks (eg, reaching approximately 40°C or at least 40°C); joint swelling; and/or difficulties with fine motor skills. In an embodiment of the method, there is an improvement in at least one symptom of sJIA in the subject after administration of the antibody.

In various embodiments of the method, the antibody improves at least one score or indicator, such as ACR JIA (e.g., ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA, and ACR100 JIA), a component of ACR JIA (e.g., number of joints with active arthritis, number of joints with limited range of motion, physician's global assessment of disease activity, acute phase reactants such as erythrocyte sedimentation rate or C-reactive protein (CRP), Children's Health Assessment Questionnaire, patient (or parent) global assessment of well-being) and/or reduction in fever (For example, in subjects with fever when the antibody is first administered), a reduction from baseline in the amount of corticosteroids (eg, glucocorticoids) administered, and/or an index of juvenile arthritis disease activity (such as the juvenile arthritis disease activity index-27). In various embodiments of the method, the improvement is characterized by at least one score or indicator, such as ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA and/or ACR100 JIA. In various embodiments of the method, improvement is characterized by at least one score or indicator, such as a physician's global Disease Activity Index score, a patient's or parent's assessment of general well-being, a Children's Health Assessment Questionnaire, number of joints with active arthritis, number of joints with limited motion, high-sensitivity C -reactive protein and/or reduction in fever (eg, in subjects with fever when the antibody is first administered). In various embodiments, the improvement is characterized by at least one biomarker. In various embodiments of the method, the antibody results in clinically inactive disease, as defined by the Wallis criteria. The Wallis criteria are defined as physician global VAS score <1/10, no active arthritis, no active uveitis, and CRP <10 mg/L. In various embodiments of the method, the antibody results in clinically inactive disease, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤1. In various embodiments of the method, the antibody results in clinically inactive disease or low disease activity, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤3.8.

In an embodiment of the method, the subject has an insufficient response to current treatment, and the subject is considered a candidate for treatment with a biological disease-modifying antirheumatic drug.

In an embodiment of the method, the age of the subject is from about 1 year to about 17 years. In other embodiments, the subject's age is from about 4 to about 6 years, or from about 12 to about 18 years.

In an embodiment of the method, the subject has either 5 or more active joints, or 2 active joints and systemic symptoms (eg, fever). In an embodiment of the method, the subject has either 5 or more active joints, or 2 or more active joints and a sJIA fever greater than about 37.5°C for at least 3 of any 7 consecutive days, despite glucocorticoids at a dose stable in for at least 3 days.

An “active joint” is a joint with (i) swelling within the joint not caused by deformity and/or (ii) limitation of movement with either pain or tenderness.

In an embodiment of the method, the JIA is a polyarticular JIA (pcJIA). In some embodiments, the pcJIA is a common oligoarticular JIA. In various embodiments, the pcJIA is a polyarticular JIA that is positive for rheumatoid factor (RF). In some embodiments, the pcJIA is an RF-negative polyarticular JIA. In an embodiment of the method, the age of the subject is from about 12 to about 14 years, or from about 7 to about 9 years.

In an embodiment, an 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.

In various embodiments, the antibody comprises VH and VL, wherein VH contains three CDRs located in the sequence of SEQ ID NO: 1, and where VL contains three CDRs located in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL antibody -6R or an antigen binding fragment thereof comprises three HCDRs (ie, HCDR1, HCDR2 and HCDR3) and three LCDRs (ie, LCDR1, LCDR2 and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7 and LCDR3 contains the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, the subject is administered at least one other DMARD. In an embodiment, at least one other DMARD is administered to a subject in parallel with or simultaneously with the antibody.

In some embodiments, the subject suffers from at least one symptom of RF-positive polyarticular JIA. In some embodiments, the subject suffers from at least one symptom of RF-positive polyarticular JIA, such as symmetrical polyarthritis deformans, which may develop into subluxation of a joint (eg, wrist and/or thumb); joint contracture (eg proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth and finger deformities such as swan neck or boutonniere deformities); chronic synovial inflammation; loss of articular cartilage and erosion of periarticular bone; normocytic chronic anemia; elevated ESR and C-reactive protein; leukocyte count; asymptomatic arthritis of the cervical spine and/or micrognathia. In various embodiments, the subject has joint subluxation (e.g., wrist and/or thumb) and/or joint contracture (e.g., proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth, and finger deformities such as swan neck or boutonniere deformities. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof). In an embodiment of the method, the age of the subject is from about 12 years to about 14 years.

In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular JIA. In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular JIA, such as symmetrical polyarthritis with decreased mobility, muscle weakness, and/or decreased physical functioning. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof). In an embodiment of the method, the age of the subject is from about 7 years to about 9 years.

In an embodiment, the subject suffers from at least one symptom of advanced oligoarticular JIA. In various embodiments, the subject suffers from at least one symptom of widespread oligoarticular JIA, such as aseptic inflammatory synovitis, which affects more than 4 joints (eg, large joints such as knees, ankles, wrists) after the first 6 months of the disease; lameness when walking; chronic anterior uveitis; chronic arthritis of the knee or ankle, leading to bone overgrowth in that limb, followed by leg length discrepancy; muscle atrophy (eg extensor muscles such as vastus lateralis, quadriceps if the knee is affected) and/or flexion contractures in the knees or wrists. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

In various embodiments, the subject suffers from at least one symptom of pcJIA, such as lameness; stiffness upon awakening; subject's reluctance to use an arm or leg; decreased activity level; joint swelling; and/or difficulties with fine motor skills.

In an embodiment of the method, there is an improvement in at least one symptom of pcJIA in the subject after administration of the antibody. In various embodiments of the method, an improvement is characterized by at least one score or indicator, such as ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA and ACR100 JIA, and is defined as an improvement of ≥3/6 of the following base set variables with a worsening of no more than 1 /6 of these (i) a physician's global assessment of disease activity (eg, using a visual analogue scale (VAS)), (ii) a patient's or parent's assessment of general well-being, (iii) a child health assessment questionnaire (eg, the Disability Index on the Assessment Questionnaire). children's health (CHAQ-DI)), (iv) number of joints with active arthritis, (v) number of joints with limited motion, and (vi) inflammatory index (e.g. high-sensitivity C-reactive protein). In an embodiment, the ACR30 JIA response is a ≥30% improvement from baseline in ≥3/6 of the baseline set variables, with a ≥30% deterioration in no more than 1/6 of them.

In various embodiments of the method, improvement in disease activity is characterized by at least one juvenile arthritis disease activity index (such as the juvenile arthritis disease activity index-27, which includes 4 indicators: a physician's overall assessment of disease activity, a parent's overall assessment of well-being /patient, number of joints with active disease and inflammatory index (hs-CRP or ESR level)).

In various embodiments of the method, improvement is characterized by at least one assessment or indicator, such as a physician's global assessment of disease activity, a patient's or parent's assessment of general well-being, a Children's Health Assessment Questionnaire, number of joints with active arthritis, number of joints with limited movement, high-sensitivity C- reactive protein and/or juvenile arthritis disease activity index (such as juvenile arthritis disease activity index-27).

In various embodiments of the method, the antibody results in clinically inactive disease, as defined by the Wallis criteria. The Wallis criteria are defined as physician global VAS score <1/10, no active arthritis, no active uveitis, and CRP <10 mg/L. In various embodiments of the method, the antibody results in clinically inactive disease, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤1. In various embodiments of the method, the antibody results in clinically inactive disease or low disease activity, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤3.8.

In an embodiment of the method, the age of the subject is from about 2 years to about 17 years.

In various embodiments, the subject has suffered from JIA for at least 6 months. In an embodiment, the subject suffered from arthritis that affected up to 4 joints during at least the first 6 months of the disease, and then progressed to 5 or more joints affected after at least the first 6 months. In some embodiments, the subject suffered from arthritis that affected up to 4 joints during the first 6 months of the disease, and then progressed to 5 or more joints affected after the first 6 months.

In an embodiment of the method, the subject has at least 5 joints with active arthritis. In an embodiment of the method, the subject suffers from arthritis that affects 5 or more joints during the first 6 months of the disease. In an embodiment of the method, the arthritis is rheumatoid factor negative. Alternatively, in an embodiment, the arthritis is rheumatoid factor positive.

In an embodiment of the method, the antibody is administered subcutaneously. In various embodiments of the method, the antibody is administered every week or every two weeks.

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

In some embodiments of the method, the subject's body weight is less than 30 kg.

In some embodiments of the method, the subject's body weight is at least about 30 kg. In some embodiments of the method, the subject's body weight is less than 60 kg.

In some embodiments of the method, the age of the subject is between 1 year and 17 years.

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

The present invention further provides a method of treating pcJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 4 mg/kg per week or biweekly where the subject's body weight is greater than or equal to 10 kg or less or equal to 60 kg.

In some embodiments of the method, the subject's body 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 two weeks or at a dose of about 2 mg/kg. mg/kg, every week.

In some embodiments of the method, the subject's body 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 once every two weeks or at a dose of approximately 2 mg/kg, once a week.

In some embodiments of the method, the subject's body 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 or about 3 mg/kg every two weeks.

In some embodiments of the method, the subject's body 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 or about 3 mg/kg once every two weeks.

In some embodiments of the method, the subject's body 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 two weeks or 2 mg/kg every week.

In some embodiments of the method, the subject's body 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 once every two weeks or 2 mg/kg once every week.

In some embodiments of the method, the subject's body 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 two weeks or at a dose of about 2 .5 mg/kg, every week.

In some embodiments of the method, the subject's body weight is greater than or equal to 10 kg and less than 30 kg, and the antibody is administered at a dose of from about 2.5 mg/kg to about 4 mg/kg once every two weeks or at a dose of approximately 2.5 mg/kg, once a week.

In some embodiments of the method, the subject's body 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 or about 4 mg/kg every two weeks.

In some embodiments of the method, the subject's body 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 or about 4 mg/kg once every two weeks.

In some embodiments of the method, the subject's body 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 two weeks or 2.5 mg/kg every week.

In some embodiments of the method, the subject's body 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 once every two weeks or 2.5 mg/kg once once a week.

The present invention further provides a method of treating pcJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week.

The present invention further provides a method of treating pcJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week.

The present invention further provides a method of treating pcJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 26.25 mg once every two weeks or once every week; where the body weight of the subject is greater than or equal to 12.5 kg and less than 16 kg, and the antibody is administered at a dose of 35 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16 kg and less than 19.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19.5 kg and less than 23 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23 kg and less than 26.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 26.5 kg and less than 30 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 30 kg and less than 37.5 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week.

The present invention further provides a method of treating pcJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once every week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 14.5 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 14.5 kg and less than 16.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16.5 kg and less than 19 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19 kg and less than 21 kg, and the antibody is administered at a dose of 78.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 21 kg and less than 23.5 kg, and the antibody is administered at a dose of 87.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23.5 kg and less than 25.5 kg, and the antibody is administered at a dose of 96.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 25.5 kg and less than 27.5 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 27.5 kg and less than 30 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 39.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 60.5 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 60.5 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week.

The present invention further provides a method of treating sJIA in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the 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 per week two weeks where the subject's body weight is greater than or equal to 30 kg and less than or equal to 210 kg.

In some embodiments of the method, the subject's body 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 every week or at a dose of about 3 mg/kg every two weeks.

In some embodiments of the method, the subject's body 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 in two weeks.

In some embodiments of the method, the subject's body 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 every week or at a dose of 3 mg/kg every two weeks.

In some embodiments of the method, the subject's body 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 weekly or at a dose of 3 mg/kg once every two weeks. weeks.

In some embodiments of the method, the subject's body 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 every week or at a dose of about 4 mg/kg every two weeks. weeks.

In some embodiments of the method, the subject's body 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 once per week or at a dose of about 4 mg/kg, once every two weeks.

In some embodiments of the method, the subject's body 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 every week or at a dose of 4 mg/kg every two weeks.

In some embodiments of the method, the subject's body 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 in two weeks.

The present invention provides an antibody for use in the treatment of JIA in a subject in need thereof, wherein the antibody specifically binds IL-6R.

In an embodiment, JIA is sJIA.

In an embodiment, an 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.

In various embodiments, the antibody comprises VH and VL, wherein VH contains three CDRs located in the sequence of SEQ ID NO: 1, and where VL contains three CDRs located in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL antibody -6R or an antigen binding fragment thereof comprises three HCDRs (ie, HCDR1, HCDR2 and HCDR3) and three LCDRs (ie, LCDR1, LCDR2 and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7 and LCDR3 contains the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, the subject is administered at least one other DMARD. In an embodiment, at least one other DMARD is administered to a subject in parallel with or simultaneously with the antibody.

In some embodiments, the subject suffers from at least one symptom of sJIA, such as arthritis in at least 1 joint for at least 6 weeks with concomitant or preceding fever lasting at least 2 weeks; transient erythematous rash mainly on the trunk and limbs; generalized lymphadenopathy; hepatomegaly and/or splenomegaly; polyserositis; weight loss; fatigue; malaise; fever; increased amount of WBC (from 25,000 to 50,000/ml ³ ); increased platelet count (eg, >1×10 ⁶ ), markedly increased ESR >100 mm/h; anemia and/or high ferritin levels compared to a healthy subject. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

In various embodiments, the subject suffers from at least one symptom of sJIA, such as lameness; stiffness upon awakening; subject's reluctance to use an arm or leg; decreased activity level; daily fever with high peaks (eg, reaching approximately 40°C or at least 40°C); joint swelling; and/or difficulties with fine motor skills. In an embodiment of the antibody, there is an improvement in at least one sJIA symptom in the subject following administration of the antibody.

In various embodiments, the antibody improves at least one score or indicator, such as the JIA ACR (e.g., JIA ACR30, JIA ACR50, JIA ACR70, JIA ACR90, and JIA ACR100), a component of the JIA ACR (e.g., number of joints with active arthritis , number of joints with limited range of motion, physician's global assessment of disease activity, acute phase reactants such as erythrocyte sedimentation rate or C-reactive protein, Children's Health Assessment Questionnaire, patient (or parent) global assessment of well-being), and/or decrease in fever (eg , in subjects with fever when the antibody is first administered), a reduction from baseline in the amount of corticosteroids (eg, glucocorticoids) administered, and/or an index of juvenile arthritis disease activity (such as the juvenile arthritis disease activity index-27). In various embodiments, the antibody improvement is characterized by at least one score or index, such as ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA, and/or ACR100 JIA. In various embodiments of the antibody, improvement is characterized by at least one score or indicator, such as a physician's global Disease Activity Index score, a patient's or parent's assessment of general well-being, a Children's Health Assessment Questionnaire, number of joints with active arthritis, number of joints with limited motion, high-sensitivity C -reactive protein and/or reduction in fever (eg, in subjects with fever when the antibody is first administered). In various embodiments, the improvement is characterized by at least one biomarker.

In various embodiments of the method, the antibody results in clinically inactive disease, as defined by the Wallis criteria. The Wallis criteria are defined as physician global VAS score <1/10, no active arthritis, no active uveitis, and CRP <10 mg/L. In various embodiments of the method, the antibody results in clinically inactive disease, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤1. In various embodiments of the method, the antibody results in clinically inactive disease or low disease activity, as determined by the disease activity index-27 of juvenile arthritis, CRP ≤3.8.

In an embodiment, the subject has an insufficient response to current treatment and the subject is considered a candidate for treatment with a biological disease-modifying antirheumatic drug.

In an embodiment, the age of the subject is from about 1 year to about 17 years. In other embodiments, the subject's age is from about 4 to about 6 years, or from about 12 to about 18 years.

In an embodiment, the subject has either 5 or more active joints, or 2 active joints and systemic symptoms (eg, fever). In an antibody embodiment, the subject has either 5 or more active joints or 2 or more active joints and a sJIA fever greater than about 37.5°C for at least 3 of any 7 consecutive days despite glucocorticoids at a dose stable in for at least 3 days.

In an embodiment, the JIA is pcJIA. In some embodiments, the pcJIA is a common oligoarticular JIA. In various embodiments, the pcJIA is an RF-positive polyarticular JIA. In some embodiments, the pcJIA is an RF-negative polyarticular JIA.

In an embodiment, an 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.

In various embodiments, the antibody comprises VH and VL, wherein VH contains three CDRs located in the sequence of SEQ ID NO: 1, and where VL contains three CDRs located in the sequence of SEQ ID NO: 2. In various embodiments, the anti-IL antibody -6R or an antigen binding fragment thereof comprises three HCDRs (ie, HCDR1, HCDR2 and HCDR3) and three LCDRs (ie, LCDR1, LCDR2 and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7 and LCDR3 contains the amino acid sequence of SEQ ID NO: 8.

In an embodiment, the antibody is sarilumab.

In various embodiments, no other DMARD is administered with the antibody. In some embodiments, the subject is administered at least one other DMARD. In an embodiment, at least one other DMARD is administered to a subject in parallel with or simultaneously with the antibody.

In some embodiments, the subject suffers from at least one symptom of RF-positive polyarticular JIA. In some embodiments, the subject suffers from at least one symptom of RF-positive polyarticular JIA, such as symmetrical polyarthritis deformans, which may develop into subluxation of a joint (eg, wrist and/or thumb); joint contracture (eg proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth and finger deformities such as swan neck or boutonniere deformities); chronic synovial inflammation; loss of articular cartilage and erosion of periarticular bone; normocytic chronic anemia; elevated ESR and C-reactive protein; leukocyte count; asymptomatic arthritis of the cervical spine and/or micrognathia. In various embodiments, the subject has joint subluxation (e.g., wrist and/or thumb) and/or joint contracture (e.g., proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth, and finger deformities such as swan neck or boutonniere deformities. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular JIA. In various embodiments, the subject suffers from at least one symptom of RF-negative polyarticular JIA, such as symmetrical polyarthritis with decreased mobility, muscle weakness, and/or decreased physical functioning. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

In an embodiment, the subject suffers from at least one symptom of widespread oligoarticular JIA, such as aseptic inflammatory synovitis, which affects more than 4 joints (eg, large joints such as knees, ankles, wrists) after the first 6 months of the disease; lameness when walking; chronic anterior uveitis; chronic arthritis of the knee or ankle, leading to bone overgrowth in that limb, followed by leg length discrepancy; muscle atrophy (eg extensor muscles, such as the vastus lateralis, quadriceps muscle when the knee is affected); and/or flexion contractures in the knees or wrists. In an embodiment, treating a subject includes reducing, slowing, stopping the progression or otherwise ameliorating any of these symptoms (or any combination thereof).

In various embodiments, the subject suffers from at least one symptom of pcJIA, such as lameness; stiffness upon awakening; subject's reluctance to use an arm or leg; decreased activity level; joint swelling; and/or difficulties with fine motor skills.

In an embodiment of the antibody, there is an improvement in at least one symptom of pcJIA in the subject after administration of the antibody. In various embodiments of an antibody, an improvement is characterized by at least one score or index, such as ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA, and ACR100 JIA, and is defined as an improvement of ≥3/6 of the following baseline set variables with a worsening of no more than 1 /6 of these (i) a physician's global assessment of disease activity (eg, using a visual analogue scale (VAS)), (ii) a patient's or parent's assessment of general well-being, (iii) a Children's Health Assessment Questionnaire (eg, CHAQ-DI), (iv) number of joints with active arthritis, (v) number of joints with limited motion, and (vi) inflammatory index (e.g. high-sensitivity C-reactive protein). In an embodiment, the ACR30 JIA response is a ≥30% improvement from baseline in ≥3/6 of the baseline set variables, with a ≥30% deterioration in no more than 1/6 of them.

In various embodiments of the antibody, improvement in disease activity is characterized by at least one juvenile arthritis disease activity index (such as the juvenile arthritis disease activity index-27, which includes 4 indicators: a physician's global assessment of disease activity, a parent's global assessment of well-being /patient, number of joints with active disease and inflammatory index (hs-CRP or ESR level)).

In various embodiments of the antibody, improvement is characterized by at least one score or indicator, such as a physician's global assessment of disease activity, a patient's or parent's assessment of general well-being, a Children's Health Assessment Questionnaire, number of joints with active arthritis, number of joints with limited motion, high-sensitivity C- reactive protein and/or juvenile arthritis disease activity index (such as juvenile arthritis disease activity index-27).

In an embodiment of the antibody, the age of the subject is from about 2 years to about 17 years.

In various embodiments, the subject has suffered from JIA for at least 6 months. In an embodiment, the subject suffered from arthritis that affected up to 4 joints during at least the first 6 months of the disease, and then progressed to 5 or more joints affected after at least the first 6 months. In some embodiments, the subject suffered from arthritis that affected up to 4 joints during the first 6 months of the disease, and then progressed to 5 or more joints affected after the first 6 months.

In an embodiment of the antibody, the subject has at least 5 joints with active arthritis. In an embodiment of the antibody, the subject has arthritis that affects 5 or more joints during the first 6 months of the disease. In an embodiment of the antibody, the arthritis is rheumatoid factor negative. Alternatively, in an embodiment, the arthritis is rheumatoid factor positive.

In an embodiment, the antibody is administered subcutaneously. In various embodiments, the antibody is administered every week or every two weeks.

In an embodiment, the antibody is administered at a dose of from about 2 mg/kg to about 4 mg/kg. In an embodiment, the dose is administered once a week or once every 2 weeks. In various embodiments, the antibody is administered at a dose of about 2 mg/kg, every week, about 2.5 mg/kg, every week, about 2 mg/kg, every two weeks, about 2.5 mg/kg, every two weeks, approximately 3 mg/kg, every two weeks, and approximately 4 mg/kg, every two weeks. In various embodiments, the antibody is used at the dosages listed in Tables 1-5.

In some embodiments, the subject's body weight is at least about 10 kg. In some embodiments, the subject's body weight is less than 30 kg.

In some embodiments, the subject's body weight is at least about 30 kg.

In some embodiments, the subject's body weight is less than 60 kg.

In various embodiments, the subject's age ranges from 1 year to 17 years.

In certain embodiments, the subject is a human and the antibody is a human antibody.

The present invention further provides an antibody for use in the treatment of pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence light chain variable region of SEQ ID NO: 2, wherein the antibody is administered at a dose of from about 2 mg/kg to about 4 mg/kg per week or biweekly where the subject's body weight is greater than or equal to 10 kg and less than or equal to 60 kg.

In some embodiments, the subject's body 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 two weeks or at a dose of about 2 mg /kg, every week.

In certain embodiments, the subject's body 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 once every two weeks or at a dose of about 2 mg/kg, once a week.

In various embodiments, the subject's body 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 or about 3 mg/kg every two weeks.

In some embodiments, the subject's body 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 or about 3 mg/kg once every two weeks.

In various embodiments, the subject's body 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 two weeks or 2 mg/kg every week.

In certain embodiments, the subject's body 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 once every two weeks or 2 mg/kg once per week .

In some embodiments, the subject's body 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 two weeks or at a dose of about 2. 5 mg/kg, every week.

In various embodiments, the subject's body 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 once every two weeks or at a dose of about 2.5 mg/kg, once a week.

In certain embodiments, the subject's body 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 or about 4 mg/kg every two weeks.

In some embodiments, the subject's body 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 or about 4 mg/kg once every two weeks.

In various embodiments, the subject's body 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 two weeks or 2.5 mg/kg every week.

In certain embodiments, the subject's body 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 once every two weeks or 2.5 mg/kg once in Week.

The present invention further provides an antibody for use in the treatment of pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence a light chain variable region of SEQ ID NO: 2, wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week.

The present invention further provides an antibody for use in the treatment of pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence a light chain variable region of SEQ ID NO: 2, wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week.

The present invention further provides an antibody for use in the treatment of pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence a light chain variable region of SEQ ID NO: 2, wherein the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 26.25 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 12.5 kg and less than 16 kg, and the antibody is administered at a dose of 35 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16 kg and less than 19.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19.5 kg and less than 23 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23 kg and less than 26.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 26.5 kg and less than 30 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 30 kg and less than 37.5 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week.

The present invention further provides an antibody for use in the treatment of pcJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence a light chain variable region of SEQ ID NO: 2, wherein the subject's body weight is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 14.5 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 14.5 kg and less than 16.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16.5 kg and less than 19 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19 kg and less than 21 kg, and the antibody is administered at a dose of 78.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 21 kg and less than 23.5 kg, and the antibody is administered at a dose of 87.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23.5 kg and less than 25.5 kg, and the antibody is administered at a dose of 96.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 25.5 kg and less than 27.5 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 27.5 kg and less than 30 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 39.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 60.5 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 60.5 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week.

The present invention further provides an antibody for use in the treatment of sJIA in a subject in need thereof, wherein the antibody specifically binds IL-6R, wherein the antibody that specifically binds IL-6R comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the sequence a light chain variable region 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 per two weeks , where the subject's body weight is greater than or equal to 30 kg and less than or equal to 210 kg.

In some embodiments, the subject's body 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 every week or at a dose of about 3 mg/kg every two weeks.

In various embodiments, the subject's body 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 per week or at a dose of about 3 mg/kg once per week. two weeks.

In certain embodiments, the subject's body 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 every week or at a dose of 3 mg/kg every two weeks.

In some embodiments, the subject's body 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 weekly or at a dose of 3 mg/kg once every two weeks .

In various embodiments, the subject's body 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 every week or at a dose of about 4 mg/kg every two weeks .

In certain embodiments, the subject's body 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 once a week or at a dose of about 4 mg/kg once a week. once in two weeks.

In some embodiments, the subject's body 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 every week or at a dose of 4 mg/kg every two weeks.

In various embodiments, the subject's body 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 weekly or at a dose of 4 mg/kg once per week. two weeks.

In certain embodiments, the antibody is contained in a pharmaceutical composition. In some embodiments, the composition is an aqueous solution in a volume of less than about 1 ml. In various embodiments, the composition is an aqueous solution in a volume of approximately 0.5 to 1 ml. In certain embodiments, the composition is an aqueous solution in a volume of about 0.75 to 1 ml. In some embodiments, the composition is an aqueous solution in a volume of about 0.5 to 0.75 ml. In various embodiments, the composition is an aqueous solution in a volume of approximately 0.15 to 0.25 ml. In certain embodiments, the composition is an aqueous solution in a volume of about 0.25 to 0.5 ml.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In fig. Figure 1 depicts the study design for two cohorts by dose for a multinational, multicenter, open-label, phase 2, 2-part study in children and adolescents aged 2 to 17 years with pcJIA who had an insufficient response to or intolerance to current therapy. or who were being considered as biologic DMARD candidates. The 2 phases of the study were an initial 12-week main treatment phase followed by a 144-week extension treatment phase. Abbreviations. EOS=end of study, EOT=end of treatment, FDA=Food and Drug Administration, f/u=follow-up, IMP=investigational drug, PK=pharmacokinetics, sIL-6Rα=soluble interleukin 6 receptor α-subunit , V=visit, Wk=week.

Notes All patients must complete an end-of-treatment (EOT) visit (V27, week 156) upon completion of treatment (last IMP injection at week 154 for dose cohort 1 and dose cohort 2 and at week 155 for dose cohort 3) or at the time of early permanent discontinuation treatment (regardless of the treatment phase).

For a patient who discontinued study treatment prematurely during the 12-week main treatment phase, an additional PK visit was required 2 weeks after the EOT visit to obtain a blood sample (V88), and IL-6 and total sIL-6 were measured at the EOT visit. 6Rα.

All patients must attend a post-treatment follow-up visit (V28) 6 weeks after the EOT visit, i.e., week 162 for patients who completed treatment and EOT+6 weeks for patients who discontinued treatment prematurely. However, patients who discontinued treatment prematurely during the main treatment phase were required to continue to complete study visits as scheduled in the protocol without treatment administration until Week 12 (in accordance with FDA guidelines for missing data).

In fig. 2 is a graphical representation of the study design for the 12-week main treatment phase described in FIG. 1 .

In fig. 3 is a graph showing the mean (with standard deviation; SD) functional serum concentrations of sarilumab over the period of time after the first subcutaneous administration of sarilumab in patients with pcJIA. Abbreviations in the graph include q2w=biweekly, qw=weekly, SC=subcutaneous, SD=standard deviation. Post-treatment concentrations below LLOQ were changed to LLOQ/2.

In fig. 4 is a graph showing the mean (with standard deviation; SD) observed residual serum concentrations of sarilumab over the period of time after the first subcutaneous administration of sarilumab in patients with pcJIA.

In fig. 5 is a graph showing the ACR30 JIA (hs-CRP) response rate (observed during treatment) during the 12-week main treatment phase.

In fig. 6 is a graph showing the ACR30 JIA (hs-CRP) response rate (non-responder imputation approach) during the 12-week main treatment phase.

In fig. Figure 7 depicts the study design for two dose cohorts for a multinational, multicenter, open-label, sequential, phase 2 study in children and adolescents aged 1 to 17 years (or country age requirements apply) with sJIA with insufficient response to or who are experiencing standard therapy intolerance and who will receive SC injections of sarilumab q2w or qw.

In fig. Figure 8 is a study flow diagram showing the distribution of patients. ALT=alanine aminotransferase; QW=every week; Q2W=every 2 weeks.

In fig. 9A-9D are graphs showing the proportions of patients achieving ACR JIA response thresholds and the mean change from baseline in JADAS-27-CRP at week 12 observed during treatment. CRP=C-reactive protein; JADAS-27-CRP=juvenile arthritis disease activity index with 27 joint counts and CRP; ACR30 JIA/70/90=juvenile idiopathic arthritis response rate of 30/70/90% according to the American College of Rheumatology; SE=standard error.

In fig. 10A-10B are graphs of the mean CRP concentration and the proportion of patients with undetectable CRP (<0.2 mg/L) during the main treatment phase who were observed during treatment. BL=baseline; CRP=C-reactive protein; SE=standard error.

In fig. 11A-11C are graphs of the proportion of patients experiencing ACR JIA responses calculated by substituting data from non-responders. CRP=C-reactive protein. ACR30 JIA/70/90=juvenile idiopathic arthritis response rate of 30/70/90% according to the American College of Rheumatology

DETAILED DESCRIPTION

The present invention provides pharmaceutical compositions and methods of using these compositions to treat JIA (eg, sJIA and pcJIA) and improve at least one symptom of the disorder. These compositions include at least one antibody that specifically binds the human interleukin-6 receptor (hIL-6R).

The effectiveness of an antibody to treat JIA is typically measured using standard methods in the art commonly used by clinicians and rheumatologists, for example, using the ACR30/50/70/90/100 juvenile idiopathic arthritis response, ACR component, changes in glucocorticoid use (for sJIA), and Juvenile Arthritis Disease Activity Index-27 (JADAS). Cm. 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 ACR JIA score is well known to clinicians and can be easily determined by experts in the diagnosis and treatment of JIA. The ACR JIA score is also known as (and is synonymous with) the pediatric ACR. For non-limiting descriptions related to the ACR JIA, see Giannini et al. (1994) "Preliminary core of set of outcome variables for use in JRA clinical trials" Arthritis Rheum. 37 Suppl 9:S428, which is incorporated herein by reference for all purposes.

As used in the claims in the Summary and Detailed Description sections of this document, the term "about" in quantitative terms refers to an amount that is plus or minus 10% of the value it changes (rounded to the nearest whole number, unless the value is divisible, such as the number of molecules or nucleotides). For example, the phrase "about 100 mg" would cover from 90 mg to 110 mg, inclusive, the phrase "about 2500 mg" would cover from 2250 mg to 2750 mg. When applying a percentage, the term "approximately" refers to an amount that is plus or minus 10% relative to the percentage. For example, the phrase "approximately 20%" would cover 18-22%, and the phrase "approximately 80%" would cover 72-88% inclusive. Additionally, where the expression "about" is used herein in conjunction with a quantitative term, it should be understood that in addition to the value of plus or minus 10%, the exact value of the quantitative term is also assumed and described. For example, the term "approximately 23%" clearly implies, describes, and includes exactly 23%.

It should be noted that the singular form refers to one or more of these objects; for example, the term "symptom" refers to one or more symptoms. Accordingly, the singular forms, "one or more" and "at least one" may be used interchangeably herein.

In addition, the expression "and/or" as used herein is to be construed as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and "B" (separately). Likewise, the term “and/or” when used in a phrase 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 (separately); B (separately) and C (separately).

It should be understood that whenever aspects are described herein by the words "comprising", other similar aspects are also described by the terms "consisting of" and/or "consisting essentially of".

JIA

Arthritis is swelling in a joint or limited range of motion in a joint with joint pain or tenderness that has persisted for at least 6 weeks, is monitored by a physician, and is not due to a primary mechanical disorder. (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 in its entirety).

JIA is an autoimmune disorder involving inflammation of the joints. The disorder usually appears in patients before age 16 years and can continue into adulthood. JIA affects 1 in 1,000 children. Typical symptoms include limping, stiffness when waking up, the child's reluctance to use an arm or leg, decreased activity level, persistent fever, joint swelling and difficulty with fine motor skills. JIA includes 7 subtypes (ie, systemic JIA, RF-positive polyarticular JIA, and RF-negative polyarticular JIA), classified by age of onset, range, and disease characteristics in the first 6 months after onset, as defined by ILAR in 2001.

In sJIA, joint inflammation may not be evident early in the disease, when noticeable signs are extra-articular in nature, delaying diagnosis, but most patients eventually develop polyarticular inflammation. Clinical features (defined by ILAR classification) include arthritis with concomitant/preceding daily fever for at least 2 weeks and one or more of a transient salmon-colored erythematous rash, generalized lymphadenopathy, hepato/splenomegaly, and serositis. In some embodiments, exclusion criteria for sJIA include psoriasis or psoriasis in a first-degree relative; presence of human leukocyte antigen B27 (HLA-B27); ankylosing spondylitis, enthesitis-associated arthritis, sacroiliitis with concomitant chronic inflammatory bowel disease, Reiter's disease in a first-degree relative; and detection of rheumatoid factor (RF) at least 2 times 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 outcomes, patients with sJIA are known to have a 50% relapse rate at 1 year; in 25% of cases of severe destructive joint disease; general growth abnormalities and macrophage activation syndrome.

sJIA fever classically presents as a daily fever with peaks that may be accompanied by one or more of a transient (non-fixed) erythematous rash, generalized lymph node enlargement, 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. 2004 Feb;31(2):390-2). The peak onset of sJIA occurs in patients aged 4 to 6 years and can sometimes occur during adolescence in patients aged 12 to 18 years.

As used herein, the term “polyarticular juvenile idiopathic arthritis” or “pcJIA” includes RF-positive polyarticular JIA, RF-negative polyarticular JIA, and advanced oligoarticular JIA.

Polyarticular JIA, a subtype of pcJIA, affects at least 5 joints. Both large and small joints may be affected, often with a symmetrical bilateral distribution, often affecting weight-bearing joints and small joints of the hands. Arthritis may be accompanied by low-grade fever. The presence of rheumatoid factor (RF) distinguishes 2 forms of polyarticular JIA: RF-positive and RF-negative polyarticular JIA.

Rheumatoid factor (RF) positive polyarticular JIA accounts for a relatively small proportion of all children and adolescents with JIA (3–5%), but it is the only subgroup of JIA that resembles adult rheumatoid arthritis (RA), a deforming symmetrical polyarthritis caused by chronic synovial inflammation , loss of articular cartilage and erosion of periarticular bone. Features of RF-positive pcJIA include a mean age of onset of 12 to 14 years, marked female predominance (female/male ratio 13:1), symmetrical involvement of small and large joints, production of polyclonal IgM RF or antibodies to CCP, genetic predisposition (association with HLA-DR4 allele), a clinical course characterized by normocytic chronic anemia (reticuloendothelial block), and acute phase proteins (elevated ESR and C-reactive protein) that rarely normalize spontaneously, as well as elevated white blood cell counts. An association with the formation of hard, mobile, painless rheumatoid nodules is possible but rare. Laboratory findings are expected to be more serious than those associated with oligoarthritis. Long-term consequences include joint subluxation (wrist and thumbs), joint contractures (proximal and distal interphalangeal joints, proximal interphalangeal joint bone overgrowth, and finger deformities (eg, swan neck or boutonniere). Asymptomatic arthritis of the cervical spine, associated with decreased extension, can lead to subluxation, usually of the C2-C3 vertebrae and fusion of the posterior vertebral elements. Arthritis of the temporomandibular joint can also be asymptomatic and lead to micrognathia (Petty, RE et al., 2004. J Rheumatol. 31). (2):390-2).

