Methods of treating pediatric patients with upatinib

Abstract

The present disclosure relates to methods of treating a disease in a pediatric patient with a JAK1 selective inhibitor upatinib. These diseases and conditions include idiopathic arthritis (pcJIA), systemic juvenile idiopathic arthritis (SJIA), juvenile psoriatic arthritis (JPsA), atopic dermatitis (AD), juvenile ankylosing spondylitis (JAS), juvenile non-radioactive spinal arthritis (nr-axSpA), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), ulcerative colitis (UC), and Crohn's disease (CD). These therapeutic methods generally include administering a therapeutically effective amount of upatinib to a pediatric patient in a dosage based on the body weight of the patient, in a stable liquid pharmaceutical composition or in a solid dosage form.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 491,665, filed March 22, 2023, and U.S. Provisional Application No. 63 / 623,994, filed January 23, 2024, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to a method of treating pediatric patients with diseases using the JAK1 selective inhibitor upadacitinib. Background Technology

[0004] Upatinib is a selective JAK1 inhibitor approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiological spondyloarthritis, and ulcerative colitis in adults, and for the treatment of atopic dermatitis in adults and adolescents aged 12 years and older weighing 40 kg or more. Upatinib is also being investigated for the treatment of adults with Crohn's disease, hidradenitis suppurativa, and systemic lupus erythematosus. The use of utpatinib in pediatric patients under 12 years of age or under 18 years of age weighing less than 40 kg has not been evaluated.

[0005] While the pharmacokinetics, safety, and tolerability of utpatinib are known in adults, their pharmacokinetics, safety, and tolerability in pediatric patients under 12 years of age or under 18 years of age and weighing less than 40 kg have not been studied. Because these conditions also occur in pediatric patients, it is desirable to provide a safe and effective dose of utpatinib in pediatric patients. In particular, it is desirable to establish weight-based dosing regimens that provide plasma exposure in pediatric patients equivalent to the doses established as effective in adults (i.e., 15 mg and 30 mg QD). Additionally, tablet formulations may be difficult for young pediatric patients to swallow, potentially leading to poor patient compliance and reduced treatment efficacy. Summary of the Invention

[0006] This disclosure provides a method of treating pediatric patients in need with utpatinib for diseases or conditions. These diseases and conditions include idiopathic arthritis (pcJIA), systemic juvenile idiopathic arthritis (SJIA), juvenile psoriatic arthritis (JPsA), atopic dermatitis (AD), juvenile ankylosing spondylitis (JAS), juvenile non-radiological spondyloarthritis (nr-axSpA), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), ulcerative colitis (UC), and Crohn's disease (CD). These treatments typically involve administering a therapeutically effective amount of utpatinib to pediatric patients in a stable liquid pharmaceutical composition or solid dosage form, based on the patient's weight. Specifically, this document provides a method of treating pediatric patients in need with a therapeutically effective amount of utpatinib in a stable liquid pharmaceutical composition twice daily or in a sustained-release tablet once daily, based on weight category.

[0007] In one aspect, a method is provided for treating juvenile idiopathic arthritis (pcJIA) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0008] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0009] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0010] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0011] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0012] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0013] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0014] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0015] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0016] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0017] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0018] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0019] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0020] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0021] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0022] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0023] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0024] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0025] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0026] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0027] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0028] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0029] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0030] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0031] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0032] In some implementations, pcJIA is a rheumatoid factor positive or rheumatoid factor negative polyarticular JIA.

[0033] In some implementation schemes, pediatric patients have a history of arthritis affecting at least five joints within the first six months of the disease.

[0034] In some implementation schemes, pediatric patients are not diagnosed with enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA).

[0035] In some implementation schemes, pediatric patients have:

[0036] a) Five or more mobile joints defined by the presence of swollen joints not due to deformity; or

[0037] b) In the absence of swelling, limited range of motion (LOM) in joints with pain and / or tenderness during movement, wherein the LOM is present in at least three joints.

[0038] In some implementation methods, pediatric patients receive ≤20 mg / m² for at least 8 weeks prior to starting administration. 2 A stable dose of methotrexate.

[0039] In some implementations, pediatric patients receive a stable dose of oral glucocorticoids not exceeding 10 mg / day or 0.2 mg / kg / day (whichever is lower) for at least one week prior to starting administration.

[0040] In some implementations, pediatric patients achieve one or more of the following: JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 response, JADAS 10 / 27 / 71 response change relative to baseline, low disease activity according to JADAS-based criteria, or remission according to JADAS-based criteria. In some implementations, pediatric patients achieve one or more of the following: JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 response, JADAS 10 / 27 / 71 response change relative to baseline, low disease activity according to JADAS-based criteria, or remission according to JADAS-based criteria, at 8, 10, 12, 14, 16, 18, 20, 22, 24, 48, or 52 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 30 response 12 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 50 response 12 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 70 response 12 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 90 response 12 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 100 response 12 weeks after the first daily administration.

[0041] In some implementations, pediatric patients achieve a JIA ACR Pediatric 30 response 24 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 50 response 24 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 70 response 24 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 90 response 24 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 100 response 24 weeks after the first daily administration.

[0042] In some implementations, pediatric patients achieve a JIA ACR Pediatric 30 response 48 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 50 response 48 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 70 response 48 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 90 response 48 weeks after the first daily administration. In some implementations, pediatric patients achieve a JIA ACR Pediatric 100 response 48 weeks after the first daily administration.

[0043] In another aspect, a method for treating systemic juvenile idiopathic arthritis (SJIA) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0044] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0045] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0046] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0047] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0048] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0049] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0050] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0051] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0052] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0053] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0054] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0055] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0056] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0057] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0058] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0059] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0060] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0061] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0062] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0063] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0064] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0065] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0066] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0067] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0068] On the other hand, a method for treating atopic dermatitis (AD) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0069] In some implementations, for pediatric patients under twelve years of age and weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0070] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0071] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0072] In some implementations, the pediatric patient is under twelve years of age and weighs between about 20 kg and less than about 30 kg. The method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0073] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0074] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0075] In some implementations, the pediatric patient is under twelve years of age and weighs approximately 30 kg or more, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0076] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0077] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0078] In some implementations, the pediatric patient is under twelve years of age and weighs approximately 30 kg or more, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0079] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0080] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0081] In some implementations, if the pediatric patient is under twelve years of age and weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient is under twelve years of age and weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient is under twelve years of age and weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0082] In some implementations, if the pediatric patient is under twelve years of age and weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient is under twelve years of age and weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient is under twelve years of age and weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0083] In some implementations, if the pediatric patient is under twelve years of age and weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient is under twelve years of age and weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient is under twelve years of age and weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0084] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0085] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0086] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0087] In some implementations, if the pediatric patient is 12 years of age or older and weighs less than about 40 kg, the method involves administering utpatinib twice daily at a dose of 8 mg each time (8 mg BID) and once daily at a dose of 30 mg (30 mg QD).

[0088] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0089] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0090] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0091] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0092] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0093] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0094] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0095] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0096] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0097] In some implementations, pediatric patients achieve an EASI 75 response 12 weeks after the first daily application. In some implementations, pediatric patients achieve an EASI 90 response 12 weeks after the first daily application. In some implementations, pediatric patients achieve an EASI 100 response 12 weeks after the first daily application. In some implementations, pediatric patients achieve an investigator's overall atopic dermatitis assessment scale (vIGA-AD) score of 0 or 1 1 12 weeks after the first daily application.

[0098] In another aspect, a method for treating juvenile psoriatic arthritis (JPsA) in pediatric patients is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0099] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0100] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0101] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0102] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0103] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0104] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0105] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0106] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0107] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0108] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0109] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0110] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0111] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0112] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0113] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0114] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0115] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0116] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0117] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0118] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0119] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0120] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0121] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0122] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0123] In another aspect, a method for treating juvenile ankylosing spondylitis (JAS) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0124] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0125] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0126] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0127] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0128] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0129] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0130] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0131] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0132] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0133] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0134] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0135] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0136] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0137] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0138] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0139] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0140] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0141] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0142] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0143] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0144] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0145] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0146] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0147] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0148] In another aspect, a method for treating non-radiological axial spondyloarthritis (nr-axSpA) in pediatric patients is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0149] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0150] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0151] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0152] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0153] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0154] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0155] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0156] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0157] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0158] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0159] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0160] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0161] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0162] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0163] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0164] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0165] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0166] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0167] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0168] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0169] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0170] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0171] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0172] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0173] In another aspect, a method for treating hidradenitis suppurativa (HS) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0174] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0175] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0176] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0177] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0178] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0179] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0180] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0181] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0182] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0183] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0184] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0185] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0186] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0187] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0188] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0189] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0190] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0191] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0192] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0193] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0194] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0195] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0196] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0197] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0198] In another aspect, a method for treating systemic lupus erythematosus (SLE) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0199] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0200] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0201] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0202] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0203] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0204] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0205] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0206] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0207] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0208] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0209] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0210] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0211] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0212] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0213] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0214] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0215] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0216] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0217] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0218] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0219] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0220] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0221] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0222] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0223] In another aspect, a method for treating ulcerative colitis (UC) in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0224] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0225] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0226] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0227] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0228] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0229] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0230] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0231] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0232] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0233] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0234] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0235] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0236] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0237] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0238] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0239] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0240] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0241] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0242] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0243] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0244] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0245] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0246] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0247] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0248] In another aspect, a method for treating Crohn's disease in a pediatric patient is provided, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a stable liquid pharmaceutical composition. In some embodiments, the therapeutically effective amount of utpatinib is administered to the pediatric patient in the form of a solid dosage form.

[0249] In some implementations, for pediatric patients weighing between approximately 10 kg and less than approximately 20 kg, the method involves administering a therapeutically effective amount of utpatinib, wherein:

[0250] (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time; or

[0251] (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time.

[0252] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein:

[0253] (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time; or

[0254] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0255] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0256] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0257] (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time.

[0258] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0259] (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time; or

[0260] (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time.

[0261] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 3 mg (3 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 4 mg (4 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID) or once daily at a dose of 15 mg (15 mg QD).

[0262] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0263] In some implementations, if the pediatric patient weighs between about 10 kg and less than about 20 kg, the method includes administering utpatinib twice daily at a dose of 6 mg (6 mg BID); if the pediatric patient weighs between about 20 kg and less than about 30 kg, the method includes administering utpatinib twice daily at a dose of 8 mg (8 mg BID); and if the pediatric patient weighs about 30 kg or more, the method includes administering utpatinib twice daily at a dose of 12 mg (12 mg BID) or once daily at a dose of 30 mg (30 mg QD).

[0264] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of a stable oral drug solution.

[0265] In some implementations, utpatinib is administered to pediatric patients in the form of a stable oral solution at a dose of 3 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, or 12 mg twice daily.

[0266] In some implementations, the oral solution contains utpatinib, a buffer and / or pH adjuster, a preservative, a sweetener, and water.

[0267] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL.

[0268] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL.

[0269] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering a therapeutically effective dose of utpatinib to the pediatric patient, wherein:

[0270] (i) Administer utpatinib once daily at a dose of 15 mg (15 mg QD); or

[0271] (ii) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

[0272] In some implementations, a therapeutically effective dose of utpatinib is administered to pediatric patients in the form of extended-release tablets.

[0273] In another aspect, a stable oral pharmaceutical formulation is provided, comprising utpatinib or its pharmaceutically acceptable salt or solid form, buffers and / or pH adjusters, preservatives, sweeteners, and water.

[0274] In some implementations, the stable oral formulation contains anhydrous free base utpatinib at a concentration of about 0.5 mg / mL.

[0275] In some implementations, the stable oral formulation contains anhydrous free base utpatinib at a concentration of about 1 mg / mL.

[0276] In some implementations, the buffer is selected from the group consisting of citrate, phosphate, tartrate, succinate, formate, acetate, and combinations thereof.

[0277] In some implementations, the pH adjuster is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.

[0278] In some embodiments, the preservative is selected from the group consisting of: sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, parabens, paraben esters, and combinations thereof.

[0279] In some implementations, the sweetener is selected from the group consisting of: sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

[0280] In some implementations, the stable oral pharmaceutical formulation comprises the anhydrous free base utpatinib, citric acid, sodium citrate, sodium benzoate, sucralose, and water.

[0281] In some embodiments, the stable oral drug solution has a pH in the range of about 2 to about 5. In some embodiments, the stable oral drug solution has a pH in the range of about 3 to about 4. In some embodiments, the stable oral drug solution has a pH in the range of about 2.5 to about 3.5. Attached Figure Description

[0282] Figure 1 This is a schematic diagram of a clinical study in pediatric patients with juvenile idiopathic arthritis of polyarticular course, according to a non-limiting embodiment of this disclosure.

[0283] Figure 2 This is a graphical depiction of the mean utpatinib plasma concentration-time curve in pediatric patients with juvenile idiopathic arthritis of polyarticular course according to a non-limiting embodiment of this disclosure.

[0284] Figures 3A-3E This is a graphical depiction of the efficacy of utpatinib at week 12 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, according to various measurements and stratified by age group, based on a non-limiting embodiment of this disclosure.

[0285] Figure 4This is a schematic diagram of a clinical study in pediatric patients with atopic dermatitis according to a non-limiting embodiment of this disclosure.

[0286] Figures 5A to 5D This is a graphical depiction of the mean utpatinib plasma concentration-time curve in pediatric atopic dermatitis patients according to a non-limiting embodiment of this disclosure.

[0287] Figure 6 This is a schematic diagram of a clinical study in pediatric patients with juvenile idiopathic arthritis of polyarticular course, according to a non-limiting embodiment of this disclosure.

[0288] Figure 7 This is a schematic diagram of patient treatment in the clinical study of Example 1.

[0289] Figures 8A to 8C This is a graphical depiction of mean utpatinib plasma concentration-time curves for various formulations in pediatric patients with juvenile idiopathic arthritis of polyarticular course, according to a non-limiting embodiment of this disclosure.

[0290] Figures 9A to 9E This is a series of graphical depictions of the efficacy of utpatinib at week 12 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, according to various measurements and stratified by age group, based on a non-limiting embodiment of this disclosure.

[0291] Figure 10A This is a graphical representation of the efficacy of utpatinib over time up to week 48 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, based on the JIA ACR response rate, according to a non-limiting embodiment of this disclosure.

[0292] Figure 10B This is a graphical representation of the efficacy of utpatinib over time up to week 48 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, based on the JADAS-27 [CRP] response rate according to a non-limiting embodiment of this disclosure.

[0293] Figure 10C This is a graphical depiction of the efficacy of utpatinib over time up to week 48 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, based on the mean change in C-CHAQ relative to baseline, according to a non-limiting embodiment of this disclosure.

[0294] Figure 10D This is a graphical depiction of the efficacy of utpatinib over time up to week 48 in pediatric patients with juvenile idiopathic arthritis of polyarticular course, based on the mean change in the total number of active joints relative to baseline, according to a non-limiting embodiment of this disclosure. Detailed Implementation

[0295] I. Definition

[0296] The chapter titles used in this chapter and throughout the publication are not intended to be restrictive.