RF-negative polyarticular JIA presents at a younger age (late childhood, 7 to 9 years) than RF-positive polyarticular JIA and accounts for 11 to 28% of all children and adolescents with JIA. It may not be as destructive and persistent as RF-positive disease, but by definition affects 5 or more joints. Radiological changes occur later in RF-negative disease than in RF-positive disease. Severe limitations in movement are usually accompanied by muscle weakness and decreased physical functioning.

Oligoarticular JIA (oJIA), another subtype of pcJIA, is the most common subtype of juvenile arthritis, accounting for approximately 50% of all patients with JIA in the United States and Western Europe. Onset occurs between 1 and 5 years of age with a peak between 2 and 3 years of age. It is defined as an aseptic inflammatory synovitis that usually affects up to 4 joints (usually larger joints such as knees, ankles, wrists) and is not associated with constitutional symptoms such as fever, weight loss, fatigue, or systemic signs of inflammation. However, if more than 4 joints are affected during the first 6 months of the disease, it is referred to as widespread oligoarthritis, as opposed to persistent oJIA, which affects up to 4 joints throughout the disease period. Children often look well despite walking with a limp. oJIA carries a risk of developing chronic anterior uveitis, especially in the presence of antinuclear antibodies (ANA) and when the disease begins in early childhood. It is usually initially asymptomatic and requires screening examination using an ophthalmic slit lamp. Chronic arthritis of the knee or ankle can lead to bone overgrowth in that limb, followed by leg length discrepancy. Muscle atrophy is found, often in the extensor muscles (eg, vastus major, quadriceps in knee lesions) and/or flexion contractures in the knees and, less commonly, the wrists.

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

One candidate treatment for JIA is interleukin-6 (IL-6) inhibition. IL-6 is a key cytokine with a wide range of biological activities, including regulation of immune reactivity, acute phase response, inflammation, tumorigenesis and hematopoiesis (Kishimoto, et al. The Cytokine Handbook (London: Academic Press). 2003, pp. 281-304) . Oversynthesis of IL-6 has been found to play a pathological role in chronic inflammatory diseases.

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. IL6Rα also exists in a soluble form, which is involved in transsignaling and causes IL6 to affect cells that do not express IL6Rα, including synovial cells in the joint (Rose-John et al. , J Leukoc Biol. 2006;80(2 ), 227-36).

Sarilumab, also referred to as SAR153191 or REGN88, is a recombinant anti-IgG1-kappa monoclonal antibody with a fully human sequence directed against the alpha subunit of the IL-6 receptor complex (IL-6Rα). Sarilumab is an effective and specific inhibitor of IL-6 signaling. By binding IL-6Rα with high affinity, sarilumab blocks IL-6 binding and interrupts the cytokine-mediated signaling cascade. In certain embodiments, interleukin-6 is a major element in the etiology of rheumatic conditions, and inhibition of signaling through it is an important part of the mechanism of action of sarilumab. In analyzes ex vivo sarilumab did not demonstrate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in relevant cell types where sarilumab binding was confirmed by fluorescence-activated cell sorter (FACS) analysis (Committee for 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).

Antibodies

The present invention provides methods that include administering to a subject an antibody or an antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term “hIL-6R” means a human cytokine receptor that specifically binds human IL-6. In certain embodiments, the antibody that is administered to a patient specifically binds to the extracellular domain of hIL-6R.

The term "antibody" as used herein refers to immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains and two light (L) chains linked by disulfide bonds, as well as multimers thereof (e.g. IgM). Each heavy chain contains 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 contains 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 hypervariable regions called CDRs, which alternate with more conserved regions called framework regions (FR). Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the antibody FR (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially altered. The amino acid consensus sequence can be determined based on side-by-side analysis of two or more CDRs.

The term "antibody" as used herein also includes antigen-binding fragments of entire antibody molecules. The terms "antigen binding portion" of an antibody, "antigen binding fragment" of an antibody, etc., as used herein, include any naturally occurring, enzymatically produced, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form complex. Antigen-binding antibody fragments can be obtained, for example, from whole antibody molecules by any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering technologies involving manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or readily available, e.g. from commercial sources, DNA libraries (including e.g. phage-antibody libraries), or it can be synthesized. DNA can be sequenced and chemically manipulated or manipulated using molecular biology techniques, for example, to arrange one or more variable and/or constant domains in a suitable configuration or to introduce codons, create cysteine residues, modify, add or remove amino acids, and etc.

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 molecules (scFv); (vi) dAb fragments and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of the antibody (e.g. a dedicated CDR, such as a CDR3 peptide), or a conformationally restricted peptide FR3-CDR3-FR4. Other engineered molecules such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tri-bodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies), small modular protein (SMIP) immunopharmaceuticals, and shark IgNAR variable domains are also included in the expression “antigen binding fragment” as used herein.

An antigen binding fragment of an antibody will typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and will typically contain at least one CDR that is adjacent to or in frame with one or more frame sequences. In antigen binding fragments containing a VH domain linked to a VL domain, the VH and VL domains may be arranged relative to each other in any suitable order. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen binding fragment of the antibody may comprise a monomeric VH or VL domain.

In certain embodiments, an antigen binding fragment of an antibody may comprise 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 in an antigen binding fragment of an 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 either be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region in various embodiments may consist of at least 2 (for example, 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in the formation of a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Additionally, an antigen binding antibody fragment, in various embodiments, may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with each other and/or with one or more monomeric VH or VL domains ( For example, via disulfide bond(s).

In specific embodiments, the antibody or antibody fragment for use in the method of the present invention may be a multispecific antibody that may be specific for different epitopes of a single target polypeptide or may contain antigen binding domains specific for epitopes of more than one target polypeptide. An exemplary antibody in a bispecific format that can be used in the context of the present invention includes the use of a C _H3 domain of a first immunoglobulin (Ig) and a C _H3 domain of a second immunoglobulin Ig, wherein the C _H3 domains of the first and second Ig differ from each other by at least one amino acid and wherein the difference of at least one amino acid reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody in which there is no difference in amino acids. In one embodiment, the first Ig C _H3 domain binds Protein A and the second Ig C _H3 domain contains a mutation that reduces or eliminates protein A binding, such as modification H95R (IMGT exon numbering; H435R EU exon numbering). The second C _H3 may additionally contain modification Y96F (according to IMGT; Y436F according to EU). Additional modifications that can be detected in the second _CH3 include: D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU) in the case of IgG1 antibodies; N44S, K52N and V82I (IMGT; N384S, K392N and V422I according to EU) in the case of IgG2 and Q15R antibodies, N44S, K52N, V57M, R69K, E79Q and V82I (according to IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I according to EU) in the case of IgG4 antibodies. The bispecific antibody format options described above are contemplated within the scope of the present invention. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, in various embodiments, can be adapted for use in the context of an anti-IL-6R antibody antigen binding fragment using standard techniques available in the art.

Fully human anti-IL-6R monoclonal antibodies may contain one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains relative to the corresponding germline sequences. 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. The present invention includes antibodies and antigen binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions and/or CDR regions are backmutated to the corresponding germline residue(s). lineage or to a conservative amino acid substitution (natural or unnatural) of the corresponding germline residue(s) (such sequence changes are referred to herein as “germline reverse mutations”). A person skilled in the art, starting with the heavy and light chain variable region sequences disclosed herein, can readily produce a variety of antibodies and antigen binding fragments that contain one or more individual germline back mutations or combinations thereof. In certain embodiments, all framework residues and/or CDR residues in the VH and/or VL domains are backmutated to a germline sequence. In other embodiments, only certain residues are backmutated into the germline sequence, e.g. only the mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2 or CDR3. In addition, the antibodies of the present invention may contain any combination of two or more germline reverse mutations within the framework regions and/or CDR regions, i.e. where certain individual residues are backmutated to the germline sequence, while certain other residues that differ from the germline sequence are maintained. Once produced, antibodies and antigen-binding fragments that contain one or more germline reverse mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced biological antagonistic or agonistic properties (in if necessary), reduced immunogenicity, etc. Antibodies and antigen binding fragments obtained using this general method are covered by the present invention.

The constant region of an antibody is important in terms of the antibody's ability to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype can be selected based on whether the antibody is required to mediate cytotoxicity.

The term “human antibody” as used herein is intended to include antibodies containing variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies provided herein may, in various embodiments, include amino acid residues not encoded by human germline immunoglobulin sequences (e.g. mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo), for example, in CDR and, in some embodiments, in CDR3. However, the term “human antibody” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences.

The term “recombinant human antibody” as used herein is intended to include all human antibodies that are produced, expressed, generated or isolated by recombinant methods, such as antibodies expressed by a recombinant expression vector transfected into a host cell (described further). below), antibodies isolated from a combinatorial library of human recombinant antibodies (described further below), antibodies isolated from an animal (e.g. mouse), which is transgenic for human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295, incorporated herein by reference in its entirety), or antibodies produced, expressed, created or isolated by any other means that involve splicing human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to mutagenesis in vitro (or, if an animal transgenic for human Ig sequences is used, then somatic mutagenesis in vivo) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from and related to human germline VH and VL sequences, may not exist naturally within the human germline antibody repertoire in vivo.

Human antibodies can occur in two forms, due to the heterogeneity of the hinge regions. In an embodiment, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain disulfide bond that links the heavy chains. In another embodiment, the dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75-80 kDa is formed, consisting of covalently linked light and heavy chains (half-antibody). These embodiments/forms are extremely difficult to separate even after affinity purification.

The frequency of occurrence of the second form in different isotypes of intact IgG is due, without limitation, to structural differences associated with the isotype of the hinge region of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. , (1993) Molecular Immunology 30:105, incorporated by reference in its entirety) to levels typically observed with the human IgG1 hinge. The present invention covers, in various embodiments, antibodies with one or more mutations in the hinge region, CH2 or CH3 region, which may be necessary, for example, in production, to increase the yield of the desired form of the antibody.

The term "isolated antibody" as used herein means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of the body, or from a tissue or cell in which the antibody is originally present or naturally produced is an “isolated antibody.” In various embodiments, the isolated antibody also includes the antibody in situ in the recombinant cell. In other embodiments, isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In various embodiments, the isolated antibody may contain substantially no other cellular material and/or other chemical compounds.

The term "specifically binds" or the like means that the antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining the presence of specific binding of an antibody to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. For example, an antibody that “specifically binds” IL-6R as used herein includes antibodies that which bind IL-6R or a portion thereof with a KD of 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 less than about 0.5 nM, as measured by surface plasmon resonance analysis. Specific binding can also be characterized by a dissociation constant of at least about 1×10 ^-6 M or less. In other embodiments, the dissociation constant is at least about 1×10 ^-7 M, 1×10 ^-8 M, or 1×10 ^-9 M. An isolated antibody that specifically binds human IL-6R may, however, exhibit cross-reactivity against other antigens, such as IL-6R molecules from other (non-human) species.

The term “surface plasmon resonance” as used herein refers to an optical phenomenon that enables real-time analysis of interactions by detecting changes in protein concentrations in a biosensor array, such as with the BIACORE system (Biacore Life Sciences at GE Healthcare, Piscataway, New Jersey).

The term "KD" as used herein is intended to refer to the equilibrium dissociation constant of the antibody-antigen interaction.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. One antigen can have more than one epitope. Thus, different antibodies can bind to different regions on the antigen and can have different biological effects. Epitopes can be conformational or linear. A conformational epitope is formed by spatially adjacent amino acids from different segments of a linear polypeptide chain. A linear epitope is formed by adjacent amino acid residues in a polypeptide chain. Under certain conditions, the epitope may include fragments of saccharides, phosphoryl groups or sulfonyl groups of the antigen.

Antibodies to IL-6R useful for the methods described herein, in various embodiments, may include one or more amino acid substitutions, insertions and/or deletions in the framework regions and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibodies were 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, the present invention includes methods comprising the use of antibodies and antigen binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more framework regions and/or CDR regions are mutated relative to the corresponding (corresponding to) the residue(s) of the germline sequence from which the antibody is derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) ( such sequence changes are referred to herein collectively as "germline mutations"). Numerous antibodies and antigen binding fragments can be constructed that contain one or more individual germline mutations or combinations thereof. In certain embodiments, all framework regions and/or CDR residues in the VH and/or VL domains are back-mutated to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, e.g. only residues located in the first 8 amino acids of FR1 or the last 8 amino acids of FR4 are mutated, or only residues located in CDR1, CDR2 or CDR3 are mutated. In other embodiments, one or more residues of the framework regions and/or CDRs are mutated to the corresponding residue(s) of another germline sequence (i.e. germline sequence that is different from the germline sequence from which the antibody was originally derived). In addition, antibodies may contain any combination of two or more germline mutations in framework regions and/or CDR regions, e.g. wherein certain individual residues are mutated to a corresponding residue of a particular germline sequence, while certain other residues that differ from the original germline sequence are retained or mutated to a corresponding residue of a different germline sequence. Once produced, antibodies and antigen-binding fragments that contain 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 biological antagonistic or agonistic properties (in the case of necessary), reduced immunogenicity, etc. The present invention covers the use of antibodies and antigen binding fragments obtained using this general method.

The present invention also includes methods employing anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the present invention includes the use of antibodies to IL-6R with amino acid sequences HCVR, LCVR and/or CDR with, for example, 10 or less, 8 or less, 6 or less, 4 or less, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein.

According to the present invention, an anti-IL-6R antibody or an antigen-binding fragment thereof, in various embodiments, comprises an HCVR, LCVR and/or a CDR comprising any of the amino acid sequences of the anti-IL-6R antibodies described in US Pat. No. 7,582,298, incorporated herein by reference. in its entirety. In certain embodiments, an anti-IL-6R antibody or antigen binding fragment thereof comprises an HCDR of HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCDR of LCVR containing the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the antibody IL-6R or an antigen binding fragment thereof comprises three HCDRs (ie HCDR1, HCDR2 and HCDR3) and three LCDRs (ie LCDR1, LCDR2 and LCDR3), wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7 and LCDR3 contains the amino acid sequence of SEQ ID NO: 8. In other specific embodiments, the anti-IL-6R antibody or antigen binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1, and LCVR containing the amino acid sequence of SEQ ID NO: 2.

In another embodiment, an anti-IL-6R antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R contains the amino acid sequence of SEQ ID NO: 11. In certain illustrative embodiments, the methods of the present invention provide the use of an anti-IL-6R antibody, designated and known in the art as sarilumab, or a biological equivalent thereof.

The amino acid sequence of SEQ ID NO: 1 is EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNSGRIGYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVTVSS.

The amino acid sequence of SEQ ID NO: 2 is DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK.

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

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

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

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

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

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

The amino acid sequence of SEQ ID NO: 9 is

EVQLVESGGGLVQPGRSLRLSCAAS RFTFDDYA MHWVRQAPGKGLEWVSG ISWNSGRI GYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYC AKGRDSFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

The amino acid sequence of SEQ ID NO: 10 is

DIQMTQSPSSVSASVGDRVTITCRAS QGISSW LAWYQQKPGKAPKLLIY GAS SLESGVPSRFSGSGSGTDFTISSLQPEDFASYYC QQANSFPYT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC.

The sequence under SEQ ID NO: 11 is MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVP EGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD.

The term "biological equivalent" as used herein refers to a molecule having similar bioavailability (rate and degree of availability) after administration at the same molar dose and under similar conditions (e.g. same route of administration) so that, taking into account both efficacy and safety, the expected effect is essentially the same as that of the comparable molecule. Two pharmaceutical compositions containing an anti-IL-6R antibody are biologically equivalent if they are pharmaceutically equivalent, meaning that they contain the same amount of active ingredient (e.g. antibodies to IL-6R) in the same dosage form, by the same route of administration, and meet the same or comparable standards. Biological equivalence can be determined, for example, by testing in vivo, comparing the pharmacokinetic parameters of the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration versus time curve (AUC).

The present invention, in certain embodiments, relates to methods comprising administering to a subject an antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2.

The present invention provides pharmaceutical compositions containing such an antibody and methods of using these compositions.

In various embodiments, an antibody comprising a heavy chain variable region of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2 is an antibody that specifically binds hIL-6R. See International Publication No. WO2007/143168, which is incorporated herein by reference in its entirety. In an embodiment, the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 9 and a light chain variable region comprising the sequence of SEQ ID NO: 10. In various embodiments, the antibody is sarilumab.

DMARD

DMARDs are medications that are used in rheumatoid arthritis and JIA to slow the progression of the disease.

DMARDs are divided into synthetic (sDMARDs) and biological (bDMARDs). sDMARDs include non-exhaustively methotrexate, sulfasalazine, leflunomide and hydroxychloroquine. bDMARDs include non-exhaustively adalimumab, golimumab, etanercept, abatacept, infliximab, rituximab and tocilizumab.

In some embodiments, no other DMARD is administered with the antibody. In some embodiments, the subject is administered at least one other DMARD. In an embodiment, at least one other DMARD is administered to a subject in parallel with or simultaneously with the antibody.

In some embodiments, the subject has had an insufficient response to current JIA treatment. In some embodiments, the subject has had an insufficient response to current JIA treatment and is being considered as a candidate for treatment with a bDMARD. In some embodiments, the subject's current treatment is a corticosteroid, sDMARD, and/or bDMARD-based treatment. By way of example, and not by way of limitation, in some embodiments, the corticosteroid is selected from prednisone, prednisolone, and methylprednisolone.

Methods of administration and compositions

The methods described herein provide for the administration of a therapeutically effective amount of an anti-IL-6R antibody to a subject. As used herein, the term “effective amount” or “therapeutically effective amount” is a therapeutic dose that results in treatment of sJIA and/or pcJIA. As used herein, the term “treatment” means normalizing one or more symptoms associated with sJIA and/or pcJIA or producing a biological effect (eg, a decrease in the level of a specific biomarker) that is associated with the underlying pathological mechanism(s) leading to the condition or symptom(s). For example, a dose of an anti-IL-6R antibody that causes improvement in any of the following symptoms or conditions associated with juvenile idiopathic arthritis is considered a "therapeutically effective amount": lameness, stiffness upon awakening, reluctance of the subject to use an arm or leg, decreased level of activity, constant fever, joint swelling, and difficulty with fine motor skills.

“Improvement” in a JIA-associated symptom, in various embodiments, refers to a decrease in the frequency of occurrence of a JIA symptom, which may correlate with an improvement in one or more JIA-associated tests, assessments, or measures (as described herein). For example, improvement may correlate with an increase from baseline in one or more ACR JIA criteria and/or a decrease from baseline in one or more of the following: corticosteroid use, juvenile arthritis disease activity index, or fever. In one embodiment, the improvement may include reducing the initial level of stiffness (e.g. joint with limited movement). As used herein, the expression "baseline" in relation to a JIA-associated parameter means the numerical value of the JIA-associated parameter for a patient before or during the entire period of administration of the antibody of the present invention. A detectable "improvement" may also be detected using at least one test, assessment, or metric described herein. In various embodiments, improvement is detected using at least one selected from the group consisting of: American College of Rheumatology (ACR) juvenile idiopathic arthritis response (eg, ACR30 JIA, ACR50 JIA, ACR70 JIA, ACR90 JIA, and ACR100 JIA). In various embodiments, the improvement is characterized by at least one score or measure, such as a physician's Global Disease Activity Index score, a patient's or parent's assessment of general well-being, a Children's Health Assessment Questionnaire, number of joints with active arthritis, number of joints with limited motion, high-sensitivity C- reactive protein. In some embodiments, improvement in sJIA symptom is a decrease in fever (eg, in subjects with fever when the antibody is first administered). In various embodiments, the improvement is characterized by at least one biomarker. In some embodiments, the improvement is characterized by an increase in the level of at least one biomarker. In some embodiments, the improvement is characterized by a decrease in the level of at least one biomarker.

In another example, treatment has not been effective when a dose of anti-IL-6R antibody does not result in detectable improvement in one or more parameters or symptoms associated with JIA, or which does not produce a biological effect that correlates with the underlying pathological(s). ) the mechanism(s) causing the condition or symptom(s) of JIA.

In some of these embodiments, the anti-IL-6R antibody is administered subcutaneously. In some of these embodiments, the anti-IL-6R antibody is sarilumab.

In accordance with the methods of the present invention, the therapeutically effective amount of anti-IL-6R antibody that is administered to a subject will vary depending on age and size (eg, body weight or body surface area) of the subject, as well as the route of administration and other factors well known to those skilled in the art.

In certain embodiments, the dose of the antibody varies depending on the body weight of the subject. In various embodiments, if the subject has a body weight of at least 30 kg (e.g. up to 60 kg, 70 kg, 80 kg, 90 kg or 100 kg), then the subject is administered a dose of 2.0 mg/kg once every 2 weeks. In other embodiments, if the subject has a body weight of at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, then the subject is administered a dose of 2.0 mg/kg once per 2 weeks. In some embodiments, if the subject has a body weight of at least 30 kg, then the subject is administered a dose of 3.0 mg/kg once every 2 weeks. In some embodiments, if the subject has a body weight of at least 30 kg, then the subject is administered a dose of 4-6 mg/kg once every 2 weeks. In other embodiments, if the subject has a body weight of at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, then the subject is administered a dose of 3.0 mg/kg once per 2 weeks. In certain embodiments, if the subject has a body weight of at least 30 kg, then the subject is administered a dose of 2.0 mg/kg once per week. In other embodiments, if the subject has a body weight of at least 30 kg and less than 40, 50, 60, 70, 80, 90, or 100 kg, then the subject is administered a dose of 2.0 mg/kg one time in Week. In various embodiments, if the subject has a body weight of 10-<30 kg, then the subject is administered a dose of 2.5 mg/kg every 2 weeks. In certain embodiments, if the subject has a body weight of 10-<30 kg, then the subject is administered a dose of 4 mg/kg every 2 weeks. In some embodiments, if the subject has a body weight of 10-<30 kg, then the subject is administered a dose of 2.5 mg/kg per week. In various embodiments, if the subject has a body weight of 10-<30 kg, then the subject is administered a dose of 5-7 mg/kg every 2 weeks. In various embodiments, if the subject has a body weight of 10-<30 kg, then the subject is administered a dose of 4 mg/kg every 2 weeks.

In certain embodiments, the dose of anti-IL-6R antibody administered to a subject is from about 10 mg to about 600 mg. In some embodiments, the dose of antibody administered to the subject is from about 25 mg to about 200 mg. In various embodiments, the dose of antibody administered to a subject is from about 60 mg to about 200 mg. For example, the present invention includes (without limitation) methods wherein: 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, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 135 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 160 mg, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, approximately 200 mg, approximately 205 mg, approximately 210 mg, approximately 215 mg, approximately 220 mg, approximately 225 mg, approximately 230 mg, approximately 235 mg, approximately 240 mg, approximately 245 mg, approximately 250 mg, approximately 255 mg, approximately 260 mg, approximately 265 mg, approximately 270 mg, approximately 275 mg, approximately 280 mg, approximately 285 mg, approximately 290 mg, approximately 295 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 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 anti-IL antibodies -6R is administered to the patient once a week or once every two weeks.

As used herein, the expression "administered from about 2.0 to about 4.0 mg/kg" means that the specified substance is administered at any value within the specified range, including the end points of the range. For example, “the dose of anti-IL-6R antibody administered to a patient is 2.0 mg/kg to 4.0 mg/kg” includes administration of 2.0 mg/kg anti-IL-6R antibody, 4.0 mg/kg anti-IL-6R antibody to IL-6R and all doses in between.

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

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

The amount of anti-IL-6R antibody administered to a patient can be expressed in milligrams of antibody per kilogram of patient body weight (ie, mg/kg). For example, the methods of the present invention comprise administering an 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's body weight. In certain embodiments, the anti-hIL6R antibody is sarilumab and is administered at a dose of from about 2 mg/kg to about 4 mg/kg. In various embodiments, the anti-hIL6R antibody is sarilumab and is administered at a dose of from about 2 mg/kg to about 3 mg/kg. In certain embodiments, the anti-hIL6R antibody is sarilumab and is administered at a dose of from about 2.5 mg/kg to about 4 mg/kg. In various embodiments, the anti-hIL6R antibody is sarilumab and is administered at a dose of about 2 mg/kg to about 3 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 mg/kg to 4 mg/kg at a frequency of once per week (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 per week (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/day. kg. In some embodiments, the anti-hIL6R antibody comprises VH and VL, wherein VH contains three CDRs located in the sequence SEQ ID NO: 1, and where VL contains three CDRs located in the sequence SEQ ID NO: 2. In other embodiments, the anti-hIL6R antibody is sarilumab.

The methods of the present invention involve administering multiple doses of an anti-IL-6R antibody to a patient over a period of time. For example, an anti-IL-6R antibody can be administered about 1-5 times per day, about 1-5 times per week, about 1-5 times per month, or about 1-5 times per year. In certain embodiments, the methods of the present invention comprise administering a first dose of an anti-IL-6R antibody to a patient at a first time point, followed by administration of at least a second dose of an anti-IL-6R antibody to the patient at a second time point. In certain embodiments, the first and second doses may contain the same amount of anti-IL-6R antibody. For example, each of the first and second doses may contain from about 10 mg to about 500 mg, from about 20 mg to about 300 mg, from about 100 mg to about 200 mg, or from about 100 mg to about 150 mg of antibody. The period of time between the first and second doses can range from approximately a few hours to several weeks. For example, the second time point (i.e. the time at which the second dose is administered) can range from about 1 hour to about 7 weeks after the first time point (i.e. time when the first dose is administered). In accordance with certain illustrative embodiments of the present invention, the second time point may be located after about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 2 days, about 3 days , approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 2 weeks, approximately 4 weeks, approximately 6 weeks, approximately 8 weeks, approximately 10 weeks, approximately 12 weeks, approximately 14 weeks or more after the first time point . In certain embodiments, the second time point is located after about 1 week or about 2 weeks. The third and subsequent doses may be administered in a similar manner throughout the patient's course of treatment. The present invention provides methods of using therapeutic compositions containing antibodies to IL-6R or antigen binding fragments thereof and optionally one or more additional therapeutic agents. The therapeutic compositions of the present invention will be administered with suitable carriers, excipients and other agents that are included in the formulations to provide improved transport, delivery, tolerability, etc. A large number of suitable formulations can be found in a reference book familiar to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, incorporated herein by reference in its entirety. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicles containing lipids (cationic or anionic) (such as LIPOFECTIN), DNA conjugates, anhydrous absorption pastes, oil-in-water emulsions and "water in oil", carbowax emulsions (polyethylene glycols 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, incorporated herein by reference in its entirety.

Various delivery systems are known and can be used to administer the pharmaceutical composition of the present invention, e.g. encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol. Chem. 262:4429-4432, incorporated herein by reference in its entirety). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucous membranes (for example, mucous membrane of the oral cavity, mucous membrane of the rectum and intestines, etc.) and can be administered together with other biologically active agents. Administration may be systemic or local. Anti-IL-6R antibody can be administered subcutaneously.

The pharmaceutical composition can also be delivered in a vesicle, such as a liposome (see Langer (1990) Science 249:1527-1533, incorporated herein by reference in its entirety). In certain situations, the pharmaceutical composition can be delivered in a controlled release system, such as using a pump or polymeric materials. In another embodiment, the controlled release system can be placed close to the target of the composition, requiring only a fraction of the systemic dose.

Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, local injection, drip infusion, etc. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared by e.g. by dissolving, suspending or emulsifying the antibody or salt thereof described above in a sterile aqueous or oily medium commonly used for injection. As the aqueous injection medium, there are, for example, saline solution, isotonic solution containing glucose and other auxiliary agents, etc. which can be used in combination with an appropriate solubilizing agent such as alcohol (e.g. ethanol), polyhydric alcohol (for example, propylene glycol, polyethylene glycol), nonionic surfactant [e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil), etc.). The oil medium used is, for example, sesame oil, soybean oil, etc., which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection solution thus obtained can be placed in a suitable ampoule.

The antibody is typically formulated as described herein and in International Publication No. WO2011/085158, which is incorporated herein by reference in its entirety.

In various embodiments, the antibody is administered as an aqueous buffer solution with a pH of approximately 6.0 containing

- approximately 21 mM histidine,

- approximately 45 mM arginine,

- approximately 0.2% (w/v) polysorbate 20,

- approximately 5% (w/v) sucrose and

- from about 100 mg/ml to about 200 mg/ml antibody.

In another embodiment, the antibody is administered as an aqueous buffer solution with a pH of approximately 6.0 containing

- approximately 21 mM histidine,

- approximately 45 mM arginine,

- approximately 0.2% (w/v) polysorbate 20,

- approximately 5% (w/v) sucrose and

- at least about 130 mg/ml antibody.

In another embodiment, the antibody is administered as an aqueous buffer solution with a pH of approximately 6.0 containing

- approximately 21 mM histidine,

- approximately 45 mM arginine,

- approximately 0.2% (w/v) polysorbate 20,

- approximately 5% (w/v) sucrose and

- approximately 131.6 mg/ml antibody.

In another embodiment, the antibody is administered as an aqueous buffer solution with a pH of approximately 6.0 containing

- approximately 21 mM histidine,

- approximately 45 mM arginine,

- approximately 0.2% (w/v) polysorbate 20,

- approximately 5% (w/v) sucrose and

- approximately 175 mg/ml antibody.

In other embodiments, the antibody is administered as a pH 6.0 aqueous buffer solution containing

- 21 mM histidine,

- 45 mM arginine,

- 0.2% (w/v) polysorbate 20,

- 5% (w/v) sucrose and

- from 100 mg/ml to 200 mg/ml antibody.

In another embodiment, the antibody is administered in the form of an aqueous buffer solution with a pH of 6.0 containing

- 21 mM histidine,

- 45 mM arginine,

- 0.2% (w/v) polysorbate 20,

- 5% (w/v) sucrose and

- at least 130 mg/ml antibody.

In another embodiment, the antibody is administered in the form of an aqueous buffer solution with a pH of 6.0 containing

- 21 mM histidine,

- 45 mM arginine,

- 0.2% (w/v) polysorbate 20,

- 5% (w/v) sucrose and

- 131.6 mg/ml antibody.

In another embodiment, the antibody is administered in the form of an aqueous buffer solution with a pH of 6.0 containing

- 21 mM histidine,

- 45 mM arginine,

- 0.2% (w/v) polysorbate 20,

- 5% (w/v) sucrose and

- 175 mg/ml antibody.

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms in a unit dose suitable for titrating the dosage of the active ingredients. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

In accordance with the methods disclosed herein, an anti-IL-6R antibody (or a pharmaceutical composition containing the antibody) can be administered to a patient using any suitable device or mechanism. For example, administration can be performed using a syringe and needle or using a reusable syringe pen and/or auto-injector delivery device. The methods of the present invention involve the use of multiple reusable pen syringes and/or autoinjector delivery devices for administering an anti-IL-6R antibody (or a pharmaceutical composition containing the antibody). Examples of such devices include, but are not limited to, AUTOPEN (Owen Mumford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Burgdorf, Switzerland), HUMALOG MIX 75/25 pen, HUMALOG pen, pen HUMALIN 70/30 (Eli Lilly and Co., Indianapolis, IN), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany). Examples of single-use pens and/or autoinjector delivery devices used in subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, the SOLOSTAR pen (Sanofi-Aventis), FLEXPEN (Novo Nordisk) and KWIKPEN (Eli Lilly), SURECLICK autoinjector (Amgen, Thousand Oaks, CA), PENLET (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA pen (Abbott Labs, North Chicago, IL), to name just a few.

In one embodiment, the antibody is administered using a pre-filled syringe. In another embodiment, the antibody is administered using a pre-filled syringe with a guard device. For example, a protective device prevents accidental injury to a healthcare worker. In various embodiments, the antibody is administered using a prefilled syringe with an ÈRIS guard (West Pharmaceutical Services Inc.). See also US Patent Nos. 5,215,534 and 9,248,242, incorporated herein by reference in their entirety.

In another embodiment, the antibody is administered using an auto-injector. In various embodiments, the antibody is administered using an auto-injector with PUSHCLICK technology (SHL Group). In various embodiments, an auto-injector is a device consisting of a syringe that delivers a dose of a composition and/or antibody to a subject. See also US Patent Nos. 9,427,531 and 9,566,395, incorporated herein by reference in their entirety.

The use of a microinfuser to deliver an anti-IL-6R antibody (or a pharmaceutical composition containing the antibody) to a patient is also provided herein. As used herein, the term “microinfuser” means a subcutaneous delivery device designed to slowly administer large volumes (e.g. up to approximately 2.5 ml or more) of the therapeutic composition over an extended period of time (e.g. approximately 10, 15, 20, 25, 30 or more minutes). See for example U.S. 6629949; US 6659982; and Meehan et al., J. Controlled Release 46:107-116 (1996), incorporated herein by reference in their entirety. Microinfusers are particularly useful for delivering large doses of therapeutic proteins contained in high concentration solutions (eg, approximately 100, 125, 150, 175, 200 mg/ml or more) and/or viscous solutions.

The antibody of the present invention, in various embodiments, is administered to subjects who suffer from a type of JIA, such as systemic juvenile idiopathic arthritis. In certain embodiments, the methods disclosed herein include the step of selecting a subject suffering from a type of JIA, such as systemic juvenile idiopathic arthritis. Diagnosis of systemic juvenile idiopathic arthritis is carried out in accordance with the classification criteria of JIA ILAR 2001 (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). In some embodiments, the patients are between about 1 year and about 17 years old. In various embodiments, the age of the patients is from about 4 to about 6 years, from about 12 to about 18 years, from about 12 to about 14 years, or from about 7 to about 9 years. In various embodiments, the subject exhibits arthritis in 5 active joints. In some embodiments, the subject exhibits arthritis in 2 active joints with systemic juvenile idiopathic arthritis fever (temperature greater than 37.5°C) for at least 3 of any 7 consecutive days, despite taking glucocorticoids at a stable dose for at least 3 days. In various embodiments, the subject has had an insufficient response to current treatment and is being considered as a candidate for treatment with a bDMARD.

The antibody of the present invention, in various embodiments, is administered to subjects suffering from pcJIA. In certain embodiments, the methods disclosed herein include the step of selecting a subject suffering from a type of JIA, such as pcJIA. Diagnosis of RF-negative or RF-positive polyarticular juvenile idiopathic arthritis subtype or disseminated oligoarticular juvenile idiopathic arthritis subtype is carried out in accordance with the JIA ILAR 2001 classification criteria (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. In some embodiments, the patients are between about 2 years old and about 17 years old. In various embodiments, the age of the patients is from about 4 to about 6 years, from about 12 to about 18 years, from about 12 to about 14 years, or from about 7 to about 9 years. In various embodiments, the subject exhibits arthritis in at least 5 active joints according to the American College of Rheumatology definition of active arthritis. In various embodiments, the subject has had an insufficient response to current treatment and is being considered as a candidate for treatment with a bDMARD.

In certain embodiments, failure to respond to prior treatment refers to subjects whose JIA is poorly controlled after receiving prior treatment (eg, a glucocorticoid joint injection and/or methotrexate) at the maximum tolerated typical dose. In one embodiment, failure to respond to prior treatment refers to subjects who have moderate to severe disease activity and evidence of poor prognosis despite prior treatment. In various embodiments, failure to respond to prior treatment refers to subjects with JIA symptom (eg, any symptom listed herein) for which no improvement or worsening has been observed despite previous treatment.

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

All publications referred to herein are incorporated herein by reference in their entirety for all purposes.

LIST OF ABBREVIATIONS

ACR: American College of Rheumatology

ADA: anti-drug antibody

AE: adverse event

AESI: Adverse Event(s) of Special Interest

ALP: alkaline phosphatase

ALT: alanine aminotransferase

ANA: antinuclear antibodies

ANC: absolute neutrophil count

anti-dsDNA antibodies: anti-double-stranded DNA antibodies

AST: aspartate aminotransferase

BP: blood pressure

BUN: blood urea nitrogen

CHAQ: Children's Health Assessment Questionnaire

COX-2: cyclooxygenase 2 inhibitors

CRF: Individual Registration Card

CRP: C-reactive protein

CSR: Clinical Study Report

CYP: cytochrome

DEC: Dose Escalation Committee

DMARD: disease modifying antirheumatic drug

DMC: Data Monitoring Committee

DNA: deoxyribonucleic acid

EBV: Epstein-Barr virus

e-CRF: electronic individual registration card

EOS: end of study

EOT: end of treatment

ESR: Erythrocyte Sedimentation Rate

GCP: Good Clinical Practice

HAQ-DI: Health Assessment Questionnaire Disability Index

HBc-Ab: antibody to hepatitis B virus core antigen

HIV: human immunodeficiency virus

HLGT: High Level Group Term

HR: heart rate

hs-CRP: high sensitivity C-reactive protein

ICF: Informed Consent Form

ICH: International Council for Harmonization

IEC: Independent Ethics Committee

IgG: immunoglobulin G

IL-6: interleukin 6

IL-6R: IL-6 receptor

ILAR: International League of Associations of Rheumatology

IMP: investigational medicinal product

IRB: Institutional Review Board

IVRS: Interactive system providing access by voice response

IWRS: Interactive system providing access via the Internet

JADAS: Juvenile Arthritis Disease Activity Index

JAK: Janus kinase

JIA: juvenile idiopathic arthritis

ACR JIA: Juvenile Idiopathic Arthritis Response According to the American College of Rheumatology

LDH: lactate dehydrogenase

LDL: low density lipoprotein

LFT: liver function tests, liver function test

LLOQ: lower limit of quantitation

mAB: monoclonal antibody

MAS: macrophage activation syndrome

mTSS: Modified Total Sharpe Score

MTX: methotrexate

NIMP: non-investigational drug

NSAID: non-steroidal anti-inflammatory drugs

oJIA: oligoarticular juvenile idiopathic arthritis

pcJIA: polyarticular course of juvenile idiopathic arthritis

PCSA: potentially clinically significant abnormality

PD: pharmacodynamics

PK: pharmacokinetics

PopPK: population pharmacokinetics

PPD: purified protein derivative

PT: preferred term

q2w: once every two weeks

qw: once a week

RA: rheumatoid arthritis

RF: rheumatoid factor

SAE: serious adverse event.

SC: subcutaneous

SD: standard deviation.

sJIA: systemic juvenile idiopathic arthritis

SOC: system organ class

SUSAR: predicted unexpected serious adverse reaction

TB: tuberculosis

TEAE: treatment-emergent adverse event

ULN: upper limit of normal

VAS visual analogue scale

WBC: white blood cells

EXAMPLES

The following examples are set forth to provide those skilled in the art with complete disclosure and description of the preparation and use of the methods and compositions described in the present invention, and are not intended to limit the scope of what the inventors of the present invention consider their invention to be. Efforts have been made to ensure accuracy in terms of numbers used (e.g. quantities, temperatures, etc.), however, some experimental errors and deviations must be taken into account.

Example 1. An open-label, dose-finding study of sarilumab with sequential escalating repeat doses administered by subcutaneous (SC) injection in children and adolescents aged 2 to 17 years with pcJIA, followed by an add-on treatment phase. (Study No. DRI13925, Study Name: Open-label, dose-finding, ascending dose-finding study of sarilumab in children and adolescents with pcJIA)

A controlled phase 2 trial (#NCT02776735) was initiated to test the human IgG1 monoclonal antibody to IL-6Rα, sarilumab, administered subcutaneously for the treatment of pcJIA. This study was a multinational, multicenter, open-label, phase 2, 2-part study in children and adolescents aged 2 to 17 years (or country age requirements apply) with pcJIA who had an insufficient response to or intolerance to current therapy. , or who were being considered as candidates for a biological disease-modifying antirheumatic drug (DMARD). The 2 phases of the study were an initial 12-week main treatment phase, followed by a 144-week extension treatment phase (see Fig. 1 and Fig. 2 ).

General design and design of the study.

12-week main treatment phase

This multinational, multicenter, open-label study included patients aged 2 to 17 years diagnosed with RF-positive or RF-negative pJIA or eoJIA according to the JIA ILAR 2001 classification criteria (1). Patients had ≥5 active joints and were considered candidates for bDMARDs by the investigators.

Patients received sarilumab by subcutaneous (SC) injection administered by a professional caregiver at the study site. Dosing regimens were tested in 2 body weight groups (group A, ≥30-60 kg and group B, 10-<30 kg) in a stepwise manner, starting with the lowest-dose sarilumab regimen in the higher body weight group, group A (Fig. .2). Dosing schedules in Groups A/B were 2.0/2.5 mg/kg Q2W, 3.0/4.0 mg/kg Q2W, and 2.0/2.5 mg/kg QW for Dosing Schedules 1 , 2 and 3 respectively. Initiation of dosing schedule 1 in arm B was permitted after review of data from the first 3 patients enrolled in the same dosing schedule in arm A after at least 4 weeks of treatment. Transition to higher dose regimens in each body weight group was permitted after review of safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) data after the first 3 patients enrolled in the current body weight and dose group completed 6 weeks of treatment. Inclusion in dose group 3 of group B was permitted after analysis of data from all other body weight and dose groups. Decisions regarding dose escalation were made by the Dose Escalation Committee (DEC). The DEC could declare a dosage to be ineffective if the first 3 patients enrolled in that dose and body weight group did not achieve an ACR30 JIA response by week 6, discontinuing enrollment in that dose and body weight group and switching patients from that regimen to the standard treatment approved by the investigator. The safety of sarilumab was formally monitored throughout the study by an independent data monitoring committee that included 3 pediatric rheumatologists.

The primary objective of the study was to examine the PK profile of 3 sarilumab dosing regimens administered over 12 weeks, with the goal of selecting one regimen for further study. Dose schedules were selected based on modeling and simulation to provide effects similar to dose schedules evaluated for RA in adults. Dosing schedule 1 corresponded to 150 mg every 2 weeks (Q2W), the lowest approved dose for adults; Dosing schedule 2 corresponded to 200 mg Q2W, the recommended approved dose for adults; and dosing schedule 3 corresponded to 150 mg every week (QW), the highest dose tested in adults, which demonstrated greater efficacy than placebo with an acceptable safety profile (20).

The 12-week main treatment phase (illustrated in Fig. 2 ) was divided into 3 parts. The first dose-finding part with sequential increasing doses, in which 3 dosing schedules (Table 1) were studied in each of 2 body weight groups: patients ≥30 kg and ≤60 kg (group A) and patients <30 kg and ≥10 kg (cohort B), in 6 evaluable patients per dose and body weight cohort (approximately 36 patients total), starting with cohort A and dose cohort 1. A second follow-up with approximately 24 additional patients (12 in each cohort body weight, ≥30 kg (group A) and <30 kg and ≥10 kg (group B)) are included directly in the selected dosing regimen to obtain a total of 18 evaluable patients per body weight group at the selected dosage schedule. The third part, where approximately 28 additional patients (70% limit in each weight group: patients ≥30 kg [arm A] and patients <30 kg and ≥10 kg [arm B]) will be enrolled directly into the selected dosing regimen to obtain a total of approximately 100 patients were treated throughout the study. These patients will make the same study site visits during the 12-week primary treatment phase as patients recruited for dose titration and arm 2; however, patients in Part 3 will not have sarilumab PK sampling visits between baseline and week 2.

The 12-week main treatment phase lasted from Visit 2 (baseline - week 0) until the time of study medication (IMP) administration at Visit 12. During the 12-week main treatment phase, patients in the lower body weight group (group B : <30 kg and ≥10 kg) were randomly assigned to schedule 1 or schedule 2 of sarilumab PK sampling to minimize the amount of blood drawn and the number of visits while maintaining assessment of the primary endpoint.

- Chart 1. Baseline, day 3, day 8, week 2, week 4, week 8 and week 12

- Chart 2. Baseline, day 5, day 12, week 2, week 4, week 8 and week 12.

Estimates Data are presented for 3 dosing schedules in both body weight groups and are from study baseline to week 12.

The primary endpoint was PK exposure, including maximum serum concentration, area under the serum concentration versus time curve calculated using the trapezoidal method during the dosing interval, and serum concentration observed before treatment administration during repeat dosing. doses. Secondary endpoints were PD, including high-sensitivity C-reactive protein (CRP) concentrations, safety, and clinical efficacy. Efficacy was determined by the proportion of patients achieving an ACR30 JIA/70/90 response, change from baseline in ACR JIA response components, and mean change in the Juvenile Arthritis Activity Index 27-Joint Score and CRP Score (JADAS-27-CRP), all at week 12 .

In addition, once subject enrollment for dose matching and Part 2 is complete, Part 3 will enroll approximately 28 additional patients directly into the selected dosing regimen to provide a total of approximately 100 treated patients for the entire study, as recommended by the health authority. These patients will make the same study site visits during the 12-week primary treatment phase as patients recruited for dose titration and arm 2; however, patients in Part 3 will not have sarilumab PK sampling visits between baseline and week 2.

An additional treatment period in the add-on treatment phase will allow data to be collected on long-term safety and clinical response to sarilumab in patients with pcJIA. This add-on treatment phase lasts up to 144 weeks for patients included in the dose-finding portion and part two, and up to 84 weeks for patients included in part three. Patients included in the dose selection portion who are already in the add-on treatment phase at the time the dosing regimen is selected and who have not received the selected dosing regimen will have their dosing regimen adjusted according to the selected dose.

To minimize the amount of blood drawn, patients in arm B (<30 kg and ≥10 kg) during dose finding and part 2 will be randomized to 1 of 2 different sarilumab PK sampling schedules. PK analyzes will combine these sampling schedules to describe the PK profile of sarilumab. PK sample collection is not planned between baseline and week 2 for patients included in part three. The total volume of blood drawn for the study will not exceed 3% of the total blood volume over 4 weeks and will not exceed 1% of the total blood volume at one time (39). In addition, scheduled frequent assessments monitor the risk to study participants.

Finally, a post-treatment follow-up period of 6 weeks after the last treatment visit to assess TEAE, PK, and PD of sarilumab is appropriate given the observed PK profiles in the adult RA program.

Statistical analysis.

A population PK model of the pooled data was developed using nonlinear mixed effects modeling to describe the PK profile of sarilumab. PD, safety, and efficacy data were analyzed using descriptive statistics only. Efficacy endpoints were analyzed based on data observed during treatment (no imputation of missing data). In addition, ACR30 JIA/70/90 results were also reported using the non-responder imputation method (non-responder status is automatically assigned to patients with insufficient data or after treatment discontinuation).

144-week/84-week add-on treatment phase.

The IMP at visit 12 was considered the first IMP for the add-on treatment phase. Only patients achieving an ACR30 JIA response at visit 12 (week 12) were allowed to continue the study into the add-on treatment phase. Patients continued to adhere to the same sarilumab dosing schedule they were assigned to during the 12-week main treatment phase of the study until the selected dosing schedule was determined. Once a dosing schedule was selected, patients who were not already adhering to that dosing schedule had their dosing schedule adjusted according to the selected dosing schedule and adhered to the new schedule of visits with more frequent monitoring (for PK, safety, and efficacy) for the first 12 weeks, compared with patients whose dosing schedule was not changed.

Patients who prematurely discontinued study treatment were assessed using the EOT procedure at Visit 27. These patients were asked 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 main treatment phase, an additional sarilumab PK assessment was performed 2 weeks after the EOT visit (EOT+2 weeks), and IL-6 and sIL6R were measured at the EOT visit. These patients were asked to complete all visits and assessments as scheduled in the protocol, with the exception of sarilumab administration, until Visit 12.

For patients included in part three, an 84-week add-on treatment phase is planned. The IMP at visit 12 is considered the first IMP for the add-on treatment phase. Patients included in the third part with the selected dosing schedule will be followed up as indicated in Table 32.

Tested Dosing Schedules

For each body weight group, 3 escalating dose schedules to be tested were identified based on PK modeling with the following rationale.

- Dose cohort 1. Dose targeting PK effect similar to that of sarilumab 150 mg q2w, lowest effective dosing schedule for adult patients with RA.

- Dose cohort 2. Dose targeting PK effect similar to that of sarilumab 200 mg q2w, recommended dosing regimen for adult patients with RA.

- Dose cohort 3. A dose targeting PK effect similar to that of the sarilumab 150 mg qw dose that resulted in the highest exposure levels in chronic dosing studies in adult patients with RA.

Table 1. Dose by body weight and dose cohort Body weight Dose cohort 1 Dose cohort 2 Dose cohort 3 Group A
≥30 kg and ≤60 kg 2 mg/kg q2w
(6 patients) 3 mg/kg q2w
(6 patients) 2 mg/kg qw
(6 patients) Group B
<30 kg and ≥10 kg 2.5 mg/kg q2w
(6 patients) 4 mg/kg q2w
(6 patients) 2.5 mg/kg qw
(6 patients)

Abbreviations. Qw=once a week, q2w=once every two weeks.

The dose (mg) administered to patients was calculated at baseline. The dose and corresponding volume of the drug remained unchanged during the 12-week main treatment phase of the study, regardless of changes in patient body weight. During the adjunctive treatment phase, the patient's body weight was measured at each visit, and the dose was adjusted to account for body weight gain only if the calculation indicated that a dose increase was necessary. The dose was limited to 150 mg for dose cohort 1 and dose cohort 3 and 200 mg for dose cohort 2, respectively. Sarilumab injectable volumes for dose cohorts 1-3 are presented in Tables 2-5 below.

Tables 2 and 3 show dose information for a patient in the high body weight group (group A). High body weight patients are patients who weigh ≥30 kg and ≤60 kg for the dose selection portion and ≥30 kg for additional patients in the second portion. Tables 4 and 5 show dose information for a patient in the low body weight group (group B). <30 kg and ≥10 kg.

Table 2. Dosage information for high body weight cohorts 1 and 3 (cohort A) Dose cohort 1 (2 mg/kg q2w) and dose cohort 3 (2 mg/kg qw) Body weight (kg) Volume per injection (ml) Appropriate Dose (mg) ≥30 and <33 0.35 61.25 ≥33 and <37.5 0.40 70 ≥37.5 and <42 0.45 78.75 ≥42 and <46.5 0.50 87.5 ≥46.5 and <50.5 0.55 96.25 ≥50.5 and <55 0.60 105 ≥55 and <59.5 0.65 113.75 ≥59.5 and <64 0.70 122.5 ≥64 and <68 0.75 131.25 ≥68 and <72.5 0.80 140 ≥72.5 0.85 (injection volume limitation) 148.75 (limit to 150 mg)

Table 3. Dosage information for cohort 2 high body weight group (cohort A) Dose cohort 2 (3 mg/kg q2w) Body weight (kg) Volume per injection (ml) Appropriate Dose (mg) ≥30 and <31 0.50 87.5 ≥31 and <34 0.55 96.25 ≥34 and <37 0.60 105 ≥37 and <39.5 0.65 113.75 ≥39.5 and <42.5 0.70 122.5 ≥42.5 and <45 0.75 131.25 ≥45 and <48.5 0.80 140 ≥48.5 and <51.5 0.85 148.75 ≥51.5 and <54.5 0.90 157.5 ≥54.5 and <57 0.95 166.25 ≥57 and <63 1.00 175 ≥63 1.1 (injection volume limitation) 192.5 (limit to 200 mg)

Tables 3 and 4 show dose information for a patient in the low body weight group (group

B): <30 kg and ≥10 kg.

Table 4. Dosage information for low body weight cohorts 1 and 3 (Cohort B) Dose cohort 1 (2.5 mg/kg q2w) and dose cohort 3 (2.5 mg/kg qw) Body weight (kg) Volume per injection (ml) Appropriate Dose (mg) ≥10 and <12.5 0.15 26.25 ≥12.5 and <16 0.20 35 ≥16 and <19.5 0.25 43.75 ≥19.5 and <23 0.30 52.5 ≥23 and <26.5 0.35 61.25 ≥26.5 and <30 0.40 70 Patients who grow to a body weight of more than 30 kg are then given
next volume ≥30 and <37.5 0.40 70 ≥37.5 and <42 0.45 78.75 ≥42 and <46.5 0.50 87.5 ≥46.5 and <50.5 0.55 96.25 ≥50.5 and <55 0.60 105 ≥55 and <59.5 0.65 113.75 ≥59.5 and <64 0.70 122.5 ≥64 and <68 0.75 131.25 ≥68 and <72.5 0.80 140 ≥72.5 0.85 (injection volume limitation) 148.75 (limit to 150 mg)

Table 5. Dosage information for cohort 2 low body weight group (cohort B) Dose cohort 2 (4 mg/kg q2w) Body weight (kg) Volume per injection (ml) Appropriate Dose (mg) ≥10 and <12.5 0.25 43.75 ≥12.5 and <14.5 0.30 52.5 ≥14.5 and <16.5 0.35 61.25 ≥16.5 and <19 0.40 70 ≥19 and <21 0.45 78.75 ≥21 and <23.5 0.50 87.5 ≥23.5 and <25.5 0.55 96.25 ≥25.5 and <27.5 0.60 105 ≥27.5 and <30 0.65 113.75 Patients who grow to a body weight of more than 30 kg are then given
next volume ≥30 and <39.5 0.65 113.75 ≥39.5 and <42.5 0.70 122.5 ≥42.5 and <45 0.75 131.25 ≥45 and <48.5 0.80 140 ≥48.5 and <51.5 0.85 148.75 ≥51.5 and <54.5 0.90 157.5 ≥54.5 and <57 0.95 166.25 ≥57 and <60.5 1.00 175 ≥60.5 and <63 1.00 175 ≥63 1.1 (injection volume limitation) 192.5 (limit to 200 mg)

The volume to be administered with each injection during the 12-week main treatment phase was calculated based on body weight at baseline (Visit 2) and maintained throughout the 12-week main treatment phase. The volume to be administered during the add-on treatment phase was adjusted based on body weight measured at each visit, if body weight increased, and if the calculation indicated a need to increase the dose. If the selected dosing schedule corresponded to one of the 3 predefined dose cohorts, patients subsequently enrolled in or switched to the selected dosing schedule used the appropriate dose listed in Tables 2-5.

Duration of study participation for each patient

The total study duration (per patient) was up to 166 weeks for patients included in the dose-finding portion and part two, and up to 106 weeks for patients included in part three.

Up to 4 weeks + 3 days of screening (up to 31 days).

12-week main treatment phase.

Up to 144 weeks of the add-on treatment phase for patients included in the dose-finding portion of part two, and up to 84 weeks of the add-on treatment phase for patients included in the third part.

6-week follow-up after treatment.

For all visits, acceptable time frames were ±3 days for dose cohorts 1 and 2 and ±1 day for dose cohort 3, using day 1 as the reference, except as follows.

For Visit 3 (Day 3), Visit 4 (Day 5), and Visit 5 (Day 8), no visit window is allowed when PK sampling occurs. For patients included in the third part, the PK sampling visits, i.e., visits 3, 4, 5 and 6, are not applicable during the main treatment phase.

Visit 6 (Day 12) ±1 day for all 3 dose cohorts.

Visit 7 (week 2) ±1 day for all 3 dose cohorts.

Visit 8 (week 4) ±2 days for dose cohorts 1 and 2 and ±1 day for dose 3 cohort.

Inclusion criteria

Criteria inclusions for this study are listed below.

1. Male and female patients aged ≥2 and ≤17 years (or country age requirements apply) at the time of the screening visit.

2. Diagnosis of RF-negative or RF-positive polyarticular JIA subtype or oJIA subtype according to the JIA ILAR 2001 classification criteria (2) with at least 5 active joints according to the ACR definition of “active arthritis” at screening (Table 6) .

3. A patient with an insufficient response to current treatment who is considered a candidate for a bDMARD based on the investigator's judgment.

4. The patient, who has reached the legal age of consent, or the parent(s) or legal guardian(s) will sign a dated written informed consent approved by the ethics committee. Consent from a minor patient should be obtained based on local guidelines, the patient's maturity, and the patient's intellectual capacity to understand the information associated with the study. In cases involving emancipated or mature minors with sufficient decision-making capacity, or where otherwise permitted by law, signed informed consent will be obtained directly from the parent(s) or legal guardian(s).

Exclusion criteria

Patients were excluded from the study for the following reasons: body weight <10 kg or >60 kg; JIA subtype other than RF-positive, RF-negative, or eoJIA; previous treatment with an IL-6 or IL-6R antagonist; treatment with any other biological agent within 5 half-lives of the first dose of sarilumab; use of parenteral or intra-articular glucocorticoid injections within 4 weeks before study baseline; active or past opportunistic infection, including tuberculosis; administration of live attenuated vaccine within 4 weeks prior to baseline; or any condition that may adversely affect the patient's participation in the study. Patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs), oral glucocorticoids, or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were excluded if the NSAID or oral glucocorticoid dose was unstable within 2 weeks before baseline or if the oral glucocorticoid dosage was greater than an equivalent dose prednisone 0.5 mg/kg/day (or 30 mg/day) if the csDMARD dosage was unstable during the 6 weeks prior to baseline or if the csDMARD dosage exceeded the recommended dosage listed on the local label. Written informed consent was required and obtained from all patients/caregivers in accordance with local regulatory guidelines.

Table 6. Subclassification of polyarticular JIA, rheumatoid factor (RF) negative, rheumatoid factor (RF) positive, and oJIA JIA subtypes Clinical
signs,
certain
classification
ILAR Criteria
exceptions (footnote a) Frequency
(% of total JIA)* Beginning (years)
Mid range Exodus RF-negative pcJIA (5,7,6) -Affects 5 or more joints in the first 6 months of the disease. -RF tests negative
-Tendosynovitis, uveitis, vasculitis a, b, c, d, e 15% 7-9 years
Two peaks
-early: 1-3 years
-late: 6-12 years - 10%
Destructive joint disease RF positive pcJIA (5) ANA -Amazing
5 or
more joints
in the first 6
months
diseases.
-RF tests
positive twice
with an interval of at least
2 months
-Tenosynovitis,
rheumatoid
nodules,
vasculitis,
syndrome
Sjögren a, b, c, e 5% 12-14 years old
10-18 years - Same as for adult RA
- Occurs in late childhood
- Severe destructive joint disease oJIA (5,7,6)
°Persistent
°Common -It hits no more
4 joints
during
diseases
-Hits more
4 joints
during
diseases a, b, c, d, e 50% 2-3 years
1-5 years - Onset at an early age
- Chronic uveitis, especially ANA+
- Leg length discrepancy
- Destructive
joint disease
- Therapy as in
pcJIA

A. Psoriasis or a history of psoriasis in patients or first-degree relatives;

b. arthritis in HLA B27-positive men, starting after age 6 years;

c. ankylosing spondylitis, enthesitis-associated arthritis, sacroiliitis with concomitant inflammatory bowel disease, Reiter's syndrome, acute anterior uveitis, or a history of 1 of these diseases in first-degree relatives;

d. presence of IgM rheumatoid factor on at least 2 occasions with an interval of at least 3 months;

e. the presence of systemic JIA in patients.

Treatments being studied

Investigational medicinal product (IMP)

Sarilumab, mAb to IL-6R (monoclonal antibody to the alpha subunit of the interleukin 6 receptor).

Compound

The drug sarilumab was provided at a concentration of 175 mg/ml in an aqueous buffer vehicle, pH 6.0. It was supplied in a 5 mL vial filled with 2.7 mL of sarilumab with an extractable volume of 2.0 mL.

Route(s) of administration

Sarilumab was administered subcutaneously into the abdomen or thigh via self-injection, or also into the forearm (lateral) by a professional or lay caregiver. Preferably, SC injection sites alternate between the 4 quadrants of the abdomen (excluding the umbilicus or waist) or thigh (front and side).

For patients who adhered to dose schedule 1 or 2 (q2w), injections were administered by a professional caregiver during the 12-week main treatment phase of the study. For patients who adhered to dose schedule 3 (weekly injections), arrangements were made to ensure IMP was administered by trained site staff or a home nurse for doses not scheduled to be administered at the study site. During the add-on treatment phase of the study, if patients or their parent(s), legal guardian(s), or caregiver(s) were willing and able to administer the injections, home injections were permitted. In these cases, training was required and provided to prepare and administer the IMP starting at Visit 10 (week 8) during the main treatment phase. This training was documented in the patient study file. Patients or parent(s) or legal guardian(s) were allowed to administer injections under supervision/control investigator(s) or representative(s) at Visit 10 (Week 8), Visit 11 (Week 10), and Visit 12 (Week 12) until home injections are permitted in the add-on treatment phase.

On days when the patient makes a study visit, IMP was administered after clinical procedures and blood collection. Diaries were provided to record information related to these injections; these diaries were kept as baseline data in the patient study files. If the caregiver was unable or unwilling to administer the IMP, arrangements were made to ensure that the IMP was administered by qualified site personnel for doses not scheduled to be administered at the study site.

Dose schedule

Sarilumab was administered q2w or qw. However, a sarilumab administration window of ±3 days for dose cohorts 1 and 2 and ±1 day for dose cohort 3 was allowed per protocol, taking into account exceptional circumstances, such as pending laboratory results, ongoing adverse events (AEs), patient scheduling difficulties , except for visit 5 (day 8). There was no administration window for visit 5 (day 8). The administration window was only ±1 day for dose cohorts 1, 2, and 3 patients at visit 7 (week 2) and ±1 day for dose cohort 3 or ±2 for dose cohorts 1 and 2 at visit 8 (week 4).

Note that overdose (accidental or intentional) of IMP was defined as at least a double dose within an interval of less than 11 days for q2w administration and less than 6 days for weekly administration.

The next dose of sarilumab was administered q2w or qw.

Dose cohort 1.

- Group A (≥30 kg and ≤60 kg): 2 mg/kg q2w

- Group B (<30 kg and ≥10 kg): 2.5 mg/kg q2w.

Dose cohort 2.

- Group A (≥30 kg and ≤60 kg): 3 mg/kg q2w

- Group B (<30 kg and ≥10 kg): 4 mg/kg q2w.

Dose cohort 3.

- Group A (≥30 kg and ≤60 kg): 2 mg/kg qw

- Group B (<30 kg and ≥10 kg): 2.5 mg/kg qw.

Changing the dose

The dose (mg) administered to patients was calculated at baseline. The dose and corresponding volume of the drug remained unchanged during the 12-week main treatment phase of the study, regardless of changes in patient body weight. During the adjunctive treatment phase, the patient's body weight was measured at each visit, and the dose was adjusted to account for body weight gain only if the calculation indicated that a dose increase was necessary. The dose was limited to 150 mg and 200 mg for dose cohorts 1 and 3 and dose cohort 2, respectively. Injection volumes depending on the patient's body weight are described in detail in Tables 2-5.

Method of assigning patients to treatment group

A list of randomized treatment set numbers was generated centrally. IMP was packaged in accordance with this list. Patients were assigned to the treatment package using an interactive voice response system (IVRS) or an interactive Internet-based system (IWRS).

Patients who meet the inclusion criteria will be enrolled and given treatment kits in 2 body weight groups (Group A: ≥30 kg and ≤60 kg for patients included during the dose selection portion, and ≥30 kg for patients included during the second and third parts; group B: <30 kg and ≥10 kg for all 3 parts).

- For the dose matching part and the second part, the planned inclusion ratio for the 2 body weight groups is 1:1.

For the third part, there is no predefined inclusion rate for the 2 body weight groups, but each body weight group will be limited to 70% (ie, 20 patients). As a result, the most unbalanced inclusion in the body weight group will be 20 versus 8 patients in the third part.

Packaging and labeling

IMP was provided in patient treatment kits containing labeled vials.

Storage conditions

The study drug was stored in a refrigerator at a temperature of 2 ^o C to 8 ^o C at the study center or at home.

ASSESSMENT OF PHARMACOKINETICS, EFFECTIVENESS AND SAFETY

Patients were scheduled to complete the 12-week main treatment phase assessment according to the schedule below (Table 7).

Pharmacokinetic measurements and timing

The blood sampling schedule for the 12-week main treatment phase can be found in Table 7. If a patient experienced an SAE, blood samples were collected at the start and end of the event, if possible, or within a short time after the start and end, to determine sarilumab concentrations. . For patients who discontinued study treatment prematurely during the primary treatment phase (at or before Visit 12), an additional sarilumab PK assessment was performed 2 weeks after the scheduled EOT assessment (3 weeks after the last IMP injection for dose cohort 3 patients or after 4 weeks after the last IMP injection [for patients in dose cohorts 1 and 2]). These patients were asked to return for an end-of-study (EOS) assessment 6 weeks after the EOT visit. Must record the date of sample collection. In patients who discontinue treatment prematurely, blood samples should be collected at the EOS visit, if possible. Serum samples were analyzed for sarilumab concentration using a validated enzyme-linked immunosorbent assay (ELISA) method.

Table 7 . - Schedule of the 12-week main phase of treatment Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up ^a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks (for patients who discontinue study treatment during the main treatment phase or do not intend to enter the additional treatment phase) Day D28 to
D1 (+3)
(maximum
31 days) D1 D3 ^{b D5b D8b D12b}
(±1) D15
(±1) D29 (±1 or 2) D43 (±1 or 3) D57 (±1 or 3) D71
(±1 or 3) D85
(±1 or 3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Suitability ^c Written informed consent and form
patient consent ^d X Inclusion/exclusion criteria ^c X X Ethnicity and race X Patient Demographics X Tanner stage and menstrual status X X Medical/surgical
anamnesis X Previous
history of medication/vaccination X Concomitant medications X X X X X X X X X X X X X Home
treatment compliance diary ^e X X X X X X X Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up ^a
PK Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks (for patients who discontinue study treatment during the main treatment phase or do not intend to enter the additional treatment phase) Day D28 to
D1 (+3)
(maximum
31 days) D1 D3b D5 ^{b D8b D12b}
(±1) D15
(±1) D29 (±1 or 2) D43 (±1 or 3) D57 (±1 or 3) D71
(±1 or 3) D85
(±1 or 3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Physical examination ^f X X X X X Optional: EBV, hepatitis B and C viruses and
HIV ^g X Tuberculin skin test with PPD for patients ≤5 years;
QuantiFERON-TB test for patients >5 years ^h X Chest X-ray ⁱ X Confirmation of suitability X Call to IVRS X X X X X X X X Introduction IMP Introduction IMP ^j X ^Xj X X X X X X Issuing IMP ^k X X X X X X X Vital Signs and Body Measurement Temperature, heart rate, BP (2 BP measurements at each scheduled time point) X X X X X Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up ^a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks (for patients who discontinue study treatment during the main treatment phase or do not intend to enter the additional treatment phase) Day D28 to
D1 (+3)
(maximum
31 days) D1 D3 ^{b D5b D8b} D12 ^b
(±1) D15
(±1) D29 (±1 or 2) D43 (±1 or 3) D57 (±1 or 3) D71
(±1 or 3) D85
(±1 or 3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Body weight X X X Height (stadiometer) ^l X X X Efficiency mark Basic kit for ACR JIA ^m disease X X X X X X X X JADAS- ²⁷ⁿ X X Security ratings AE/SAE registration | | TB risk assessment X X X X X X X X Local tolerance X X X X X X X X Laboratory research Hematological examination ^o X ^{Xo Xo Xo} X X X X X X Biochemical study ^{p Xp Xp} X X X X X ^Xp Fasting lipidogramq X X X Optional: HbA1c ^r X hs-CRP X X X X X X X X ESR X X RF X Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up ^a
PK Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks (for patients who discontinue study treatment during the main treatment phase or do not intend to enter the additional treatment phase) Day D28 to
D1 (+3)
(maximum
31 days) D1 D3 ^{b D5b} D8 ^b D12 ^b
(±1) D15
(±1) D29 (±1 or 2) D43 (±1 or 3) D57 (±1 or 3) D71
(±1 or 3) D85
(±1 or 3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 ANA/anti-dsDNA antibody X X Urinalysis ^s X Blood serum testing for pregnancy in menstruating women ^t X Local urine testing for pregnancy in menstruating women ^u X X X X PK and PD Serum PK of sarilumab ^v
Group A (≥30 kg and ≤60 kg) X X X X X X X X X X Serum PK of sarilumab ^v
Group B (<30 kg and ≥10 kg)
Schedule 1 X X X X X X X X Serum PK of sarilumab ^v Group B (<30 kg and ≥10 kg) Chart 2 X X X X X X X X Antibodies to sarilumab ^v X X

Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up ^a
PK Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks (for patients who discontinue study treatment during the main treatment phase or do not intend to enter the additional treatment phase) Day D28 to
D1 (+3)
(maximum
31 days) D1 D3 ^{b D5b D8b} D12 ^b
(±1) D15
(±1) D29 (±1 or 2) D43 (±1 or 3) D57 (±1 or 3) D71
(±1 or 3) D85
(±1 or 3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 IL-6 and total sIL-6Rα X X ^Xw Pharmacogenomics (optional) Collection of saliva samples ^x X

A. For patients who discontinue treatment during the 12-week primary treatment phase (at or before Visit 12), an additional sarilumab PK assessment will be performed 2 weeks after the EOT visit (EOT+2 weeks). For patients included in part three, visit 88 is not applicable.

b. Sample collection for sarilumab PK determination between visit 2 and visit 7 varies between patients: visit 3 (day 3), visit 4 (day 5), visit 5 (day 8), visit 6 (day 12) for group A (≥30 kg ); during the following visits and days: Visit 3 (Day 3), Visit 5 (Day 8), for Schedule 1 Group B (<30 kg); during the following visits and visit days: Visit 4 (Day 5), Visit 6 (Day 12) for Schedule 2 Group B (<30 kg). Sample collection for sarilumab PK determination can be done at home. A PK diary will be provided to record the date and time of sample collection. For Visit 3 (Day 3), Visit 4 (Day 5), and Visit 5 (Day 8), no sample collection window is allowed. For visit 6 (day 12), a window of ±1 day is allowed. For patients included in Part 3, visits 3, 4, 5 and 6 are not applicable. However, additional hematological testing should be performed before the second administration of sarilumab (see footnote "o" for details).

c. At the discretion of the investigators, laboratory tests mentioned in the ^{E 24} exclusion criterion may be repeated through repeat testing at a central laboratory between the screening visit and the first IMP administration to ensure patient eligibility for the ^{E 24} exclusion criterion. ^{A specific locally approved consent form will be signed by patients seeking genetic testing for Gilbert's syndrome (patient consent/assent must be obtained prior to this study and local regulatory requirements must be followed).}

d. Prior to all screening assessments, the patient (if he/she has reached the legal age of consent in accordance with local regulatory requirements), parent(s) or legal guardian(s) must sign a dated written informed consent form approved by the EC. The patient, parent(s), and legal guardian(s) will receive information about the purpose(s) of the study and procedures from the investigator. Separate written consent forms must be obtained from the parent(s) or legal guardian(s) who authorize his/her child to participate in additional collection of saliva samples for the pharmacogenomic study and authorize the sponsor to retain their remaining/unused blood samples for future studies

e. . A separate (locally approved) informed consent form is completed by all patients requiring genetic testing for Gilbert's disease in accordance with local regulatory requirements. Signed patient consent forms must be obtained from the patient in accordance with local regulatory requirements and his/her maturity in understanding the study information.

f. Home IMP Administration Diary to be completed for IMP administered at home.

g. A complete physical examination will be performed at Visit 1 (Day -28 to Day -1, up to Day 31), Visit 2 (Day 1, Week 0), Visit 8 (Week 4), Visit 9 (Week 6), and Visit 12 (week 12), where the examination includes examination of the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic and musculoskeletal systems.

h. Not necessary. Based on the investigator's opinion, screening may determine Epstein-Barr virus (EBV) titer, including IgG and IgM; Based on the patient’s family and medical history, as well as the conclusion of the investigator, during screening, hepatitis B virus surface antigen (HBs-Ag), antibody to hepatitis B virus surface antigen (HBs-Ab), and common antibodies to hepatitis B virus core antigen can be determined (HBc-Ab) and hepatitis C virus antibody (HCV-Ab). HIV serological testing will only be performed based on the investigator's opinion for patients suspected of having HIV. For Argentina and Germany only: serology for hepatitis B and C viruses and HIV should be performed at the screening visit for all patients to check the appropriate exclusion criterion ^{E 14} .

i. Purified protein product (PPD) skin testing should be performed in patients ≤5 years of age prior to baseline visit 2 (Day 1, Week 0). Patients should be assessed within 48 to 72 hours after undergoing the PPD skin test. For patients who have not been tested within 72 hours, the skin test should be repeated. When determining skin test results, risk assessment (TB exposure and/or recent immigration from a country with a high TB prevalence) and vaccination history should be taken into account. See exclusion criteria ^{E 13} for full details. The interferon-gamma (IFN-r) release assay, the QuantiFERON-TB test, will be performed for patients aged >5 years. (1) After initial screening for TB, if the PPD or QuantiFERON result is negative but the clinical suspicion for TB is above average, the patient should be retested for TB at any time during the study based on the assessment of the investigator. The QuantiFERON-TB test will be considered in a younger patient population ( ≤ 5 years) based on local presence of PPD, local TB screening regulations, and investigator judgment.

j. Chest X-rays should only be performed on patients if deemed necessary based on the investigator's judgment or in accordance with local TB screening guidelines prior to initiation of biologic therapy for patients with JIA who have not had a chest X-ray within 3 months before baseline visit 2 (day 1, week 0).

k. The study drug should be administered biweekly to patients in cohorts 1 and 2 and once weekly to patients in cohort 3. Arrangements will be made for home nurses to administer IMPs to patients in cohort 3. with a 3 dose schedule for intermediate visits (administration at home if possible). Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of a hypersensitivity reaction. For Germany only: After the first administration of IMP, the patient must be observed for at least 1 hour to assess local tolerance. For the dose-finding portion and portion two, patients who have not achieved an American College of Rheumatology (ACR) JIA response of 30 by the end of the 12-week primary treatment period will be withdrawn from the study treatment to receive standard of care according to the clinical judgment of the investigator. The juvenile idiopathic arthritis ACR response, including the ACR30 JIA response, will be provided by the sponsor to the investigator for assessment of this criterion only after Visit 12. For patients who completed the primary treatment phase at Visit 12 (week 12) but do not continue the study into the extension treatment phase in the expansion population For reasons other than lack of ACR30 JIA response, the IMP injection will not be given at Visit 12.

l. The investigational drug will be given to patients who are in the dose schedule 3 cohort during the main treatment phase.

m. Height will be measured using a stadiometer at the study sites during the study.

n. The ACR Juvenile Idiopathic Arthritis Core Set includes the physician's global assessment of disease severity, patient's or parent(s)/guardian(s)'s overall assessment of well-being, number of joints with active arthritis (defined as swelling not caused by deformity OR limitation of movement with either pain or sensitivity, or both), number of joints with limited movement, Children's Health Assessment Questionnaire (CHAQ), hs-CRP (2,3,4). During screening, only the number of joints with active arthritis and the number of joints with limited movement will be assessed.