[0297] When describing numerical ranges, it is explicitly assumed that each intermediate number within the range has the same precision. For example, for the range 6 to 9, the numbers 7 and 8 are assumed in addition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly assumed. In the same manner, all described ratios also include all sub-ratios falling within a wider range.

[0298] Unless the context clearly indicates otherwise, the singular forms “a”, “an”, and “the” contain plural referents.

[0299] The term "about" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the stated value (i.e., having the same function or result). In many cases, the term "about" may include numbers rounded to the nearest significant figure.

[0300] Unless the context otherwise requires, the term “comprising” is used on the basis that it is clearly understood that the term will be interpreted as inclusive rather than exclusive, and that the applicant intends that the term be interpreted in the same way in interpreting this patent (including the claims below).

[0301] The term "AUC" refers to the area under the curve. AUC is the definite integral of a curve describing the change in plasma drug concentration as a function of time.

[0302] Term "C" max "Refers to T" max The plasma concentration of the reference drug, expressed herein as ng / mL, is the result of oral administration of a single dose or an indicated number of doses of a dosage form or pharmaceutical composition (such as the dosage forms and compositions disclosed herein). Unless specifically indicated, C max This refers to the observed maximum overall concentration.

[0303] As used herein, the terms “treating” and “therapy” are intended to include therapeutic measures for a disease or condition that produce any clinically desired or beneficial effect (including, but not limited to, relief or reduction of one or more symptoms; regression, slowing or cessation of the progression of the disease or condition).

[0304] As used herein, the term "pediatric patient" refers to a human patient under the age of 18. The terms "patient" and "subject" are used interchangeably in this document.

[0305] "Pharmaceutically acceptable salts" are those that retain the bioavailability and properties of a free base and are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, monomalic acid, monooxalic acid, tartaric acids such as monotartaric acid (e.g., (+)-tartaric acid or (-)-tartaric acid or mixtures thereof), and amino acids (e.g., (+)-amino acids or (-)-amino acids or mixtures thereof). These salts can be prepared by methods known to those skilled in the art. Examples of pharmaceutically acceptable utpatinib salts can be found in WO 2017 / 066775, which is incorporated herein by reference in its entirety.

[0306] II. JAK1 inhibition

[0307] Upatinib ((3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide) or a pharmaceutically acceptable salt or solid form thereof is an oral Janus kinase (JAK) inhibitor exhibiting unique selectivity for the JAK1 receptor. Upatinib has the following structure:

[0308]

[0309] The dose strength of utpatinib described in this application is based on the weight of the anhydrous free base utpatinib present in the active ingredient delivered to the patient. For example, “15 mg utpatinib” or “UPA 15 mg” refers to 15 mg of neutral utpatinib free base present in the active ingredient, excluding any co-formations (e.g., solvents or water molecules) of anti-anions of solvates or hydrates (including hemihydrates) or pharmaceutically acceptable salts that may also be present in the active ingredient. Thus, for example, administration of “15 mg utpatinib” comprises administering 15.4 mg of crystalline utpatinib free base hemihydrate (each utpatinib free base molecule contains 1 / 2 water co-formation molecule) to the patient, delivering 15 mg of anhydrous free base utpatinib. In another instance, the dosage of “30 mg utpatinib” or “UPA 30 mg” refers to 30 mg of neutral utpatinib free base present in the active ingredient, excluding any co-formations (e.g., solvents or water molecules) of anti-anionic salts that may also be present in the active ingredient. Thus, for example, administration of “30 mg utpatinib” comprises administering 30.7 mg of crystalline utpatinib free base hemihydrate (each utpatinib free base molecule contains 1 / 2 water co-formation molecule) to the patient, delivering 30 mg of anhydrous utpatinib free base.

[0310] III. Pharmaceutical Compositions and Routes of Administration

[0311] Upatinib can be administered to human patients either on its own or in the form of a pharmaceutical composition, wherein utpatinib is mixed with a biologically suitable carrier or excipient at a dose that treats or improves the disease or condition as described herein. Mixtures of these compounds can also be administered to patients as a simple mixture or as a suitable formulated pharmaceutical composition.

[0312] The pharmaceutical compositions disclosed herein can be prepared in ways known per se, for example by conventional methods of mixing, dissolving, granulating, coating, grinding, emulsifying, encapsulating, embedding, or lyophilizing.

[0313] Therefore, pharmaceutical compositions used according to this disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulation depends on the chosen route of administration.

[0314] In some embodiments, the pharmaceutical composition is a capsule dosage form. In some embodiments, the pharmaceutical composition is a tablet dosage form. In some embodiments, the tablet is a controlled-release formulation, such as a sustained-release tablet (also referred to herein as a modified-release formulation or a sustained-release formulation). Examples of solid dosage forms containing utpatinib can be found in WO2017 / 066775, which is incorporated herein by reference in its entirety.

[0315] In some embodiments, the composition is a stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition is a stable oral solution. In some embodiments, the stable liquid pharmaceutical composition is a stable oral suspension. Suitable stable liquid pharmaceutical compositions comprise utpatinib or its pharmaceutically acceptable salt or solid form, and excipients such as buffers, preservatives, sweeteners, flavorings, pH adjusters, solvents, etc. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical solution comprising utpatinib, buffers and / or pH adjusters, preservatives, sweeteners, and water. In some embodiments, the stable liquid pharmaceutical composition is a stable oral pharmaceutical suspension comprising utpatinib, buffers and / or pH adjusters, preservatives, sweeteners, and water.

[0316] The concentration of utpatinib in a stable liquid pharmaceutical composition can vary. For palatability reasons, as the bitterness of utpatinib is difficult to mask at higher concentrations (see, for example, Example 6), utpatinib is typically present at about 1 mg / mL or less. In some embodiments, the stable pharmaceutical composition is an oral solution comprising utpatinib at concentrations ranging from about 0.3 mg / mL to about 1.2 mg / mL, such as from about 0.3 mg / mL to about 0.7 mg / mL, or from about 0.8 mg / mL to about 1.2 mg / mL. In some embodiments, the oral solution comprises utpatinib at concentrations of about 1 mg / mL, such as from about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL, or about 1.2 mg / mL. In some embodiments, the oral solution comprises utpatinib at concentrations of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution comprises utpatinib at a concentration of 1.0 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0317] In some embodiments, the oral solution contains a pH adjuster. Suitable pH adjusters include acids, such as inorganic or organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, and phosphoric acid. As used herein, the term "organic acid" refers to an organic (i.e., carbon-based) compound characterized by acidity. Generally, organic acids are relatively weak acids (i.e., they do not completely dissociate in the presence of water), such as carboxylic acids (-CO2H). In some embodiments, the pH adjuster is an organic acid. Suitable organic acids include, but are not limited to, benzoic acid, toluene, salicylic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-(4-isobutylphenyl)propionic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid (L), aspartic acid (L), α-methylbutyric acid, camphoric acid (+), camphor-10-sulfonic acid (+), cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1, 2-Disulfonic acid, ethanesulfonic acid, fumaric acid, furoic acid, galactobionic acid, gentic acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, isovaleric acid, lactobionic acid, lauric acid, levulinic acid, malic acid, maleic acid, malonic acid, mandelic acid, mesylic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, oleic acid, palmitic acid, pamoic acid, phenylacetic acid, pyroglutamic acid, pyruvic acid, sebacic acid, stearic acid, tartaric acid, and undecenoic acid. In some embodiments, the pH adjuster is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof. In some embodiments, the pH adjuster is citric acid.

[0318] In some embodiments, the stable liquid pharmaceutical composition comprises a buffer. Suitable buffers include, but are not limited to, citrates, phosphates, tartrates, succinates, glycine salts, glycerophosphates, formates, and acetates. In some embodiments, the buffer is selected from the group consisting of citrates, phosphates, tartrates, succinates, formates, acetates, and combinations thereof. In some embodiments, the buffer is selected from the group consisting of citrates and phosphates. In some embodiments, the buffer is sodium citrate.

[0319] The amount of pH adjuster and / or buffer can be varied. Typically, the respective concentrations are adjusted to provide the desired pH range for the resulting stable liquid pharmaceutical composition. In some embodiments, the stable liquid pharmaceutical composition has a pH in the following ranges: about 2 to about 5, about 3 to about 4, about 2 to about 3, about 4 to about 5, about 2.0 to about 2.5, about 2.5 to about 3.0, about 3.0 to about 3.5, about 3.5 to about 4.0, about 4.0 to about 4.5, about 4.5 to about 5.0, about 3.0 to about 3.1, about 3.0 to about 3.2, about 3.0 to about 3.3, about 3.1 to about 3.2, about 3.1 to about 3.3, about 3.1 to about 3.4, about 3.1 to about 3.5, about 3.2 to about 3.3, about 3.2 to about 3.4, about 3.2 to about 3.5, about 3.3 to about 3.4, and about 3.3 to about 3.5. In some embodiments, the stable liquid pharmaceutical composition has a pH of about 3.0, or about 3.1, or about 3.2.

[0320] In some embodiments, the stable liquid pharmaceutical composition comprises a preservative. Suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, ascorbic acid, potassium sorbate, 4-hydroxybenzoic acid, 4-hydroxybenzoic acid esters, methylparaben, propylparaben, sodium metabisulfite, and combinations thereof. In some embodiments, the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, 4-hydroxybenzoic acid, propylparaben esters, and combinations thereof.

[0321] In some embodiments, the stable liquid pharmaceutical composition comprises a sweetener. The sweetener can be any sweetener or combination of sweeteners, in natural or artificial forms, or as a combination of natural and artificial sweeteners. Examples of natural sweeteners include fructose, sucrose, glucose, maltose, mannose, galactose, lactose, stevia, honey, etc. Examples of artificial sweeteners include sucralose, isomaltulose, maltodextrin, saccharin, aspartame, acesulfame K, neotame, etc. In some embodiments, the sweetener comprises one or more sugar alcohols. Sugar alcohols are polyols derived from monosaccharides or disaccharides, having a partially or fully hydrogenated form. Sugar alcohols have, for example, about 4 to about 20 carbon atoms, and include erythritol, arabinitol, ribitol, isomaltulitol, maltitol, eurythritol, idutitol, mannitol, xylitol, lactitol, sorbitol, and combinations thereof (e.g., hydrogenated starch hydrolysates). In some implementations, the sweetener is selected from the group consisting of: sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

[0322] In some embodiments, the stable oral medication solution contains one or more flavoring agents. Any palatable or aromatic substance capable of altering the taste, aroma, or both of the solution can be used. Flavoring agents can be natural or synthetic. Suitable flavoring agents include, but are not limited to, flavoring packets such as cherry, orange, lemon, lime, bubblegum, grape, strawberry, mango, etc.

[0323] In some implementations, the stable oral medication solution contains a taste modifier. Suitable taste modifiers include, but are not limited to, salts such as sodium chloride and monoammonium glycyrrhizate to enhance sweetness.

[0324] In some embodiments, the stable pharmaceutical composition is an oral solution comprising utpatinib, citric acid, sodium citrate, sodium benzoate, a sweetener, and water.

[0325] In some embodiments, the stable pharmaceutical composition comprises an amount of citric acid in the range of about 0.1 mg / mL to about 1 mg / mL.

[0326] In some embodiments, the stable pharmaceutical composition comprises an amount of sodium citrate ranging from about 0.01 mg / mL to about 1 mg / mL.

[0327] In some embodiments, the stable pharmaceutical composition comprises an amount of sodium benzoate in the range of about 0.01 mg / mL to about 0.1 mg / mL.

[0328] In some embodiments, the stable pharmaceutical composition contains a sweetener in an amount ranging from about 1 mg / mL to about 50 mg / mL.

[0329] In a particular embodiment, the stable pharmaceutical composition is an oral solution having the formulation provided in Table 1.

[0330] Table 1. Formulation of Upatinib Oral Solution (1 mg / mL)

[0331] Components mg / mL Upatinib 0.3-1.2 Citric acid, anhydrous 0.15-0.35 Sodium citrate dihydrate 0.03-0.06 Sodium benzoate 0.02-0.06 Sucralose 7-11 purified water Appropriate amount, reaching 1mL

[0332] The pH of a stable oral solution can vary. In some embodiments, the stable oral solution has a pH in the range of about 2 to about 5. In some embodiments, the stable oral solution has a pH in the range of about 3 to about 4. In some embodiments, the stable oral solution has a pH in the range of about 2.5 to about 3.5.

[0333] IV. Pediatric Drug Administration

[0334] In some implementations, the pediatric patient is under 18 years of age. In some implementations, the pediatric patient is under 12 years of age. In some implementations, the pediatric patient is under 6 years of age. In some implementations, the pediatric patient is about 2 years old to less than about 6 years old, about 6 years old to less than about 12 years old, or about 12 years old to less than about 18 years old. In some implementations, the pediatric patient is about 2 years old to about 18 years old, such as about 2 years old, about 3 years old, about 4 years old, about 5 years old, about 6 years old, about 7 years old, about 8 years old, about 9 years old, about 10 years old, about 11 years old, about 12 years old, about 13 years old, about 14 years old, about 15 years old, about 16 years old, about 17 years old, or about 18 years old. In some implementations, the pediatric patient is two years old or older. In some implementations, the pediatric patient is about 2 years old to less than 12 years old.

[0335] In some embodiments, the pediatric patient weighs at least about 10 kg. In some embodiments, the pediatric patient weighs about 10 kg to less than about 30 kg, such as about 20 kg to less than about 20 kg, or about 20 kg to less than about 30 kg. In some embodiments, the pediatric patient weighs 30 kg or more. In some embodiments, the pediatric patient is about 2 years old to less than 12 years old and weighs less than 40 kg. In some embodiments, the pediatric patient is 12 years old or older and weighs less than 40 kg.

[0336] In some implementations, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method involves administering 3 mg of utpatinib (3 mg BID) twice daily in the form of an oral solution.

[0337] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 1.0 mg / mL.

[0338] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and a 3 mg dose is provided by BID in the form of about 3 mL of a solution containing about 1 mg / mL.

[0339] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0340] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and a 3 mg dose is provided by BID in the form of about 6 mL of a solution containing about 0.5 mg / mL.

[0341] In some implementations, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method involves administering 6 mg of utpatinib (6 mg BID) twice daily in the form of an oral solution.

[0342] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 1.0 mg / mL.

[0343] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and a 6 mg dose is provided by BID in the form of about 6 mL of a solution containing about 1 mg / mL.

[0344] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0345] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and a 6 mg dose is provided by BID in the form of about 12 mL of a solution containing about 0.5 mg / mL.

[0346] In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering 4 mg of utpatinib (4 mg BID) twice daily in the form of an oral solution. In some implementations, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method involves administering 8 mg of utpatinib (8 mg BID) twice daily in the form of an oral solution.

[0347] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 1.0 mg / mL.

[0348] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and an 8 mg dose is provided by BID in the form of about 8 mL of a solution containing about 1 mg / mL.

[0349] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0350] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and an 8 mg dose is provided by BID in the form of about 16 mL of a solution containing about 0.5 mg / mL.

[0351] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 6 mg of utpatinib (6 mg BID) twice daily in the form of an oral solution.

[0352] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 12 mg of utpatinib (12 mg BID) twice daily in the form of an oral solution.

[0353] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 1.0 mg / mL.