O. The principle of calculating the disease activity index representing juvenile arthritis has been explained in this document.

p. Hematological examination (blood should be drawn BEFORE administration of the drug): hemoglobin, hematocrit, red blood cell count (RBC) and red blood cell morphology (if the red blood cell count is abnormal), white blood cell count (WBC) (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count , absolute neutrophil count (ANC). Additional hematology testing should be performed at Visit 6 (Day 12 ± 1 day) for cohorts with dose regimens 1 and 2 to obtain results before the second dose of sarilumab (Visit 7: Week 2, Day 15) or before or during Visit 5 (day 8) for the dose schedule 3 cohort (not before visit 4 [day 5]) to obtain results before the second dose of sarilumab. For patients included in the dose-finding portion and the second portion, additional hematologic testing may be performed at a central laboratory or a local laboratory to confirm the neutrophil count and platelet count before administration of the second dose of sarilumab. For patients enrolled in Part 3 without Study Site Visit 6, additional hematology testing will be performed at the local laboratory prior to the second dose of sarilumab, but no earlier than Day 12. If a local laboratory is used, the central laboratory sample for hematology testing will still be performed. should be collected prior to IMP administration at Visit 7 (Day 15, Week 2) as planned for cohorts with dose schedules 1 and 2, and at Visit 5 (Day 8) for cohort with dose schedule 3. For all patients, additional hematology laboratory assessment at Visit 2 (Day 1) should be considered before the second dose of sarilumab at Visit 5 (Day 8) for patients in the Dosing Schedule 3 cohort or at Visit 7 (Week 2, Day 15) for Schedule cohorts administration of doses 1 and 2.

q. Biochemical study (blood should be collected BEFORE administration of the drug). A complete chemistry panel will be performed at the screening visit, baseline visit 2 (day 1, week 0) and visit 12 (week 12) or at EOT only: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine and creatinine clearance. glomerular filtration rate (using modified Schwartz formula), calcium, phosphate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (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.

r. Fasting lipid profile (blood should be drawn BEFORE drug administration). Triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. It is required that patients fast for at least 8 hours before the test.

s. Not necessary. HbA1c levels will be measured only based on the patient's medical history and the investigator's judgment.

t. Urine dipstick test: specific gravity, pH, glucose, blood, protein, nitrates, leukocyte esterase, bilirubin. If any dipstick test parameter is abnormal, the urine sample should be sent to a central laboratory for analysis. In case of a positive result for proteins, a microscopic analysis is carried out by the central laboratory.

u. For women who have started menstruating, a serum test to determine the presence of pregnancy is required during the screening visit.

v. For women who begin menstruating, local urine testing for pregnancy should be performed at Visit 2 (Week 0, Day 1), Visit 8 (Week 4), Visit 10 (Week 8), and Visit 12 (Week 12). Urine testing for pregnancy can be done locally. Presence of pregnancy should be tested using a urine pregnancy test prior to exposure to IMP and EOT.

w. Blood samples will be collected BEFORE IMP administration on dosing days during the treatment period. If a patient experiences an SAE, blood samples should be collected at the onset and completion of the event, if possible, or within a short time after the onset and completion, to determine sarilumab concentrations and to assess anti-drug antibodies (ADA). In the dose titration portion, and in the second portion, if a patient discontinues study treatment prematurely during the 12-week primary treatment phase, an additional PK visit is required 2 weeks after the EOT visit to collect blood samples (visit 88).

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

y. The parent(s) or legal guardian(s) must sign a separate informed consent form prior to the optional collection of a saliva sample for a pharmacogenomic study. Specimens are preferably collected at Baseline Visit 2 (Day 1, Week 0), but can be collected at any visit. The patient may also have to sign an informed consent form depending on his/her age, local regulatory requirements, and maturity level in understanding the study information. A patient is still eligible to participate in the study if he/she or his/her parent(s) or legal guardian(s) do not wish for him/her to participate in the collection of saliva samples.

Pharmacokinetic Variables

PK variables for sarilumab included maximum observed serum concentrations (Cmax) and the area under the serum concentration-time curve (AUC) calculated using the trapezoidal method during the dosing interval (AUC0-τ), after the first dose, the concentration observed before administration of the treatment during repeated dosing (Ctrough) from baseline to week 12.

A population PK (PopPK) model of the pooled data was developed using nonlinear mixed effects modeling to describe the PK profile of sarilumab. The following PK parameters were calculated using the PopPK model for functional sarilumab in serum (PopPK analysis should be reported separately). PK parameters included, but were not limited to, the parameters listed in Table 8.

Table 8. List of pharmacokinetic parameters and definitions

Pharmacokinetic parameter

Definition_____________________________________________

Cmax Maximum observed serum concentration

Ctrough Concentration observed before administration of treatment during repeated dosing

tmax Time to reach Cmax

AUC 0-τ Area under the serum concentration-time curve calculated using the trapezoidal method during the dosing interval (τ)

Performance ratings

Response from ACR JIA

This study used the ACR JIA response rate to assess signs and symptoms (see Table 7). ACR JIA 30/50/70/90/100 (ACR30 JIA/50/70/90/100 response was defined as a patient in whom 3 of the 6 baseline set variables improved by at least 30%/50%/70%/90 %/100% compared to baseline, with no more than 1 of the remaining variables worsening by more than 30%.

The basic set for ACR JIA included 6 variables.

1. General assessment of disease activity by a physician

2. Assessment of general well-being by the patient/parent

3. Functional abilities as measured by the Children's Health Assessment Questionnaire (CHAQ)

4. Number of joints with active arthritis (from 0 to 71 joints)

5. Number of joints with limited movement (from 0 to 67 joints)

6. High sensitivity C-reactive protein.

During the 12-week main treatment phase, the ACR JIA disease core set will be assessed at each study site visit except Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8) and Visit 6 (Day 12) ). During the add-on treatment phase (for patients who remain on the current dose (adherent to the selected dosing schedule), the ACR JIA core set will be assessed periodically at weeks 24, 48, 72, 96 (EOT for part three), 120 (not applicable for Part 3), 144 (not applicable for Part 3), and EOT (Week 156 for the dose titration portion and Part 2/Week 96 for Part 3) For patients who change their selected dosing schedule during the add-on treatment phase.

General assessment of disease activity by the physician

The investigator was asked to rate the patient's disease activity on a 100-millimetre (mm) horizontal visual analogue scale (VAS) with landmarks where 0 was considered the best disease activity and 100 was considered the worst disease activity.

Patient/parent assessment of general well-being

Patient/parent ratings of general well-being were measured using a 100-mm horizontal VAS. The form was asked to be completed by the patient or the same parent or guardian to ensure consistency.

Children's Health Assessment Questionnaire (CHAQ)

The CHAQ was a self-administered survey or instrument for children ≥8 years of age and a parent/proxy-administered instrument for children <8 years of age. The CHAQ was a general measure of the health status of children aged 1 to 19 years. The assessment consisted of 43 items in total and took approximately 10 minutes to complete. The CHAQ questionnaire was completed before IMP doses and at subsequent time points (according to guidelines provided by the Health Economics and Outcomes Research Unit). The evaluation period was 1 week (Singh, G. et al. 1994 Arthritis Rheum 1994 Dec;37(12):1761-9).

The median CHAQ scores corresponding to mild, mild to moderate, and moderate disability reported at the time the CHAQ was created were 0.13, 0.63, and 1.75, respectively (Dempster, H. et al. , 2001 Arthritis Rheum 44(8):1768–74).

To eliminate inconsistencies that may have been introduced as a result of growth and

development, parents were asked to mark only those difficulties that arose due to illness (for example, if the child could not perform an activity because his/her age was too young, the answer was marked as “not applicable”). Response options assessing difficulty were based on a 5-point Likert scale

(0=no difficulty, 1=some difficulty, 2=great difficulty, 3=impossible to perform and 4=not applicable).

The CHAQ was divided into 3 parts.

1. Disability index. 41 items assessing the ability to function in daily life, further divided into 8 subscales/domains: dressing and grooming; climb; eating; walking; hygiene; reaching; grip and vigorous activity. For each domain, the degree of difficulty in performing daily functions, the need to use special aids or devices, and the need for assistance from another person was assessed.

To calculate the CHAQ-DI, the score for each domain was first calculated.

- The question with the highest score determined the score for that functional area

- If assistive aids or devices were used or assistance was required to perform tasks in a specific area, a minimum score of 2 was recorded for the relevant functional area

- The 8 subscales/domains were averaged to calculate a mean score, which was an index of disability (with a range of 0 to 3).

Lower disability index scores indicate better health status/better health-related quality of life/fewer signs and symptoms, while higher disability index scores indicate worse health status/worse HRQL/more signs and symptoms (Singh , G. et al. 1994 Arthritis Rheum. 1994 Dec;37(12):1761-90; Klepper S. 2003 Arthritis Rheum. 49(3):435-43). The minimum clinically significant improvement in the CHAQ disability index was a decrease in score of 0.13. The minimum clinically significant worsening in the CHAQ disability index was a change in median score of 0.75 (Dempster, H. et al. , 2001 Arthritis Rheum. 44(8):1768-74).

2. Discomfort index . Determined by the degree of pain over the past week, assessed by VAS (with reference points “0 - no pain” and “100 - very severe pain”). To calculate the CHAQ discomfort index, the distance from the left edge of the VAS at item 67 to the respondent's mark was measured and multiplied by 0.2. The range was from 0 to 3.

3. State of health . A measure of the patient's or parent's overall assessment of the disease.

To calculate the CHAQ health status score, the distance from the left edge of the VAS item 69 to the respondent's mark was measured and multiplied by 0.2. The range was from 0 to 3.

Number of joints with active arthritis and number of joints with limited movement

An “active joint” was defined as a joint with swelling within the joint not caused by deformity OR limited range of motion with 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).

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

The 67 joints studied for limitation of motion were the same joints as those studied for active disease, with the exception of the sternoclavicular (n=2) and acromioclavicular (n=2). Formal joint counts were performed by a trained assessor. Joint tenderness was defined as pain caused by pressure on the joints from the thumb and index finger of the assessor.

High sensitivity C-reactive protein (hs-CRP)

hs-CRP was assessed at each visit. See Table 7. High-sensitivity C-reactive protein levels were directly correlated with IL-6R activity. Active dosing regimens were expected to have the effect of acutely lowering C-reactive protein (CRP) levels.

Juvenile arthritis disease activity index

This study used the JADAS index to assess disease activity (see Table 7). JADAS included 4 indicators.

1. Physician's overall assessment of disease activity as measured by a 10-centimeter (cm) VAS, where 0=no activity and 10=maximum activity.

2. Parent/patient global assessment of well-being measured using a 10 cm VAS, where 0=very good and 10=very poor.

3. Number of joints with active disease.

4. Inflammation index. hs-CRP or ESR level.

Erythrocyte sedimentation rate is normalized on a scale from 0 to 10 using 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 before calculation at 120.

Or hs-CRP is normalized on a scale from 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 before calculation converted to 110.

The JADAS was calculated as a simple linear sum of scores across its 4 components. See Consolaro, A. et al. 2009 Arthritis Rheum. 61(5):658-66. JADAS-27 included the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (first to third), proximal interphalangeal joints, hip, knee and ankle joints. JADAS has proven to be a valid tool for assessing disease activity in JIA and has potential application in standard clinical care, surveillance testing, and clinical trials (there same).

Pharmacodynamic measurements and timing

The pharmacodynamic effects of sarilumab were assessed by measuring the following biomarkers: hs-CRP, IL-6 and total sIL-6Rα.

Concentrations of highly sensitive CRP were measured using a nephelometry (HS) assay with an LLOQ of 0.20 mg/L in Covance CLS.

Serum IL-6 concentrations were determined using a validated quantitative sandwich enzyme-linked immunosorbent assay with an LLOQ of 3.12 pg/mL in Covance CLS

Serum total sIL-6Rα concentrations were measured using a validated ELISA method with an LLOQ of 15 ng/mL (DOH1163) at Covance.

The blood sampling schedule can be found in the study design in Table 7.

Clinical and laboratory assessments

Summary statistics (including count, mean, median, SD, minimum, and maximum) of all laboratory variables (central laboratory values and changes from baseline) were calculated for each study visit or assessment (baseline, each post-baseline time point , endpoint) by dose cohort and organized by biological function. Incidence of PCSA and abnormal laboratory values at any time during the TEAE period were summarized by biological function and dose cohort. For lipids at baseline, the NCEP APTIII classification was used. The incidence of neutropenia, thrombocytopenia, and lymphopenia by maximum severity was summarized.

Pharmacokinetic data analysis

Functional sarilumab serum concentrations were summarized using descriptive statistics. All PK analyzes were performed using the PK population. It consisted of all patients in the safety group who had at least 1 non-missing post-dose sarilumab concentration value. Residual functional sarilumab serum concentrations were summarized using descriptive statistics (including number, arithmetic and geometric means, SD, SE of mean (SEM), CV, minimum, median and maximum) by dose, overall and weight group bodies for every visit. Samples were considered unsuitable for these analyzes if the time of previous dosing was <11 days or >17 days prior to the time of sampling for biweekly dosing regimens; <5 days or >9 days prior to sampling time for weekly dosing regimens. Concentrations below the LLOQ were set to zero for predose (week 0) samples. Other concentrations below LLOQ were replaced by LLOQ/2. The PopPK model was developed using nonlinear mixed effects modeling to describe the PK profile of sarilumab. The PopPK model was presented in a separate document from the CSR.

Pharmacodynamic data analysis

Serum concentrations of IL-6, total sIL-6Rα, and hs-CRP from baseline to week 12 were summarized using descriptive statistics (including count, arithmetic and geometric means, SD, SEM, CV, minimum, median, and maximum) across dose and body weight group for each visit.

Analysis of pharmacokinetic-pharmacodynamic data

Exploratory analyzes were performed to examine exposure-response relationships with key efficacy endpoints and/or biomarkers. Results of exposure-response relationships with key efficacy endpoints were presented in a document separate from the CSR.

Demographics and other characteristics at baseline

The results reported herein are from the dose-finding portion of the 12-week main phase of this study.

Demographics

Demographics and patient characteristics were described for the treatment population in Table 9 by treatment group. Overall, patients were predominantly female (64.3%) and Caucasian (78.6%), with similar distributions across body weight and dose groups. The 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 (21.4%) patients were recruited in South American countries and 33 (78.6%) patients were enrolled in the Western regions and the rest of the world. These demographic characteristics were comparable across the three dose cohorts within each body weight group. Detailed characteristics at baseline are presented in Table 9.

Medical history

There were a total of 9 [69.2%], 11 [78.6%], and 9 [60.0%] patients in dose cohorts 1, 2, and 3, respectively, with any medical history. The most common primary SOC was infections and infestations, observed in a total of 11 patients, more than half of which were observed in dose cohort 2 (6 [42.9%] patients). One patient in arm A, assigned to dose cohort 2, had a history of bowel problems due to a surgical procedure 3.5 years prior to study entry, which met the exclusion criterion 21 and subsequently led to eventual discontinuation of the study.

At baseline, patients had high disease activity, with a mean JADAS-27-CRP of 20.6, a mean number of active joints of 13.9, and a mean CRP of 9.5 mg/L. Concomitant and previous drug use was balanced between body weight groups (Table 21).

Table 9. Demographics and Patient Characteristics at Baseline—Treatment Population Body weight group Cohort by dose All combined doses 1 2 3 ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All Age (years) Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Mean (SD) 12.3 6.5 9.6 13.1 4.7 8.9 13.7 4.7 8.3 13.0 5.2 8.9 (3.3) (3.2) (4.3) (3.4) (1.9) (5.1) (3.0) (2.4) (5.2) (3.1) (2.5) (4.8) Median value 13.0 6.0 9.0 15.0 4.0 7.5 13.0 4.0 8.0 13.0 4.5 8.5 Min: Max 7:17 2:11 2:17 8:16 3:7 3:16 9:17 2:9 2:17 7:17 2:11 2:17 Age group (years) [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Children (2-11) 2 6 8 3 7 10 1 9 10 6 22 28 (28.6%) (100%) (61.5%) (42.9%) (100%) (71.4%) (16.7%) (100%) (66.7%) (30.0%) (100%) (66.7%) Teenagers (12- 5 0 5 4 0 4 5 0 5 14 0 14 17) (71.4%) (38.5%) (57.1%) (28.6%) (83.3%) (33.3%) (70.0%) (33.3%)

Weight, kg) Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Mean (SD) 47.3 20.4 34.9 43.8 20.1 31.9 43.8 18.9 28.8 45.0 19.7 31.7 (9.4) (6.7) (16.1) (9.9) (6.8) (14.8) (7.7) (6.0) (14.2) (8.8) (6.1) (14.8) Median value 50.7 21.1 30.1 44.4 18.2 29.3 43.8 16.7 27.2 46.3 18.4 29.1 Min: Max 30.1: 11.5: 11.5: 30.0: 12.0: 12.0: 34.5: 12.4: 12.4: 30.0: 11.5: 11.5: 59.0 29.5 59.0 55.5 28.6 55.5 52.9 28.7 52.9 59.0 29.5 59.0

Table 9. - continued Body weight group Cohort by dose All combined doses 1 2 3 ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All Quantity 7 6 13 7 7 14 6 9 15 20 22 42 ≥ 30 kg 7 0 7 7 0 7 6 0 6 20 0 20 (100%) (53.8%) (100%) (50.0%) (100%) (40.0%) (100%) (47.6%) < 30 kg 0 6 6 0 7 7 0 9 9 0 22 22 (100%) (46.2%) (100%) (50.0%) (100%) (60.0%) (100%) (52.4%)

Body mass index
(BMI) (kg/ ^m2 ) Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Mean (SD) 20.3 14.4 17.6 19.1 16.0 17.6 18.6 15.7 16.9 19.4 15.5 17.3 (3.1) (1.4) (3.9) (3.2) (1.0) (2.8) (2.5) (1,2) (2.3) (2.9) (1.3) (3.0) Median value 19.9 14.7 16.5 17.6 15.5 17.1 19.4 15.4 15.7 19.3 15.4 16.3 Min: Max 16.5: 11.8 : 11.8 : 15.1 : 15.3 : 15.1 : 15.1 : 14.3 : 14.3 : 15.1 : 11.8 : 11.8: 26.2 15.5 26.2 24.7 17.5 24.7 21.3 18.3 21.3 26.2 18.3 26.2

BMI group (kg/ ^m2 ) [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Normal (<25) 6 6 12 7 7 14 6 9 15 19 22 41 (85.7%) (100%) (92.3%) (100%) (100%) (100%) (100%) (100%) (100%) (95.0%) (100%) (97.6%) Excess body weight (≥25- 1 0 1 0 0 0 0 0 0 1 0 1 thirty) (14.3%) (7.7%) (5.0%) (2.4%) Obesity (≥30) 0 0 0 0 0 0 0 0 0 0 0 0

Table 9. - continued Body weight group Cohort by dose All combined doses 1 2 3 ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All Height (cm) Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Mean (SD) 152.3 117.5 136.2 151.0 110.3 130.6 153.3 108.6 126.5 152.2 111.5 130.9 (11.4) (17.5) (22.8) (10.5) (17.0) (25.1) (11.4) (16.4) (26.7) (10.5) (16.5) (24.7) Median value 154.0 120.0 138.0 154.0 109.0 132.0 154.0 103.0 133.0 154.0 109.5 134.0 Min: Max 135:165 89:138 89:165 133:161 88:131 88:161 136:168 92:135 92:168 133:168 88:138 88:168 Gender [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Female 5 5 10 5 3 8 3 6 9 13 14 27 (71.4%) (83.3%) (76.9%) (71.4%) (42.9%) (57.1%) (50.0%) (66.7%) (60.0%) (65.0%) (63.6%) (64.3%) Male 2 1 3 2 4 6 3 3 6 7 8 15 (28.6%) (16.7%) (23.1%) (28.6%) (57.1%) (42.9%) (50.0%) (33.3%) (40.0%) (35.0%) (36.4%) (35.7%) Race [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Caucasian/White 6 3 9 7 5 12 4 8 12 17 16 33 (85.7%) (50.0%) (69.2%) (100%) (71.4%) (85.7%) (66.7%) (88.9%) (80.0%) (85.0%) (72.7%) (78.6%) Negroids 0 0 0 0 0 0 0 0 0 0 0 0 Mongoloids/representatives of the eastern race 0 0 0 0 0 0 0 0 0 0 0 0 Unknown 1 2 3 0 0 0 2 0 2 3 2 5 (14.3%) (33.3%) (23.1%) (33.3%) (13.3%) (15.0%) (9.1%) (11.9%) Data missing 0 1 1 0 2 2 0 1 1 0 4 4 (16.7%) (7.7%) (28.6%) (14.3%) (11.1%) (6.7%) (18.2%) (9.5%)

Table 9. - continued Body weight group Cohort by dose All combined doses 1 2 3 ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All Region [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 West 3 1 4 1 3 4 2 6 8 6 10 16 (42.9%) (16.7%) (30.8%) (14.3%) (42.9%) (28.6%) (33.3%) (66.7%) (53.3%) (30.0%) (45.5%) (38.1%) South America 1 3 4 2 0 2 2 1 3 5 4 9 (14.3%) (50.0%) (30.8%) (28.6%) (14.3%) (33.3%) (11.1%) (20.0%) (25.0%) (18.2%) (21.4%) Rest of the world 3 2 5 4 4 8 2 2 4 9 8 17 (42.9%) (33.3%) (38.5%) (57.1%) (57.1%) (57.1%) (33.3%) (22.2%) (26.7%) (45.0%) (36.4%) (40.5%) Tanner stage [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Stage I 2 5 7 1 7 8 1 9 10 4 21 25 (28.6%) (83.3%) (53.8%) (14.3%) (100%) (57.1%) (16.7%) (100%) (66.7%) (20.0%) (95.5%) (59.5%) Stage II 0 1 1 1 0 1 2 0 2 3 1 4 (16.7%) (7.7%) (14.3%) (7.1%) (33.3%) (13.3%) (15.0%) (4.5%) (9.5%) Stage III 1 0 1 2 0 2 1 0 1 4 0 4 (14.3%) (7.7%) (28.6%) (14.3%) (16.7%) (6.7%) (20.0%) (9.5%) Stage IV 2 0 2 1 0 1 0 0 0 3 0 3 (28.6%) (15.4%) (14.3%) (7.1%) (15.0%) (7.1%) Stage V 2 0 2 2 0 2 2 0 2 6 0 6 (28.6%) (15.4%) (28.6%) (14.3%) (33.3%) (13.3%) (30.0%) (14.3%)

Abbreviations. BMI=body mass index

Region 1 (Western countries). Czech Republic, Germany, Spain, Netherlands, Great Britain, Finland, France and Italy.

Region 2 (South America). Argentina, Chile and Mexico

Region 3 (Rest of the World). Poland and Russia

Percentages were calculated using the number of patients assessed as the denominator.

Characteristics of the disease at the initial point in time

Disease characteristics at baseline were described for the treatment population in Table 10 by treatment group. These disease characteristics at baseline were comparable across the three dose cohorts within each body weight group. The distribution of patients with RF-negative pcJIA, RF-positive pcJIA, and e-oJIA was 64.3%, 21.4%, and 14.3%, respectively. The distribution of RF-negative pcJIA was similar in the 2 groups by body weight, while Group A had approximately twice as many patients with RF-positive pcJIA and half as many patients with e-oJIA compared with Group B.

As expected based on the age of the dose cohorts, the mean duration of JIA since diagnosis was longer 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]) in dose cohorts. The median number of active joints and joints with limited motion were 10.0 (range: 5.0 to 45.0) and 8.0 (range: 1.0 to 46.0), respectively, with a distribution of 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 JADAS-27-CRP value at baseline was 19.3 (range: 8.5 to 35.5) (23.2 [range: 9.2 to 33.8] and 16.8 [range: 8.5 to 35.5] in groups A and B, respectively), reflecting a population with highly active disease. The median hs-CRP value at baseline 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] in groups A and B, respectively). The distribution of ANC was similar across body weight and dose groups.

Overall, 76.2% of patients included in the study received concomitant csDMARD treatment and 31.0% received concomitant oral glucocorticoids; 28.6% of patients received ≥1 course of bDMARD treatment that was discontinued before study entry. Other patient and disease characteristics were comparable across body weight groups.

Table 10 - Disease characteristics at baseline - treated population Body weight group Cohort by dose All combined doses 1 2 3 ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All ≥ 30 kg < 30 kg All Subtype JIA [n (%)] Quantity 7 6 13 7 7 14 6 9 15 20 22 42 RF positive 2 2 4 3 0 3 1 1 2 6 3 9 (28.6%) (33.3%) (30.8%) (42.9%) (21.4%) (16.7%) (11.1%) (13.3%) (30.0%) (13.6%) (21.4%) RF negative 5 4 9 3 5 8 4 6 10 12 15 27 (71.4%) (66.7%) (69.2%) (42.9%) (71.4%) (57.1%) (66.7%) (66.7%) (66.7%) (60.0%) (68.2%) (64.3%) Common 0 0 0 1 2 3 1 2 3 2 4 6 oligoarticular (14.3%) (28.6%) (21.4%) (16.7%) (22.2%) (20.0%) (10.0%) (18.2%) (14.3%)

Duration of JIA since diagnosis (years) Quantity 7 6 13 7 7 14 6 9 15 20 22 42 Mean (SD) 4.3 (5.7) 2.2 (2.7) 3.4 (4.5) 5.3 (6.2) 1.5 (2.2) 3.4 (4.9) 4.1 (4.0) 1.4 (0.9) 2.5 (2.8) 4.6 (5.2) 1.7 (1.9) 3.1 (4.1) Median value 0.8 1.1 0.9 1.6 0.5 1.1 3.8 1.9 1.9 2.6 1.1 1.2 Min: Max 0.3 : 15.1 0.3 : 7.2 0.3 : 15.1 0.6 : 15.1 0.2 : 6.3 0.2 : 15.1 0.3 : 11.2 0.1 : 2.6 0.1 : 11.2 0.3 : 15.1 0.1 : 7.2 0.1 : 15.1 Rheumatoid factor [n(%)] Quantity 6 6 12 7 7 14 6 9 15 19 22 41 Positive (≥ 15 0 0 0 3 0 3 1 1 2 4 1 5 IU/ml) (42.9%) (21.4%) (16.7%) (11.1%) (13.3%) (21.1%) (4.5%) (12.2%) Negative (< 15 12 4 eleven 5 8 13 15 21 36 IU/ml) 6 (100%) 6 (100%) (100%) (57.1%) 7 (100%) (78.6%) (83.3%) (88.9%) (86.7%) (78.9%) (95.5%) (87.8%)

Determining medication adherence

A given administration was considered non-compliant if the patient did not take the scheduled dose of IMP as required by the protocol. The percentage of adherence for a patient was defined as the number of administrations that were consistent with the treatment regimen divided by the total number of administrations that the patient was scheduled to take on or before the date of the last dose.

The overall compliance rate was 97.6%. The IMP adherence rate was 96.4%. Compliance rates were similar across body weight and dose groups. One patient in Dose 2 Cohort B had an adherence rate of <80% due to dose interruptions caused by neutropenia. None of the patients received the wrong dose or overdose.

Of the 42 patients included (group A=20, group B=22), 34 completed the 12-week main phase of treatment (group A=17; group B=17) and 8 patients discontinued treatment: 5 due to treatment-emergent adverse events ( AE), 2 due to lack of effectiveness in the opinion of the investigator and 1 due to poor adherence to treatment (Fig. 8).

Pharmacokinetic and pharmacodynamic evaluation

Serum concentration of functional sarilumab

All pre-dose functional sarilumab serum concentrations were below the LLOQ (0.3125 mg/L). Individual functional serum concentrations during the 12-week main treatment phase with descriptive statistics were analyzed for each treatment group. The observed mean (SD) concentrations of sarilumab after the first SC administration are shown in FIG. 3 . Profiles of observed mean (SD) residual sarilumab concentrations over time are shown in FIG. 4 .

Pharmacokinetic parameters

Descriptive statistics for sarilumab PK parameters estimated based on the population PK model (POH0516) are shown in Table 11A after first dosing and in Table 11B after repeat dosing. Sarilumab exhibited nonlinear PK with target-mediated drug distribution in patients suffering from pcJIA ( Figure 3 ). AUC0-τ is the AUC with a dosing interval of 2 weeks for the q2w regimen or one week for the qw regimen. After repeated SC doses of sarilumab for weeks 10-12, "AUC0-14 days" was used to compare the effects of different q2w and qw regimens (AUC0-14 days=2 x AUC0-τ for the qw regimen and AUC0-14 days=AUC0-τ for circuits q2w).

Table 11A. - Mean (CV%) [median] individual exposure to sarilumab after first SC administration in pediatric patients with pcJIA Cohort
by dose Group
by body weight Dose
mg/kg N Cmax
mg/l AUC0- τ day*mg/l Through
mg/l 1 Group A
≥ 30 kg 2 mg/kg q2w 7 7.69 (46.8)
[8.63] 53.2 (45.6)
[57.7] 0.626 (63.0)
[0.620] Group B
< 30 kg 2.5 mg/kg q2w 6 9.08 (21.2)
[9.68] 63.4 (30.2)
[66.2] 0.537 (47.7)
[0.470] 2 Group A
≥ 30 kg 3 mg/kg q2w 7 14.5 (19.4)
[15.2] 123 (24.0)
[133] 1.84 (68.7)
[1.69] Group B
< 30 kg 4 mg/kg q2w 7 18.7 (21.0)
[17.5] 167 (25.7)
[158] 3.77 (42.5)
[4.34] 3 Group A
≥ 30 kg 2 mg/kg qw 6 11.0 (21.2)
[10.8] 61.3 (21.7)
[60.8] 8.07 (31.9)
[7.87] Group B
< 30 kg 2.5 mg/kg qw 9 8.29 (34.6)
[8.63] 45.3 (36.4)
[48.2] 5.22 (38.9)
[5.96]

Table 11B. - Mean (CV%) [median] individual exposure to sarilumab following repeated SC administration for weeks 10–12 or weeks 11–12 in pediatric patients with pcJIA Cohort
by dose Group
by body weight Dose
mg/kg N Cmax
mg/l AUC0- τ day*
mg/l Through
mg/
l 1 Group A
≥ 30 kg 2 mg/kg q2w 5 13.2 (13.6)
[12.6] 114 (17.5)
[116] 1.99 (85.6)
[1.40] Group B
< 30 kg 2.5 mg/kg q2w 5 14.1 (26.5)
[13.7] 118 (36.6)
[101] 1.83 (101)
[1.27] 2 Group A
≥ 30 kg 3 mg/kg q2w 6 26.4 (26.2)
[24.4] 269 (33.6)
[250] 8.46 (68.2)
[8.25] Group B
< 30 kg 4 mg/kg q2w 7 30.1 (19.7)
[31.1] 310 (26.1)
[331] 11.9 (41.2)
[13.1] 3 Group A
≥ 30 kg 2 mg/kg qw 6 38.8 (22.7)
[39.3] 250 (24.4)
[254] 30.4 (28.2)
[31.4] Group B
< 30 kg 2.5 mg/kg qw 5 31.4 (22.4)
[29.9] 203 (25.0)
[197] 25.1 (29.2)
[27.3]

Abbreviations. AUC0 τ: area under the serum concentration versus time curve during an interdose interval τ of 2 weeks (q2w schedule) or one week (qw schedule), Cmax=maximum observed serum concentration, Ctrough=concentrations observed before dosing treatments during repeated dosing, CV=coefficient of variation, pcJIA=polyarticular juvenile idiopathic arthritis, q2w=biweekly, qw=weekly, SC=subcutaneous.

Bayesian impact derived from a population PK model

After repeated SC administration of q2w and qw for weeks 10–12, sarilumab exposure increased more than dose proportionally, with AUC0–14 days increasing 2.4–2.6-fold with 1.5–1.6-fold increase in sarilumab dose times in dose cohort 2 compared with dose cohort 1, and increased 3.4- to 4.4-fold when the sarilumab dose was 2-fold in dose cohort 3 compared with dose cohort 1.

Accumulation to values of 1.9-2.2 times greater for dose cohorts 1 and 2 and accumulation to values of 4.1-4.5 times greater for dose cohort 3 at week 12 compared to the first dose were observed. (Table 22) Dosing regimens tested in the 2 body weight groups achieved similar effects for each dose cohort. The variability of Cmax and AUC0-τ after repeated SC doses in patients suffering from pcJIA ranged from 13.6 to 36.6%.

Data from a 12-week dose-finding study were analyzed. Data were analyzed for patients divided into 2 groups based on body weight: group A (30–60 kg) and group B (10 to <30 kg). As described above, patients received sequential escalating doses of sarilumab. Dose 1 (group A/B): 2.0/2.5 mg/kg q2w; dose 2 (group A/B): 3/4 mg/kg q2w; dose 3 (group A/B): 2.0/2.5 mg/kg qw. Doses for pcJIA were aimed at achieving effects similar to 150 mg q2w, 200 mg q2w, and 150 mg qw for adults. As described above, the primary outcome was pharmacokinetics (PK) and secondary outcomes were safety, PD, and efficacy of sarilumab.

Data show that the study included 42 patients (20/22 in groups A/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 value were 4.6/1.7 years, 17.2/11.0, and 22.2/19.1 in groups A/B, respectively. As in adult patients, sarilumab exhibited a nonlinear PK with target-mediated drug distribution. After repeated SC administrations, exposure increased more than dose proportionally and accumulated to values of 1.9-4.5 times greater over 12 weeks. Sarilumab exposure was similar in both groups by body weight at each dose (Table 12) and comparable to corresponding adult doses. Adverse events that occurred during treatment were recorded in 36/42 (85.7%) patients (comparable across dose and body weight groups); infections (28/42, 66.7%) were the most common AEs. We identified 12 cases of grade 3/4 neutropenia, mostly in dose cohort 3 (n=6) and cohort B (n=8). None of these were associated with infection; everything was resolved in a few days. Overall, 4 patients discontinued treatment due to neutropenia and 1 patient discontinued treatment due to elevated alanine aminotransferase levels. No serious AEs, gastrointestinal perforations, or deaths were observed. By week 12, as observed while on treatment, all patients achieved ACR30 JIA; 50%, 62% and 100% of patients achieved ACR70 JIA at doses 1, 2 and 3, respectively; the mean change from baseline in JADAS27-CRP for doses 1, 2, and 3 was -74.6%, -73.1%, and -87.9%, respectively.

.

Pharmacokinetic findings

Sarilumab exhibited nonlinear PK with target-mediated drug distribution in pcJIA patients. After repeated SC administration, sarilumab exposure increased more than proportionally to dose, accumulating to values of 1.9-4.5 times greater over 12 weeks. For each dose cohort, dosing regimens tested in the 2 body weight groups showed similar effects. For additional analysis of data from patient group A (30-60 kg) and patient group B (10 to <30 kg), sarilumab was observed to exhibit non-linear PK with target-mediated drug distribution. In addition, all dosing regimens were effective in reducing disease activity. The safety profile was consistent with class effects; A higher incidence of neutropenia was observed at dose 3 and in patients with body weight between 10 and <30 kg.

Concentrations of CRP, ESR, IL-6 and sIL-6R

Descriptive statistics of hs-CRP, ESR, IL-6, and total sIL-6Rα concentrations from baseline to week 12 were analyzed for each treatment group. Mean (SE) concentration profiles of CRP, ESR, IL-6, and sIL-6Rα over time were obtained for each cohort. Following SC administration of sarilumab, the mean suppression of CRP and increase in sIL-6Rα was greater in dose cohorts 2 and 3 than in dose cohort 1. Mean CRP concentrations were reduced over 2 to 4 weeks in dose cohorts 2 and 3, with greater and more rapid reductions. a decrease was observed in dose cohorts 2 and 3 than in dose cohort 1 (Fig. 10A). Changes in mean CRP concentrations from baseline to week 12 were 7.4-5.8 mg/L, 14.6-0.5 mg/L, and 6.5-0.1 mg/L at doses 1, 2, and 3 respectively. All patients achieved normal CRP concentrations at doses 2 and 3 within weeks 2–6. At week 4, the majority of patients achieved CRP levels below the detection limit (<0.2 mg/L) at doses 2 and 3 (71.4% and 83.3%, respectively, as observed during treatment) compared with 25. 0% at dose 1. This effect was maintained over time with 66.7% and 90.9% of patients achieving a CRP <0.2 mg/L at week 12 at doses 2 and 3, respectively, compared to 30.0% at dose 1 (Fig. 10B).

The high mean CRP value in dose 1 cohort A was primarily due to one patient whose CRP level remained elevated (40–110 mg/L) during the 12-week main treatment phase.

The erythrocyte sedimentation rate at week 12 is consistent with what was observed for CRP. Overall, mean erythrocyte sedimentation rate (ESR) decreased and mean IL-6 and sIL-6Rα concentrations increased at week 12. As with CRP levels, greater decreases were observed in dose cohorts 2 and 3 with mean change from baseline to weeks 12 from 22.2 to 18.2 mm/h, from 21.4 to 6.9 mm/h, and from 21.9 to 4.4 mm/h in dose cohorts 1, 2, and 3, respectively.

Pharmacodynamic-pharmacokinetic relationship of biomarkers

Exploratory analyzes were performed to elucidate exposure-response relationships with PD biomarkers. Individual concentrations of CRP, ESR, IL-6, and sIL-6Rα were plotted against serum trough concentrations at week 12. There was no apparent relationship between individual IL-6 levels and trough sarilumab concentrations. Data show that total sIL-6Rα levels increased with increasing residual sarilumab concentrations after repeated doses in individual pcJIA patients. C-reactive protein levels were lower (≤1 mg/L) in selected patients with residual sarilumab concentrations >1 mg/L compared with patients with residual sarilumab concentrations ≤1 mg/L. CRP suppression was greater in patients in dose cohorts 2 and 3 than in patients in dose cohort 1. Erythrocyte sedimentation rate was lower (≤10 mm/hour) in selected patients with residual sarilumab concentrations >1 mg/L compared with patients with residual sarilumab concentrations ≤1 mg/L. ESR suppression was greater in patients in dose cohorts 2 and 3 than in patients in dose cohort 1.

Following SC administration of sarilumab, the suppression of CRP and the increase in sIL-6Rα were greater in dose cohorts 2 and 3 than in dose cohort 1. Overall, mean ESR concentrations decreased and mean IL-6 and sIL-6Rα concentrations increased compared with baseline in week 12.

Safety of the 2-week main treatment phase . Overall exposure (patient-years of treatment) was similar across dose and body weight groups: 4.6 and 5.0 patient-years in groups A and B, respectively.

No serious AEs or deaths were observed (Table 23). The most commonly observed AEs were infections 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 due to upper respiratory tract infections (n=9 [21.4%]; Table 25). No serious infections were reported. No cases of pneumonia or tuberculosis were detected. One case of oral candidiasis occurred (Dose Cohort 3, Group A), which resolved spontaneously without corrective treatment and without interruption of sarilumab treatment. None of the patients discontinued treatment due to any infection.

Prespecified laboratory monitoring identified 12 patients with transient grade 3/4 neutropenia (28.6%). 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 required treatment interruption per protocol (1 each in dose cohort 2, arm B; dose cohort 3, arms A and B). None of the cases of neutropenia were associated with infection 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 additional potentially clinically significant abnormalities. In particular, no cases of drug-induced liver injury as defined by Hay's law were observed (21).

Per-protocol permanent discontinuation due to AE occurred in 5 patients (11.9%). Of these cases, 1 was grade 3 neutropenia at week 2 dosing in dose cohort 1, arm A; 3 were grade 4 neutropenia in dose cohort 3, arm B, and 1 was alanine aminotransferase (ALT) elevation in dose cohort 1, arm A (>5 × upper limit of normal [ULN] at week 4).

Seven patients reported local reactions after injection (4 in group A and 3 in group B). These reactions were primarily erythema and pain; all were mild to moderate in intensity; none resulted in discontinuation of treatment. Two patients tested positive for drug antibodies at week 12: one in dose cohort 1, arm A (neutralizing antibody positive; treatment discontinued due to ALT >5 × ULN at week 4); one in dose cohort 3, arm B (no neutralizing antibody positivity; treatment discontinued due to grade 4 neutropenia after first injection).

EFFICIENCY MARK

ACR JIA Response Rate

In this study, the ACR JIA response rate was used to assess signs and symptoms. ACR JIA response 30/50/70/90/100 was defined as a patient in whom 3 of 6 core set variables improved by at least 30%/50%/70%/90%/100% from baseline, with In this case, no more than one of the remaining variables worsened by more than 30%.

ACR JIA response rates were calculated using the direct observation method for those taking the treatment ("as observed while on the treatment") and by imputation for patients who discontinued treatment ("non-responder imputation approach" when patients who discontinued treatment were automatically considered non-responders at post-treatment visits). ACR JIA response rates across all dose and body weight groups at week 12 are summarized in Table 13. ACR JIA response rate accuracy estimates are shown in Table 33.

As observed during treatment, at week 12, the ACR30 JIA response rate was 100% across all dose and body weight groups. ACR70 JIA response rates were 50.0%, 61.5%, and 100% in dose cohorts 1, 2, and 3, respectively. At week 12, ACR30 JIA response rates were 76.9%, 92.9%, and 73.3% in dose cohorts 1, 2, and 3, respectively, as calculated by the nonresponder imputation approach. ACR70 JIA response rates were 38.5%, 57.1%, and 73.3% in dose cohorts 1, 2, and 3

respectively.

Overall, in a watch-over-treatment approach, the emergence of an ACR30 JIA response was observed from the first assessment at week 2 across all dose and body weight groups. The rate reached a plateau of 100% at weeks 4 and 8 for dose cohort 2, groups A and B, respectively, and at weeks 6 and 8 for dose cohort 3, groups A and B, respectively, while the response rate in dose cohort 1 was unstable until week 12 ( Fig. 5 ). The results of the substitution approach for non-responder subjects are shown in FIG. 6 .

ACR JIA Components

Data were collected regarding components of the ACR JIA during the 12-week main treatment phase. A summary of the ACR JIA components at week 12 is presented in Table 14. At week 12, all dose cohorts and body weight groups showed reductions from baseline in all ACR JIA components, which were generally greater in dose cohorts 2 and 3 compared with dose cohort 1. The number of joints with active arthritis decreased in patients in all dose cohorts in both body weight groups during the 12-week main treatment phase. The largest reduction in mean at week 12 was observed in patients in dose cohort 3, group A (-16.5). The number of joints with restricted motion decreased in patients in all dose cohorts in both body weight groups during the 12-week main treatment phase. The largest reduction in mean at week 12 was observed in patients in dose cohort 3, arm B (-11.3). Physician global VAS score decreased in patients in all dose cohorts in both body weight groups during the 12-week main treatment phase. The greatest decrease in mean value at week 12 was observed in patients in dose cohort 3, group B (-5.0). Patient total VAS scores decreased in patients in all dose cohorts in both body weight groups during the 12-week main treatment phase. The largest reduction in mean at week 12 was observed in patients in dose cohort 3, arm B (-5.7). Overall, CHAQ-DI scores decreased for patients in all dose cohorts in both body weight groups during the 12-week main treatment phase. The largest reduction in mean at week 12 was observed in patients in arm B, dose cohort 2 (-1.0). Mean hs-CRP concentrations decreased in all dose cohorts for both body weight groups at week 12. Mean CRP concentrations decreased over weeks 2–4 in dose cohorts 2 and 3. The high mean CRP in dose cohort 1 of group A was the first The queue was driven by one patient whose CRP levels remained elevated (40–110 mg/L) during the 12-week main treatment phase. The largest reduction in mean at week 12 was observed in patients in arm B, dose cohort 2 (-15.2).

Juvenile arthritis disease activity index

Disease activity was assessed using the JADAS-27 CRP score. JADAS-27 CRP scores were analyzed over time in each dose cohort and body weight group. JADAS-27 summary (ESR) data during the 12-week main treatment phase are presented in Table 15. Investigator-reported TEAEs are shown in Table 30. Data show that compared to baseline, all dose cohorts and body weight groups showed a decrease in score JADAS-27 CRP from week 2. At week 12, mean percent change from baseline was -74.6%, -73.1%, and -87.9% in dose cohorts 1, 2, and 3, respectively.

Table 13 - JIA-ACR Week 12 Response Rate Summary - Efficacy Population As observed during treatment Imputation approach for non-responders ^a JIA-ACR30 JIA-ACR50 JIA-ACR70 JIA-ACR90 JIA-
ACR100 JIA-ACR30 JIA-ACR50 JIA-ACR70 JIA-ACR90 JIA-
ACR100 Cohort 1, Group A 5/5(100%) 4/5(80.0%) 3/5(60.0%) 3/5(60.0%) 0/5 5/7(71.4%) 4/7(57.1%) 3/7(42.9%) 3/7(42.9%) 0/7 Cohort 1, Group B 5/5(100%) 5/5(100%) 2/5(40.0%) 1/5(20.0%) 0/5 5/6(83.3%) 5/6(83.3%) 2/6(33.3%) 1/6(16.7%) 0/6 Cohort 1, total 10/10(100%) 9/10(90.0%) 5/10(50.0%) 4/10(40.0%) 0/10 10/13(76.9%) 9/13(69.2%) 5/13(38.5%) 4/13(30.8%) 0/13 Cohort 2, Group A 6/6(100%) 5/6(83.3%) 3/6(50.0%) 2/6(33.3%) 0/6 6/7(85.7%) 5/7(71.4%) 3/7(42.9%) 2/7(28.6%) 0/7 Cohort 2, Group B 7/7(100%) 7/7(100%) 5/7(71.4%) 2/7(28.6%) 2/7(28.6%) 7/7(100%) 7/7(100%) 5/7(71.4%) 2/7(28.6%) 2/7(28.6%) Cohort 2, total 13/13(100%) 12/13(92.3%) 8/13(61.5%) 4/13(30.8%) 2/13(15.4%) 13/14(92.9%) 12/14(85.7%) 8/14(57.1%) 4/14(28.6%) 2/14(14.3%) Cohort 3, Group A 6/6(100%) 6/6(100%) 6/6(100%) 4/6(66.7%) 2/6(33.3%) 6/6(100%) 6/6(100%) 6/6(100%) 4/6(66.7%) 2/6(33.3%) Cohort 3, Group B 5/5(100%) 5/5(100%) 5/5(100%) 3/5(60.0%) 2/5(40.0%) 5/9(55.6%) 5/9(55.6%) 5/9(55.6%) 3/9(33.3%) 2/9(22.2%) Cohort 3, total 11/11(100%) 11/11(100%) 11/11(100%) 7/11(63.6%) 4/11(36.4%) 11/15(73.3%) 11/15(73.3%) 11/15(73.3%) 7/15(46.7%) 4/15(26.7%)

a Patients who discontinue treatment are automatically considered non-responders at post-treatment discontinuation visits.

Table 14 - Summary of ACR JIA Component Data at Week 12 by Dose Cohort and by Body Weight Cohort - Efficacy Population Body weight group A
( ≥ 30 kg) Body weight group B
(<30 kg) Body weight groups A and
B

Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3

Number of active joints (0-71)

Baseline

Quantity 7 7 6 6 7 9 13 14 15 Average value 19.3 14.6 17.7 11.7 8.3 12.7 15.8 11.4 14.7 Week 12 Quantity 5 6 6 6 7 6 eleven 13 12 Average value 7.2 5.0 1.2 2.2 1.0 1.3 4.5 2.8 1.3 Average change -14.4 -10.5 -16.5 -9.5 -7.3 -12.5 -11.7 -8.8 -14.5 Average value -78.5 -72.6 -91.6 -73.2 -86.2 -80.9 -75.6 -79.9 -86.2 % change Number of active 2/5 0/6 2/6 2/5 4/7 3/5 4/10 4/13 5/11 joints=0 (40.0%) (33.3%) (40.0%) (57.1%) (60.0%) (40.0%) (30.8%) (45.5%) Number of joints with limited movement Baseline Quantity 7 7 6 6 7 9 13 14 15 Average value 10.3 9.3 16.5 10.5 7.6 10.6 10.4 8.4 12.9 Week 12 Quantity 5 6 6 6 7 6 eleven 13 12 Average value 3.4 2.7 8.7 5.5 1.6 0.8 4.5 2.1 4.8 Average change -7.8 -6.8 -7.8 -5.0 -6.0 -11.3 -6.3 -6.4 -9.6 Average value -75.5 -52.4 -59.1 -45.1 -69.8 -89.8 -58.9 -61.8 -74.5 % change

Doctor's overall VAS score (0-10)

Baseline

Quantity 7 7 6 6 7 9 13 14 15 Average value 4.6 4.3 4.1 4.7 5.2 4.0 4.7 4.8 4.1 Week 12 Quantity 5 6 6 6 7 5 eleven 13 eleven Average value 1.7 2.0 1.1 1.8 0.9 0.6 1.7 1.4 0.8 Average change -3.3 -2.7 -3.1 -3.0 -4.3 -5.0 -3.1 -3.5 -3.9 Average value -66.3 -48.5 -77.5 -61.0 -81.4 -87.4 -63.4 -66.2 -82.5 % change

Patient's overall VAS score (0-10)

Baseline

Quantity 7 7 6 6 7 9 13 14 15 Average value 4.6 6.3 5.3 7.2 5.5 5.3 5.8 5.9 5.3 Week 12
Quantity 5 6 6 6 7 5 eleven 13 eleven

Table 14. Continued Body weight group A
( ≥ 30 kg) Body weight group B
(<30 kg) Body weight groups A and
B

Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3

Average value 1.2 1.8 0.8 1.8 1.7 0.3 1.5 1.8 0.5 Average change -3.6 -4.9 -4.6 -5.4 -3.8 -5.7 -4.6 -4.3 -5.1 Average value -66.2 -74.7 -85.2 -71.9 -65.6 -93.3 -69.3 -69.8 -88.9

CHAQ-DI (0-3)

Baseline

Quantity 7 7 6 6 7 9 13 14 15 Average value 1.1 0.9 0.7 1.5 1.3 0.9 1.3 1.1 0.8 Week 12 Quantity 5 6 6 6 7 5 eleven 13 eleven Average value 0.5 0.4 0.3 0.5 0.3 0.6 0.5 0.3 0.4 Average change -0.8 -0.7 -0.4 -0.9 -1.0 -0.8 -0.9 -0.9 -0.6 Change in average -68.1 -67.2 -83.3 -64.4 -74.2 -69.6 -66.1 -71.3 -76.4 values in %

hs-CRP (mg/l)

Baseline

Quantity 7 7 6 6 7 9 13 14 15 Average value 10.9 13.7 5.8 3.2 15.4 7.0 7.4 14.6 6.5 Week 12
Quantity 5 6 6 6 6 6 eleven 12 12 Average value 9.6 0.6 0.1 2.7 0.4 0.1 5.8 0.5 0.1 Average change -5.5 -11.5 -5.7 -0.5 -15.2 -8.2 -2.8 -13.4 -7.0

Abbreviations. CHAQ-D1=Child Health Assessment Questionnaire Disability Index, hs-CRP=high-sensitivity C-reactive protein, VAS=visual analog scale.

Table 15 - Summary of JADAS-27 CRP Data During the 12-Week Main Treatment Phase by Dose Cohort and by Body Weight Cohort - Efficacy Population Body weight group A ( ≥ 30 kg) Body weight group B (<30 kg) Body weight groups A and B Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Baseline Quantity 7 7 6 6 7 9 13 14 15 Average value 22.9 22.5 21.1 21.3 17.0 19.3 22.1 19.8 20.0 Change in average
values 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Change in average 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 values in % V7/Week 2 Quantity 7 7 6 6 7 8 13 14 14 Average value 18.1 17.5 12.2 14.1 12.2 10.6 16.2 14.8 11.3 Change in average
values -4.8 -5.1 -8.9 -7.2 -4.9 -9.9 -5.9 -5.0 -9.5 Change in average -22.4 -21.3 -41.8 -34.7 -31.5 -48.8 -28.1 -26.4 -45.8 values in % V8/Week 4 Quantity 6 7 6 6 7 6 12 14 12 Average value 16.7 13.4 10.9 12.7 9.8 9.1 14.7 11.6 10.0 Change in average
values -8.5 -9.1 -10.2 -8.6 -7.2 -12.8 -8.5 -8.2 -11.5 Change in average -33.2 -41.9 -49.9 -34.5 -44.0 -57.9 -33.9 -42.9 -53.9 values in % V9/Week 6 Quantity 6 7 6 6 7 5 12 14 eleven Average value 13.7 11.0 6.2 9.7 8.9 5.9 11.7 10.0 6.0 Change in average
values -11.5 -11.5 -15.0 -11.6 -8.1 -16.8 -11.5 -9.8 -15.8 Change in average -46.7 -52.0 -69.7 -55.6 -48.4 -73.2 -51.1 -50.2 -71.3 values in % V10/Week 8 Quantity 5 6 6 6 7 5 eleven 13 eleven Average value 10.5 9.8 3.8 9.0 7.3 4.2 9.7 8.5 3.9 Change in average
values -13.6 -14.0 -17.4 -12.3 -9.7 -18.6 -12.9 -11.7 -17.9 Change in average -58.9 -60.4 -83.1 -54.3 -58.2 -78.9 -56.4 -59.2 -81.2 values in % V11/Week 10 Quantity 5 5 6 6 6 5 eleven eleven eleven Average value 8.5 6.5 3.8 7.3 6.1 2.6 7.9 6.3 3.3 Change in average
values -15.6 -15.3 -17.4 -13.9 -11.9 -20.1 -14.7 -13.5 -18.6 Change in average value in %
V12/Week 12 -67.6 -72.5 -81.4 -59.6 -65.6 -86.8 -63.2 -68.7 -83.9 Quantity 5 6 6 5 6 5 10 12 eleven Average value 7.7 7.6 2.7 4.6 4.0 1.7 6.2 5.8 2.2 Change in average
values -16.4 -16.2 -18.5 -18.1 -13.2 -21.1 -17.2 -14.7 -19.7 Change in average value in % -69.7 -69.9 -86.3 -79.5 -76.3 -89.8 -74.6 -73.1 -87.9

Conclusions regarding effectiveness

Improvement in signs and symptoms, as assessed by ACR JIA response, was observed in all dose cohorts and body weight groups from week 2 using either a follow-up approach during treatment or a imputation approach for non-responder subjects. No dose cohort discontinued treatment prematurely due to lack of efficacy. Two patients discontinued treatment due to lack of efficacy as judged by the investigator, 1 in dose cohort 1, arm B at week 10, and the other in dose cohort 3, arm B at week 4. Using a follow-up approach during treatment at week 12, the ACR30 JIA response rate was 100% (34/34) across all dose cohorts and body weight groups, with dose cohorts 2 and 3 resulting in a more rapid and sustained ACR30 response JIA compared to dose cohort 1 (Fig. 9A). At week 12, as calculated using the nonresponder substitution approach, 77%, 93%, and 73% of patients achieved ACR30 JIA (dose cohorts 1, 2, and 3, respectively; Fig. 11). A larger proportion of patients also achieved higher response thresholds: 50%, 62%, and 100% of patients achieved ACR70 JIA responses and 40%, 31%, and 64% of patients achieved ACR90 JIA responses in dose cohorts 1, 2, and 3, respectively, at week 12 as observed during treatment (FIGS. 9B, 9C; results from the non-responder imputation approach are shown in FIGS. 11B, 11C). All ACR JIA components were reduced by each of the 3 sarilumab dosing regimens (Table 26).

There was a trend toward faster ACR JIA responses in dose cohorts 2 and 3 compared with dose cohort 1. In the watch-over-treatment approach, the ACR30 JIA response rate reached a plateau of 100% within the first 2 months of sarilumab treatment for dose cohorts 2 and 3. 3, arms A and B, while the response rate in dose cohort 1 was unstable until week 12.

Reductions in disease activity assessed by JADAS-27 CRP were observed in patients across all dose cohorts and body weight groups at week 12, with mean percentage changes from baseline -74.6%, -73.1% and - 87.9% in dose cohorts 1, 2, and 3, respectively, and were also observed from week 2 onwards (Fig. 9D). In a retrospective analysis at week 12, 20 patients achieved low disease activity (LDA; JADAS-27-CRP ≤3.8): 6, 5, and 9 patients in dose cohorts 1, 2, and 3, respectively. Clinically inactive disease (CID), defined as JADAS-27-CRP ≤1, was achieved in 3 patients (1 in dose cohort 2 and 2 in dose cohort 3). CID, as defined by the Wallis criteria, was achieved in 9 patients (3, 2, and 4 patients in dose cohorts 1, 2, and 3, respectively) (22). Thirteen patients had no active joints at week 12, 4 in each of dose cohorts 1 and 2, and 5 in dose cohort 3 (Table 27).

DISCUSSION

The experimental sarilumab dosing regimens tested in the study were selected based on modeling and simulation data from the PK of sarilumab in adult patients with RA. Body weight range, body composition, and drug metabolism in pediatric patients differ from those in adults, and response to treatment and side effects may vary by age. As a result, direct extrapolation of pediatric doses from adult doses without testing in pediatric clinical trials cannot be recommended (23, 24). The clearance of monoclonal antibodies often increases in a nonlinear manner with increasing body weight (25), so given the range of body weight and age in the pcJIA population, body weight-adjusted doses were considered appropriate for this study. Dosing schedules tested in patients with pcJIA were selected based on a population-based PK simulation to achieve similar exposure in both body weight groups that would be comparable to exposure in the dosing schedules studied in adult patients with RA. The results of the study confirmed the accuracy of the original design of the body weight-based model. Sarilumab exhibited nonlinear PK with target-mediated drug distribution. Body weight-adjusted dosing regimens produced comparable effects in the two body weight groups, and the achieved effects were comparable to fixed-dose regimens tested in adults with RA.

In this study, treatment with sarilumab was associated with a decrease in mean CRP values and a decrease in ESR, demonstrating functional inhibition of IL-6 in patients suffering from pcJIA (20). In particular, reduction in CRP levels is known to be a direct consequence of IL-6 neutralization and indicates the effectiveness of IL-6 neutralization in patients with RA (26–28). The reduction in mean CRP values was more pronounced in dose cohorts 2 and 3, with more 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.

ACR JIA response was observed from week 2 across all sarilumab dosing regimens. Based on ACR70 JIA, the reduction in disease signs and symptoms was greater and sustained in dose cohorts 2 and 3 compared with dose cohort 1. As assessed by JADAS-27-CRP, more patients achieved CID or LDA in dose cohort 3 than in dose cohorts 1 or 2. These efficacy results are consistent with clear trends observed in PD results (i.e., CRP concentrations), further supporting the relationship between IL-6 neutralization and therapeutic response (20, 29). Together with the less consistent effect on CRP at dose 1, these results support exclusion of the dose 1 cohort for further study.

The treatment response rates observed in this study compare favorably with data published in a larger cohort of pcJIA patients treated with the IL-6R blocker tocilizumab (18). Current results suggest that treatment with sarilumab may meet the goals of recent guidelines published by an international task force, which established disease remission as the ultimate treatment goal and recommended that ≥50% improvement in disease activity be achieved within 3 months and that treatment goals be maintained once achieved. (eleven). The study described here included patients with established disease, one third of whom had already failed ≥1 treatment with a biologic treatment. However, of the 24 patients in dose cohorts 2 or 3, at 3 months, 23 and 19 achieved ACR50 JIA and ACR70 JIA, respectively, 14 achieved JADAS-27-CRP LDA, and 9 had no active joints. Long-term follow-up during the add-on phase will provide insight into the ability of sarilumab to meet long-term treatment goals and maintain durable clinical remission once achieved.

The types of AEs observed with sarilumab in the study were consistent with those observed with sarilumab treatment in adult patients and the class effects of IL-6 antagonists in pediatric patients (18, 30–32). Several local injection site reactions were reported, all of which were mild to moderate in intensity, indicating good local tolerability; this is important for pediatric patients because fear of pain from syringe injection is common. The most common AEs were infections and neutropenia. Infection rates were primarily driven by upper respiratory tract infections, which are common in the pediatric population, and were balanced across body weight and dose groups. Serious infections, infections resulting in treatment discontinuation, and opportunistic infections were not reported.

Per study protocol, absolute neutrophil counts (ANC) were assessed periodically during the treatment period, including after the first dose of sarilumab and before the second dose. This careful hematologic monitoring, with the first postdose assessment on day 12 for the Q2W regimen and on days 5–8 for the QW regimen, resulted in the identification of 12 cases of grade 3/4 neutropenia. In adult patients receiving sarilumab or tocilizumab, the lowest ANC value was recorded several days (until day 7) after the first treatment administration, after which ANC values recovered, consistent with class effects (33). Based on these data from adult studies, the timing of the assessments in this study helped explain the numerical imbalance of events in dose cohort 3 (n=6, including 4 events detected on day 5) compared with the other 2 dose schedules (n=3 at both doses 1 and 2).

Of the 12 cases of grade 3/4 neutropenia, 8 occurred in group B. A clear trend toward increased incidence of neutropenia in younger patients with lower body weight was also observed in pcJIA patients treated with tocilizumab (34, 35). There is no definitive mechanism to explain why younger patients are more prone to neutropenia than older pediatric or adult patients, but a higher prevalence of neutropenia in children has generally been reported (36). Neutropenia accounted for the majority of treatment discontinuations caused by AEs (n=4/5): 3 cases were grade 4 neutropenia that led to treatment discontinuation according to protocol-defined criteria, and 1 case was grade 3 neutropenia in a patient whose initial ANC value was below 2000/mm ³ . It is important to note that none of the cases of grade 3/4 neutropenia identified in this study were associated with infection, and most cases resolved within a few days. This observation is consistent with data obtained in children and adults treated with tocilizumab or sarilumab, with additional data supporting the conclusion that neutropenia caused by IL-6 inhibition does not lead to an increased 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 infections, the neutropenia data obtained in this study, together with the dynamics of ANC in adults after administration of tocilizumab or sarilumab, argue against cohort selection doses 3 (32, 33, 37). This careful choice reduces the risk of neutropenia, especially in young children who are at increased risk. In addition, the use of a dosing schedule of once every 2 weeks in dose cohort 2 provided a longer time to recovery of ANC.

After reviewing all data from the 12-week dose-finding portion of the study, Dose Cohort 2 was selected as the optimal sarilumab regimen to enroll additional patients in the second part of the main treatment phase of the study, as well as to continue into the second part for patients who were already enrolled into dose cohorts 1 or 3. Dose cohort 2 regimen demonstrated a favorable balance between efficacy and safety compared with cohorts 1 and 3. This dosing regimen provided similar exposure and mirrored the efficacy profile of the equivalent adult dosing regimen 200 mg Q2W, the recommended approved dosage for adults with RA (20, 30, 31). Dose Cohort 2 also followed a once-every-2-week dosing schedule (compared to Dose Cohort 3's once-weekly dosing schedule), which reduces injection stress, which is particularly relevant in children, and, as mentioned above, increases recovery time ANC.

Additional data regarding the safety and efficacy of sarilumab in pcJIA patients over time in a larger cohort of patients will be provided by enrolling additional patients who will receive the selected dosing schedule and be followed in the add-on treatment phase. As noted, this study was not blinded and did not include placebo or an active comparator. This has been attributed to the ethical concerns associated with exposing children to treatment failure, given the potential chronic and severe nature of the disease and the available data on IL-6 inhibition in adults and children with arthritis (18, 38). These issues were reflected in the study design, with a sequential approach to test doses and frequent monitoring, in the use of an independent data monitoring committee to formally assess the safety of sarilumab throughout the study, in the use of DEC to monitor patient response to treatment, and in the ability of DEC discontinue treatment of patients with any dose considered ineffective and return them to the investigator-approved standard of care.

In conclusion, in patients suffering from pcJIA, sarilumab exhibited nonlinear PK with target-mediated drug distribution, exhibited a safety profile consistent with the class effects of IL-6 antagonists, and reduced disease activity. This 12-week dose-finding portion of the main phase of the study showed that dose cohort 2 (3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10 to <30 kg) achieved effects similar to those of the approved 200 mg Q2W dosage for adults with RA. Dose Cohort 2 provides a good balance between safety/tolerability and efficacy in patients with pcJIA and will be further studied as the optimal dosing schedule for sarilumab in pcJIA.

Example 2 . An open-label, dose-finding study of sarilumab with sequential escalating repeat doses administered by subcutaneous (SC) injection in children and adolescents aged 1 to 17 years with systemic juvenile idiopathic arthritis (sJIA), followed by an adjunctive treatment phase. (Study No. DRI13926, Study Name: Sarilumab Repeated Dose Tabulation Study in Children and Adolescents with Systemic Juvenile Idiopathic Arthritis)

A controlled phase 2 trial [NCT02991469] is planned to test the human IgG1 monoclonal antibody to IL-6Rα, sarilumab, administered subcutaneously for the treatment of sJIA. This study targets children and adolescents aged 1 to 17 years with sJIA, a subtype of JIA that resembles adult Still's disease, a relatively rare inflammatory disorder (estimated incidence worldwide is 0.22 and 0.34 per 100,000 for men and women, respectively; Bennett, AN et al. , Adult onset Still's disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil (Oxford 2004;43(6):795-9). It is planned to test 3 sarilumab dosing regimens in this pediatric population.

Study plan

Protocol description

The DRI13926 study is a multinational, multicenter, open-label, sequential, phase 2 study in children and adolescents aged 1 to 17 years (or country age requirements apply) with sJIA with an insufficient response to or intolerance to standard therapy and who will receive SC sarilumab injections q2w or qw. The 2 phases are as follows.

1. 12-week main treatment phase, divided into 2 parts.

- The first part with dose selection with sequential escalating doses, in which at least 2 dosing schedules will be studied in 2 groups according to body weight: patients weighing ≥30 kg and ≤60 kg (group A) and patients <30 kg and ≥10 kg (group B), in 6 evaluable patients per dosing schedule and body weight group (at least 24 patients total). Study enrollment will be stratified by body weight and dosing schedule, starting with Cohort A (≥30 kg and ≤60 kg) and Dose Cohort 2.

- A second follow-up where approximately 24 additional patients (12 in each body weight group ≥30 kg [arm A] and <30 kg and ≥10 kg [arm B]) will be enrolled directly into the selected dosing regimen (determined based on pooled data from patients included in Part 1) to obtain a total of 18 evaluable patients per body weight group for the selected dosing regimen.

The 12-week main treatment phase continues from Visit 2 (baseline - Week 0) until the time of study medication (IMP) administration at Visit 12 (Week 12). During the 12-week primary treatment phase, to minimize the amount of blood drawn and the number of visits while maintaining assessment of the primary endpoint, patients in arm B (<30 kg and 210 kg) will be randomly assigned to the following sarilumab PK sampling schedules 1 or 2 .

- Chart 1. Baseline, day 3, day 8, week 2, week 4, week 8 and week 12

- Chart 2: Baseline, Day 5, Day 12, Week 2, Week 4, Week 8 and Week 12

2. 144-week add-on treatment phase.

The IMP at visit 12 is considered the first IMP for the add-on treatment phase.

Only patients achieving an ACR JIA 30 response (febrile) at Visit 12 (week 12) will be allowed to continue the study into the add-on treatment phase. Patients will continue to follow the same sarilumab dosing schedule they were assigned to during the 12-week main treatment phase of the study until the selected dosing schedule is determined. Once a dosing schedule is selected, patients who have not already adhered to that dosing schedule will have their dosing schedule adjusted according to the selected dosing schedule and will adhere to the new schedule of visits with more frequent monitoring (for PK, safety, and efficacy) for the first 12 weeks, compared with patients whose dosing schedule was not changed.