[0354] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and a 6 mg dose is provided by BID in the form of about 6 mL of a solution containing about 1 mg / mL.

[0355] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and the 12 mg dose is provided by BID in the form of about 12 mL of about 1 mg / mL solution.

[0356] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0357] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and a 6 mg dose is provided by BID in the form of about 12 mL of a solution containing about 0.5 mg / mL.

[0358] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and a 12 mg dose is provided by BID in the form of about 24 mL of a solution containing about 0.5 mg / mL.

[0359] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in the form of a sustained-release formulation.

[0360] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 8 mg of utpatinib (8 mg BID) twice daily in the form of an oral solution.

[0361] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 12 mg of utpatinib (12 mg BID) twice daily in the form of an oral solution.

[0362] In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, such as about 0.8 mg / mL, 0.9 mg / mL, or about 1.0 mg / mL to about 1.1 mg / mL or about 1.2 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.9 mg / mL to about 1.1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 1.0 mg / mL.

[0363] In some implementations, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and an 8 mg dose is provided by BID in the form of about 8 mL of a solution containing about 1 mg / mL.

[0364] In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, such as about 0.3 mg / mL, 0.4 mg / mL, or about 0.5 mg / mL to about 0.6 mg / mL or about 0.7 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of 0.5 mg / mL.

[0365] In some implementations, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and an 8 mg dose is provided by BID in the form of about 16 mL of a solution containing about 0.5 mg / mL.

[0366] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 30 mg of utpatinib once daily (30 mg QD) in the form of a sustained-release formulation.

[0367] The maximum concentration (C) achieved by the above-mentioned administration max The dosage can vary depending on factors such as dosage, patient weight, and individual patient metabolism of utpatinib.

[0368] In some implementations, when utpatinib was administered by BID to pediatric subjects with an immediate-release oral solution as described herein, an average C10 concentration was achieved in the range of approximately 20 g / mL to approximately 160 ng / mL. max .

[0369] In some implementations, when utpatinib was administered twice daily in pediatric subjects at a dose of 3 mg or 4 mg each time (3 mg or 4 mg BID), an average C10 concentration was achieved in the range of approximately 25 ng / mL to approximately 50 ng / mL. maxSuch as about 25 ng / mL to about 35 ng / mL, about 25 ng / mL to about 33 ng / mL, about 25 ng / mL to about 31 ng / mL, about 25 ng / mL to about 29 ng / mL or about 25 ng / mL to about 27 ng / mL.

[0370] In some implementations, when utpatinib was administered twice daily in pediatric subjects at a dose of 6 mg or 8 mg (6 mg or 8 mg BID), an average C10 concentration in the range of approximately 40 ng / mL to approximately 100 ng / mL was achieved. max Such as about 40 ng / mL to about 95 ng / mL, about 40 ng / mL to about 90 ng / mL, about 40 ng / mL to about 85 ng / mL, about 40 ng / mL to about 80 ng / mL, about 40 ng / mL to about 75 ng / mL, about 40 ng / mL to about 70 ng / mL, about 40 ng / mL to about 65 ng / mL, about 40 ng / mL to about 60 ng / mL, about 40 ng / mL to about 55 ng / mL, about 40 ng / mL to about 50 ng / mL, or about 40 ng / mL to about 45 ng / mL.

[0371] In some implementations, when 15 mg extended-release tablets (15 mg QD) as described herein were administered once daily to pediatric subjects, an average C-level of utpatinib was achieved in the range of approximately 45 ng / mL to approximately 50 ng / mL. max Such as about 45 ng / mL to about 49 ng / mL, about 45 ng / mL to about 48 ng / mL, about 45 ng / mL to about 46 ng / mL, or about 45 ng / mL to about 46 ng / mL.

[0372] In some implementations, when 30 mg extended-release tablets (30 mg QD) as described herein were administered once daily to pediatric subjects, an average C-level of utpatinib was achieved in the range of approximately 150 ng / mL to approximately 160 ng / mL. max Such as about 152 ng / mL to about 159 ng / mL, about 153 ng / mL to about 158 ​​ng / mL, about 154 ng / mL to about 156 ng / mL or about 154 ng / mL to about 155 ng / mL.

[0373] The mean 24-hour exposure (AUC) achieved by the above-mentioned administration 0-24 The dosage can vary depending on factors such as dosage, patient weight, eating and fasting conditions, and individual patient metabolism of utpatinib.

[0374] In some implementations, when utpatinib was administered by BID to pediatric subjects with an immediate-release oral solution as described herein, a mean AUC in the range of approximately 200 ng·h / mL to approximately 700 ng·h / mL was achieved. 0-24 .

[0375] In some implementations, when utpatinib was administered twice daily in pediatric subjects at a dose of 3 mg or 4 mg each time (3 mg or 4 mg BID), a mean AUC in the range of approximately, such as approximately 220 ng·h / mL to approximately 270 ng·h / mL was achieved. 0-24 Such as about 220 ng·h / mL to about 265 ng·h / mL, about 220 ng·h / mL to about 260 ng·h / mL, about 220 ng·h / mL to about 255 ng·h / mL, about 220 ng·h / mL to about 250 ng·h / mL, about 220 ng·h / mL to about 245 ng·h / mL, about 220 ng·h / mL to about 240 ng·h / mL, about 220 ng·h / mL to about 235 ng·h / mL, about 220 ng·h / mL to about 230 ng·h / mL, or about 220 ng·h / mL to about 225 ng·h / mL.

[0376] In some implementations, when administered twice daily to pediatric subjects at a dose of 6 mg or 8 mg (6 mg or 8 mg BID), a mean AUC of utpatinib in the range of approximately 340 ng·h / mL to approximately 590 ng·h / mL was achieved. 0-24Such as about 340 ng·h / mL to about 580 ng·h / mL, about 340 ng·h / mL to about 570 ng·h / mL, about 340 ng·h / mL to about 560 ng·h / mL, about 340 ng·h / mL to about 550 ng·h / mL, about 340 ng·h / mL to about 540 ng·h / mL, about 340 ng·h / mL to about 530 ng·h / mL, about 340 ng·h / mL to about 520 ng·h / mL, about 340 ng·h / mL to about 510 ng·h / mL, about 340 ng·h / mL to about 500 ng·h / mL, about 340 ng·h / mL to about 490 ng·h / mL, about 340 ng·h / mL to about 480 ng·h / mL, about 340 ng·h / mL to about 470 ng·h / mL, about 340 ng·h / mL L to about 460 ng·h / mL, about 340 ng·h / mL to about 450 ng·h / mL, about 340 ng·h / mL to about 440 ng·h / mL, about 340 ng·h / mL to about 430 ng·h / mL, about 340 ng·h / mL to about 420 ng·h / mL, about 340 ng·h / mL to about 410 ng·h / mL, about 340 ng·h / mL to about 400 ng·h / mL, about 340 ng·h / mL to about 390 ng·h / mL, about 340 ng·h / mL to about 380 ng·h / mL, about 340 ng·h / mL to about 370 ng·h / mL, about 340 ng·h / mL to about 360 ng·h / mL, about 340 ng·h / mL to about 350 ng·h / mL, or about 340 ng·h / mL to about 345 ng·h / mL. In some implementations, when administered twice daily to pediatric subjects at a dose of 6 mg or 8 mg (6 mg or 8 mg BID), a mean AUC of utpatinib in the range of approximately 570 ng·h / mL to approximately 590 ng·h / mL was achieved. 0-24 Such as about 570 ng·h / mL to about 590 ng·h / mL, about 570 ng·h / mL to about 588 ng·h / mL, about 570 ng·h / mL to about 586 ng·h / mL, about 570 ng·h / mL to about 584 ng·h / mL, about 570 ng·h / mL to about 582 ng·h / mL, or about 570 ng·h / mL to about 580 ng·h / mL.

[0377] In some implementations, when 15 mg extended-release tablets (15 mg QD) as described herein were administered once daily to pediatric subjects, a mean AUC of utpatinib was achieved in the range of approximately 45 ng·h / mL to approximately 50 ng·h / mL. 0-24Such as about 45 ng·h / mL to about 49 ng·h / mL, about 46 ng·h / mL to about 48 ng·h / mL, or about 47 ng·h / mL to about 48 ng·h / mL.

[0378] In some implementations, when 30 mg extended-release tablets (30 mg QD) as described herein were administered once daily to pediatric subjects, a mean AUC of utpatinib in the range of approximately 650 ng / mL to approximately 680 ng / mL was achieved. 0-24 Such as about 660 ng·h / mL to about 670 ng·h / mL or about 665 ng·h / mL to about 670 ng·h / mL.

[0379] The disclosed methods typically involve administering utpatinida orally to the patient daily for a period of time. In some embodiments, administration continues at the same dose and frequency throughout the treatment period. The duration of the treatment period can vary. For example, the treatment period can be at least 14 days, at least one month, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, 20 years, 50 years, or longer. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 156 weeks. In some embodiments, the treatment period is at least 156 weeks.

[0380] V. Treatment of pediatric patients with juvenile idiopathic arthritis of a polyarticular course

[0381] In some implementations, pediatric patients are diagnosed with polyarticular juvenile idiopathic arthritis (pcJIA), including rheumatoid factor positive or negative polyarticular JIA, extended oligoarticular JIA, or systemic JIA with active arthritis and no active systemic features.

[0382] Nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary support for the treatment of JIA because they are believed to be the least toxic agents in children. They provide symptom relief but are not considered disease-modifying. Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) and sulfasalazine are effective for JIA, while hydroxychloroquine, D-penicillamine, and auranofen are ineffective. Most children respond to MTX therapy, which has acceptable toxicity, but remission is rare. Systemic use of corticosteroids is frequent in all JIA symptoms to varying degrees, but is less desirable, especially for JIA, due to numerous adverse effects. Systemic and intra-articular corticosteroids are used in conjunction with NSAIDs and DMARDs for JIA. Intra-articular (IA) corticosteroid injections are recommended in patients with JIA who have active arthritis, regardless of the use of additional concomitant therapy. However, IA steroids are frequently used and often induce long-term remission in children with oligoarticular JIA.

[0383] Many effective biologics are now available for the treatment of pediatric jaundice (PCJIA) and can induce remission when used as monotherapy or in combination with methotrexate (MTX) or other synthetic DMARDs. However, many patients still fail to achieve remission or remain in a low disease activity state with these agents, or lose response over time. Furthermore, considering the potential safety concerns associated with the immunomodulatory effects of biologics, and given that all biologics are administered by injection, the approval of novel oral treatment options with improved benefit / risk profiles for PCJIA is desirable. Therefore, it is hoped that alternative therapies for the treatment of PCJIA can be provided for pediatric patients.

[0384] It is known that JAK inhibition suppresses the IL-6 pathway, and IL-6 is known to be involved in the pathogenesis of RA and juvenile idiopathic arthritis (JIA). See, for example, Ou et al., Clin Rheumatol. 2002, 21:52-6; Mangge et al., Arthritis Rheum. 1995, 38(2):211-20; and Mellins et al., NatRev Rheumatol. 2011, 7(7):416-26. In particular, inhibition of the JAK1 subtype blocks the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, and IL-15, which are known contributors to inflammatory conditions. By modulating these pro-inflammatory cytokine pathways, utpatinib offers the potential for effective treatment of inflammatory or autoimmune diseases. Without being bound by any particular theory, it is believed that, based on the differentiated selectivity spectrum of JAK inhibition, utpatinib may demonstrate an improved benefit / risk spectrum compared to other less selective JAK inhibitors or other treatment strategies for patients with inflammatory diseases. In particular, utpatinib is believed to provide therapeutic benefit in pcJIA.

[0385] In adults, the area under the curve (AUC) of plasma utpatinib concentration estimated by the model over steady state from 0 to 24 hours after multiple doses of 15 mg and 30 mg once daily (QD) is as follows. 0-24 The concentrations were 362 ng·h / mL and 720 ng·h / mL, respectively. Therefore, this article discloses the pediatric doses for achieving such exposure levels, as described above.

[0386] As disclosed herein, a prototype oral solution formulation was developed to allow for appropriate and flexible dosing in young pediatric patients. Under fasting conditions, two 6 mg doses of utpatinib oral solution (1 mg / mL) administered 12 hours apart produced approximately 30% and 20% higher C6 levels, respectively, compared to a single 15 mg QD of utpatinib (in a phase 3 RA study). maxAnd AUC; these results support the selection of utpatinib dosage in pediatric subjects in the study of Example 1.

[0387] Therefore, in one aspect, a method for treating pediatric patients with pcJIA using weight-based pediatric dosing as disclosed above is provided. This method typically involves administering utpatinib to the pediatric patient in the form of a stable oral formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0388] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0389] In some embodiments, the pediatric patient has a weight in the range of about 10 kg to less than about 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and the 6 mg dose is administered as a BID in the form of about 6 mL of about 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and the 6 mg dose is administered as a BID in the form of about 12 mL of about 0.5 mg / mL solution.

[0390] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0391] In some embodiments, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0392] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0393] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0394] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0395] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0396] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0397] In some implementation schemes, according to the International Federation of Rheumatology Societies (ILAR) criteria, pediatric patients have a history of arthritis affecting at least 5 joints within the first 6 months of the disease (for extended oligoarticular JIA: affecting ≤4 joints within the first 6 months of the disease and subsequently affecting >4 joints).

[0398] In some implementation schemes, pediatric patients are not diagnosed with enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA).

[0399] In some implementations, pediatric patients have five or more mobilities defined as having swollen joints (not due to deformity), or, in the absence of swelling, limited joint movement (LOM) plus pain and / or tenderness during movement, wherein the LOM is present in at least three mobilities.

[0400] In some implementations, pediatric patients are receiving methotrexate. In such implementations, patients should have taken ≤20 mg / m² for at least 8 weeks prior to starting administration. 2 The stable dose.

[0401] In some implementations, pediatric patients are receiving oral glucocorticoids. In such implementations, patients should take a stable dose (not exceeding 10 mg / day or 0.2 mg / kg / day, whichever is lower) for at least one week before starting administration.

[0402] In some implementations, patients achieve one or more of the following: JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 response, JADAS 10 / 27 / 71 response change relative to baseline, low disease activity or remission according to JADAS-based criteria. In some implementations, patients achieve one or more of the JIA ACR Pediatric 30 / 50 / 70 / 90 / 100 response at 12, 24, or 48 weeks.

[0403] In some implementation schemes, pediatric patients are selected based on the absence of any persistent or active uveitis, active TB infection requiring parenteral antibiotic treatment, chronic relapsing infection and / or active viral infection, active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or a positive result for β-D-glucan within 3 months prior to the start of treatment.

[0404] In some implementations, pediatric patients have not received intra-articular or parenteral corticosteroid treatment within the previous 4 weeks prior to starting administration.

[0405] In some implementation schemes, pediatric patients do not have the following medical history: any malignancy other than successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix; recurrent or disseminated (even solitary) herpes zoster; disseminated (even solitary) herpes simplex; human immunodeficiency virus (HIV) infection; previous organ transplantation requiring continuous immunosuppression; gastrointestinal perforation (other than appendicitis or penetrating injury); diverticulitis or a significantly increased risk of gastrointestinal perforation; or previous exposure to JAK inhibitors.