Patients who prematurely discontinue study treatment will be assessed using the EOT procedure at Visit 27. These patients will be asked to return for an end-of-study (EOS) assessment 6 weeks after the EOT visit (EOT+6 weeks). For patients who discontinue study treatment during the 12-week primary treatment phase, an additional sarilumab PK assessment will be performed 2 weeks after the EOT visit (EOT+2 weeks), and IL-6 and sIL-6R will be measured at the EOT visit. . These patients will be asked to complete all visits and assessments as scheduled in the protocol, with the exception of sarilumab administration, until Visit 12.

Tested Dosing Schedules

For each body weight group, 3 escalating dose schedules were identified that were initially planned for testing based on PK modeling with the following rationale.

- Dose cohort 1: dose targeting PK effect similar to that of sarilumab 150 mg q2w, lowest dose

effective dose for adult patients with RA

- Dose cohort 2: dose targeting PK effect similar to that of sarilumab 200 mg q2w, the recommended dosing schedule for adult patients with RA

- Dose cohort 3: dose targeting PK effect similar to that of sarilumab 150 mg qw dose, which

resulted in the highest exposure levels in chronic dosing studies in adult patients with RA. See Table 1 for dose information by body weight group and by dose cohort that will be used in this study. See also FIG. 7.

The dose (mg) administered to patients will be calculated at baseline. The dose and corresponding volume of drug will remain the same during the 12-week main treatment phase of the study, regardless of changes in the patient's body weight. During the adjunctive treatment phase, the patient's body weight will be measured at each visit, and the dose will be adjusted to account for body weight gain only if the calculation indicates that a dose increase is necessary. The dose will be limited to 200 mg for dose cohort 2 and 150 mg for dose cohort 3, respectively. Sarilumab injectable volumes for dose cohorts are presented in Tables 2-5 below.

Although the 12-week main treatment phase begins at Visit 2 (Baseline - Week 0) and continues up to and including Visit 12 (Week 12), the IMP at Visit 12 will only be administered to patients who are about to enter the add-on treatment phase. , and after Visit 12, assessments are completed, including efficacy, safety, and PK/PD assessments.

Duration of study participation for each patient

The total study duration (per patient) is expected to be up to 166 weeks

- Up to 4 weeks + 3 days of screening (up to 31 days)

- 12 week main treatment period

- Up to 144 weeks of additional treatment phase

- 6-week follow-up after treatment

For all visits, an acceptable time frame of ±3 days for Dose Cohort 2 (including any potential q2w intermediate dose) and ±1 day for Dose Cohort 3 (including any potential qw intermediate dose) using Day 1 as the reference, except that

- for Visit 3 (Day 3), Visit 4 (Day 5) and Visit 5 (Day 8) no visit window is allowed when PK sampling occurs.

- Visit 6 (Day 12) ±1 day for all dose cohorts.

- Visit 7 (week 2) ±1 day for all dose cohorts.

- Visit 8 (week 4) ±2 days for dose cohort 2 and ±1 day for dose cohort 3.

Rules for stopping treatment for grade 3/4 neutropenia with sJIA

For grade 4 neutropenia without evidence of infection, temporary discontinuation of sarilumab treatment was recommended, which could be reinstituted based on careful benefit-risk assessment by the investigator once the ANC value became greater than 1000/mm ³ . Reduction of ANC is a pharmacodynamic class effect of interleukin 6 (IL-6) antagonists that is observed in both adult and pediatric patients treated with anti-IL-6 antibodies. Following repeated dosing of sarilumab in long-term studies of adults with rheumatoid arthritis (RA), reductions in ANC were generally transient and were not associated with an increased risk of infections. In pediatric patients, although limited published data are currently available, the use of IL-6 antagonists has not been associated with an increased risk of infections in patients with grade 3/4 neutropenia. Table 31 shows the occurrence of grade 3 and grade 4 neutropenia based on the lowest neutrophil count recorded in the study.

Patient selection

Inclusion criteria

1. Male and female patients aged ≥1 and ≤17 years at the time of the screening visit.

2. Diagnosis of sJIA subtype according to JIA ILAR 2001 classification criteria JIA Petty, RE et al. 2001. J Rheumatol. 2004;31(2):390-2) with the following screening features:

- ≥5 active joints or

- ≥2 active joints at screening with systemic JIA fever >37.5°C for 3 days preceding baseline or for at least 3 of any 7 consecutive days at screening despite stable dose glucocorticoids during at least 3 days.

3. A patient with an insufficient response to current treatment who is considered a candidate for a bDMARD based on the investigator's judgment.

4. The patient, who has reached the legal age of consent, or the parent(s) or legal guardian(s) signs a dated written informed consent approved by the Ethics Committee (EC). Consent from a minor patient should be obtained based on local guidelines, the patient's maturity, and the patient's intellectual capacity to understand the information associated with the study. In cases involving emancipated or mature minors with sufficient decision-making capacity, or where otherwise permitted by law, signed informed consent will be obtained directly from the parent(s) or legal guardian(s).

Treatments being studied

Investigational drug

Sarilumab, mAb to IL-6R.

Compound

The drug sarilumab will be provided at a concentration of 175 mg/ml in an aqueous buffer vehicle, pH 6.0. The drug will be supplied in a 5 ml vial filled with 2.7 ml of sarilumab with an extractable volume of 2.0 ml.

Route(s) of administration

Sarilumab will be administered subcutaneously in the abdomen or thigh as a self-injection, or also in the forearm (lateral) by a professional or lay caregiver. Preferably, SC injection sites alternate between the 4 quadrants of the abdomen (excluding the umbilicus or waist) or thigh (front and side).

For patients who adhere to Dosing Schedule 2 (q2w), injections will be administered by a professional caregiver during the 12-week main treatment phase of the study. See fig. 1. For patients following Dose Schedule 3 (weekly injections), arrangements should be made to ensure that IMP is administered by qualified site staff or a home nurse for doses not scheduled to be administered at the study site. During the add-on treatment phase of the study, if patients or their parent(s), legal guardian(s), or caregiver(s) were willing and able to administer the injections, home injections will be permitted. In these cases, training will be required and provided to prepare and administer the IMP, beginning at Visit 10 (Week 8) during the main treatment phase. This training must be documented in the patient study file. Patients or parent(s) or legal guardian(s) are allowed to administer injections under the supervision/control of the investigator(s) or representative(s) at Visit 10 (Week 8), Visit 11 (Week 10), and Visit 12 (week 12) until home injections are permitted during the adjunctive treatment phase.

On days when the patient has a study visit, IMP will be administered after clinical procedures and blood collection. Diaries will be provided to record information related to these injections; these diaries will be kept as baseline data in the patient study files. If the caregiver is unable or unwilling to administer the IMP, arrangements should be made to ensure that the IMP is administered by qualified site personnel for doses not scheduled to be administered at the study site.

Dose schedule

Sarilumab should be administered q2w or qw. However, a sarilumab administration window of ±3 days for Dose Cohort 2 (including any potential q2w bridge dose) is permitted ±1 day for Dose Cohort 3 (including any potential qw bridge dose) as per protocol, subject to exceptional circumstances such as expected results laboratory tests, ongoing adverse events (AEs), patient scheduling difficulties other than visit 5 (day 8). There is no administration window for Visit 5 (Day 8). The administration window will only be ±1 day for dose cohorts 2 and 3 patients at visit 7 (week 2) and ±1 day for dose cohort 3 or ±2 for dose cohort 2 at visit 8 (week 4). Note that overdose (accidental or intentional) of IMP is defined as at least twice the dose over an interval of less than 11 days for q2w administration and less than 6 days for weekly administration.

The next dose of sarilumab should be administered q2w or qw.

Dose cohort 2.

- Group A (>30 kg and ≤60 kg): 3 mg/kg q2w

- Group B (<30 kg and 210 kg): 4 mg/kg q2w.

Dose cohort 3.

- Group A (>30 kg and ≤60 kg): 2 mg/kg qw

- Group B (<30 kg and 210 kg): 2.5 mg/kg qw.

Dose Cohort 3 is also being tested as a biweekly dosing regimen while maintaining the same PK effect. Therefore the range is as follows:

- patients with body weight less than 30 kg: 5 to 7 mg/kg q2w (dose 2 is 4 mg/kg q2w),

- patients with a body weight of 30 kg or more: 4 to 6 mg/kg q2w (dose 2 is 3 mg/kg q2w)

Changing the dose

The dose (mg) administered to patients will be calculated at baseline. The dose and corresponding volume of drug will remain the same during the 12-week main treatment phase of the study, regardless of changes in the patient's body weight. During the adjunctive treatment phase, the patient's body weight will be measured at each visit, and the dose will be adjusted to account for body weight gain only if the calculation indicates that a dose increase is necessary. The dose will be limited to 200 mg for dose cohort 2 and 150 mg for dose cohort 3, respectively. Volumes to be administered for dose cohorts 2-3 based on patient body weight are described herein. See tables 2-5.

Packaging and labeling

IMP will be provided in patient treatment kits containing labeled vials. The contents of the instructions for use comply with regional regulatory specifications and requirements. One set contains one bottle.

Storage conditions and shelf life

The study drug should be stored refrigerated between 2 ^° C and 8 ^° C at the study site or at home.

Table 17. 12-week main phase of sJIA treatment Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks
(for patients,
which
stop
study treatment
during the main
phases
treatment or not
are going to cross
in phase
additional treatment Day D-28 to
D-1 (+3)
(Maximum
31 days) D1 D3 b D5 b D8 b D12 b
( ± 1) D15
( ± 1) D29 ( ± 1 or 2) D43 ( ± 1 or 3) D57 ( ± 1 or
3) D71 ( ± 1 or
3) D 85 ( ± 1 or
3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Suitability ^c Written informed consent and patient consent form d X Inclusion/exclusion criteria ^c X X Ethnicity and race X Patient Demographics X Tanner stage and menstrual status X X Medical/surgical history X Previous medication/vaccination history X Concomitant medications X X X X X X X X X X X X X Patient IMP Adherence Diary ^e X X X X X X X Physical examination f X X X X X

Table 17. Continued Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks
(for patients,
which
stop
study treatment
during the main
phases
treatment or not
are going to cross
in phase
additional treatment Day D-28 to
D-1 (+3)
(maximum
31 days) D1 D3 b D5 b D8 b D12b ​
( ± 1) D15
( ± 1) D29 ( ± 1 or 2) D43 ( ± 1 or 3) D57 ( ± 1 or
3) D71 ( ± 1 or
3) D 85 ( ± 1 or
3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Optional: EBV, hepatitis B and C viruses and HIV g X Tuberculin skin test with PPD for patients ≤5 years; QuantiFERON-TB test for patients >5 years h X Chest X-ray i X Confirmation of suitability X Call to IVRS X X X X X X X X Introduction IMP Administration of investigational medicinal product (IMP) j X Xj X X X X X X Issuing IMP k X X X X X X Vital Signs and Body Measurement Patient's fever/rash diary l X X X X X X X X X Temperature, heart rate, BP
(2 BP measurements at each scheduled time point) X X X X X Body weight X X X Height (stadiometer) m X X X Efficiency mark Basic set for the disease ACR JIA/JADAS-27 n X X X X X X X X

Table 17. Continued Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks
(for patients,
which
stop
study treatment
during the main
phases
treatment or not
are going to cross
in phase
additional treatment Day D-28 to
D-1 (+3)
(maximum
31 days) D1 D3 b D5 b D8 b D12 b
( ± 1) D15
( ± 1) D29 ( ± 1 or 2) D43 ( ± 1 or 3) D57 ( ± 1 or
3) D71 ( ± 1 or
3) D 85 ( ± 1 or
3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Systemic signs of sJIA o X X X X X X X X X Security assessment Adverse Event/SAE Data Recording | | Tuberculosis risk assessment X X X X X X X X Local tolerance X X X X X X X X Laboratory research Hematological examination ^p X X Xp Xp X X X X X X Biochemical research q X X X X X X X Xq Fasting lipidogram r X X X Optional: glycosylated hemoglobin (HbA1c) s X hs-CRP X X _X t _X t _X t _X t X X X X X X ESR X X X X X ANA/anti-ds DNA antibody X X Fibrinogen/D-dimer u X Ferritin u x x x x x x x Urinalysis v X Serum testing for pregnancy in menstruating women w X

Table 17. Continued Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks
(for patients,
which
stop
study treatment
during the main
phases
treatment or not
are going to cross
in phase
additional treatment Day D-28 to
D-1 (+3)
(maximum
31 days) D1 D3 b D5 b D8 b D12b ​
( ± 1) D15
( ± 1) D29 ( ± 1 or 2) D43 ( ± 1 or 3) D57 ( ± 1 or
3) D71 ( ± 1 or
3) D 85 ( ± 1 or
3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Urine testing for pregnancy in menstruating women x X X X X Reducing the dose of glucocorticoids X X X X Pharmacokinetics and pharmacodynamics Serum sarilumab (PK)
Group A (≥30 kg and ≤60 kg) X X X X X X X X X X Sarilumab serum (PK) y
Group B (<30 kg and ≥10 kg)
Schedule 1 X X X X X X X X Sarilumab serum (PK) y
Group B (<30 kg and ≥10 kg)
Schedule 2 X X X X X X X X Antibodies to sarilumab y X X IL-6 and total sIL-6R X X X z Pharmacogenomics Collection of saliva samples aa X

Table 17. Continued Screening (4 weeks) Baseline visit Main phase of treatment
(12 weeks) Follow-up a
P.K. Visit V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V88
EOT+2 weeks
(for patients,
which
stop
study treatment
during the main
phases
treatment or not
are going to cross
in phase
additional treatment Day D-28 to
D-1 (+3)
(maximum
31 days) D1 D3 b D5 b D8 b D12b ​
( ± 1) D15
( ± 1) D29 ( ± 1 or 2) D43 ( ± 1 or 3) D57 ( ± 1 or
3) D71 ( ± 1 or
3) D 85 ( ± 1 or
3) A week Wk 0 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12

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, JADAS=juvenile arthritis disease activity index, ACR JIA=American College of Rheumatology Juvenile Idiopathic Arthritis Response, PK=pharmacokinetics, PPD=purified protein derivative, q2w=once every two weeks, SAE=serious adverse event, sIL-6R=soluble interleukin-6 receptor, sJIA=systemic juvenile idiopathic arthritis, TB=tuberculosis, V=visit, Wk=week.

a For patients who discontinue study treatment during the 12-week main treatment phase (at or before Visit 12), an additional PK assessment will be performed 2 weeks after the EOT visit (EOT+2 weeks).

b Sampling for pharmacokinetics at the following visits and days: Visit 3 (D3), Visit 4 (D5), Visit 5 (D8), Visit 6 (D12) for group A (≥30 kg); during the following visits and days: visit 3 (D3), visit 5 (D8), for schedule 1 group B (<30 kg); during the following visits and visit days: Visit 4 (D5), Visit 6 (D12) for Schedule 2 Group B (<30 kg). Sampling for PK determination can be done at home. For Visit 3 (D3), Visit 4 (D5), and Visit 5 (D8), no sample collection window is allowed. For visit 6 (D12), a window of ±1 day is allowed. Please seek additional hematology testing during the sampling period to determine PK.

c At the discretion of the investigators, laboratory tests referred to in exclusion criterion 27 may be repeated through repeat testing at a central laboratory between the screening visit and the first IMP administration to ensure patient suitability for exclusion criterion 27. A specific locally approved consent form will be signed patients requiring genetic testing for Gilbert's syndrome (patient consent/assent must be obtained prior to this test and local regulatory requirements must be followed).

d Prior to all screening assessments, the patient (if he/she has reached the legal age of consent in accordance with local regulatory requirements), parent(s) or legal guardian(s) must sign a dated written informed consent form approved by the EC . The patient, parent(s), and legal guardian(s) will receive information about the purpose(s) of the study and procedures from the investigator. Separate written consent forms must be obtained from the parent(s) or legal guardian(s) who authorize his/her child to participate in additional collection of saliva samples for the pharmacogenomic study and authorize the sponsor to retain their remaining/unused blood samples for future studies Separate ( a locally approved) informed consent form is completed by all patients requiring genetic testing for Gilbert's disease in accordance with local regulatory requirements. Signed patient consent forms must be obtained from the patient in accordance with local regulatory requirements and his/her maturity in understanding the study information.

e Patient diary for IMP administration, which must be completed for IMP administered at home.

f A complete physical examination will be performed at Visit 1 (D-28 to D-1, up to 31 days), Visit 2 (D1, week 0), Visit 8 (week 4), Visit 9 (week 6), and Visit 12 (week 12), where the examination includes examination of the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic and musculoskeletal systems.

g Optional. Based on the investigator's opinion, screening may determine Epstein-Barr virus (EBV) titer, including IgG and IgM; Based on the patient’s family and medical history, as well as the conclusion of the investigator, during screening, hepatitis B virus surface antigen (HBs-Ag), antibody to hepatitis B virus surface antigen (HBs-Ab), and common antibodies to hepatitis B virus core antigen can be determined (HBc-Ab) and hepatitis C virus antibody (HCV-Ab). HIV serological testing will only be performed based on the investigator's opinion for patients suspected of having HIV.

For Germany only: serological tests for hepatitis B and C viruses and HIV must be carried out at the screening visit for all patients in order to check the corresponding exclusion criterion 18.

i. Purified protein product (PPD) skin testing should be performed on patients ≤5 years of age prior to baseline visit 2 (D1, week 0). Patients should be assessed within 48 to 72 hours after undergoing the PPD skin test. For patients who have not been tested within 72 hours, the skin test should be repeated. Risk assessment (TB exposure and/or recent immigration from a country with a high TB prevalence) should be taken into account when determining skin test results. See exclusion criteria 17 for full details. The interferon-gamma (IFN-r) release assay, the QuantiFERON-TB test, will be performed in patients aged >5 years (1). After initial screening for TB, if the PPD or QuantiFERON result is negative but the clinical suspicion for TB is above average, the patient should be rescreened for TB at any time during the study based on the assessment of the investigator. The Quantiferon TB test will be considered in a younger patient population ( ≤ 5 years) based on local presence of PPD, local TB screening regulations, and investigator judgment.

Chest X-rays should only be performed on patients if deemed necessary based on the investigator's judgment or in accordance with local TB screening guidelines prior to initiation of biologic therapy for patients with JIA who have not had a chest X-ray within 3 months before baseline visit 2 (D1, week 0).

j The study drug should be administered q2w to patients in Dose Cohort 2 and once weekly for patients in Dose Cohort 3. Arrangements will be made for home nurses to administer IMP to patients in Dose Cohort 3 for intermediate visits (home administration if Maybe). Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of a hypersensitivity reaction. Patients who have not achieved an American College of Rheumatology (ACR JIA) 30 juvenile idiopathic arthritis response by the end of the 12-week primary treatment period will be withdrawn from the study treatment to receive standard care according to the clinical judgment of the investigator. The ACR JIA response, including the ACR30 JIA response, will be provided by the sponsor to the investigator for evaluation of this criterion only after V12. For patients who complete the primary treatment phase at V12 but do not continue the study in the add-on treatment phase for reasons other than lack of ACR30 JIA response, the IMP injection at Visit 12 will not be given.

For Germany only: After the first administration of IMP, the patient must be observed for at least 1 hour to assess local tolerance.

k The investigational drug will be given to patients who are in dose cohort 3 during the main treatment phase.

l The patient's fever/rash diary will include recording of tympanic temperature and reporting of rash (if present) at home each day between screening and baseline visits and for at least 7 days prior to each subsequent scheduled ACR JIA Core Performance Set assessment visit. Temperature should be taken at least twice a day at fixed points, upon waking and before going to bed, and at any time if a fever is suspected.

m Additional data should be collected on height measured as close as possible to the time point 1 year before baseline. Height will be measured using a stadiometer at the study sites during the study.

n The ACR Juvenile Idiopathic Arthritis Core Set includes the physician's global assessment of disease severity, the patient's or parent(s)/guardian(s) global assessment of well-being, the number of joints with active arthritis (defined as swelling not caused by deformity OR limitation of movement with either pain or with tenderness or both), number of joints with limitation of motion, Children's 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. 1997;40(7):1202-9; , T. et al., , 2011 American College of Rheumatology recommendations for the treatment of juvenile 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 movement will be assessed. The calculation principle of the JADAS index is explained in this document.

o Systemic signs of sJIA include fever, transient salmon-colored erythematous rash, generalized lymph node enlargement, hepatomegaly, splenomegaly, serositis, and other complications at screening, baseline, and visit 12. At week 2, week 4, week 6, week 8, and week 10 there will be Assess only fever and transient, erythematous, salmon-colored rash.

p Hematological examination (blood should be drawn BEFORE administration of the drug): hemoglobin, hematocrit, red blood cell count (RBC) and red blood cell morphology (if the red blood cell count is abnormal), white blood cell count (WBC), white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils ), platelet count, absolute neutrophil count (ANC). An additional hematologic study should be performed at Visit 6 (Day 12 ± 1 day) for patients in Dose Cohort 2 to obtain results prior to Visit 7 (Day 15, Week 2), before the second dose of sarilumab is administered. For dose cohort 3 patients, additional hematologic testing should be performed before or at Visit 5 (Day 8), but not earlier than Visit 4 (Day 5), and results should be reviewed before the second sarilumab injection at Visit 5 (Day 8). Additional hematology testing may be performed at a central laboratory or at a local laboratory to confirm that the ANC and platelet count are not within the protocol limits for temporary or permanent discontinuation of study drug. If a local laboratory is used, a central laboratory specimen for hematology testing should still be collected prior to IMP administration at Visit 7 (Day 15, Week 2) as planned for Cohort 2, and at Visit 5 (Day 8) for Cohort 3. For all In patients, a hematologic laboratory evaluation at Visit 2 (Day 1) should be reviewed prior to administration of the second dose of sarilumab at Visit 5 (Day 8) for patients in Dose Cohort 3 or at Visit 7 (Week 2, Day 15) for Dose Cohort 2.

q Biochemical study (blood should be collected BEFORE administration of the drug). A complete chemistry panel will be performed at the screening visit, baseline visit 2 (day 1, week 0) and visit 12 (week 12) or at EOT only: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine and creatinine clearance. glomerular filtration rate, calcium, phosphate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (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.

r Fasting lipid profile (blood should be drawn BEFORE drug administration): Triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. It is required that patients fast for at least 8 hours before the test.

s Optional. HbA1c levels will be measured only based on the patient's medical history and the investigator's judgment.

t hs-CRP will be measured on days 3 and 8 in patients with body weight ≥30 kg (group A). For patients with body weight <30 kg (group B) in schedule group PK 1, hs-CRP will be measured on days 3 and 8. For patients with body weight <30 kg (group B) in schedule group PK 2, hs-CRP will be measured on days 5 and 12.

u If Macrophage Activation Syndrome (MAS) is suspected, a ferritin test, blood count (RBC, WBC, platelet and hemoglobin), AST/ALT, triglyceride and fibrinogen tests should be ordered if determined by the investigator. This document describes the clinical and laboratory features of the diagnosis of MAS.

v Urine dipstick test: specific gravity, pH, glucose, blood, protein, nitrites, leukocyte esterase, bilirubin. If any dipstick test parameter is abnormal, the urine sample should be sent to a central laboratory for analysis. In case of a positive result for proteins, a microscopic analysis is carried out by the central laboratory.

w For women who have started menstruating, a serum pregnancy test is required at the screening visit.

x For women who begin menstruating, a serum pregnancy test should be performed at screening and a local urine pregnancy test should be performed at Visit 2 (Week 0, Day 1), Visit 8 (Week 4), Visit 10 (Week 8) and visit 12 (week 12). Urine testing for pregnancy can be done locally. Presence of pregnancy should be tested using a urine pregnancy test prior to exposure to IMP and EOT.

y Blood samples will be collected BEFORE IMP administration on dosing days during the treatment period. If a patient experiences an SAE, blood samples should be collected at the onset and completion of the event, if possible, or within a short time after the onset and completion/*98+- to determine sarilumab concentrations and to assess anti-drug antibodies (ADA).

z For patients who discontinue study treatment prematurely during the primary treatment phase, IL-6 and total sIL-6R will be measured at EOT assessment.

aa Parent(s) or legal guardian(s) must sign the Written Subject Information Form prior to collecting a saliva sample for a pharmacogenomic study. Specimens are preferably collected at baseline visit 2 (D1, week 0), but can be collected at any visit. The patient may also sign the WSI depending on his/her age, local regulatory requirements, and maturity level in understanding the study information. A patient is still eligible to participate in the study if he/she or his/her parent(s) or legal guardian(s) do not wish for him/her to participate in the collection of saliva samples.

Table 18. Study design for patients who continue to take the current dose (selected dosing schedule) from the dose selection part or who are recruited directly into the selected dosing schedule during the second part Additional treatment phase
(up to 144 weeks of sarilumab exposure after V12) Follow-up
after treatment
(6 weeks) Visit V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26 V27 a V28 b Day D 113 ( ± 1 or 3) D 141 ( ± 1 or 3) D 169 ( ± 1 or 3) D 225 ( ± 1 or 3) D 281 ( ± 1 or 3) D 337 ( ± 1 or 3) D 421 ( ± 1 or 3) D 505 ( ± 1 or 3) D 589 ( ± 1 or 3) D 673 ( ± 1 or 3) D 757 ( ± 1 or 3) D 841 ( ± 1 or 3) D 925 ( ± 1 or 3) D 1009 ( ± 1 or 3) Wk 156/
EOT EOS: Wk 162/ (EOT+6 weeks) A week Wk 16 Wk 20 Wk 24 Wk 32 Wk 40 Wk 48 Wk 60 Wk 72 Wk 84 Wk 96 Wk 108 Wk 120 Wk 132 Wk 144 Concomitant medications X X X X X X X X X X X X X X X X Patient IMP Adherence Diary c X X X X X X X X X X X X X X X Physical
examination d X X X X X X X X X Call to IVRS X X X X X X X X X X X X X X X X Tanner stage and menstrual status X X X X X X X X Treatment Investigational drug
Introduction (IMP) e X X X X X X X X X X X X X X Issuing IMP X X X X X X X X X X X X X X Vital Signs and Body Measurement Diary
fever/rash
patient f X X X X X X X X X X X X X X X

Table 18. Continued Additional treatment phase
(up to 144 weeks of sarilumab exposure after V12) Follow-up
after treatment
(6 weeks) Visit V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26 V27 a V28 b Day D 113 ( ± 1 or 3) D 141 ( ± 1 or 3) D 169 ( ± 1 or 3) D 225 ( ± 1 or 3) D 281 ( ± 1 or 3) D 337 ( ± 1 or 3) D 421 ( ± 1 or 3) D 505 ( ± 1 or 3) D 589 ( ± 1 or 3) D 673 ( ± 1 or 3) D 757 ( ± 1 or 3) D 841 ( ± 1 or 3) D 925 ( ± 1 or 3) D 1009 ( ± 1 or 3) Wk 156/
EOT EOS: Wk 162/ (EOT+6 weeks) A week Wk 16 Wk 20 Wk 24 Wk 32 Wk 40 Wk 48 Wk 60 Wk 72 Wk 84 Wk 96 Wk 108 Wk 120 Wk 132 Wk 144 Temperature, heart rate, blood pressure (2 BP measurements at each scheduled time point) X X X X X X X X X X X X X X X X Body weight X X X X X X X X X X X X X X X X Height (stadiometer) g X X X X X X X Efficiency mark Basic set for ACR JIA/JADAS-27 h X X X X X X X Systemic signs
sJIA i X X X X X X X X Security assessment AE/SAE registration | | Tuberculosis risk assessment X X X X X X X X X X X X X X X X Tuberculin skin test with PPD for patients ≤5 years; QuantiFERON-TB test for patients >5 years X X X Local tolerance X X X X X X X X X X X X X X X

Table 18. Continued Additional treatment phase
(up to 144 weeks of sarilumab exposure after V12) Follow-up
after treatment
(6 weeks) Visit V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26 V27 a V28 b Day D 113 ( ± 1 or 3) D 141 ( ± 1 or 3) D 169 ( ± 1 or 3) D 225 ( ± 1 or 3) D 281 ( ± 1 or 3) D 337 ( ± 1 or 3) D 421 ( ± 1 or 3) D 505 ( ± 1 or 3) D 589 ( ± 1 or 3) D 673 ( ± 1 or 3) D 757 ( ± 1 or 3) D 841 ( ± 1 or 3) D 925 ( ± 1 or 3) D 1009 ( ± 1 or 3) Wk 156/
EOT EOS: Wk 162/ (EOT+6 weeks) A week Wk 16 Wk 20 Wk 24 Wk 32 Wk 40 Wk 48 Wk 60 Wk 72 Wk 84 Wk 96 Wk 108 Wk 120 Wk 132 Wk 144 Laboratory research Hematological examination j X X X X X X X X X X X X X X X Biochemical study k X X X X X X X X X X X X X X X Fasting lipidogram l X X X X X X X hs-CRP X X X X X X X ESR X X X X X X X ANA/anti-ds DNA antibody X X X X X X X Fibrinogen/D-dimer and ferritin m X X X X Urine test to check for pregnancy
menstruating women n X X X X X X X X X X X X X X X Pharmacokinetics Sarilumab
in blood serum (PK) o X X X X X X X Antibodies to sarilumab o X X X X X X X

Abbreviations. AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, 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 sensitivity C-reactive protein, IMP=investigational drug, IVRS=interactive voice response system, IL =interleukin, JADAS=juvenile arthritis disease activity index, ACR JIA=American College of Rheumatology juvenile idiopathic arthritis response, PK=pharmacokinetics, PPD=purified protein derivative, q2w=every two weeks, SAE=serious adverse event, sJIA=systemic juvenile idiopathic arthritis, TB=tuberculosis, V=visit, Wk=week.

a Visit 27 is the planned end of treatment (EOT) visit for the study. If patients discontinue study treatment prematurely, EOT will occur 1 week after the last IMP injection for Dose Cohort 3 and 2 weeks after the last IMP injection for Dose Cohort 2.

b Visit 28 is the planned end-of-study (EOS) visit for the study. If patients discontinue study treatment prematurely, these patients will be asked to return for an EOS assessment 6 weeks after the EOT visit (EOT+6 weeks). This EOS visit (EOT+6 weeks) will be applicable to all patients in both the main treatment phase and the add-on treatment phase.

c Patient diary for IMP administration to be completed for IMP administered at home.

d A complete physical examination will be performed at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), Visit 22 (Week 96), Visit 24 (Week 120), Visit 26 (Week 144), visit 27 EOT and visit 28 EOS, where the examination includes examination of the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic and musculoskeletal systems.

e IMP should be administered q2w to patients in dose cohort 2 and once weekly for patients in dose cohort 3. For patients who have completed the add-on phase, if the selected dosing schedule is administered once every two weeks (q2w), then the latter IMP injection will be given at week 154; If the selected dosing schedule is once-weekly (qw), the final IMP injection will be given at week 155. Patients will have an EOT assessment at visit 27 (week 156). For patients who discontinue study treatment prematurely during the add-on treatment phase, it will be preferable to undergo an EOT assessment 2 weeks after the last IMP injection for Dose Cohort 2 patients and 1 week after the last IMP injection for Dose Cohort 3 patients. patient is unable to adhere to the planned schedule, the EOT visit will be used for evaluation at the next protocol-defined visit after the last IMP injection. Patients are asked to return to the center 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 a hypersensitivity reaction. At Visit 27 (Week 156), no IMP injections will be given.

f The patient's fever/rash diary will include recording of tympanic temperature and reporting of rash (if present) at home for at least 7 days prior to each subsequent scheduled ACR JIA Performance Core Set assessment visit. Temperature should be taken at least twice a day at fixed points, upon waking and before going to bed, and at any time if a fever is suspected.

g Additional data should be collected on height measured as close as possible to the time point 1 year before baseline. Height will be measured using a stadiometer at the study sites during the study.

h The basic set for the ACR JIA includes the physician's overall assessment of disease severity, the patient's or parent/legal guardian's overall assessment of well-being, the number of joints with active arthritis, which is defined as swelling in the joint not caused by deformity OR limitation of movement with either pain or tenderness, or both), number of restricted joints, Children's Health Assessment Questionnaire (CHAQ), hs-CRP, and fever. The calculation principle of the JADAS index is explained in this document.

o Systemic signs of sJIA include fever, transient salmon-colored erythematous rash, generalized lymph node enlargement, hepatomegaly, splenomegaly, serositis, and other complications at week 156 (EOT visit). At week 24, week 48, week 72, week 96, week 120, week 144, and week 162 (EOS visit) only fever and a transient salmon-colored erythematous rash will be assessed.

j Hematological examination (blood should be drawn BEFORE administration of the drug): hemoglobin, hematocrit, red blood cell count (RBC) and red blood cell morphology (if the red blood cell count is abnormal), white blood cell count (WBC) (neutrophils, lymphocytes, monocytes, eosinophils, basophils), count platelets, absolute neutrophil count (ANC).

k Biochemical study (blood should be collected BEFORE administration of the drug). ALT, AST, ALP, lactate dehydrogenase (LDH), total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. A complete biochemical study should be performed at the 27th EOT visit.

l Lipidogram (blood should be drawn BEFORE drug administration). Triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. It is required that patients fast for at least 8 hours before the test.

m If MAS is suspected, a ferritin test, blood count (RBC, WBC, platelet, and hemoglobin), AST/ALT, triglyceride, and fibrinogen tests should be ordered if determined by the investigator. Refer to the clinical and laboratory features for diagnosing MAS described in this document.

n For women who have started menstruating, a urine pregnancy test should be performed prior to the administration of the IMP injection at each scheduled visit and at EOT. Urine testing for pregnancy can be done locally.

o Blood samples will be collected BEFORE IMP administration on dosing days during the treatment period. If a patient experiences an SAE, blood samples should be collected at the onset and completion of the event, if possible, or within a short time after the onset and completion, to determine sarilumab concentrations and to assess anti-drug antibodies (ADA).

Table 19: Study Design for Patients Who Change Dosing Schedule (During the Extension Phase) Visit
(total of 144 weeks of sarilumab exposure after V12) Subsequent
observation
after treatment
(6 weeks) Visit V101 V102 V103 V104 V105 V106 V107 V108 V109 V110 V111 V112 V113 V114 V115 V116 V117 V118 V119 V27 a V28 b Day at a given dose D 1
( ± 1
or 3) D 15
( ± 1
or 3) D 29
( ± 1
or 3) D 43
( ± 1
or 3) D 57
( ± 1
or 3) D 85
( ± 1
or 3) D 113
( ± 1
or 3) D 141
( ± 1
or 3) D 169
( ± 1
or 3) D
225
( ± 1
or 3) D
281
( ± 1
or 3) D
337
( ± 1
or 3) D 421
( ± 1
or 3) D 505
( ± 1
or 3) D 589
( ± 1
or 3) D 673
( ± 1
or 3) D 757
( ± 1
or 3) D 841
( ± 1
or 3) D 925
( ± 1
or 3) EOT EOS:
(EOT
+ 6 weeks) Week at this dose Wk
0 Wk
2 Wk
4 Wk
6 Wk
8 Wk
12 Wk
16 Wk
20 Wk
24 Wk
32 Wk
40 Wk
48 Wk
60 Wk
72 Wk
84 Wk
96 Wk
108 Wk
120 Wk
132 See Table 1 for weeks
between the patient's last visit during the treatment period and EOT (EOT
+ 6 weeks) Tanner stage and menstrual status X X X X X X X X Concomitant medications X X X X X X X X X X X X X X X X X X X X X Patient IMP Adherence Diary c X X X X X X X X X X X X X X X X X X X X Physical examination d X X X X X X X X X X Call to IVRS X X X X X X X X X X X X X X X X X X X X X Introduction IMP Administration of investigational medicinal product (IMP) e X X X X X X X X X X X X X X X X X X X Issuing IMP X X X X X X X X X X X X X X X X X X X

Table 19. Continued Visit
(total of 144 weeks of sarilumab exposure after V12) Subsequent
observation
after treatment
(6 weeks) Visit V101 V102 V103 V104 V105 V106 V107 V108 V109 V110 V111 V112 V113 V114 V115 V116 V117 V118 V119 V27 a V28 b Day at a given dose D 1
( ± 1
or 3) D 15
( ± 1
or 3) D 29
( ± 1
or 3) D 43
( ± 1
or 3) D 57
( ± 1
or 3) D 85
( ± 1
or 3) D 113
( ± 1
or 3) D 141
( ± 1
or 3) D 169
( ± 1
or 3) D
225
( ± 1
or 3) D
281
( ± 1
or 3) D
337
( ± 1
or 3) D 421
( ± 1
or 3) D 505
( ± 1
or 3) D 589
( ± 1
or 3) D 673
( ± 1
or 3) D 757
( ± 1
or 3) D 841
( ± 1
or 3) D 925
( ± 1
or 3) EOT EOS:
(EOT
+ 6 weeks) Week at this dose Wk
0 Wk
2 Wk
4 Wk
6 Wk
8 Wk
12 Wk
16 Wk
20 Wk
24 Wk
32 Wk
40 Wk
48 Wk
60 Wk
72 Wk
84 Wk
96 Wk
108 Wk
120 Wk
132 See Table 1 for weeks
between the patient's last visit during the treatment period and EOT (EOT
+ 6 weeks) Vital Signs and Body Measurement Patient's fever/rash diary f X X X X X X X X X X X X X X X X X X X X X Temperature, heart rate, blood pressure (2 BP measurements at each scheduled time point) X X X X X X X X X X X X X X X X X X X X X Body weight X X X X X X X X X X X X X X X X X X X Height (stadiometer) g X X X X X X X Efficiency mark Basic set for the disease ACR JIA/JADAS-27 h X X X X X X X X X X X X System features sJIA i X X X X X X X X X X X X Security assessment Adverse Event/SAE Data Recording | | Tuberculosis risk assessment X X X X X X X X X X X X X X X X X X X X X

Table 19. Continued Visit
(total of 144 weeks of sarilumab exposure after V12) Subsequent
observation
after treatment
(6 weeks) Visit V101 V102 V103 V104 V105 V106 V107 V108 V109 V110 V111 V112 V113 V114 V115 V116 V117 V118 V119 V27 a V28 b Day at a given dose D 1
( ± 1
or 3) D 15
( ± 1
or 3) D 29
( ± 1
or 3) D 43
( ± 1
or 3) D 57
( ± 1
or 3) D 85
( ± 1
or 3) D 113
( ± 1
or 3) D 141
( ± 1
or 3) D 169
( ± 1
or 3) D
225
( ± 1
or 3) D
281
( ± 1
or 3) D
337
( ± 1
or 3) D 421
( ± 1
or 3) D 505
( ± 1
or 3) D 589
( ± 1
or 3) D 673
( ± 1
or 3) D 757
( ± 1
or 3) D 841
( ± 1
or 3) D 925
( ± 1
or 3) EOT EOS:
(EOT
+ 6 weeks) Week at this dose Wk
0 Wk
2 Wk
4 Wk
6 Wk
8 Wk
12 Wk
16 Wk
20 Wk
24 Wk
32 Wk
40 Wk
48 Wk
60 Wk
72 Wk
84 Wk
96 Wk
108 Wk
120 Wk
132 See Table 1 for weeks
between the patient's last visit during the treatment period and EOT (EOT
+ 6 weeks) Tuberculin skin test with PPD for patients ≤5 years; QuantiFERON-TB test for patients >5 years X X X Local tolerance X X X X X X X X X X X X X X X X X X X X Laboratory research Hematological examination j X X X X X X X X X X X X X X X X X X X Biochemical study k X X X X X X X X X X X X X X X X X X X Fasting lipidogram l X X X X X X X X X X hs-CRP X X X X X X X X X X X X ESR X X X X X X X X ANA/anti-ds DNA antibody X X X X X X X X Ferritin/fibrinogen/D-dimer m X X X X X Urine testing for pregnancy in menstruating women n X X X X X X X X X X X X X X X X X X

Table 19. Continued Visit
(total of 144 weeks of sarilumab exposure after V12) Subsequent
observation
after treatment
(6 weeks) Visit V101 V102 V103 V104 V105 V106 V107 V108 V109 V110 V111 V112 V113 V114 V115 V116 V117 V118 V119 V27 a V28 b Day at a given dose D 1
( ± 1
or 3) D 15
( ± 1
or 3) D 29
( ± 1
or 3) D 43
( ± 1
or 3) D 57
( ± 1
or 3) D 85
( ± 1
or 3) D 113
( ± 1
or 3) D 141
( ± 1
or 3) D 169
( ± 1
or 3) D
225
( ± 1
or 3) D
281
( ± 1
or 3) D
337
( ± 1
or 3) D 421
( ± 1
or 3) D 505
( ± 1
or 3) D 589
( ± 1
or 3) D 673
( ± 1
or 3) D 757
( ± 1
or 3) D 841
( ± 1
or 3) D 925
( ± 1
or 3) EOT EOS:
(EOT
+ 6 weeks) Week at this dose Wk
0 Wk
2 Wk
4 Wk
6 Wk
8 Wk
12 Wk
16 Wk
20 Wk
24 Wk
32 Wk
40 Wk
48 Wk
60 Wk
72 Wk
84 Wk
96 Wk
108 Wk
120 Wk
132 See Table 1 for weeks
between the patient's last visit during the treatment period and EOT (EOT
+ 6 weeks) Pharmacokinetics and pharmacodynamics Serum sarilumab (PK) o X X X X X X X X X X X X Antibodies to sarilumab o X X X X X X X X

Abbreviations. AE=adverse 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, IVRS=interactive voice response system,

JADAS=juvenile arthritis disease activity index, ACR JIA=American College of Rheumatology juvenile idiopathic arthritis response, PK=pharmacokinetics, PPD=purified protein derivative, SAE=serious adverse event, sJIA=systemic juvenile idiopathic arthritis, TB=tuberculosis, V=visit, Wk=week.

a Visit 27 is the planned end of treatment (EOT) visit for the study. If patients discontinue study treatment prematurely, EOT will occur 1 week after the last IMP injection for Dose Cohort 3 and 2 weeks after the last IMP injection for Dose Cohort 2.

b Visit 28 is the planned end-of-study (EOS) visit for the study. If patients discontinue study treatment prematurely, these patients will be asked to return for an EOS assessment 6 weeks after the EOT visit (EOT+6 weeks). This EOS visit (EOT+6 weeks) will be applicable to all patients in both the main treatment phase and the add-on treatment phase.

c Patient diary for IMP administration to be completed for IMP administered at home.

d A complete physical examination includes examination of the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic and musculoskeletal systems

e Study drug should be administered q2w to patients in dose cohort 2 and once weekly for patients in dose cohort 3. For patients who have completed the add-on treatment phase, if the selected dosing schedule is administered once every two weeks (q2w), then the last IMP injection will be given 2 weeks before EOT; If the selected dosing schedule is once weekly (qw), then the last IMP injection will be given 1 week before the EOT. Patients will undergo an EOT assessment at Visit 27 (Week 156). For patients who are prematurely studied during the add-on treatment phase, it will be preferable to undergo an EOT assessment 2 weeks after the last IMP injection for Dose Cohort 2 patients and 1 week after the last IMP injection for Dose Cohort 3 patients. In the event that the patient cannot adhere to the planned schedule, the EOT visit will be used for evaluation at the next protocol-defined visit after the last IMP injection. Patients are asked to return to the center 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 a hypersensitivity reaction. At Visit 27 (Week 156), no IMP injections will be given.

f The patient's fever/rash diary will include recording of tympanic temperature and reporting of rash (if present) at home for at least 7 days prior to each subsequent scheduled ACR JIA Performance Core Set assessment visit. Temperature should be taken at least twice a day at fixed points, upon waking and before going to bed, and at any time if a fever is suspected.

g Additional data should be collected on height measured as close as possible to the time point 1 year before baseline. Height will be measured using a stadiometer at the study sites during the study.

h The ACR Juvenile Idiopathic Arthritis Core Set includes the physician's global assessment of disease severity, the patient's or parent/legal guardian's global assessment of well-being, the number of joints with active arthritis, which is defined as swelling in a joint not caused by deformity OR limitation of movement with either pain or tenderness , or both, number of restricted joints, Children's Health Assessment Questionnaire (CHAQ), hs-CRP, and fever. The calculation principle of the JADAS index is explained in this document.

i Only fever and a transient salmon-colored erythematous rash will be assessed.

j Hematological examination (blood should be drawn BEFORE administration of the drug): hemoglobin, hematocrit, red blood cell count (RBC) and red blood cell morphology (if the red blood cell count is abnormal), white blood cell count (WBC) (neutrophils, lymphocytes, monocytes, eosinophils, basophils), count platelets, absolute neutrophil count (ANC).

k Biochemical study (blood should be collected BEFORE administration of the drug). ALT, AST, ALP, lactate dehydrogenase (LDH), total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. A complete biochemical study should be performed at the 27th EOT visit.

l Lipidogram (blood should be drawn BEFORE drug administration). Triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. It is required that patients fast for at least 8 hours before the test.

m If MAS is suspected, a ferritin test, blood count (RBC, WBC, platelet, and hemoglobin), AST/ALT, triglyceride, and fibrinogen tests should be ordered if determined by the investigator.

n For women who have started menstruating, a urine pregnancy test should be performed prior to receiving the IMP injection at the scheduled visits mentioned in the study design above. Urine testing for pregnancy can be done locally.

o Blood samples will be collected BEFORE IMP administration on dosing days during the treatment period. If a patient experiences an SAE, blood samples should be collected at the onset and completion of the event, if possible, or within a short time after the onset and completion, to determine sarilumab concentrations and to assess anti-drug antibodies (ADA).

Sample Processing Procedure for Pharmacokinetic Determination

It is extremely important to collect all blood samples as close to the days specified in the protocol as possible (see the sample collection schedule in the study design in Table 17). The reasons for missed or lost blood samples should be documented. Special procedures may be used to collect, store, and transport serum. See table 20.

Table 20. Sample handling procedure for sarilumab and anti-sarilumab antibody Sample type Functional sarilumab Antibody to sarilumab Matrix Blood serum Blood serum Blood sample volume 0.5 ml* 0.5 ml ^a Anticoagulant Absent Absent Blood Handling Procedures See procedure manual. See procedure manual. Storage conditions
Transportation conditions
blood serum 9 months at -20°C or below
80°C (preferred)
In dry ice 24 months at -20°C or below 80°C (preferred)
In dry ice

a For a study visit with blood collection for samples to determine both PK and sarilumab antibodies (eg, Baseline Visit 2), 1 mL of blood is recommended. The blood serum is divided equally into 2 aliquots to obtain one aliquot of serum for PK determination and one aliquot of serum for determination of antibodies to sarilumab.

Bioanalytical method

Serum levels of functional sarilumab and anti-sarilumab antibodies will be determined using validated bioanalytical methods.

Pharmacokinetic parameters

The PopPK model will be developed using nonlinear mixed effects modeling to describe the PK profile of sarilumab. The following PK parameters will be calculated using the PopPK model for functional sarilumab in serum. PK parameters will include, without limitation, the following: C _max , C _troug h, t _max and AUC0-τ.

Table 21 - Patient and disease characteristics at baseline* Cohort by dose All All All 1 (2.0/-2.5 mg/kg Q2W)† 2 (3.0/-4.0 mg/kg Q2W)‡ 3 (2.0/-2.5 mg/kg QW)§ Body weight group Group A (30-60 kg) Group B (10-<30 kg) A+B A+B A+B A+B Patients n=20 n=22 N=42 n=13 n=14 n=15 Age, mean (SD) years 13.0 (3.1) 5.2 (2.5) 8.9 (4.8) 9.6 (4.3) 8.9 (5.1) 8.3 (5.2) Children (2-11 years), n (%) 6 (30.0) 22 (100.0) 28 (66.7) 8 (61.5) 10 (71.4) 10 (66.7) Body weight, mean (SD) kg 45.0 (8.8) 19.7 (6.1) 31.7 (14.8) 34.9 (16.1) 31.9 (14.8) 28.8 (14.2) Women, n (%) 13 (65.0) 14 (63.6) 27 (64.3) 10 (76.9) 8 (57.1) 9 (60.0) Race, n (%) Caucasians 17 (85.0) 16 (72.7) 33 (78.6) 9 (69.2) 12 (85.7) 12 (80.0) Negroids 0 0 0 0 0 0 Mongoloids 0 0 0 0 0 0 Unknown 3 (15.0) 2 (9.1) 5 (11.9) 3 (23.1) 0 2 (13.3) Region, n (%) West 6 (30.0) 10 (45.5) 16 (38.1) 4 (30.1) 4 (28.6) 8 (53.3) South America 5 (25.0) 4 (18.2) 9 (21.4) 4 (30.1) 2 (14.3) 3 (20.0) Characteristics of the disease Polyarticular RF(+) JIA, n (%) 6 (30.0) 3 (13.6) 9 (21.4) 4 (30.8) 3 (21.4) 2 (13.3) Polyarticular RF(-) JIA, n (%) 12 (60.0) 15 (68.2) 27 (64.3) 9 (69.2) 8 (57.1) 10 (66.7) Common oligoarticular JIA, n (%) 2 (10.0) 4 (18.2) 6 (14.3) 0 3 (21.4) 3 (20.0) Duration of JIA, mean, years (SD) 4.6 (5.2) 1.7 (1.9) 3.1 (4.1) 3.4 (4.5) 3.4 (4.9) 2.5 (2.8) Number of active joints (0-71), mean (SD) 17.2 (10.4) 11.0 (6.9) 13.9 (9.2) 15.8 (10.5) 11.4 (7.3) 14.7 (9.6) Number of joints with limited movement (0-67), mean (SD) 11.8 (11.2) 9.6 (8.3) 10.6 (9.7) 10.4 (9.0) 8.4 (8.2) 12.9 (11.6) Physician's overall VAS score (0-10), mean (SD) 4.4 (2.0) 4.6 (2.6) 4.5 (2.3) 4.7 (2.1) 4.8 (2.2) 4.1 (2.6) Patient's overall VAS score (0-10)
mean (SD) 5.4 (1.7) 5.9 (2.1) 5.7 (1.9) 5.8 (2.3) 5.9 (1.8) 5.3 (1.7) CHAQ-DI (0-3), mean (SD) 0.9 (0.8) 1.2 (0.8) 1.1 (0.8) 1.3 (0.8) 1.1 (0.7) 0.8 (0.8) JADAS-27 CRP, mean value (SD) 22.2 (7.2) 19.1 (7.7) 20.6 (7.6) 22.1 (6.8) 19.8 (8.0) 20.0 (8.1) CRP, average value, mg/l (SD) 10.4 (14.7) 8.7 (19.2) 9.5 (17.0) 7.4 (13.9) 14.6 (24.1) 6.5 (10.4) ESR, average value, mm/h (SD) 28.0 (28.3) 15.4 (13.1) 21.8 (22.9) 22.2 (24.5) 21.4 (25.9) 21.9 (20.1) ANC, mean value, cells/mm ³ (SD) 4,200 (1,600) 5,200
(2,000) 4,700 (1,800) 4,100 (2,100) 4,900 (1,600) 5,100 (1,800) Previous treatment and treatment at baseline, n (%) csDMARD at baseline 17 (85.0) 15 (68.2) 32 (76.2) 8 (61.5) 12 (85.7) 12 (80.0) Methotrexate 15 (75.0) 15 (68.2) 30 (71.4) 8 (61.5) 10 (71.4) 12 (80.0) System GC at baseline 5 (25.0) 8 (36.4) 13 (31.0) 4 (30.8) 3 (21.4) 6 (40.0) Any previous bDMARD 6 (30.0) 6 (27.3) 12 (28.6) 5 (38.5) 3 (21.4) 4 (26.7) Etanercept 5 (25.0) 5 (22.7) 10 (23.8) 4 (30.8) 2 (14.3) 4 (26.7) Adalimumab 2 (10.0) 1 (4.5) 3 (7.1) 1 (7.7) 2 (14.3) 0

*ANC=absolute neutrophil count; bDMARD=biological DMARD; CHAQ-DI=Children's Health Assessment Questionnaire Disability Index; CRP=C-reactive protein; csDMARD=traditional synthetic DMARD; DMARD=disease-modifying antirheumatic drug; ESR=erythrocyte sedimentation rate; GC=glucocorticoid; JADAS-27 CRP=Juvenile Arthritis Disease Activity Index 27 Joint C-Reactive Protein Score; JIA=juvenile idiopathic arthritis; n=total number of patients who met the criterion at least once during treatment; QW=every week; Q2W=every 2 weeks; RF=rheumatoid factor; SD=standard deviation; VAS=visual analogue scale; yrs=years.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

Table 22. PK data for sarilumab at first administration and 12 weeks after repeated administrations* n C _max AUC _0- τ C _through mg/l (CV%) day mg/l (CV%) mg/l (CV%) First SC introduction Group A (30-60 kg) 2.0 mg/kg Q2W 7 7.69 (47) 53.2 (46) 0.63 (63) 3.0 mg/kg Q2W 7 14.5 (19) 123 (24) 1.84 (69) 2.0 mg/kg QW 6 11.0 (21) 61.3 (22) 8.07 (32) Group B (10-<30 kg) 2.5 mg/kg Q2W 6 9.08 (21) 63.4 (30) 0.54 (48) 4.0 mg/kg Q2W 7 18.7 (21) 167 (26) 3.77 (43) 2.5 mg/kg QW 9 8.29 (35) 45.3 (36) 5.22 (39) Repeat SC administration (weeks 10-12 or weeks 11-12)† Group A (30-60 kg) 2.0 mg/kg Q2W 5 13.2 (14) 114 (18) 1.99 (86) 3.0 mg/kg Q2W 6 26.4 (26) 269 (34) 8.46 (68) 2.0 mg/kg QW 6 38.8 (23) 250 (24) 30.4 (28) Group B (10-<30 kg) 2.5 mg/kg Q2W 5 14.1 (27) 118 (37) 1.83 (101) 4.0 mg/kg Q2W 7 30.1 (20) 310 (26) 11.9 (41) 2.5 mg/kg QW 5 31.4 (22) 203 (25) 25.1 (29)

*AUC _0- τ=area under the serum concentration versus time curve during a dosing interval τ of 2 weeks (Q2W regimen) or 1 week (QW regimen); C _max =maximum observed serum concentration; C _trough =concentration observed before administration of treatment during repeated dosing; CV% = coefficient of variation; n=total number of patients who met the criterion at least once during treatment; QW=once a week; Q2W=once every 2 weeks; SC=subcutaneous.

†Q2W dosing regimens were tested over weeks 10–12; QW dosing schedules were tested over weeks 11–12.

Table 23. Investigator-reported AEs* Cohort by dose All doses 1 (2.0/2.5 mg/kg Q2W)† 2 (3.0/4.0 mg/kg Q2W)‡ 3 (2.0/2.5 mg/kg QW)§ Patient weight group Group A
(30-60 kg) Group B
(10-<30 kg) A+B A+B A+B A+B Number of included patients 20 22 42 13 14 15 Cumulative exposure to treatment, PY 4.6 5.0 9.7 3.1 3.3 3.3 Generalized data, n (%) [n _E /100 PY] A.E. 16 (80.0) [973] 20 (90.9) [1.210] 36 (85.7) [1.097] 11 (84.6) [785] 12 (85.7) [1.273] 13 (86.7) [1.209] SAE 0 0 0 0 0 0 AEs resulting in death 0 0 0 0 0 0 AEs leading to treatment discontinuation 2 (10.0) [43.3] 3 (13.6) [59.5] 5 (11.9) [51.7] 2 (15.4) [65.4] 0 3 (20.0) [90.7] Neutropenia 1 (5.0) [21.6] 3 (13.6) [59.5] 4 (9.5) [41.4] 1 (7.7) [32.7] 0 3 (20.0) [90.7] Elevated ALT level 1 (5.0) [21.6] 0 1 (2.4) [10.3] 1 (7.7) [32.7] 0 0 AE with overall frequency ≥5%, n (%) [nE/100 PY] Neutropenia 3 (15.0) [64.9] 8 (36.4) [178.6] 11 (26.2) [124.2] 3 (23.1) [98.1] 3 (21.4) [121.2] 5 (33.3) [151.2] Upper respiratory tract infection 5 (25.0) [108.1] 4 (18.2) [99.2] 9 (21.4) [103.5] 4 (30.8) [130.8] 2 (14.3) [90.9] 3 (20.0) [90.7] Nasopharyngitis 3 (15.0) [86.5] 1 (4.5) [19.8] 4 (9.5) [51.7] 1 (7.7) [32.7] 2 (14.3) [90.9] 1 (6.7) [30.2] Erythema at the injection site 1 (5.0) [43.2] 2 (9.1) [59.5] 3 (7.1) [51.7] 0 3 (21.4) [151.6] 0 Rhinitis 1 (5.0) [21.6] 2 (9.1) [39.7] 3 (7.1) [31.0] 2 (15.4) [65.4] 0 1 (6.7) [30.2] Leukopenia 1 (5.0) [21.6] 2 (9.1) [39.7] 3 (7.1) [31.0] 1 (7.7) [32.7] 2 (14.3) [60.6] 0 Conjunctivitis 0 3 (13.6) [79.4] 3 (7.1) [41.4] 0 2 (14.3) [90.9] 1 (6.7) [30.2] Diarrhea 1 (5.0) [21.6] 2 (9.1) [39.7] 3 (7.1) [31.0] 0 2 (14.3) [60.6] 1 (6.7) [30.2] Bronchitis 0 3 (13.6) [59.5] 3 (7.1) [31.0] 0 1 (7.1) [30.3] 2 (13.3) [60.5]

*AE=Adverse events occurring during treatment; ALT=alanine aminotransferase; n=total number of patients who met the criterion at least once during treatment; n _E =number of events; PY=patient-years; QW=every week; Q2W=every 2 weeks; SAE=severe AE. All terms in accordance with MedDRA 21.0.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

Table 24. Absolute neutrophil count based on the lowest value recorded in the study* Cohort by dose All doses 1 (2.0/2.5 mg/kg Q2W)† 2 (3.0/4.0 mg/kg Q2W)‡ 3 (2.0/2.5 mg/kg QW)§ Patient weight group Group A (30-60 kg) Group B (10-<30 kg) A+B A+B A+B A+B Number of included patients 20 22 42 13 14 15 Neutropenia based on the lowest neutrophil count observed in the study, n (%) Level 3:
≥500-1000 cells/mm ³ 4 (20.0) 3 (13.6) 7 (16.7) 3 (23.1) 2 (14.3) 2 (13.3) Degree 4:
<500 cells/mm ³ 0 5 (22.7) 5 (11.9) 0 1 (7.1) 4 (26.7)

*n=total number of patients who met the criterion at least once during treatment; QW=every week; Q2W=every 2 weeks.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

Table 25. All infections reported by the investigator* Cohort by dose All doses 1 (2.0/2.5 mg/kg Q2W)† 2 (3.0/4.0 mg/kg Q2W)‡ 3 (2.0/2.5 mg/kg QW)§ Patient weight group Group A (30-60 kg) Group B (10-<30 kg) A+B A+B A+B A+B Number of included patients 20 22 42 13 14 15 Cumulative effect of treatment, PY 4.6 5.1 9.7 3.1 3.3 3.3 Generalized data, n (%) [n _E /100 PY] Upper respiratory tract infection 5 (25.0) [108.1] 4 (18.2) [99.2] 9 (21.4) [103.5] 4 (30.8) [130.8] 2 (14.3) [90.9] 3 (20.0) [90.7] Rhinitis 1 (5.0) [21.6] 2 (9.1) [39.7] 3 (7.1) [31.0] 2 (15.4) [65.4] 0 1 (6.7) [30.2] Gastroenteritis 1 (5.0) [21.6] 1 (4.5) [19.8] 2 (4.8) [20.7] 1 (7.7) [32.7] 1 (7.1) [30.3] 0 Nasopharyngitis 3 (15.0) [86.5] 1 (4.5) [19.8] 4 (9.5) [51.7] 1 (7.7) [32.7] 2 (14.3) [90.9] 1 (6.7) [30.2] Pharyngotonsillitis 1 (5.0) [21.6] 0 1 (2.4) [10.3] 1 (7.7) [32.7] 0 0 Bacterial upper respiratory tract infection 0 1 (4.5) [19.8] 1 (2.4) [10.3] 1 (7.7) [32.7] 0 0 Bronchitis 0 3 (13.6) [59.5] 3 (7.1) [31.0] 0 1 (7.1) [30.3] 2 (13.3) [60.5] Conjunctivitis 0 3 (13.6) [79.4] 3 (7.1) [41.4] 0 2 (14.3) [90.9] 1 (6.7) [30.2] Cystitis 1 (5.0) [21.6] 0 1 (2.4) [10.3] 0 0 1 (6.7) [30.2] Microbial eczema 0 1 (4.5) [19.8] 1 (2.4) [10.3] 0 1 (7.1) [30.3] 0 Viral gastritis 0 1 (4.5) [19.8] 1 (2.4) [10.3] 0 0 1 (6.7) [30.2] Oral candidiasis 1 (5.0) [21.6] 1 (2.4) [10.3] 0 0 1 (6.7) [30.2] Otitis media 0 1 (4.5) [19.8] 1 (2.4) [10.3] 0 1 (7.1) [30.3] 0 Pharyngitis 1 (5.0) [21.6] 0 1 (2.4) [10.3] 0 1 (7.1) [30.3] 0 Bacterial pharyngitis 1 (5.0) [21.6] 0 1 (2.4) [10.3] 0 0 1 (6.7) [30.2] Tonsillitis 0 1 (4.5) [19.8] 1 (2.4) [10.3] 0 1 (7.1) [30.3] 0 Chicken pox 0 1 (4.5) [19.8] 1 (2.4) [10.3] 0 1 (7.1) [30.3] 0 Viral upper respiratory tract infection 0 1 (4.5) [19.8] 1 (2.4) [20.7] 0 0 1 (6.7)

*n _E =number of events; PY=patient-years; QW=every week; Q2W=every 2 weeks. All terms in accordance with MedDRA 21.0.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

Table 26. Change in mean ACR JIA component values compared to baseline in week 12* Cohort by dose 1 (2.0/2.5 mg/kg Q2W)† 2 (3.0/4.0 mg/kg Q2W)‡ 3 (2.0/2.5 mg/kg QW)§ Group according to patient’s body weight‖ A+B A+B A+B Number of included patients 13 14 15 ACR component, mean (% change in mean) [SE] Number of active joints (0-71) B.L. 15.8 [2.92] 11.4 [1.95] 14.7 [2.48] Change from BL in week 12 −11.7 (−76) [1.93] −8.8 (−80) [1.39] −14.5 (−86) [3.13] Number of joints with limited movement B.L. 10.4 [2.49] 8.4 [2.18] 12.9 [3.00] Change from BL in week 12 −6.3 (−59) [1.45] −6.4 (−62) [1.88] −9.6 (−75) [2.27] Doctor's overall VAS score (0-10) B.L. 4.7 [0.58] 4.8 [0.61] 4.1 [0.68] Change from BL in week 12 −3.1 (−63) [0.73] −3.6 (−66) [0.68] −3.9 (−83) [0.73] Patient's overall VAS score (0-10) B.L. 5.8 [0.64] 5.9 [0.48] 5.3 [0.45] Change from BL in week 12 −4.6 (−69) [0.70] −4.3 (−70) [0.47] −5.1 (−89) [0.59] CHAQ-DI (0-3) B.L. 1.3 [0.21] 1.1 [0.20] 0.8 [0.21] Change from BL in week 12 −0.9 (−66) [0.17] −0.9 (−71) [0.19] −0.6 (−76) [0.14] CRP (mg/l) B.L. 7.4 [3.84] 14.6 [6.43] 6.5 [2.68] Change from BL in week 12 −2.8 [2.62] −13.4 [7.42] −7.0 [3.32]

*ACR=American College of Rheumatology; BL=baseline; CHAQ-DI=Children's Health Assessment Questionnaire Disability Index; CRP=C-reactive protein; ACR30 JIA/70/90=juvenile idiopathic arthritis response rate of 30/70/90% according to the American College of Rheumatology; QW=every week; Q2W=every 2 weeks; SE=standard error; VAS=visual analogue scale.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

-Body weight group A: 30-60 kg, body weight group B: 10-<30 kg.

Table 27. Patients who achieved clinically inactive disease or low disease activity at week 12 (observed cases)* Cohort by dose Cohort by dose 1 (2.0/2.5 mg/kg Q2W)† 2 (3.0/4.0 mg/kg Q2W)‡ 3 (2.0/2.5 mg/kg QW)§ Patient weight group A+B A+B A+B Number of included patients 13 14 15 Number of active joints=0, n (%) 4/10 (40) 4/13 (31) 5/11 (45) Clinically inactive disease according to JADAS-27-CRP ≤1, n (%) 0/10 (0) 1/12 (8)** 2/11 (18) Clinically inactive disease or JADAS-27-CRP LDA ≤3.8, n (%) 6/10 (60) 5/12 (42)** 9/11 (82) Clinically inactive disease according to Wallis criteria††, n (%) 3/10 (30) 2/13 (15) 4/11 (36)

*CRP=C-reactive protein; JADAS-27-CRP=juvenile arthritis disease activity index with 27 joint counts and CRP; LDA=low disease activity; n=total number of patients who met the criterion at least once during treatment; QW=every week; Q2W=every 2 weeks; VAS=visual analogue scale.

†Dose 1, 2.0 mg/kg Q2W for patients weighing 30-60 kg and 2.5 mg/kg Q2W for patients weighing 10-<30 kg.

‡Dose 2, 3.0 mg/kg Q2W for patients weighing 30-60 kg and 4.0 mg/kg Q2W for patients weighing 10-<30 kg.

§Dose 3, 2.0 mg/kg QW for patients weighing 30-60 kg and 2.5 mg/kg QW for patients weighing 10-<30 kg.

Body weight group A: 30-60 kg, body weight group B: 10-<30 kg.

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

††Wallis criteria are defined as physician global VAS score <1/10, no active arthritis, no active uveitis, and CRP <10 mg/L.

Secondary end point(s)

12-week main treatment phase

The following parameters will be analyzed during the 12-week open-label main treatment phase.

- Safety

o Adverse events, vital signs, physical examination, laboratory values

o Assessment of acceptability (local tolerance)

- Efficiency

O Response rate to therapy ACR30 JIA/50/70/90/100 (fever-free) at week 12

o Change from baseline in individual ACR JIA components at week 12

o Change from baseline in Juvenile Arthritis Disease Activity Index-27 (JADAS) at week 12

O Changes in glucocorticoid use, which will be assessed descriptively using a line plot of prednisone-equivalent glucocorticoid dose from baseline to the end of the 12-week main treatment period for each individual patient by dose cohort and by body weight group

- Pharmacodynamics

O Changes in biomarkers associated with IL-6 (eg, changes in levels of high-sensitivity C-reactive protein [hs-CRP], IL-6, sIL-6R)

Additional treatment phase

- Safety

o Adverse events, vital signs, physical examination, laboratory values

o Assessment of acceptability (local tolerance)

- Efficiency

o ACR JIA response rates of 30/50/70/90/100 (febrile) at weeks 24, 48, and every 24 weeks until the end of the study. Change from baseline in index-27 disease activity representing juvenile arthritis at weeks 24, 48, and every 24 weeks until the last visit

o - Change from baseline in individual ACR JIA components at weeks 24 and 48 and every 24 weeks until the end of the study

o - Proportion of patients receiving glucocorticoids by dose category (prednisone-equivalent dose of glucocorticoids 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 compared to baseline

o - Proportion of patients not taking glucocorticoids who do not experience exacerbations of JIA at weeks 24, 48 and every 24 weeks thereafter until the end of the study

O Changes in glucocorticoid use, which will be assessed descriptively using a line plot of prednisone-equivalent glucocorticoid dose from baseline to the end of the treatment period for each individual patient by dose cohort and by body weight cohort

Exploratory endpoint

12 week main treatment period

- Proportion of patients with fever due to systemic JIA at baseline who were fever-free at week 12

- Proportion of patients with rash due to systemic JIA at baseline who were rash free at week 12

Additional treatment phase

· Height assessment in years 1, 2, and 3, including height velocity and height standard deviation (SD), for patients who have never received growth hormone and have not achieved Tanner stage 5 by the end of the first year of treatment.

· Proportion of patients with fever at baseline who were fever-free at weeks 24, 48, and every 24 weeks until the end of the study.

Proportion of patients with rash due to systemic JIA at baseline who were rash-free at weeks 24, 48, and every 24 weeks until the end of the study.

Effectiveness endpoints

Response from ACR JIA

This study will use the ACR JIA rating scale to assess signs and symptoms. ACR JIA 30/50/70/90/100 will be assessed in weeks 12, 24, 48, 72, 96, 120, 144 and 156 (EOT). ACR JIA response 30/50/70/90/100 (without fever) is defined as a patient in whom 3 of the 6 core set variables improved by at least 30%/50%/70%/90%/100% vs. with baseline, with no more than 1 of the remaining variables worsening by more than 30%.

The basic set for ACR JIA includes 6 variables plus fever for sJIA.

- General assessment of disease activity by the physician

- Assessment of general well-being by the patient/parent

- Functional abilities as measured by the Children's Health Assessment Questionnaire (CHAQ)

- Number of joints with active arthritis (from 0 to 71 joints)

- Number of joints with limited movement (from 0 to 67 joints)

- High sensitivity C-reactive protein

- Fever (within the previous 7 days)

- The JIA ACR baseline will be assessed at each study site visit except Visit 3 (Day 3), Visit 4 (Day 5), Visit 5 (Day 8), Visit 6 (Day 12) and the EOS visit. Temperature should be taken 7 days before the ACR assessment.

Baseline variable estimates for the ACR30 JIA and changes from baseline for each dose cohort and body weight group will be summarized across visits using means, standard errors, and corresponding 95% CIs. ACR30 JIA/50/70/90/100 responses using ESR instead of hs-CRP will also be summarized using the same methods.

General assessment of disease activity by the physician

A general physician assessment of disease activity will be performed at screening, at baseline before IMP administration, and at each center visit until the EOT visit. The examiner will be asked to rate the patient's disease activity on a 100 mm horizontal visual analogue scale (VAS) with landmarks, where 0 is considered the best disease activity and 100 is considered the worst disease activity.

Patient/parent assessment of general well-being

Patient/parent assessment of general well-being will be measured using a 100 mm horizontal VAS at screening, at predose baseline, and at each center visit prior to the EOT visit. The form must be asked to be completed by the patient or the same parent or guardian to ensure consistency.

Children's Health Assessment Questionnaire (CHAQ)

The CHAQ is a self-administered survey or instrument for children ≥8 years of age and a parent/proxy-administered instrument for children <8 years of age. The CHAQ is a general measure of the health of children aged 1 to 19 years. The Spearman correlation coefficient between disability index values obtained from questionnaires completed by parents and disability index values obtained from questionnaires completed by other children (>8 years) was 0.84 (n = 29; P < 0.001), indicating that that parents can give accurate answers for their children. The face validity of the instrument was assessed by a panel of 20 health professionals and parents of 22 healthy children. The assessment consists of 43 items in total and takes approximately 10 minutes to complete. The CHAQ will be completed before IMP doses and at subsequent time points. The evaluation period is 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 CHAQ data will be recorded in the eCRF.