[0406] In some implementations, the pediatric patients are not using known moderate or strong inhibitors (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, and phenytoin).

[0407] In some implementation schemes, pediatric patients were not receiving biological therapy (etanercept, infliximab, adalimumab, abatacept, golimumab, tocilizumab, ustekinumab, certolizumab pegol, canakinumab, anakinra).

[0408] In some implementation schemes, pediatric patients are not using JAK inhibitors (e.g., commercially available utpatinib). Tofacitinib ruxolitinib Baricitinib Peficitinib Abrocitinib [PF-04965842] or filgotinib.

[0409] In some implementation schemes, pediatric patients have moderate to severe pcJIA activity.

[0410] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0411] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0412] VI. Treatment of pediatric patients with systemic juvenile idiopathic arthritis

[0413] In some implementations, pediatric patients are diagnosed with systemic juvenile idiopathic arthritis (SJIA), also known as Stear's disease or systemic juvenile rheumatoid arthritis. SJIA is formally a subtype of juvenile idiopathic arthritis (JIA), but its pathophysiology is most consistent with an autoinflammatory condition. SJIA affects not only the joints but also other parts of the body, including the liver, lungs, and heart. The course of SJIA is highly variable, typically beginning with a period of several months of peak fever and rash, accompanied by varying degrees of joint pain and arthritis. Currently, there is no cure for SJIA, but it can be managed. Traditionally, typical treatment goals for children with SJIA have included using nonsteroidal anti-inflammatory drugs (NSAIDs) and / or high-dose oral or IV corticosteroids to relieve pain and control symptoms. Recently, disease-modifying biological and non-biological antirheumatic drugs (DMARDs) have become available. However, there remains a desire in the art to provide pediatric patients with safe, well-tolerated, and effective alternative non-biological DMARD therapies for the treatment of SJIA.

[0414] It is known that JAK inhibition suppresses the IL-6 pathway, and IL-6 is known to be involved in the pathogenesis of RA and juvenile idiopathic arthritis (JIA). See, for example, Ou et al., Clin Rheumatol. 2002, 21:52-6; Mangge et al., Arthritis Rheum. 1995, 38(2):211-20; and Mellins et al., Nat Rev Rheumatol. 2011, 7(7):416-26. In particular, inhibition of the JAK1 subtype blocks the signaling of many important pro-inflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, and IL-15, which are known contributors to inflammatory conditions. By modulating these pro-inflammatory cytokine pathways, utpatinib offers the potential for effective treatment of inflammatory or autoimmune diseases. Without being bound by any particular theory, it is believed that, based on the differentiated selectivity spectrum of JAK inhibition, utpatinib may demonstrate an improved benefit / risk spectrum compared to other less selective JAK inhibitors or other treatment strategies for patients with inflammatory diseases. In particular, utpatinib is believed to provide therapeutic benefit in SJIA.

[0415] This article discloses pediatric dosing to achieve exposure levels consistent with those in adult patients, as described above (i.e., based on weight). Therefore, in one aspect, a method for treating pediatric patients with SJIA using weight-based pediatric dosing as disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral formulation or extended-release tablet. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0416] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0417] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0418] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0419] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution of approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution of approximately 0.5 mg / mL.

[0420] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0421] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0422] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0423] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0424] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0425] In some implementation schemes, pediatric patients have moderate to severe active sJIA.

[0426] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0427] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0428] VII. Treatment of pediatric patients with atopic dermatitis

[0429] In some implementations, pediatric patients are diagnosed with atopic dermatitis (AD; also known as atopic eczema). AD is an inflammatory, pruritic, chronic or chronically relapsing skin disease. Common clinical features include erythema, edema, dryness, erosion / epidermal exfoliation, exudation and crusting, and lichenification, but these vary with patient age and the chronicity of the lesions. Pruritus is a hallmark of the condition and is responsible for a large portion of the disease burden borne by patients and their families (Williams, N. Engl. J. Med. 2005, 352(22): 2314-24). AD is one of the most common skin diseases, affecting up to 20% of children. In approximately 70% of cases, AD begins in children under 5 years of age (Williams et al., Atopic dermatitis: the epidemiology, causes, and prevention of atopic eczema. Cambridge, United Kingdom: Cambridge University Press, 2000: 41-59). For patients with moderate to severe Alzheimer's disease (AD) that is refractory to topical therapy, long-term oral treatment options are limited; most conventional oral immunosuppressive therapies are off-label, have limited efficacy data, and are unsuitable for long-term treatment due to their safety profiles. Therefore, there is a desire in the art to provide safe, well-tolerated, and effective therapies for the treatment of AD in pediatric patients.

[0430] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating pediatric patients with Alzheimer's disease (AD) using the weight-based pediatric dosing method disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0431] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating AD in adult patients.

[0432] In some embodiments, for pediatric patients under twelve years of age and weighing between approximately 10 kg and less than approximately 20 kg, the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in approximately 3 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 0.5 mg / mL.

[0433] In some embodiments, for pediatric patients under twelve years of age and weighing between approximately 10 kg and less than approximately 20 kg, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0434] In some embodiments, for pediatric patients under twelve years of age and weighing between approximately 20 kg and less than approximately 30 kg, the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in approximately 4 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 0.5 mg / mL.

[0435] In some embodiments, for pediatric patients under twelve years of age and weighing between approximately 20 kg and less than approximately 30 kg, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0436] In some embodiments, for pediatric patients under twelve years of age and weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0437] In some embodiments, for pediatric patients under twelve years of age and weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0438] In some embodiments, for pediatric patients under twelve years of age and weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0439] In some implementations, for pediatric patients under twelve years of age and weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in the form of a sustained-release tablet. In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 30 mg of utpatinib once daily (30 mg QD) in the form of a sustained-release formulation.

[0440] In some embodiments, the pediatric patient is twelve years of age or older and weighs less than about 40 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and the 8 mg dose is administered as a BID in about 8 mL of a solution containing about 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and the 8 mg dose is administered as a BID in about 16 mL of a solution containing about 0.5 mg / mL.

[0441] In some implementations, the pediatric patient is twelve years of age or older and weighs less than about 40 kg, and the method involves administering 15 mg of utpatinib once daily (15 mg QD) in the form of a sustained-release tablet. In some implementations, the pediatric patient weighs about 30 kg or more, and the method involves administering 30 mg of utpatinib once daily (30 mg QD) in the form of a sustained-release formulation.

[0442] In some implementations, pediatric patients achieve one or more of the following: a validated Investigator's Global Assessment of Atopic Dermatitis (vIGA-AD) score of 0 or 1, or an eczema area and severity index of at least 75% (EASI 75), 90% (EASI 90), or 100% (EASI 100). In some implementations, at 8, 10, 12, 14, 16, 18, 20, 22, 24, 48, or 52 weeks after the first daily application, pediatric patients achieve one or more of the following: a validated Investigator's Global Assessment of Atopic Dermatitis (vIGA-AD) score of 0 or 1, or an eczema area and severity index of at least 75% (EASI 75), 90% (EASI 90), or 100% (EASI 100). In some implementations, pediatric patients achieve an eczema area and severity index of 75 at 12 weeks after the first daily application. In some implementations, pediatric patients achieved an eczema area and severity index of 90 12 weeks after the first daily application. In some implementations, pediatric patients achieved an eczema area and severity index of 100 12 weeks after the first daily application. In some implementations, pediatric patients achieved a vIGA-AD score of 0 or 1 1 1 12 weeks after the first daily application. In some implementations, pediatric patients achieved a vIGA-AD score of 0 1 ...

[0443] In some implementation schemes, pediatric patients are diagnosed with severe AD.

[0444] In some implementation schemes, pediatric patients have moderate to severe pcJIA activity.

[0445] In some implementations, pediatric patients do not respond adequately to one or more TCSs.

[0446] In some implementations, pediatric patients do not respond adequately to one or more biological therapies.

[0447] VIII. Treatment of pediatric patients with juvenile psoriatic arthritis

[0448] In some implementations, pediatric patients are diagnosed with juvenile psoriatic arthritis (JPsA). JPsA is a chronic, systemic inflammatory disease, a subtype of spondyloarthritis (SpA), characterized by its association with both arthritis and psoriasis. The course of JPsA is typically characterized by flare-ups and remissions. Without treatment, JPsA patients may experience persistent inflammation, progressive joint damage, disability, and a shortened life expectancy. Initial treatment for musculoskeletal symptoms consists of nonsteroidal anti-inflammatory drugs (NSAIDs) and topical corticosteroid injections, while topical therapies are used for initial treatment of psoriasis. For subjects who do not respond well to these measures or experience toxicity, systemic therapy with non-biological disease-modifying antirheumatic drugs (non-biological DMARDs) (e.g., methotrexate [MTX], leflunomide [LEF], sulfasalazine [SSZ]) and cyclosporine A is recommended for inadequately responsive subjects, followed by anti-tumor necrosis factor (TNF) therapy. Other biologic therapies (e.g., IL-12 / 23 or IL-17 inhibitors) have also been recommended as alternatives to anti-TNF inhibitors in selected PsA patients. See, for example, Gossec et al., Ann Rheum Dis. (2016) 75:499-510; Coates et al., Arthritis Rheumatol. (2016) 68:1060-71. However, despite the beneficial results achieved by currently available biologics, approximately 40% of patients do not show at least a 20% improvement in the American College of Rheumatology (ACR) score, and only 58% to 61% of PsA patients achieve clinical remission after 1 year of treatment, with only about 43% achieving sustained remission for at least 1 year. See, for example, Gossec et al., Ann Rheum Dis. (2016) 75:499-510; Alamanos et al., J Rheumatol. (2003) 30:2641-2644; Savolainen et al., J Rheumatol. (2003) 30:2460-8; Sandborn, Dig Dis. (2010) 28:536-42; Saber et al., Arthritis Res Therapy (2010) 12:R94; Perrotta et al., J Rheumatol. (2016) 43:350-5.

[0449] Therefore, there remains a clear medical need for alternative treatment options for juvenile psoriatic arthritis (JPsA). Consequently, there is a desire in the field to provide safe, well-tolerated, and effective therapies for JPsA in pediatric patients.

[0450] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating JPsA in pediatric patients using the weight-based pediatric dosing method disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0451] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating JPsA in adult patients.

[0452] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0453] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0454] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0455] In some embodiments, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0456] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0457] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0458] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0459] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0460] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0461] In some implementations, pediatric patients have moderate to severe JPsA activity.

[0462] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0463] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0464] IX. Treatment of pediatric patients with juvenile ankylosing spondylitis

[0465] In some implementations, the pediatric patient has juvenile ankylosing spondylitis (JAS). JAS is a chronic inflammatory rheumatic disease that primarily affects the axial skeleton and is characterized by chronic back pain (including nocturnal back pain), morning stiffness, enthesitis, peripheral arthritis, and extra-articular manifestations.

[0466] Due to the debilitating nature of ankylosing spondylitis (AS), irreversible structural damage frequently occurs, negatively impacting patients' lives. Currently, there is no cure for AS; therefore, the primary goal of treatment is to maximize patients' quality of life by controlling disease signs and symptoms, preventing structural damage, and maintaining bodily functions, ideally through achieving sustained clinical remission or at least reducing disease activity. Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line treatments for AS, followed by biological disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, for patients with inadequate responses to NSAIDs. While TNF and IL-17 inhibitors are effective for some AS patients, others do not meet individual treatment goals despite these approved therapies. AS is a difficult disease to treat, based on the low efficacy shown by IL-6 inhibitors tocilizumab and sarilumab, as well as IL-12 / 23 inhibitors ustekinumab and T-cell blocking inhibitor abatacept. See, for example, Sieper et al., Ann. Rheum. Dis. 2014, 73: 95-100; Sieper et al., Ann. Rheum. Dis. 2015, 74: 1051-1057; Deodhar et al., Arthritis and Rheumatology 2019, 71: 258-270; and Song et al., Ann. Rheum. Dis. 2011, 70: 1108-1110.

[0467] Therefore, there remains a clear medical need for alternative treatment options for juvenile ankylosing spondylitis (JAS). Consequently, there is a desire in the field to provide safe, well-tolerated, and effective therapies for the treatment of AS in pediatric patients.

[0468] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating pediatric patients with JAS using weight-based pediatric dosing as disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0469] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating JAS in adult patients.

[0470] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0471] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0472] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0473] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution of approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution of approximately 0.5 mg / mL.

[0474] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0475] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0476] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0477] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0478] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0479] In some implementation schemes, pediatric patients have moderate to severe active JAS.

[0480] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0481] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0482] X. Treatment of pediatric patients with non-radiological axial spondyloarthritis

[0483] In some implementations, the pediatric patient is diagnosed with non-radiological axial spondyloarthritis (nr-axSpA). nr-axSpA is a chronic inflammatory rheumatic disease that primarily affects the axial skeleton and is characterized by chronic back pain (including nocturnal back pain), morning stiffness, enthesitis, peripheral arthritis, and extra-articular manifestations. nr-axSpA is an “early” form of ankylosing spondylitis (AS) and shares many of the same features.

[0484] Due to the debilitating nature of nr-axSpA, irreversible structural damage frequently occurs, negatively impacting patients' lives. Currently, there is no cure for nr-axSpA; therefore, the primary goal of treatment is to maximize patients' quality of life by controlling disease signs and symptoms, preventing structural damage, and maintaining bodily functions, ideally through achieving sustained clinical remission or at least reducing disease activity. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for AS, followed by biological disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors, for patients with inadequate responses to NSAIDs. While TNF and IL-17 inhibitors are effective for some AS patients, for others, these approved therapies fail to address individual treatment goals. AS is a difficult-to-treat disease, based on the low efficacy shown by IL-6 inhibitors tocilizumab and sarilumab, IL-12 / 23 inhibitors ustekinumab, and T-cell blocking inhibitor abatacept. See, for example, Sieper et al., Ann. Rheum. Dis. 2014, 73:95-100; Sieper et al., Ann. Rheum. Dis. 2015, 74:1051-1057; Deodhar et al., Arthritis and Rheumatology 2019, 71:258-270; and Song et al., Ann. Rheum. Dis. 2011, 70:1108-1110. Therefore, there is a desire in the art to provide safe, well-tolerated, and effective therapies for the treatment of nr-axSpA in pediatric patients.

[0485] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating pediatric patients with nr-axSpA using the weight-based pediatric dosing method disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0486] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating nr-axSpA in adult patients.

[0487] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0488] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0489] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0490] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution of approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution of approximately 0.5 mg / mL.

[0491] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0492] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0493] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0494] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0495] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0496] In some implementation schemes, pediatric patients have moderate to severe active nr-axSpA.

[0497] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0498] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0499] XI. Treatment of pediatric patients with hidradenitis suppurativa

[0500] In some implementations, pediatric patients are diagnosed with hidradenitis suppurativa (HS). HS is a debilitating skin condition of the apocrine glands (sweat glands found in certain parts of the body) and hair follicles, characterized by swollen, painful, chronically inflamed lesions or lumps. HS is confined to body areas containing apocrine glands, such as the armpits, nipple-areola complex, groin, perineum, perianal region, and periumbilical region. Immunological abnormalities of the hair follicles are presumed to play a role in the etiology of this disease. HS is a relapsing or chronic inflammatory condition that particularly affects young people, with an average age of onset of 23 years. This poorly understood disease is considered underreported among those who have it, but it is estimated to affect about 1% of the general population in the West, and women are often 2 to 5 times more likely to be affected than men (Naldi, L. Epidemiology. In: Hidradenitis Suppurativa; Jemec et al., eds.; Heidelberg: Springer. 2006).

[0501] HS is characterized by recurrent inflammatory nodules, abscesses, and fistulas, and occurs when the apocrine gland opening is blocked by sweat or cannot drain properly due to incomplete gland development. The trapped secretions in the gland force sweat and bacteria into the surrounding tissue, causing subcutaneous induration, inflammation, and infection. HS lesions (i.e., nodules, abscesses, and sinuses) are painful and may be foul-smelling, with purulent discharge. This array of signs and symptoms causes significant discomfort and social stigma for patients and has a profound impact on their quality of life.

[0502] Current treatments for moderate to severe hepatitis B (HS) include short- or long-term oral or topical antibiotics, retinol, intralesional steroids, oral steroids, immunosuppressants (such as cyclosporine or methotrexate), radiation, laser therapy, and the tumor necrosis factor-α (TNF-α) antagonist adalimumab. However, adalimumab is the only approved treatment for HS, and other TNF antagonists such as etanercept have failed to show improvement in HS over a 24-week treatment period (Adams et al., Arch Dermatol. 146(5):501-504, 2010). Given the limited success rate of HS treatment and the debilitating nature of the disease, there is an urgent need for an effective treatment. Therefore, it is desirable to provide safe, well-tolerated, and effective therapies for the treatment of HS in pediatric patients.

[0503] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating HS in pediatric patients using weight-based pediatric dosing as disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0504] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating HS in adult patients.

[0505] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0506] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0507] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0508] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution of approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution of approximately 0.5 mg / mL.

[0509] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0510] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0511] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0512] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0513] In some embodiments, the pediatric patient weighs approximately 30 kg or more, and the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation. In some embodiments, the pediatric patient weighs approximately 30 kg or more, and the method involves administering 30 mg of utpatinib once daily (30 mg QD) in a sustained-release formulation. In some embodiments, the pediatric patient has moderate to severe HS.

[0514] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0515] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0516] XII. Treatment of pediatric patients with systemic lupus erythematosus

[0517] In some implementations, the pediatric patient has systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by antibodies against nuclear and cytoplasmic antigens, multi-system inflammation, variable clinical presentation, and a course of alternating relapses and remissions. SLE causes widespread inflammation and tissue damage in affected organs, including joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms of SLE vary depending on the affected organ but may include fatigue, rash, fever, and joint pain or swelling.

[0518] Currently, there is no cure for SLE, and existing therapies focus on improving quality of life by controlling symptoms and minimizing erythema flare-ups, primarily through the use of immunosuppressive drugs such as hydroxychloroquine and corticosteroids, and immunomodulatory agents such as belimumab and aniluma. Despite these treatments, significant unmet medical needs remain for patients with SLE. Therefore, there is a desire in the field to provide safe, well-tolerated, and effective therapies for the treatment of SLE in pediatric patients.

[0519] As described above and in Example 1 below, this document discloses pediatric dosing (i.e., based on weight) to achieve exposure levels consistent with efficacy in adult patients. Therefore, in one aspect, a method for treating pediatric patients with SLE using weight-based pediatric dosing as disclosed above is provided. This method generally involves administering utpatinib to the pediatric patient in the form of a stable oral formulation or extended-release tablet. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0520] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating SLE in adult patients.

[0521] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0522] In some embodiments, the pediatric patient has a weight in the range of about 10 kg to less than about 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and the 6 mg dose is administered as a BID in the form of about 6 mL of about 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and the 6 mg dose is administered as a BID in the form of about 12 mL of about 0.5 mg / mL solution.

[0523] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0524] In some embodiments, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0525] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0526] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0527] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0528] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0529] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0530] In some implementation schemes, pediatric patients are diagnosed with moderate to severe active SLE.

[0531] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0532] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0533] XIII. Treatment of pediatric patients with ulcerative colitis

[0534] In some implementations, pediatric patients are diagnosed with ulcerative colitis (UC). UC is one of the two main forms of idiopathic inflammatory bowel disease (IBD). UC is a chronic, relapsing inflammatory disease of the large intestine, characterized primarily by inflammation and ulceration of the mucosal layer and occasionally the submucosa. The hallmark clinical symptoms of UC include bloody diarrhea accompanied by rectal urgency and tenesmus. The clinical course is characterized by exacerbations and remissions. Although treatment options are available for patients with UC, significant unmet treatment needs remain. Therefore, there is a desire in the art to provide safe, well-tolerated, and effective therapies for the treatment of UC in pediatric patients.

[0535] This article discloses pediatric dosing to achieve exposure levels consistent with those in adult patients, as described above (i.e., based on weight). Therefore, in one aspect, a method for treating UC in pediatric patients using weight-based pediatric dosing as disclosed above is provided. This method involves treating pediatric patients with UC by administering utpatinib in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0536] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating UC in adult patients.

[0537] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0538] In some embodiments, the pediatric patient has a weight in the range of about 10 kg to less than about 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of about 1 mg / mL, and the 6 mg dose is administered as a BID in the form of about 6 mL of about 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of about 0.5 mg / mL, and the 6 mg dose is administered as a BID in the form of about 12 mL of about 0.5 mg / mL solution.

[0539] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0540] In some embodiments, the pediatric patient weighs between approximately 20 kg and less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0541] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0542] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0543] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0544] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0545] In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation. In some implementations, the pediatric patient weighs approximately 30 kg or more, and the method involves administering 30 mg of utpatinib once daily (30 mg QD) in a sustained-release formulation. In some implementations, the pediatric patient has moderate to severe active UC.

[0546] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0547] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0548] XIV. Treatment of pediatric patients with Crohn's disease

[0549] In some implementations, pediatric patients are diagnosed with Crohn's disease (CD). CD is one of the two main forms of idiopathic inflammatory bowel disease (IBD). CD is characterized by significant pathological symptoms, including abdominal pain, diarrhea, weight loss / malnutrition, fatigue, and a progressive nature leading to complications such as fistulas, strictures, and abscesses. Approximately 80% of patients diagnosed with CD require at least one disease-related surgery at some point in their lives (Munkholm P, Langholz E, Davidsen M, et al. Gastroenterology. 1993, 105(6):1716-23). ​​Despite the availability of treatment options for patients with CD, significant unmet medical needs remain. Therefore, there is a desire in the art to provide safe, well-tolerated, and effective therapies for the treatment of CD in pediatric patients.

[0550] This article discloses pediatric dosing to achieve exposure levels consistent with those in adult patients, as described above (i.e., based on weight). Therefore, in one aspect, a method for treating UC in pediatric patients using weight-based pediatric dosing as disclosed above is provided. This method involves treating pediatric patients with UC by administering utpatinib in the form of a stable oral pharmaceutical formulation or extended-release tablets. The amount of utpatinib administered, the oral dosage form, and the frequency of administration (e.g., once daily or twice daily) will vary according to the patient's weight.

[0551] In some implementations, weight-based pediatric dosing provides exposure levels consistent with the efficacy of treating UC in adult patients.

[0552] In some embodiments, the pediatric patient has a weight in the range of approximately 10 kg to less than approximately 20 kg, and the method comprises administering 3 mg of utpatinib twice daily in the form of an oral solution (3 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 3 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 3 mg dose is administered as a BID in the form of approximately 6 mL of approximately 0.5 mg / mL solution.

[0553] In some embodiments, the pediatric patient weighs between approximately 10 kg and less than approximately 20 kg, and the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0554] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 4 mg of utpatinib twice daily in the form of an oral solution (4 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 4 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 4 mg dose is administered as a BID in the form of approximately 8 mL of approximately 0.5 mg / mL solution.

[0555] In some embodiments, the pediatric patient has a weight in the range of approximately 20 kg to less than approximately 30 kg, and the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution of approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution of approximately 0.5 mg / mL.

[0556] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 6 mg of utpatinib twice daily in the form of an oral solution (6 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 6 mg dose is administered as a BID in approximately 6 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 6 mg dose is administered as a BID in approximately 12 mL of a solution containing approximately 0.5 mg / mL.

[0557] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 8 mg of utpatinib twice daily in the form of an oral solution (8 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 8 mg dose is administered as a BID in approximately 8 mL of a solution containing approximately 1 mg / mL. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 8 mg dose is administered as a BID in approximately 16 mL of a solution containing approximately 0.5 mg / mL.

[0558] In some embodiments, for pediatric patients weighing approximately 30 kg or more, the method comprises administering 12 mg of utpatinib twice daily in the form of an oral solution (12 mg BID). In some embodiments, the oral solution contains utpatinib at a concentration of approximately 1 mg / mL, and the 12 mg dose is administered as a BID in approximately 12 mL of approximately 1 mg / mL solution. In some embodiments, the oral solution contains utpatinib at a concentration of approximately 0.5 mg / mL, and the 12 mg dose is administered as a BID in approximately 24 mL of approximately 0.5 mg / mL solution.

[0559] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0560] In some implementations, for pediatric patients weighing approximately 30 kg or more, the method involves administering 15 mg of utpatinib once daily (15 mg QD) in a sustained-release formulation.

[0561] In some implementation schemes, pediatric patients have moderate to severe active CD.

[0562] In some implementations, pediatric patients do not respond adequately to one or more DMARDs.

[0563] In some implementations, pediatric patients do not respond adequately to one or more TNF blockers.

[0564] example

[0565] Example 1: Evaluation of utpatinib in pediatric subjects with polyarticular juvenile idiopathic arthritis. Pharmacokinetics and Safety

[0566] Test Plan

[0567] This is a phase 1, multi-dose, open-label study consisting of three parts in approximately 124 pediatric subjects aged 2 to under 18 years with pcJIA. A schematic diagram of the study is shown below. Figure 1 Part 1 is a multi-dose, open-label, multi-cohort study. Two sequentially escalating dose levels (low and high dose levels) were evaluated in the 12- to <18-year-old age group (Group 1), and a single dose level (low dose) was evaluated in two younger age groups (Group 2: 6- to <12-year-old, and Group 3: 2- to <6-year-old). The low-dose and high-dose cohorts in age group 1 each enrolled 9 participants. The low-dose cohorts in age groups 2 and 3 each enrolled approximately 18 participants.

[0568] Upatinib doses were administered based on the subjects' weight, according to three defined weight categories for each dose level. The study enrolled at least 10 subjects weighing less than 30 kg. Recruitment was conducted using an age-based staggered approach. Subjects who completed Part 1 and benefited from the study drug without ongoing special concern or serious adverse events, based on investigator clinical judgment and with the consent of the subject / family, could be enrolled in Part 2 to receive open-label utpatinib. Part 2 was an open-label long-term extension to evaluate the long-term safety and tolerability of utpatinib. Subjects in Part 2 received open-label utpatinib at low dose levels corresponding to each weight category. At week 156, if the investigator considered that the subject was still benefiting from treatment, they could choose to continue treatment until the end of the study. Part 3 was an additional safety cohort. This additional safety cohort, consisting of approximately 70 subjects enrolled from all age groups (2 years to <18 years), was added to evaluate the long-term safety and tolerability of utpatinib without intensive pharmacokinetic sample collection. Part 3 was open to age groups that had completed Part 1. Part 3 participants received open-label utpatinib at low dose levels corresponding to each weight category and followed the same visit schedule as participants in Part 2 after baseline and screening visits, without intensive pharmacokinetic sampling. During the study, dose adjustments were made for any weight category after reviewing the results of participants who completed Part 1.

[0569] Qualification Standards

[0570] ● Male or female subjects, aged 2 to under 18 years, and with a total weight of 10 kg or more at the time of screening.

[0571] ●According to the International Federation of Rheumatology Societies (ILAR) criteria, a diagnosis of pcJIA (polyarticular JIA with positive or negative rheumatoid factor, extended oligoarticular JIA, or systemic JIA with active arthritis and no active systemic features) is made, wherein the history of arthritis affects at least 5 joints within the first 6 months of the disease (for extended oligoarticular JIA: ≤4 joints affected within the first 6 months of the disease and >4 joints affected thereafter).

[0572] ●Subjects must not have been diagnosed with enthesitis-associated arthritis (ERA) or juvenile psoriatic arthritis (JPSA).

[0573] ● At the time of screening, five or more active joints are defined as having swollen joints (not due to deformity), or, in the absence of swelling, limited joint movement (LOM) plus pain and / or tenderness during movement, wherein the LOM is present in at least three active joints.

[0574] ● If you are currently receiving methotrexate (MTX), administer ≤20 mg / m² before and including day 1 of the study. 2 The subjects should take a stable dose of MTX for at least 12 weeks, including at least 8 weeks before and including day 1 of the study; in addition, subjects should take folic acid or folinic acid according to local standards of care.

[0575] ● If oral glucocorticoids are taken, they must be taken at a stable dose (not exceeding 10 mg / day or 0.2 mg / kg / day, whichever is lower) before and including day 1 of the study.

[0576] ● No Previous exposure to JAK inhibitors.

[0577] ●Students had no persistent or active uveitis within 3 months prior to Day 1 of the study.

[0578] ● Patients had not received intra-articular or parenteral corticosteroid treatment in the four weeks prior to Day 1 of the study.

[0579] ●Apart from successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix, there is no history of malignant tumors.

[0580] ● No clinically significant history of medication or alcohol abuse within the past 6 months (as determined by the investigator).

[0581] ● No history of allergic reactions or significant sensitivity to the components of the study drug (and its excipients) and / or other similar products.

[0582] ● No current or past history of infection, including:

[0583] ● No history of recurrent or disseminated (or even solitary) herpes zoster;

[0584] ● No history of disseminated (or even solitary) herpes simplex;

[0585] ● No one is infected with HIV;

[0586] ● The subject does not have active TB or meets the TB exclusion parameters (specific requirements for TB testing are provided in the instruction manual);

[0587] ● No active infection requiring parenteral antibiotic treatment within 30 days prior to Day 1 of the study or oral antibiotic treatment within 14 days prior to Day 1;

[0588] ●Based on the investigator's clinical assessment, there were no chronic relapsing infections and / or active viral infections that would make the subject an unsuitable candidate for the study;

[0589] ● No active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as defined below:

[0590] ■HBV: Sensitivity for detection in qualitative HBV deoxyribonucleic acid (DNA) PCR test in subjects who are positive (+) for hepatitis B surface antigen (HBsAg) or positive (+) for hepatitis B core antibody (HBcAb);

[0591] ■HCV: HCV ribonucleic acid (RNA) that can be detected in any subject with anti-HCV antibody (HCVAb).

[0592] ●Subjects Not yet They are previous recipients of organ transplants that require sustained immune suppression.

[0593] ●According to the researchers' judgment, there was no history of gastrointestinal perforation (other than appendicitis or penetrating injury), diverticulitis, or a significantly increased risk of gastrointestinal perforation.

[0594] ●Symptoms that do not interfere with drug absorption, including but not limited to short bowel syndrome.