The median CHAQ scores corresponding to mild, mild to moderate, and moderate disability reported at the time the CHAQ was created were 0.13, 0.63, and 1.75, respectively (Dempster, H. et al., 2001 Arthritis Rheum 44(8):1768-7).

To eliminate inconsistencies that may have been introduced by growth and development, parents are asked to note only those difficulties that arose due to illness (for example, if a child cannot perform an activity because his/her age is too young, answer marked as "not applicable"). Response options assessing difficulty are based on a 5-point Likert scale (0=no difficulty, 1=some difficulty, 2=A LOT of difficulty, 3=impossible to perform, and 4=not applicable).

Part 1 of the CHAQ is a disability index that contains 41 items assessing the ability to function in activities of daily living. These are further divided into the following 8 subscales/domains. 1. Dressing and grooming; 2. rise; 3. eating; 4. walking; 5. hygiene; 6. reaching; 7. grip and 8. vigorous activity. For each domain, we assessed (a) the degree of difficulty in performing daily functions (items 6–9, 12–13, 16–18, 21–22, 34–38, 41–44, 47–51, and 54–58); (b) the need to use special aids or devices (paragraphs 24-27, 60-62) and (c) the need for assistance from another person (paragraphs 29-30, 64-65).

- To calculate the Children's Health Assessment Questionnaire Disability Index (CHAQ-DI), a score for each domain is first calculated.

o The question with the highest score determines the score for that functional area

o If assistive aids or devices are used or assistance is required to perform tasks in a specific area, a minimum score of 2 is recorded for the relevant functional area

o The 8 subscales/domains are averaged to calculate a mean score, which is a disability index (range 0 to -3).

Lower disability index scores indicate better health status/better health-related quality of life (HRQL)/fewer signs and symptoms, while higher disability index scores indicate worse health status/worse health-related quality of life (HRQL)/more signs and symptoms. The minimum clinically significant improvement in the CHAQ disability index is a decrease in score of 0.13. The minimum clinically significant deterioration in the CHAQ disability index is a change in the median score of 0.75 (20, 19).

CHAQ Part 2 is a discomfort index and CHAQ Part 3 is a health status index; both are measured on separate 15cm scales.

The CHAQ discomfort index is determined by the degree of pain over the past week, as assessed by the VAS (with reference points of “0 - no pain” and “100 - very severe pain”).

· To calculate the CHAQ discomfort index (item 67)

- it is necessary to measure the distance from the left edge of the VAS in point 67 to the respondent’s mark and multiply by 0.2. The range is from 0 to 3. The discomfort index value can be rescaled on a scale from 0 to 100.

The CHAQ Part 3 Health Status Measure measures the patient's or parent's global assessment of illness.

· To calculate health status according to CHAQ (item 69)

- it is necessary to measure the distance from the left edge of the VAS in point 69 to the respondent’s mark and multiply by 0.2. The range is from 0 to 3. The health value can be rescaled on a scale from 0 to 100.

Number of joints with active arthritis and number of joints with limited movement

An active joint is defined as a joint with:

- swelling in the joint not caused by deformation OR

- limitation of movement, either with pain or tenderness

Seventy-one (71) joints will be assessed for active disease by counting the number of active joints with swelling not due to deformity OR limitation of motion, or pain, tenderness, or both (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.

Cervical spine (counts as 1 joint), temporomandibular (2 joints, right and left), sternoclavicular (2 joints), acromioclavicular (2 joints), shoulder (2 joints), elbow (2 joints), carpal (2 joints), metacarpophalangeal (total 10 joints, 5 on each side), proximal interphalangeal (total 10 joints, 5 on each side), distal interphalangeal (total 8 joints, 4 on each side), hip ( 2 joints), knee (2 joints), ankle (2 joints), subtalar (2 joints), tarsometatarsal (2 joints), metatarsophalangeal (10 joints, 5 on each side) joints and interphalangeal joint of the foot (10 joints, each 5 on each side), a total of 71 joints.

Sixty-seven (67) joints that will be evaluated for limitation of motion are the same joints as those evaluated for active disease, with the exception of the sternoclavicular (n=2) and acromioclavicular (n=2) ). The formal joint count will be performed by a trained assessor. Joint tenderness was defined as pain caused by pressure on the joints from the thumb and index finger of the assessor.

High sensitivity C-reactive protein

High-sensitivity C-reactive protein will be assessed at Visit 1 (Day -28 to Day -1, up to Day 31), Baseline Visit 2 (Week 0, Day 1), Visit 7 (Week 2), Visit 8 (Week 4 ), Visit 9 (Week 6), Visit 10 (Week 8), Visit 11 (Week 10), Visit 12 (Week 12), and at each visit in the add-on treatment phase from Visit 13 (Week 16) to Visit 27 EOT (Week 156) for patients who continue to take the selected dose; from visit 101 (week 0) to visit 108 (week 12), at visit 109 (week 24), visit 112 (week 48), visit 114 (week 72), visit 116 (week 96), visit 118 (week 120) and visit 27 EOT. For patients with body weight <30 kg (group B) in schedule group PK 1, hs-CRP will be measured on days 3 and 8. For patients with body weight <30 kg (group B) in schedule group PK 2, hs-CRP will be measured on days 5 and 12. High-sensitivity C-reactive protein levels directly correlate with IL-6R activity. Active dosing regimens are expected to have a dramatic CRP-lowering effect.

juvenile arthritis disease activity index

JADAS includes 4 indicators.

1. Physician's global assessment of disease activity as measured by a 10 cm VAS, where 0=no activity and 10=maximum activity.

2. Parent/patient global assessment of well-being measured using a 10 cm VAS, where 0=very good and 10=very poor.

3. Number of joints with active disease.

4. The erythrocyte sedimentation rate is normalized on a scale from 0 to 10 using the following formula:

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

ESR values <20 mm/h are converted to 0 and ESR values >120 mm/h are converted to 120 before calculation.

The JADAS will be calculated as a simple linear sum of scores across its 4 components (Consolaro, A. et al. , 2009 Arthritis Rheum. 61(5):658-623). The overall JADAS-27 score and change from baseline will be summarized across visits (including count, mean, standard error, SD, median, minimum, and maximum) for each dose cohort and body weight group (if applicable).

JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (first to third), proximal interphalangeal joints, hip, knee and ankle joints. JADAS has proven to be a valid tool for assessing disease activity in JIA and has potential application in standard clinical care, surveillance testing, and clinical trials (23). JADAS-27 will be counted on Visit 12 (Week 12), Visit 15 (Week 24), Visit 18 (Week 48),

visit 20 (week 72), visit 22 (week 96), visit 24 (week 120), visit 26 (week 144) and visit 27 EOT (week 156) for patients who remain on the selected dose; from visit 101 (week 0) to visit 106 (week 12), at visit 109 (week 24), visit 112 (week 48), visit 114 (week 72), visit 116 (week 96), visit 118 (week 120) and EOT Visit 27 for patients who switched to the selected dose.

Systemic signs of sJIA

Information on systemic signs of sJIA, including fever, transient salmon-colored erythematous rash, generalized lymph node enlargement, hepatomegaly, splenomegaly, serositis, and other complications, will be collected at screening visit 1 (day -28 to day -1, up to day 31) for confirmation of diagnosis, at visit 2 (week 0), visit 12 (week 12) and visit 27 (week 156); At Visit 15 (Week 24), Visit 18 (Week 48), and every 24 weeks until the end of the study, only information on fever and a transient salmon-colored erythematous rash will be collected.

General systemic signs, including fever and rash associated with sJIA, will be collected at all visits when assessing the core components of the ACR JIA.

The rash associated with sJIA is a transient, erythematous, salmon-colored rash.

Absence of rash is defined as absence of rash associated with sJIA recorded in the patient diary 7 days prior to the day of assessment.

Absence of fever is defined as no temperature readings ≥37.5 ^o C within 7 days before the visit when assessing the core components of the ACR JIA.

The effect of treatment on fever and rash will be assessed at week 12 compared to baseline.

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

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

Evaluation of glucocorticoid use

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 who do not experience JIA exacerbations at weeks 24, 48, 72 and 104 will be pooled across each dose cohort and body weight group for comparison with the proportion at baseline. The prednisone-equivalent glucocorticoid dose in mg/kg/day at a given time point (ie, weeks 0, 24, 48, 72, or 104) will be calculated based on glucocorticoids taken during the 2 weeks prior to that time point. A JIA exacerbation at a given time point (i.e., weeks 24, 48, 72, or 104) was defined as failure to maintain an ACR50 JIA response, fever (any temperature ≥37.5°C), or ESR 220 mm/hour between the previous visit and at this point in time.

Prednisone-equivalent glucocorticoid dose (primary value and change from baseline) will be summarized across visits (mean, standard deviation, median, etc.) across dose cohorts and body weight groups. In addition, the prednisone-equivalent dose of glucocorticoids at each visit during the treatment period (both the baseline and the previously established dose period in the extension population) will be plotted for each individual patient by dose cohort and by body weight group.

Growth estimates

Effects on growth will be assessed using height velocity and height SD for patients who have never received growth hormone and have not achieved Tanner stage 5 by the end of the first year of treatment.

The growth rate (centimeters per year) will be calculated based on the change in height and the time interval between height measurements. Pre-treatment growth rates will be assessed using height measured as close as possible to the time point 1 year before baseline, assuming measurements were obtained between 9 and 24 months before baseline. Subsequently, growth rates in years 1 and 2 of treatment will be calculated. Growth measurements that are as close as possible to the 1 year and 2 year cutoff time points will be used.

Height will be measured in a standing position using a wall-mounted stadiometer. When measuring height, children will be measured without shoes, hats or hair ornaments at a fixed right angle above the head, with the head, shoulders, buttocks and heels pressed against the wall and feet pressed together. Due to slight changes in the child's posture, each measurement will take three consecutive measurements for each child. The average of the three measurements will be considered the child's true height if the measurements are within 0.3 cm. If the measurements differ by >0.3 cm, they will be repeated and averaged when they are within the acceptable range. The measurements used to calculate the growth rate will be made as indicated in the rating schedule.

Height will be measured using validated methods at the research site. The expected normal growth rate over a given interval for a given patient will be calculated as the difference from the World Health Organization (WHO) mean height value; World Health Organization. Child Growth Standards WHO Anthro (version 2011) and macros. URL: http://www.who .int/childgrowth/software/en/) for the patient's age and sex, divided by the change in age. Growth rates will be compared to expected normal growth rates before treatment and during 1, 2, and 3 years of treatment.

Growth SD coefficients will be calculated (see below) using WHO standards (there same). Reference populations have mean SD coefficients of 0, and values between -2 and +2 are generally considered to be the normal range. SD coefficient = (observed value - median value of the reference population)/SD value of the reference population.

To estimate the effect on growth, the change from baseline in the growth SD in years 1, 2, and 3 of treatment will be descriptively summarized using the mean, SD, and 95% CI. The proportions of patients with growth rates exceeding WHO expectations will be summarized before treatment and during 1, 2 and 3 years of treatment. Average growth rates will be compared with WHO expected normal growth rates before treatment and at 1, 2 and 3 years.

Physical examination

A complete physical examination will be performed at Screening Visit 1 (Day -28 to Day -1, up to Day 31), Visit 2 (Day 1, Week 0), Visit 8 (Week 4), Visit 9 (Week 6), Visit Visit 12 (Week 12), Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), Visit 22 (Week 96), Visit 24 (Week 120), Visit 26 (Week 144) and Visit 27 EOT (week 156) for patients who remain on the selected dose; at visit 101 (week 0), visit 104 (week 6), visit 106 (week 12), visit 109 (week 24), visit 112 (week 48), visit 114 (week 72), visit 116 (week 96), visit 118 (week 120), EOT visit 27, and EOS visit 28 for patients who switched to the selected dose. Any clinically significant abnormalities should be reported to the patient's eCRF as a medical history if observed and already known at Visit 1 (day -28 to day -1, up to day 31) and should be reported as a medical history. AE if seen at Visit 2 (Day 1, Week 0) and subsequent visits. Any clinically significant abnormality on physical examination that is known at the screening visit should be reported as a medical history and not as an AE. Clinically significant changes or worsening from baseline reported after the screening visit should be reported as AEs.

Body weight

Body weight should be determined with the patient wearing underwear or very light clothing (without outer clothing or accessories) and without shoes, as well as with an empty bladder. It is recommended to use the same scales throughout the study. Body weight is determined with an accuracy of 0.1 kg.

It is recommended to use the same scales throughout the study. Body weight will be determined at Screening Visit 1 (Day -28 to Day -1, through Day 31), Baseline Visit 2 (Day 1, Week 0), Visit 12 (Week 12), and at all follow-up visits. for patients who continue to take the selected dose; from Visit 101 (Week 0) to Visit 119 (Week 132), at Visit 27 EOT and Visit 28 EOS, except at Visit 102 (Week 2) and Visit 104 (Week 6), for patients who switched to the selected dose.

Pharmacodynamic parameters

The pharmacodynamic effects of sarilumab will be assessed by measuring the following biomarkers: hs-CRP, IL-6, sIL-6R.

Assessment schedule

The schedule for collecting blood samples can be found in the study diagram (see Tables 17-19). IL-6 and total sIL-6R will be measured at Baseline Visit 2 (Week 0) and Visit 12 (Week 12). For patients who discontinue study treatment prematurely during the primary treatment phase, IL-6 and total sIL-6R will be measured at EOT assessment.

Pharmacogenomics

The parent(s) or legal guardian(s) will be required to sign a separate ICF form for the collection of saliva samples. Deoxyribonucleic acid samples for genomic studies will be dual coded according to International Council for Harmonization (ICH) Guide 15. Deoxyribonucleic acid samples can be stored for up to 15 years after the last clinical trial report (CSR) date and can be used for research purposes.

The goal of genomic analysis is to identify genomic associations with clinical or biomarker response to target modulation, with disease prognosis and progression, or with other clinical outcome measures. These data can be used or combined with data collected from other studies to identify genomic markers that can predict response and elucidate disease mechanisms. Analyzes may include sequencing or single nucleotide polymorphism studies of candidate genes and surrounding genomic regions. May also conduct genome-wide studies, including but not limited to single nucleotide polymorphism analysis, genomic sequencing, and transcriptome sequencing. If indicated, genomic analysis may also be performed to identify markers associated with toxicity. Patients are eligible for research even if they and their parents or legal guardians do not wish to participate in the collection of samples for pharmacogenomic studies.

Any unused or remaining serum samples collected for drug or ADA concentration measurements may be stored and used for exploratory biomarker studies related to sJIA, IL-6Rα pathway inhibition by antibodies, treatment response (PD and/or prognostic), for investigation of unexpected AEs or to identify markers associated with toxicity. Samples may be stored for up to 15 years after the CSR date or as required by local regulations.

Abbreviations. HLA-B27=human leukocyte antigen-B27, ILAR=International League of Associations of Rheumatology, JIA=juvenile idiopathic arthritis, RF=rheumatoid factor.

a Specific exclusion criteria: a=psoriasis or psoriasis in a first-degree relative; b=presence of human leukocyte antigen B27, male gender and age over 6 years;

c=ankylosing spondylitis, enthesitis-associated arthritis, sacroiliitis with concomitant chronic inflammatory bowel disease, Reiter's disease in

first degree relative; d=detection of rheumatoid factor (RF) at least 2 times at least 3 months apart.

Table 32. Study design for patients enrolled directly under the selected dosing schedule in Part Three Additional treatment phase
(up to 84 weeks of sarilumab exposure after V12 for part three [part 3]) Follow-up
after treatment
(6 weeks) Visit V13 ^{a V14a} V15 V16 ^{a V16.1b} V17 ^a V18 V19 V20 V21 V27/EOT ^c V28/EOS ^d Day D 113
(±1 or 3) D 141
(±1 or 3) D 169
(±1 or 3) D 225
(±1 or 3) D 253
(±1 or 3) D 281
(±1 or 3) D 337
(±1 or 3) D 421
(±1 or 3) D 505
(±1 or 3) D 589
(±1 or 3) Wk 96 for
parts 3 EOT+6Wk:
Wk 102 for part 3 A week Wk 16 Wk 20 Wk 24 Wk 32 Wk 36 Wk 40 Wk 48 Wk 60 Wk 72 Wk 84 Concomitant medications X X X X X X X X Home medication adherence diary ^e X X X X X X X Physical examination ^f X X X X Call to IVRS X X X X X X X X Tanner stage and menstrual status X X X X X Treatment Introduction IMP ^g X X X X X X Issuing IMP X X X X X X Vital Signs Temperature, heart rate, BP X X X X X X X X Body weight X X X X X X X X Height (stadiometer) ^h X X X X Efficiency Basic set for ACR JIA ⁱ X X X X JADAS- ^27j X X X X Security assessment AE/SAE registration X X X X X X X X Tuberculosis risk assessment X X X X X X X X Tuberculin skin test with PPD for patients ≤5 years; QuantiFERON-TB test for patients >5 years X Local tolerance X X X X X X X Laboratory research Hematological examination ^k X X X X X X X ^k Biochemical study ^l X X X X X X ^Xl Fasting lipidogram ^m X X X ^m hs-CRP X X X X ⁱ ESR X X X X ANA/anti-dsDNA ⁿ X X ^Xn Local urine testing for pregnancy in menstruating women ^o X X X X X X X Pharmacokinetics and ADA Sarilumab in serum ^p X X X X X Antibodies to sarilumab ^p X X X X X Abbreviations. ADA=drug antibody, AE=adverse event, ALP=alkaline phosphatase, ALT=alanine aminotransferase, ANA=antinuclear antibody, ANC=absolute neutrophil count, AST=aspartate aminotransferase, 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, IVRS=interactive voice response system, JADAS=disease activity index representing is juvenile arthritis, ACR JIA=American College of Rheumatology juvenile idiopathic arthritis response, PK=pharmacokinetics, PPD=purified protein derivative, SAE=serious adverse event, TB=tuberculosis, V=visit, Wk=week, yrs=years.

a Visits 13, 14, 16 and 17 are not applicable for patients in the third part.

b Visit 16.1 only applies to part 3 patients.

c Visit 27 (week 96 for part three) is the planned end of treatment (EOT) visit for the study. If patients discontinue study treatment prematurely, EOT will occur 2 weeks after the last IMP injection.

d Visit 28 (week 102 for part three) is the planned end-of-study (EOS) visit for the study. If patients discontinue study treatment prematurely, these patients will be asked to return for an EOT assessment 2 weeks after the last IMP injection and for an EOS assessment 6 weeks after the EOT visit (EOT +6 weeks). EOT and EOS visits will apply to all patients who discontinue treatment prematurely in both the main treatment and add-on treatment phases.

e IMP Home Diary to be completed for IMP administered at home.

f A complete physical examination will be performed at Visit 15 (Week 24), Visit 18 (Week 48), Visit 20 (Week 72), and Visit 27 (EOT), where the examination includes examination of the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, nervous, lymphatic and musculoskeletal systems.

g Investigational medicinal product (IMP) should be administered once every two weeks (q2w). Patients should be monitored for at least 30 minutes after IMP administration for any signs or symptoms of a hypersensitivity reaction. The last IMP injection will be given at week 94; Patients will then complete the EOT assessment at Visit 27 (Week 96 for Part Three). There will be no IMP injections given at Visit 27.

h Height will be measured using a stadiometer at the study sites during the study.

i The American College of Rheumatology (ACR JIA) Juvenile Idiopathic Arthritis Core Set includes the physician's global assessment of disease severity, the patient's or parent's global assessment of well-being, the number of joints with active arthritis (defined as swelling in a joint not caused by deformity OR limitation of movement or pain, with either tenderness or both), number of limited joints, Children's Health Assessment Questionnaire (CHAQ), and hs-CRP. If the patient discontinues treatment prematurely before week 48, hs-CRP testing should be performed at the central laboratory at EOT.

j Calculation of the disease activity index representing juvenile arthritis

k Hematological examination (blood should be drawn BEFORE administration of the drug): hemoglobin, hematocrit, red blood cell count (RBC) and red blood cell morphology (if the red blood cell count is abnormal), white blood cell count (WBC) (neutrophils, lymphocytes, monocytes, eosinophils, basophils), count platelets, absolute neutrophil count (ANC). If the patient discontinues treatment prematurely before week 48, testing must be performed at a central laboratory at EOT.

l Biochemical study (blood should be collected BEFORE administration of the drug). ALT, AST, ALP, total bilirubin, conjugated bilirubin, unconjugated bilirubin, and albumin will be tested. A full chemistry panel should be performed at EOT visit 27 (week 96 for part three). If the patient discontinues treatment prematurely before week 48, testing must be performed at a central laboratory at EOT.

m Lipidogram (blood should be drawn BEFORE drug administration). Triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. It is required that patients fast for at least 8 hours before the test. At EOT, testing will only be performed on patients who discontinue treatment prematurely before week 48 and should be performed by a central laboratory.

n At EOT, ANA/anti-dsDNA testing will only be performed on patients who discontinue treatment prematurely before week 48 and should be performed by a central laboratory.

o For women who have started menstruating, urine pregnancy tests should be performed prior to IMP administration at each scheduled visit and at EOT. Urine testing for pregnancy can be done locally.

p Blood samples will be collected BEFORE IMP administration on dosing days during the treatment period. If a patient experiences an SAE, blood samples should be collected at the onset and completion of the event, if possible, or within a short time after the onset and completion, to determine sarilumab concentrations and to assess anti-drug antibodies (ADA).

Table 33 - ACR JIA Response Rate Accuracy Estimates Expected W12 response rate for selected dosing schedule ^a Sample size FWHM 95%CI Pooled patients who will be included in the selected dose from the dose selection part and the second part 90% 36 9.8% 85% 36 11.7% 80% 36 13.1% 75% 36 14.1% 70% 36 15.0% 65% 36 15.6% 60% 36 16.0% 50% 36 16.3% 40% 36 16.0% Pooled patients who will be included in the selected dose from all 3 parts 90% 60 7.6% 85% 60 9.0% 80% 60 10.1% 75% 60 11.0% 70% 60 11.6% 65% 60 12.1% 60% 60 12.4% 50% 60 12.7% 40% 60 12.4% Abbreviations. CI=confidence interval, W12=week 12, ACR JIA=American College of Rheumatology juvenile idiopathic arthritis. a The expected W12 response rate for the selected dosing schedule is estimated based on the effect sizes observed with tocilizumab (27).
Note. “Sample size” represents the estimated number of patients who will be enrolled at the selected dose and who will complete the 12-week primary treatment period; assumed a 15% dropout rate.

Links

1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390-2.

2. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet (London) 2007;369:767-78.

3. Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009;11:229-29.

4. Oberle EJ, Harris JG, Verbsky JW. Polyarticular juvenile idiopathic arthritis - epidemiology and management approaches. Clin Epidemiol 2014;6:379-93.

5. Shepherd J, Cooper K, Harris P, Picot J, Rose M. The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation. Health Technol Assess (Winchester) 2016;20:1-222.

6. Hissink Muller PCE, Brinkman DMC, Schonenberg D, Koopman-Keemink Y, Brederije ICJ, Bekkering WP, et al. A comparison of three treatment strategies in recent onset non-systemic Juvenile Idiopathic Arthritis: initial 3-months results of the BeSt for Kids-study. Pediatr Rheumatol Online J 2017;15.

7. Lovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, et al. Risk, timing, and predictors of disease flare after discontinuation of anti-tumor necrosis factor therapy in children with polyarticular forms of juvenile idiopathic arthritis with clinically inactive disease. Arthritis Rheumatol (Hoboken) 2018;70:1508-18.

8. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum 2012;64:2012-21.

9. Guzman J, Oen K, Tucker LB, Huber AM, Shiff N, Boire G, et al. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort. Ann Rheum Dis 2015;74:1854-60.

10. Simonini G, Ferrara G, Pontikaki I, Scoccimarro E, Giani T, Taddio A, et al. Flares after withdrawal of biological therapies in juvenile idiopathic arthritis: clinical and laboratory correlates of remission duration. Arthritis Care Res 2018;70:1046-51.

11. Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulfraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis 2018;77:819-28.

12. Swart J, Giancane G, Horneff G, Magnusson B, Hofer M, Alexeeva E, et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biological or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther 2018;20:285.

13. De Benedetti F, Robbioni P, Massa M, Viola S, Albani S, Martini A. Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol 1992;10:493-8.

14. Spirchez M, Samasca G, Iancu M, Bolba C, Miu N. Relation of interleukin-6, TNF-alpha and interleukin-1alpha with disease activity and severity in juvenile idiopathic arthritis patients. Clin Lab 2012;58:253-60.

15. De Benedetti F. Targeting interleukin-6 in pediatric rheumatic diseases. Curr Opin Rheumatol 2009;21:533-7.

16. De Benedetti F, Pignatti P, Gerloni V, Massa M, Sartirana P, Caporali R, et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis. J Rheumatol 1997;24:1403-9.

17. KEVZARA. Instructions for use of the drug in the USA. Available at: https://www-accessdata-fda-gov/drugsatfda_docs/label/2017/761037s000lbl.pdf [accessed 14 March 2018].

18. Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomized, double-blind withdrawal trial. Ann Rheum Dis 2015;74:1110-17.

19. Product labeling for ACTEMRA (tocilizumab). [accessed 24 May 2019].

20. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, et al. Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomized SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis 2014;73:1626-34.

21. Guidelines for the management of drug-induced liver injury: Pre-marketing clinical evaluation. Available at: https://www-fda-gov/media/116737/download [accessed 09 July 2019].

22. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthrit Care Res 2011;63:929-36.

23. Germovsek E, Barker CIS, Sharland M, Standing JF. Pharmacokinetic-pharmacodynamic modeling in pediatric drug development, and the importance of standardized scaling of clearance. Clin Pharmacokinet 2019;58:39-52.

24. Barker CIS, Standing JF, Kelly LE, Hanly Faught L, Needham AC, Rieder MJ, et al. Pharmacokinetic studies in children: recommendations for practice and research. Arch Dis Child 2018;103:695.

25. Gill KL, Machavaram KK, Rose RH, Chetty M. Potential sources of inter-subject variability in monoclonal antibody pharmacokinetics. Clin Pharmacokinet 2016;55:789-805.

26. Kojima T, Yabe Y, Kaneko A, Hirano Y, Ishikawa H, Hayashi M, et al. Monitoring C-reactive protein levels to predict favorable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Modern rheumatology 2013;23:977-85.

27. Madhok R, Crilly A, Watson J, Capell HA. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indicators of disease activity. Ann Rheum Dis 1993;52:232-4.

28. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008;112:3959-64.

29. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum Dis 2008;67:1516-23.

30. Fleischmann R, van Adelsberg J, Lin Y, Castelar-Pinheiro GD, Brzezicki J, Hrycaj P, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol (Hoboken) 2017;69:277-90.

31. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a Phase III study. Arthritis Rheumatol (Hoboken) 2015;67:1424-37.

32. Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NM, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomized, double-blind, parallel-group phase III trial. Ann Rheum Dis 2017;76:840-47.

33. Emery P, Rondon J, Parrino J, Lin Y, Pena-Rossi C, van Hoogstraten H, et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford) 2018;58:849-58.

34. Pardeo M, Wang J, Ruperto N, Alexeeva E, Chasnyk V, Schneider R, et al. Neutropenia during tocilizumab treatment is not associated with infection risk in systemic or polyarticular-course juvenile idiopathic arthritis. J Rheumatol 2019. Available at: https://www-ncbi-nlm-nih-gov/pubmed/30824645 [accessed 29 August 2019].

35. European Medicines Agency evaluation report on ACTEMRA (tocilizumab). Available at: https://www-ema-europa-eu/en/documents/variation-report/roactemra-h-c-955-ii-0072-epar-assessment-report-variation_en.pdf [accessed 28 May 2019].

36. Hsieh MM, Everhart JE, Byrd-Holt DD, Tisdale JF, Rodgers GP. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med 2007;146:486-92.

37. Moots RJ, Sebba A, Rigby W, Ostor A, Porter-Brown B, Donaldson F, et al. Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (Oxford) 2017;56:541-49.

38. Genovese MC, van Adelsberg J, Fan C, Graham NMH, van Hoogstraten H, Parrino J, et al. Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes. Rheumatology 2018;57:1423-31.

39. European Medicines Agency. Ethical considerations for clinical trials on medicinal products conducted with the pediatric population. Recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use London: European Medicines Agency. 2008.

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LIST OF SEQUENCES

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Gly Ala Ser

1

<210> 8

<211> 9

<212> PROTEIN

<213> Homo sapiens

<220>

<221> MISC_FEATURE

<222> (1)..(9)

<223> light chain complementarity determining region 3

<400> 8

Gln Gln Ala Asn Ser Phe Pro Tyr Thr

15

<210> 9

<211> 446

<212> PROTEIN

<213> Homo sapiens

<220>

<221> MISC_FEATURE

<222> (1)..(446)

<223> Heavy chain

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe

65 70 75 80

Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 10

<211> 214

<212> PROTEIN

<213> Homo sapiens

<220>

<221> MISC_FEATURE

<222> (1)..(214)

<223> Light chain

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 11

<211> 358

<212> PROTEIN

<213> Homo sapiens

<220>

<221> MISC_FEATURE

<222> (1)..(358)

<223> extracellular domain of human interleukin-6 receptor

<400> 11

Met Val Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro

1 5 10 15

Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg

20 25 30

Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro

35 40 45

Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys

50 55 60

Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg

65 70 75 80

Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys

85 90 95

Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val

100 105 110

Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser

115 120 125

Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr

130 135 140

Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp

145 150 155 160

Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys

165 170 175

Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met

180 185 190

Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe

195 200 205

Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val

210 215 220

Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp

225 230 235 240

Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg

245 250 255

Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp

260 265 270

Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His

275 280 285

Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser

290 295 300

Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser

305 310 315 320

Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr

325 330 335

Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr

340 345 350

Ser Leu Pro Val Gln Asp

355

<---

Claims (26)

1. A method of treating juvenile idiopathic arthritis (JIA) in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds the interleukin 6 (IL-6) receptor and contains the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10, where the antibody is administered subcutaneously at a dose of 2 to 4 mg/kg once a week or once every two weeks. 2. The method according to claim 1, wherein the JIA is a polyarticular JIA (pcJIA). 3. The method of claim 1 or 2, wherein the subject has had an insufficient response to treatment comprising a corticosteroid, a synthetic disease-modifying antirheumatic drug (sDMARD) and/or a biological DMARD, and the subject is being considered a candidate for treatment with a biological disease-modifying antirheumatic drug (DMARD). 4. Method according to any one of paragraphs. 1-3, wherein treatment of the subject includes an improvement in the subject's American College of Rheumatology (ACR) Juvenile Idiopathic Arthritis score, an improvement in the subject's ACR JIA component, a decrease in the level of corticosteroids administered to the subject compared to the level before administration of the antibody, a decrease in the activity index disease representing juvenile arthritis in the subject, achieving clinically inactive disease according to the Wallis criteria, or any combination thereof. 5. Method according to any one of paragraphs. 1-4, where subject: (a) has five or more active joints; or (b) suffers from arthritis in two or more joints with concomitant or preceding daily fever with peaks for at least 3 days, which is accompanied by one or more of a transient erythematous rash; generalized enlargement of lymph nodes; hepatomegaly, splenomegaly, serositis or combinations thereof. 6. Method according to any one of paragraphs. 1-5, where the dose of the antibody is administered in a pharmaceutical composition. 7. Method according to any one of paragraphs. 1-6, where the age of the subject is from 1 year to 17 years, the subject has a body weight of at least 10 kg, less than 30 kg, or less than 60 kg. 8. A method of treating polyarticular JIA (pcJIA) in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds to the IL-6 receptor and contains the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: : 10, where the antibody is administered at a dose of 2 to 4 mg/kg once a week or once every two weeks, where the age of the subject is from 2 to 17 years. 9. The method of claim 8, wherein the subject has a body weight greater than or equal to 10 kg and less than or equal to 60 kg. 10. A method of treating polyarticular JIA (pcJIA) in a subject in need thereof, comprising administering an effective amount of an antibody that specifically binds the IL-6 receptor and comprising the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10, where the antibody is administered subcutaneously and (a) where the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; (b) wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week; (c) where the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 26.25 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 12.5 kg and less than 16 kg, and the antibody is administered at a dose of 35 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16 kg and less than 19.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19.5 kg and less than 23 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23 kg and less than 26.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 26.5 kg and less than 30 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 30 kg and less than 37.5 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the subject's body 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 50.5 kg and less than 55 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 55 kg and less than 59.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 59.5 kg and less than 64 kg, and the antibody is administered at a dose of 122.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 64 kg and less than 68 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 68 kg and less than 72.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; or where the body weight of the subject is greater than or equal to 72.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; or (d) where the body weight of the subject is greater than or equal to 10 kg and less than 12.5 kg, and the antibody is administered at a dose of 43.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 12.5 kg and less than 14.5 kg, and the antibody is administered at a dose of 52.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 14.5 kg and less than 16.5 kg, and the antibody is administered at a dose of 61.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 16.5 kg and less than 19 kg, and the antibody is administered at a dose of 70 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 19 kg and less than 21 kg, and the antibody is administered at a dose of 78.75 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 21 kg and less than 23.5 kg and the antibody is administered at a dose of 87.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 23.5 kg and less than 25.5 kg, and the antibody is administered at a dose of 96.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 25.5 kg and less than 27.5 kg, and the antibody is administered at a dose of 105 mg once every two weeks or once a week; where the body weight of the subject is greater than or equal to 27.5 kg and less than 30 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 30 kg and less than 39.5 kg, and the antibody is administered at a dose of 113.75 mg once every two weeks or once a week; wherein the body weight of the subject 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 two weeks or once a week; wherein the body weight of the subject is greater than or equal to 42.5 kg and less than 45 kg, and the antibody is administered at a dose of 131.25 mg once every two weeks or once a week; wherein the subject's body weight is greater than or equal to 45 kg and less than 48.5 kg, and the antibody is administered at a dose of 140 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 48.5 kg and less than 51.5 kg, and the antibody is administered at a dose of 148.75 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 51.5 kg and less than 54.5 kg, and the antibody is administered at a dose of 157.5 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 54.5 kg and less than 57 kg, and the antibody is administered at a dose of 166.25 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 57 kg and less than 60.5 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 60.5 kg and less than 63 kg, and the antibody is administered at a dose of 175 mg once every two weeks or once a week; wherein the body weight of the subject is greater than or equal to 63 kg, and the antibody is administered at a dose of 192.5 mg once every two weeks or once a week. 11. Method according to claim 9, where: if the subject's body weight is greater than or equal to 10 kg and less than 30 kg, the antibody is administered at a dose of 2.5 to 4 mg/kg once every two weeks or at a dose of 2.5 mg/kg once a week or, if the subject's body weight is greater than or equal to 30 kg and less than or equal to 60 kg, the antibody is administered at a dose of 2 to 3 mg/kg once every two weeks or at a dose of 2 mg/kg once a week. 12. Method according to claim 11, where: if the subject's body weight is greater than or equal to 30 kg and less than or equal to 60 kg, the antibody is administered at a dose of 3 mg/kg once every two weeks or, if the subject's body 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 two weeks. 13. Method according to any one of paragraphs. 1-12, wherein the subject suffers from at least one symptom of pcJIA, wherein the at least one symptom is lameness, stiffness upon awakening; reluctance to use an arm or leg; decreased activity level; joint swelling; and/or difficulties with fine motor skills. 14. Method according to any one of paragraphs. 1-13, where the subject's age is 12-17 years. 15. Method according to any one of paragraphs. 1-14, where the method further comprises administering at least one other disease-modifying antirheumatic drug (sDMARD). 16. Method according to any one of paragraphs. 1-15, where the antibody is sarilumab.

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