[0595] ● No known moderate or strong inhibitors (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine) or inducers (e.g., carbamazepine, rifampin, phenobarbital, and phenytoin) of drug-metabolizing enzymes were used within 30 days prior to the first dose of the study drug until the end of Part 1 of the study. From the start of Part 2 or Part 3 of the study until the completion of the study, no known strong cytochrome P450 3A isotype subfamily (CYP3A) inhibitors or inducers were used systemically.

[0596] Prohibited drugs and therapies

[0597] In addition to the drugs listed in the eligibility criteria, the following are not permitted:

[0598] ■ Prior use of biologics must have been discontinued before Day 1 of the study (etanercept, 4 weeks; infliximab, adalimumab, or abatacept, 8 weeks; golimumab, 10 weeks; tocilizumab, uterotumab, and cetuzumab, 12 weeks; canatumab, 10 weeks; anaprost, 1 week) and is prohibited during the study. Note: If there is appropriate documentation of undetectable drug levels of any of the above-approved biologics measured by commercially available assays, there is no minimum washout period before baseline.

[0599] ■ Immunosuppressive drugs must have been discontinued at least 30 days or 5 half-lives prior to administration of the study drug until the end of the study.

[0600] ■ Within 30 days prior to the first dose of the study drug and until the end of Part 1 of the study, a moderate or strong inhibitor (e.g., amiodarone, clarithromycin, fluconazole, ciprofloxacin, itraconazole, ketoconazole, quinidine, fluoxetine, and paroxetine) or inducer (e.g., carbamazepine, rifampin, phenobarbital, and phenytoin) of the drug-metabolizing enzyme is known to be currently in use. From the start of Part 2 or Part 3 until the end of the study, a known strong CYP3A inhibitor or inducer is used systemically.

[0601] ■ Live vaccines are not permitted during Part 1 of the study participation. If the subject and investigator choose to administer a live vaccine, these vaccinations should be completed at least 4 weeks (8 weeks in Japan) before the first dose of the study drug, with appropriate precautions, if possible (according to local labeling). Although not mandatory, vaccines recommended by local guidelines should be considered. If a live vaccine must be administered during Part 2 or Part 3 of the study participation, the study drug should be kept at least 4 weeks (8 weeks in Japan) before vaccination and at least 4 weeks (8 weeks in Japan) after vaccination. Thereafter, the study drug may be resumed at the investigator's discretion with appropriate precautions.

[0602] ■ The investigational drug must have been discontinued within 30 days or 5 drug half-lives (whichever is longer) before the first dose. The investigational drug is also prohibited during the investigation period.

[0603] ■ JAK inhibitors (e.g., commercially available utpatinib) Tofacitinib Ruxolitinib Baricitinib pefritinib Abuxitinib [PF-04965842] or fegastinib was a prohibited drug during the study period.

[0604] The following are permitted concomitant medications / therapies:

[0605] ■ Stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs)

[0606] ■ Stable doses of low-dose glucocorticoids (≤0.2 mg / kg / day prednisone; maximum daily dose, 10 mg)

[0607] ■ Stable dose of methotrexate ([MTX]); ≤20 mg / m² 2 Body surface area per week

[0608] Study drugs and duration of treatment

[0609] The study drug was utpatinib in the following forms and doses: 7.5 mg tablets, orally; 15 mg tablets, orally; 30 mg tablets, orally; 1 mg / mL solution, orally; and 0.5 mg / mL solution, orally. In Part 1, the dose was administered according to three weight categories. Subjects were categorized based on age groups, and the dose administered over seven consecutive days was based on the three different weight categories for each dose level shown in Table 2. The doses evaluated in this study were predicted to provide plasma exposures of utpatinib in each weight category equivalent to those provided by the extended-release formulations at 15 mg QD and 30 mg QD in adult RA subjects. The dose was selected based on allometric (weight-based) scaling of utpatinib pharmacokinetic parameters (volume of distribution and clearance parameters) in healthy adults and adult subjects with RA, as well as pharmacokinetic simulations across different weight categories.

[0610] The dose chosen for this study is due to the difference in oral bioavailability between extended-release tablets and oral solutions. Based on population pharmacokinetic analyses from Phase 1 to Phase 3 studies, the median (90% prediction range) plasma exposure of utpatinib in adult RA patients using the extended-release formulation was 15.1 ng / mL (8.96 ng / mL to 32.7 ng / mL) for a 15 mg QD and 30.0 ng / mL (18.1 ng / mL to 63.8 ng / mL) for a 30 mg QD within the dosing interval; similar exposures were predicted in pediatric patients, respectively, based on pharmacokinetic simulations within each weight category, using both low and high doses (Table 2). During the study, doses were adjusted for any weight category after reviewing the results of subjects who completed Part 1.

[0611] Table 2. Upatinib administration by weight category and dose level

[0612]

[0613] BID = twice daily; QD = once daily

[0614] Part 2 participants received open-label utpatinib at the low dose levels described in Table 2. At week 156, if the investigators deemed the participants still to be benefiting from treatment, they could choose to continue treatment at low dose levels equivalent to each weight category until the end of the study.

[0615] Dosage adjustment standards

[0616] For each subject, the utpatinib dose in Part 1 was based on the subject's weight at screening and the designated study cohort. When preliminary pharmacokinetic and clinical data from at least four subjects in a cohort were available (following intensive pharmacokinetic sampling on day 7 of Part 1), these data were used to adjust the doses of enrolled subjects (including those in Parts 2 and 3) and subsequently enrolled subjects, if necessary. Additional criteria were considered for making dose adjustment decisions for Part 1 to ensure safe and effective exposure.

[0617] Subjects receiving utpatinib in Part 2 will continue to receive the same dose until their next scheduled visit (unless the investigator deems an early dose adjustment necessary). At the next scheduled visit, subjects in Part 2 will receive utpatinib according to the dosing regimen (Table 2) for the remainder of the study duration. Subjects weighing >30 kg may opt to receive utpatinib oral solution if they are unable to swallow tablets (see Table 2). For subjects undergoing dose adjustments in Part 2, blood samples for utpatinib pharmacokinetics were collected from subjects at an unscheduled visit 4–6 weeks after the dose adjustment visit, before and 1 hour and 2 hours after dosing. The times of the last two doses administered before the pre-dose trough pharmacokinetic sample and the time of blood sample collection were recorded, accurate to the minute. Blood samples for clinical laboratory testing were also collected at the same unscheduled visit.

[0618] Subjects in Parts 2 and 3 were administered the drug at a low dose level for each weight category (Table 2) or as determined based on data available from Part 1. Changes in subject weight category were determined by the investigator at any study visit in Parts 2 and 3. Pharmacokinetic blood samples were collected from subjects in Parts 2 and 3 when the dose was changed due to changes in subject weight.

[0619] Research objectives and endpoints

[0620] Part 1:

[0621] To evaluate the pharmacokinetics, safety, and tolerability of utpatinib at multiple doses in pediatric subjects with pcJIA. To evaluate the palatability of utpatinib oral solution in pediatric subjects. To evaluate the descriptive efficacy of utpatinib in pcJIA.

[0622] Part 2:

[0623] To evaluate the long-term safety and tolerability of utpatinib in pediatric subjects with pcJIA who completed Part 1. To evaluate the descriptive efficacy of utpatinib in pcJIA.

[0624] Part 3:

[0625] To evaluate the long-term safety and tolerability of utpatinib in pediatric subjects with pcJIA. To evaluate the descriptive efficacy of utpatinib in pcJIA.

[0626] During Parts 2 and 3, at two consecutive visits at week 8 or thereafter, subjects who did not achieve at least 20% improvement from baseline in the total number of active joints (joints with swelling not due to deformity or joints with LOM and pain, tenderness, or both) discontinued the study medication and were treated according to local standards of care at the investigator's discretion.

[0627] Safety endpoint

[0628] Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), physical examination results, changes in vital signs, and clinical laboratory tests (hematology and chemistry) during the treatment period, serving as a measure of safety and tolerability throughout the study duration.

[0629] Pharmacokinetic endpoints

[0630] For Part 1, non-compartmental methods were used to determine the values ​​of utpatinib pharmacokinetic parameters, including C. max Time to reach maximum observed plasma concentration (T) max The area under the curve (AUC) of plasma concentration versus time during the 7-day dosing interval. tau Apparent oral clearance (CL / F) and half-life under steady state.

[0631] effectiveness endpoint

[0632] The following efficacy parameters were used to determine the JIA American College of Rheumatology (ACR) response and to collect the Juvenile Arthritis Disease Active Score (JADAS):

[0633] ●The total number of movable joints as defined below:

[0634] ● Joints that are not swollen due to deformity, or

[0635] ● Joints with limited mobility (LOM) and pain, tenderness, or both.

[0636] ● Number of joints with LOM

[0637] ●Children's Health Assessment Questionnaire (C-HAQ)

[0638] ● Physician's overall assessment of disease activity (Visual Analog Scale [VAS])

[0639] ● Patient / caregiver overall health assessment (VAS)

[0640] ●Erythrocyte sedimentation rate (ESR)

[0641] ■C-Reactive Protein (CRP)

[0642] Based on these parameters, the following comprehensive efficacy endpoints will be evaluated:

[0643] ●JIA ACR Pediatrics 30 / 50 / 70 / 90 / 100 Response

[0644] ● Changes in JADAS 10 / 27 / 71 response relative to baseline, and JADAS-based criteria for low disease activity and remission (if deemed useful and appropriate).

[0645] Example 2: Upatinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA) Pharmacokinetics; Analysis of Intermediate Results from Example 1

[0646] Purpose

[0647] The primary objective of this analysis was to characterize the pharmacokinetics of utpatinib in a Phase 1 study in children with pcJIA (PK analysis in Example 1).

[0648] method

[0649] Patients diagnosed with pcJIA (N=51) were enrolled in one of four groups in an open-label, multiple-dose study (Group 1, 12 years to <18 years, low dose; Group 2, 12 years to <18 years, high dose; Group 3, 6 years to <12 years, low dose; Group 4, 2 years to <6 years, low dose). Low and high doses were selected to provide plasma exposure in pediatric patients equivalent to 15 mg and 30 mg QD doses of ER tablet formulations, respectively, in adults. Patients received a weight-based dose of utpatinib in either a twice-daily (BID) immediate-release (IR) oral solution or a QD extended-release (ER) tablet formulation. Pharmacokinetic assessment was performed at steady state on day 7 of the study, after which all patients could continue the study at a low dose.

[0650] result

[0651] Table 3 provides a summary of the demographic data of the enrolled subjects. Pharmacokinetic results from 49 patients with evaluable drug concentrations on day 7 of the study are reported.

[0652] In Group 1, the geometrically mean maximum plasma concentration of utpatinib at steady state (C max ) and AUC 0-24 The values ​​were 35.1 ng / mL and 269 ng·h / mL, respectively.

[0653] In group 2, the geometric mean of utpatinib C max and AUC 0-24 The concentrations were 69.8 ng / mL and 553 ng·h / mL, respectively.

[0654] In group 3, the geometric mean of utpatinib C max and AUC 0-24 The values ​​were 51.0 ng / mL and 346 ng·h / mL, respectively.

[0655] In group 4, the geometric mean of utpatinib C max and AUC 0-24 The concentrations were 46.6 ng / mL and 369 ng·h / mL, respectively.

[0656] The median time to reach maximum utpatinib concentration was approximately 3 hours and 1 hour; and the harmonized mean functional half-lives for the QD ER tablet and BIDIR solution regimens were approximately 5 hours and 2 hours, respectively. Apparent oral clearance of utpatinib increased with increasing body weight in patients with pcJIA. Mean plasma concentration-time curves for utpatinib in each group are presented according to the dosing regimen. Figure 2 Overall, the data indicate that plasma exposure to utpatinib in pediatric patients with pcJIA was comparable to that in target adult RA patients, at both low and high dose levels, in dosing regimens evaluated with ER tablets or IR solutions. These results support the use of weight-based dosing regimens in pediatric utpatinib studies.

[0657] Table 3. Summary of demographic data of enrolled pediatric pcJIA patients

[0658] a. Two subjects were excluded from the pharmacokinetic analysis. One subject mistakenly received half a dose, and the PK sample collection for the other subject was incomplete.

[0659] Example 3: Safety of utpatinib in pediatric patients with polyarticular juvenile idiopathic arthritis Efficacy and efficacy: Interim analysis of an open-label phase 1 trial (interim results analysis from week 12 of Example 1)

[0660] Purpose

[0661] The aim of this study was to evaluate the safety and efficacy of utpatinib in pediatric patients with pcJIA by age group.

[0662] method

[0663] This open-label, three-part, phase 1 trial (NCT03725007) enrolled pediatric patients aged 2 to <18 years with pcJIA and ≥5 mobile joints at 31 research centers in North America, Europe, and Asia. In Part 1, two sequentially escalating UPA dose groups (low: 3 mg or 4 mg twice daily oral solution, or 15 mg once daily tablet; high: 6 mg or 8 mg oral solution, or 30 mg tablet) were administered for 7 days based on body weight (10 kg to <20 kg, 20 kg to <30 kg, and ≥30 kg) and age group (2 years to <6 years, 6 years to <12 years, and 12 years to <18 years). In Part 2 (a long-term extension of Part 1) and Part 3 (an additional safety cohort), low-dose UPA (3 mg or 4 mg oral solution, or 15 mg tablet) was administered for up to 156 weeks based on body weight. Efficacy endpoints included American College of Rheumatology (ACR) responses of 30, 50, and 70; Childhood Health Assessment Questionnaire (C-HAQ); and a juvenile arthritis disease activity score of 27 at week 12 in patients treated in Parts 1 and 2. This is an interim analysis.

[0664] result

[0665] A total of 57 pediatric patients with a mean (SD) age of 9.5 (4.4) years, 78.9% being female, and a mean (SD) weight of 38.1 (20.4) kg received UPA. In Part 1, 8 of the 51 patients (15.7%) reported adverse events (AEs) within 7 days; no patients reported serious AEs or AEs leading to treatment discontinuation. In Parts 2 and 3, 52 of the 57 patients (91.2%) reported AEs of predominantly mild to moderate severity (Table 4). The rate of AEs was generally highest in patients aged 12 to <18 years. The most common AEs of particular concern included elevated creatine phosphokinase (n = 6 / 57, 10.5%), liver disease (n = 3 / 57, 5.3%), and neutropenia (n = 2 / 57, 3.5%). Of the 19 patients in the 12- to <18-year-old age group, 6 (31.6%) reported serious adverse events (AEs) and 2 (10.5%) reported AEs leading to treatment discontinuation. No deaths occurred. At week 12, a high proportion of patients in all age groups achieved ACR30, ACR50, and ACR70 responses (respectively...). Figure 3A , Figure 3B and Figure 3C ). refer to Figures 3A-3C The numbers above the bars represent the proportion of patients with a response (n / N). Improvements in C-HAQ and JADAS-27 scores from baseline to week 12 were observed in all age groups (respectively...). Figure 3D and Figure 3EOverall, in a high proportion of pediatric patients with pcJIA at week 12 of this interim analysis, utpatinib was safe and well-tolerated and associated with improved disease activity.

[0666] Table 4. Interim safety analysis of utpatinib over 156 weeks

[0667]

[0668] Example 4: Pharmacokinetics, safety, and tolerability of utpatinib in children with atopic dermatitis

[0669] The aim of this study was to characterize the pharmacokinetics (PK), safety, and tolerability of utpatinib in children with severe atopic dermatitis (AD).

[0670] method

[0671] This was an open-label, multiple-dose study. AD patients (N=35) were enrolled into four cohorts (cohort 1, 6 years to <12 years, low dose; cohort 2, 6 years to <12 years, high dose; cohort 3, 2 years to <6 years, low dose; cohort 4, 2 years to <6 years, high dose). Upatinib was administered based on body weight as a BID oral solution or QD extended-release tablet. Low and high doses were selected to provide plasma exposure in pediatric patients equivalent to 15 mg and 30 mg QD doses, respectively, in adults. Pharmacokinetics (PK) was evaluated on day 7 after the first dose. Safety was evaluated throughout the study. Efficacy parameters were collected at specified time points.

[0672] result

[0673] The geometric mean C under steady state max The AUCs within 0–24 hours were 33.1 ng / mL and 35.2 ng / mL, and 249 ng·h / mL and 264 ng·h / mL, respectively, in cohort 1 and cohort 3; and 95.5 ng / mL and 101 ng / mL, and 523 ng·h / mL and 625 ng·h / mL, respectively, in cohort 2 and cohort 4.

[0674] Upatinib is generally safe and well-tolerated. The most common adverse events (AEs) are COVID infection, headache, and abdominal discomfort. No new safety risks have been identified compared to the known safety profile of utpatinib.

[0675] Of the 29 subjects with available interim efficacy results at week 12, 34.5% achieved a validated Investigator AD Overall Assessment Scale score of 0 or 1, and 69.0% achieved an eczema area and severity index of at least 75% at week 12 with utpatinib treatment. Overall, these findings support further investigation of utpatinib in an upcoming phase 3 clinical trial in pediatric AD patients using a weight-based dosing regimen.

[0676] Example 5: Upatinib for the treatment of severe atopic dermatitis in pediatric subjects

[0677] This is an open-label, multi-dose, phase 1 study to evaluate the pharmacokinetics (PK), safety, and tolerability of utpatinib in pediatric subjects with severe atopic dermatitis (AD). The study is ongoing.

[0678] Research Design

[0679] A schematic diagram of the research design is shown in Figure 4 Provided in [the document / source]. Reference. Figure 4 The study consists of two parts.

[0680] Part 1 was a multi-dose, open-label, multi-cohort study consisting of two sequentially escalating dose groups (low and high dose levels) across two age groups (Group 1: 6 years to <12 years, Group 2: 2 years to <6 years). Upatinib doses were administered based on subject weight, according to predefined weight categories at each dose level, with at least four subjects in each weight category (Table 5). The objective of Part 1 was to evaluate the pharmacokinetics, activity, safety, and tolerability of multiple doses of utpatinib in pediatric subjects with severe atopic dermatitis, and to evaluate the palatability of the utpatinib oral solution in pediatric subjects.

[0681] Part 2 was a multi-dose, open-label, long-term extension to evaluate the long-term safety and tolerability of utpatinib. Part 2 participants received open-label utpatinib at low dose levels corresponding to each weight category.

[0682] Table 5. Upatinib administration by weight class and dose level in subjects aged 2 years to <12 years

[0683]

[0684] BID = twice daily; QD = once daily

[0685] *At least 4 children will be enrolled in each weight category.

[0686] Subjects who completed Part 1 were enrolled in Part 2 and received an open-label, low-dose utpatinib. During Part 2 of the study, concomitant topical medications for AD were permitted at the investigator's discretion. Subjects whose Eczema Area Severity Index (EASI) score worsened by 25% or more compared to their baseline EASI score at any two consecutive scheduled study visits after week 4, or whose EASI score did not achieve at least a 50% improvement compared to baseline at two consecutive visits at week 8 or thereafter, discontinued the study medication and were treated according to local standards of care at the investigator's discretion.

[0687] Key Qualification Standards

[0688] Male or female participants aged 2 to under 12 years at screening, with a baseline total weight of 10 kg or more, were eligible for inclusion. The criteria for AD included:

[0689] ●Subjects diagnosed with AD and who developed symptoms at least 6 months prior to baseline.

[0690] ● The subjects met the Hanifin and Rajka criteria for AD.

[0691] ● Active diseases defined by the following disease activity criteria at screening and baseline visit (all criteria must be met):

[0692] ○Eczema area and severity index score ≥21;

[0693] ○ The validated Investigator Overall Assessment of AD (vIGA-AD) score is equal to 4;

[0694] ○AD affects ≥15% of body surface area

[0695] ● A documented history of inadequate response or intolerance to topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) (within 12 months prior to baseline visit), or where the use of TCS and TCI is medically undesirable for them.

[0696] research group

[0697] Between January 31, 2019 and March 18, 2022, a total of 32 subjects were enrolled in the study and received at least one dose of utpatinib. Enrollment for cohort 4 is ongoing. An additional 20 subjects failed the screening. The most common reason for pre-screening failure was that subjects did not meet the Hanifin and Rayka criteria for AD. One subject (3.1%) in Part 1 and 10 subjects (32.3%) in Part 2 discontinued utpatinib. In Part 2, the most common reasons for discontinuation were lack of efficacy (n=4, 12.9%) and adverse events (n=3, 9.7%).

[0698] The median duration of uropatinib exposure for all study participants was 7.0 days (range: 1 to 9 days) in Part 1 and 170 days (range: 1 to 770 days) in Part 2 (Table 6).

[0699] Table 6. Duration of Exposure

[0700]

[0701] Demographic data (Table 7) and baseline disease characteristics (Table 8) of all enrolled participants were summarized. The majority of participants receiving utpatinib were female (n = 18, 56.3%), white (n = 19, 59.4%), and had a median age of 6.0 years (range: 2 to 11 years).

[0702] Preliminary Clinical Pharmacokinetics

[0703] A summary of uropatinib pharmacokinetic parameters on day 7 is provided below. Figure 5A , Figure 5B , Figure 5C and Figure 5D And as shown in Table 9. For cohorts 1, 2, 3, and 4, 9, 8, 6, and 0 subjects received utpatinib with the original dosing regimen, respectively, and 0, 0, 2, and 6 subjects received utpatinib with the revised dosing regimen, respectively. One additional subject was enrolled in cohort 3 but withdrew informed consent prior to the PK assessment. Therefore, this subject was not included in the PK analysis. For the analysis of plasma concentration versus time curves and pharmacokinetic parameters, data from all these subjects were aggregated based on cohort and dosage form. Figures 5A-5D (and Table 9).

[0704] Preliminary clinical efficacy

[0705] Clinical efficacy parameters were collected as exploratory measures and to facilitate a benefit-risk assessment to justify continued use of low-dose utpatinib during Part 2 (the long-term safety and tolerability portion of the study). No formal statistical comparisons were planned. Since all cohorts received low-dose utpatinib in Part 2, the efficacy of the overall cohort was pooled.

[0706] The pharmacokinetic activity of utpatinib was demonstrated through efficacy outcome measures, which evaluated improvement relative to baseline at multiple study time points. As of the data cutoff, in the overall cohort, 9 / 27 subjects (33.3%) achieved a validated Investigator's Global Assessment of Atopic Dermatitis Scale (vIGA-AD) score of 0 or 1 (a reduction of at least two grades relative to baseline) at week 12 (Table 10), indicating clear or nearly clear skin. Notably, although 10 subjects in cohorts 1, 2, and 3 required dose escalation to adequately achieve the target plasma exposure to utpatinib, activity was observed in the overall cohort.

[0707] As of the data cutoff, for the overall cohort, 19 / 27 subjects (70.4%) achieved at least a 75% change in eczema area and severity index relative to baseline (EASI 75) at week 12 (Table 11). As of the data cutoff, for the overall cohort, the mean and median percentage changes in EASI score relative to baseline at week 12 were -79.8% and -82.9%, respectively (Table 12). Tables 10 through 12 present the results for the overall cohort, the cohort aged 2 to <6 years, the cohort aged 6 to <12 years, subjects enrolled under the original dosing regimen, and subjects enrolled after readjustment of the dosing regimen to achieve the target utpatinib plasma exposure.

[0708] Efficacy results were also summarized from a subgroup of eight subjects in cohorts 3 and 4 who were treated with the revised utpatinib dosing regimen from the start of the study. Although efficacy results were available from only seven of these subjects at week 12, all subjects achieved an EASI 75 response at week 12. The percentage changes in EASI 75, vIGA-AD 0 / 1, and EASI score relative to baseline in these subjects were consistent with those in the overall population at the corresponding time points. For the 10 subjects enrolled in regimen version 3.0 or earlier who increased their dose at different time points due to the dose modification implemented with regimen v4.0, response rates, as measured by EASI 75 and vIGA-AD scores of 0 or 1 (a decrease of at least two grades relative to baseline), showed numerical improvement 12 weeks after the dose escalation.

[0709] Table 7. Demographic Statistics

[0710]

[0711]

[0712] Table 8. Baseline Disease Characteristics

[0713]

[0714] BSA = Body Surface Area

[0715] EASI = Eczema Area and Severity Index

[0716] Table 9. Summary of pharmacokinetic parameters of utpatinib in pediatric subjects with Alzheimer's disease (AD)

[0717]

[0718] AUC 0-24 =Area under the plasma concentration-time curve during the last 24-hour dosing interval; BID = twice daily; C max = Maximum concentration; CL ss / F = Apparent systemic clearance after oral administration (at steady state); ER = Sustained release; IR = Immediate release; QD = Once daily; t 1 / 2 = Half-life; T max =Time to reach maximum concentration

[0719] a. Median (Minimum - Maximum).

[0720] b. Harmonic mean (pseudo-standard deviation); half-life over the dosing interval.

[0721] c. AUC of the prepared solution 0-24 Calculated as AUC 0-12 ×2.

[0722] Note: Unless otherwise stated, parameters are expressed as geometric mean (mean, % coefficient of variation).

[0723] Table 10. Subjects who achieved vIGA-AD of 0 or 1 and a reduction of at least two grades from baseline at week 12 The proportion (as observed)

[0724]

[0725] Precise confidence intervals based on the Clopper-Pearson method.

[0726] Table 11. Percentage of subjects who achieved EASI 75 at week 12 (as observed) (Intention-to-treat population)

[0727]

[0728] Precise confidence intervals based on the Clopper-Pearson method.

[0729] Table 12. Changes and percentage changes in EASI at week 12 (as observed) (Intention-to-treat population)

[0730] IQR = Interquartile Range

[0731] SD = Standard Deviation

[0732] Example 6: Upatinib immediate-release liquid formulation

[0733] For pediatric use, oral solutions were developed to improve acceptability (palliativeness and swallowability), stability, and manufacturability. Specifically, stable oral solutions of the drug at 1 mg / mL and 0.5 mg / mL were prepared. Upatinib has good solubility at low pH (as shown in Table 13). Therefore, low-pH buffers such as citrate, phosphate, tartrate, and formate are suitable for preparing oral solutions. Buffers with higher pH ranges such as succinate and acetate are also suitable (refer to Example 7), but would result in oral suspensions. Citrate buffer was chosen because it has a favorable pKa (approximately 3.1), close to the final pH of the oral solution. Therefore, formulations were developed based on the solubility of utpatinib in liquid, with the addition of citric acid and sodium citrate to completely dissolve utpatinib.

[0734] At concentrations above 0.1 mg / mL, utpatinib has a strong bitter taste. Acceptable and palatable formulations have a bitterness intensity below 1.0. Therefore, sweeteners, masking agents, or flavor modifiers and flavorings can reduce the bitterness of utpatinib. Sweeteners or combinations of sweeteners, such as acesulfame potassium, sodium saccharin, sucralose, neotame, sucrose, maltitol, and xylitol, are suitable for this oral solution. Flavor modifiers such as sodium chloride, citric acid, and monoammonium glycyrrhizate are also suitable for this oral solution. Flavorings such as cherry, orange, bubble gum, strawberry, and mango can improve the acceptability of the formulation.

[0735] Upatinib oral solution contains water and a sweetener, both of which are potential sources of microbial growth. Upatinib oral solution is also a multi-dose formulation. Therefore, preservatives are added to the formulation to prevent microbial proliferation. Based on the final pH of the oral solution, preservatives such as sodium benzoate and propylparaben are suitable. Other preservatives, such as sodium metabisulfite, benzoic acid, parabens, potassium sorbate, and parabens, may also be used based on the final pH of the oral solution or suspension.

[0736] Upatinib oral solution C (1 mg / mL) contains citric acid, sodium citrate, sucralose, sodium benzoate, and water. 1 mg / mL oral solution C is clear and colorless to pale yellow. The compositions of some 1 mg / mL and 0.5 mg / mL oral solutions are shown in Table 14.

[0737] Table 13. Solubility of utpatinib in different aqueous media at 37℃.

[0738]

[0739]

[0740] Table 14. Composition of the proposed utpatinib oral solution

[0741]

[0742] Example 7. Immediate-release or sustained-release utpatinib liquid formulation (suspension)

[0743] Immediate-release oral suspensions are prepared to accommodate higher dose intensities or higher pH levels. The buffers, preservatives, and sweeteners listed in Example 6 may be suitable for this formulation. Typically, sustained-release liquid formulations are prepared using release rate modifiers (such as ion exchange resins) to provide sustained release of utpatinib for once-daily administration. The liquid dosage form comprises an utpatinib-ion exchange resin complex. The utpatinib-ion exchange resin complex comprises utpatinib or a pharmaceutically acceptable salt thereof bound to an ion exchange resin. Suitable ion exchange resins include, but are not limited to, sulfonated copolymers comprising styrene and divinylbenzene. In some such embodiments, the mobile or exchangeable cation is a sodium ion. An exemplary cation exchange resin is AmberLite. TM IRP 69 (DuPont).

[0744] Example 8: Safety of utpatinib in pediatric patients with polyarticular juvenile idiopathic arthritis Efficacy and efficacy: Interim analysis of an open-label phase 1 trial (interim results analysis from week 1 to week 48)

[0745] This embodiment provides additional data up to week 48 of the study described in Embodiment 1.

[0746] Purpose

[0747] The aim of this study was to evaluate the pharmacokinetics, efficacy, and safety of utpatinib in pediatric patients with polyarticular juvenile idiopathic arthritis (pcJIA).

[0748] method

[0749] As described in Example 1 above, this was an open-label phase 1 study that enrolled patients aged 2 to <18 years with pcJIA. Patients received weight-based doses of utpatinib via either a twice-daily (BID) oral solution or a once-daily (QD) extended-release tablet (see Table 15). The study included a 7-day pharmacokinetic assessment, followed by a long-term efficacy and safety evaluation up to 156 weeks, including an additional long-term safety cohort. This interim analysis included all available pharmacokinetic and safety data, as well as efficacy data, collected up to week 48, excluding patients enrolled in the long-term safety cohort. A schematic diagram of the study design, including weight categories, is provided as follows. Figure 6 supply.

[0750] Table 15. Upatinib Dosing in Subjects Aged 2 to <12 Years by Weight Class and Dosage Level

[0751]

[0752] BID = twice daily; QD = once daily

[0753] *At least 4 children will be enrolled in each weight category.

[0754] result

[0755] Patients and treatment

[0756] A summary of the patient's treatment was provided as follows Figure 7 Table 16 provides a summary of patient demographics and disease characteristics. Referring to Table 16, the majority of enrolled patients were female (45 / 57, 78.9%) and had RF-negative polyarticular jIA (42 / 57, 73.7%). Enrolled patients were 2 to 17 years old, with a mean disease duration of 3 years. At baseline, 23 patients (40.4%) were receiving methotrexate, 11 patients (19.3%) were receiving oral corticosteroids, and 14 patients (24.6%) reported prior use of bDMARDs.

[0757] Table 16. Baseline Demographic Statistics and Disease Characteristics

[0758] bDMARD, a biological antirheumatic drug to improve disease; CRP, C-reactive protein (normal range ≤2.87 mg / L); JIA, juvenile idiopathic arthritis; ESR, erythrocyte sedimentation rate (normal range 3 mm / h-15 mm / h); pcJIA, polyarticular juvenile idiopathic arthritis; n, number of patients; RF, rheumatoid factor; SD, standard deviation.

[0759] Pharmacokinetics

[0760] Compared with the adult reference curve simulated by pharmacokinetic analysis based on utpatinib data from the phase 3 RA study, the mean plasma concentration-time curves by dose level and formulation are presented as follows: Figures 8A-8C The reference values ​​for adult RA represent the median (dashed line) and (5th, 95th) percentile (shaded area) of utpatinib model-predicted plasma concentrations in adult patients with RA following QD tablet administration. These reference pharmacokinetic curves were simulated using a previously developed RA patient model. The sign of the decrease in opacity (12–24 hours) of the IR BID regimen was reproduced from the observed data (0–12 hours) to illustrate the difference in dosing frequency between the BID oral solution and QD tablet formulations.

[0761] Summary of pharmacokinetic parameters of utpatinib at steady state (i.e., on day 7) following administration of utpatinib to patients enrolled in Part 1 is provided in Table 17. During the pharmacokinetic assessment, 13 patients in Group 3 and 12 patients in Group 4 received revised doses, and all other patients received the original dose. Upatinib Cmax was reached approximately 3 hours and 1 hour after administration of the ER tablet and IR oral solution formulations, respectively. Upatinib function t 1 / 2 For ER tablets, the QD dosing interval is approximately 5 hours, and for IR solutions, the BID dosing interval is approximately 2 hours.

[0762] Table 17. Geometric mean of pharmacokinetic parameters of utpatinib by study group and dosing regimen (Part 1) (Average, %CV)

[0763]

[0764] AUC, the area under the plasma concentration-time curve from 0 to 24 hours (AUC) 0-24 Or the area under the plasma concentration-time curve (AUC) within the dose interval. tau BID, twice daily; C max Maximum plasma concentration; CL ss / F, apparent oral clearance at steady state; CL ss / F_adjustment, CL for adjusting bioavailability ss / F; n, number of patients; QD, once daily; T max The time to reach maximum plasma concentration; functional t 1 / 2 Functional half-life.

[0765] a. Median (from minimum to maximum value).

[0766] b. Harmonic mean (pseudo-standard deviation).

[0767] c. For QD tablets, AUC 0-24 =AUCtau For BID oral solution, AUC 0-24 =AUC tau ×2.

[0768] d. CL adjusted for differences in bioavailability between formulations ss / F. For QD films, CL ss / F_adjustment = 0.684 × CL ss / F; For BID oral solution, CL ss / F_adjustment=CL ss / F.

[0769] en = 8.

[0770] fn = 11.

[0771] g. For group 3, the C of ER tablets and IR oral solution formulations max AUC 0-24 and CL ss / F_ Adjust and combine them together.

[0772] hn = 18.

[0773] i. One patient was excluded because he received an incorrect dose throughout Part 1, and another patient was excluded because he did not receive a dose on day 7 due to an adverse event (AE) of vomiting.

[0774] jn = 10.

[0775] effect

[0776] As of the data cutoff date, 50 of the 51 patients from Parts 1 and 2 had usable efficacy results at week 12, and 37 patients had usable efficacy results by week 48. At week 48, 35 of the 37 patients were being treated with the revised utpatinib dosing regimen. Summary data for JIA ACR 30 / 50 / 70 response, C-HAQ, and JADAS-27CRP at week 12 are presented in [reference to table / data]. Figures 9A to 9EOverall, the percentages of patients achieving a JIA ACR 30 / 50 / 70 / 90 / 100 response at week 12 in Parts 1 and 2 were 91.8% / 89.8% / 69.4% / 49.0% / 32.7%. Both younger age groups (2 years to <6 years and 6 years to <12 years) showed similar improvements in JIA ACR response, and the older age group (12 years to <18 years) had a numerically lower JIA ACR response rate compared to the younger age groups, though this was not statistically significant. Response to utpatinib was rapid, with 61.2% of patients achieving a JIA ACR 30 as early as week 1. JIA ACR response continued to improve at week 24 and typically remained so until week 48. Figure 10A Other key efficacy measures, including C-HAQ, total number of active joints, physician's overall assessment of disease activity (VAS), patient / parent's overall assessment of overall health status (VAS), and JADAS-27CRP, JADAS-27ESR, ESR, and CRP, are summarized in Table 18. Improvements relative to baseline were observed in all age groups at week 12 for these efficacy measures, and the changes relative to baseline were consistent across age groups. Changes in JADAS-27ESR were similar to those in JADAS-27CRP. At week 12, 29 out of 50 patients (58%) achieved JADAS-27CRP ≤3.8, and 16 out of 50 patients (32%) achieved JADAS-27CRP ≤1. The proportion of patients achieving these responses further increased at week 24 and generally remained at week 48. Figure 10B , Figure 10C and Figure 10D ).

[0777] Table 18. Summary of efficacy endpoints selected at week 12 (Part 1 and Part 2)

[0778]

[0779] discuss

[0780] In this open-label phase 1 study, utpatinib administered as a fixed dose for each weight category was effective and well-tolerated in pediatric patients with pcJIA. The pharmacokinetics of utpatinib observed in pediatric patients with pcJIA for both the QD regimen using the ER formulation and the BID regimen using the IR formulation were consistent with the pharmacokinetics of the corresponding formulations characterized in adults.

[0781] The original dosing regimen for utpatinib was selected using pharmacokinetic data from adult patients with RA and allometric scaling based on body weight for clearance and volume of distribution. The goal was to achieve utpatinib exposure in patients with pcJIA comparable to the optimal exposure seen in adult RA patients. In this study, preliminary population pharmacokinetic analysis indicated that the apparent oral clearance of utpatinib in pediatric patients was underestimated when using estimates of utpatinib clearance with a typical index of 0.75 from adult RA patients to describe the relationship between body weight and clearance. Therefore, a revised dosing regimen was developed for young pediatric patients (mostly 6 to <12 years and 2 to <6 years) to enable utpatinib exposure comparable to the target exposure in adults with RA. Based on previous analyses, the median (5th and 95th percentile) areas of utpatinib at steady-state plasma concentration-time (AUC) in adult patients with RA in phase 3 trials following daily administration of 15 mg and 30 mg ER tablets, respectively, were 358 (234, 701) and 708 (466, 1332) ng·h / mL. These figures were compared with the target median exposure (AUC) in adults. 0–24 Compared to the relative median AUC of utpatinib within each group in this study, 0-24 The range was approximately 0.77 to 1.07 (Table 19). In most young pediatric patients receiving the revised dose, the observed utpatinib exposure was almost identical to the target exposure in adult patients, at a ratio of 1.01.

[0782] In this study, the IR BID oral solution formulation was used in patients with low body weight (i.e., <30 kg) or those unable to swallow tablets. Although different pharmacokinetic profiles were observed due to varying dosing frequencies, achieving similar AUC values ​​for utpatinib would be beneficial. 0-24 Therefore, the BID oral solution is expected to provide similar efficacy to the QD tablet in pcJIA. This is supported by previous exposure-response analyses of key efficacy endpoints in adult RA patients, where a model developed based on data from the BID capsule formulation in a phase 2 study successfully predicted the efficacy of the QD tablet formulation observed in a phase 3 study. The analysis showed that the predicted efficacy provides similar AUC. 0-24 The utpatinib BID IR and QD ER regimens will achieve similar efficacy responses.

[0783] Based on a descriptive analysis of efficacy endpoints, improvements in measures of pcJIA disease activity, pain, function, and overall health were observed at week 12 following utpatinib administration in this study and generally maintained until week 48. Improvements with utpatinib were observed in the evaluated age groups, which included pcJIA patients aged 2 years to <18 years, with numerically higher response rates in patients aged 2 years to <12 years compared to those aged 12 years to <18 years. Notably, most patients in the oldest age group had longer disease duration and prior bDMARD exposure. In contrast, most patients in the younger age group had shorter disease duration and no prior bDMARD exposure (Table 16). No patients had a history of uveitis, and no uveitis events occurred during the study. The safety profile of utpatinib in pediatric patients with pcJIA is generally consistent with the known safety profile of utpatinib in adults and adolescents with inflammatory symptoms.

[0784] Overall, utpatinib was well tolerated and effective in patients with pcJIA across all age groups (2 years to <18 years), with plasma exposure comparable to that in adult RA patients at the evaluated dosing regimens. No new safety risks were observed in patients with pcJIA, and based on the safety and efficacy results from studies to date, the benefit-risk profile of utpatinib is assessed as favorable.

[0785] Table 19. Plasma exposure of utpatinib between pediatric patients with pcJIA and adult patients with RA Compare

[0786]

[0787] ER, sustained-release; pcJIA, polyarticular juvenile idiopathic arthritis; RA, rheumatoid arthritis.

Claims

1. A method for treating polyarticular juvenile idiopathic arthritis (pcJIA) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (ii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

2. The method of claim 1, wherein the pediatric patient is given a stable oral solution of 3 mg uropatinib twice daily, 4 mg uropatinib twice daily, 6 mg uropatinib twice daily, 8 mg uropatinib twice daily, or 12 mg uropatinib twice daily.

3. The method of claim 2, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

4. The method according to claim 2 or 3, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

5. The method according to any one of claims 1 to 4, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

6. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 30 response 12 weeks after the first daily administration.

7. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 50 response 12 weeks after the first daily administration.

8. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 70 response 12 weeks after the first daily administration.

9. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 90 response 12 weeks after the first daily administration.

10. A method for treating systemic juvenile idiopathic arthritis (SJIA) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

11. The method of claim 10, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

12. The method of claim 11, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

13. The method according to claim 11 or 12, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

14. The method of claim 10, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

15. A method for treating atopic dermatitis (AD) in a pediatric patient under the age of twelve, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

16. The method of claim 15, wherein the pediatric patient is given a stable oral solution of 3 mg utpatinib twice daily, 4 mg utpatinib twice daily, 6 mg utpatinib twice daily, 8 mg utpatinib twice daily, or 12 mg utpatinib twice daily.

17. The method of claim 16, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

18. The method according to claim 16 or 17, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

19. The method of claim 15, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

20. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 75 response 12 weeks after the first daily administration.

21. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 90 response 12 weeks after the first daily administration.

22. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an EASI 100 response 12 weeks after the first daily administration.

23. The method according to any one of claims 15 to 19, wherein the pediatric patient achieves an investigator's overall atopic dermatitis assessment scale (vIGA-AD) score of 0 or 1 1 12 weeks after the first daily application.

24. A method for treating psoriatic arthritis (PsA) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

25. The method of claim 24, wherein the pediatric patient is given a stable oral solution of 3 mg uropatinib twice daily, 4 mg uropatinib twice daily, 6 mg uropatinib twice daily, 8 mg uropatinib twice daily, or 12 mg uropatinib twice daily.

26. The method of claim 25, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

27. The method according to claim 25 or 26, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

28. The method of claim 24, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

29. A method for treating ankylosing spondylitis (AS) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

30. The method of claim 29, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

31. The method of claim 30, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

32. The method according to claim 30 or 31, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

33. The method of claim 29, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

34. A method for treating non-radiological axial spondyloarthritis (nr-axSpA) in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

35. The method of claim 34, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

36. The method of claim 35, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

37. The method according to claim 35 or 36, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

38. The method of claim 34, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

39. A method for treating hidradenitis suppurativa in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

40. The method of claim 39, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

41. The method of claim 40, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

42. The method according to claim 40 or 41, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

43. The method of claim 39, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

44. A method for treating systemic lupus erythematosus in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

45. The method of claim 44, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 8 mg twice daily.

46. ​​The method of claim 45, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

47. The method according to claim 45 or 46, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

48. The method of claim 44, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

49. A method for treating ulcerative colitis in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (ii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

50. The method of claim 49, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

51. The method of claim 50, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

52. The method according to claim 50 or 51, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

53. The method of claim 49, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

54. A method for treating Crohn's disease in a pediatric patient, the method comprising administering a therapeutically effective amount of utpatinib to the pediatric patient, wherein... When the weight of the pediatric patient is in the range of approximately 10 kg to less than approximately 20 kg: (i) Administer utpatinib (3 mg BID) twice daily at a dose of 3 mg each time, or (ii) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. In cases where the pediatric patient's weight is in the range of approximately 20 kg to less than approximately 30 kg: (i) Administer utpatinib (4 mg BID) twice daily at a dose of 4 mg each time, or (ii) Administer utpatinib (8 mg BID) twice daily at a dose of 8 mg each time; and In cases where the pediatric patient weighs approximately 30 kg or more: (i) Administer utpatinib (6 mg BID) twice daily at a dose of 6 mg each time. (ii) Administer utpatinib (12 mg BID) twice daily at a dose of 12 mg each time. (iii) Administer utpatinib once daily at a dose of 15 mg (15 mg QD), or (iv) Administer utpatinib once daily at a dose of 30 mg (30 mg QD).

55. The method of claim 54, wherein utpatinib is administered to the pediatric patient in the form of a stable oral solution at a dose of 3 mg twice daily, a dose of 4 mg twice daily, a dose of 6 mg twice daily, a dose of 8 mg twice daily, or a dose of 12 mg twice daily.

56. The method of claim 55, wherein the stable oral drug solution comprises utpatinib, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

57. The method according to claim 55 or 56, wherein the oral solution comprises utpatinib at a concentration of about 0.5 mg / mL or about 1 mg / mL.

58. The method of claim 54, wherein utpatinib is administered to the pediatric patient in the form of a sustained-release tablet at a dose of 15 mg once daily or a dose of 30 mg once daily.

59. A stable oral pharmaceutical solution comprising utpatinib or a pharmaceutically acceptable salt or solid form thereof, a buffer and / or a pH adjuster, a preservative, a sweetener, and water.

60. The stable oral drug solution according to claim 59, wherein the stable oral drug solution comprises anhydrous free base utpatinib at a concentration of about 0.5 mg / mL.

61. The stable oral drug solution according to claim 59, wherein the stable oral drug solution comprises anhydrous free base utpatinib at a concentration of about 1 mg / mL.

62. The stable oral pharmaceutical solution according to claim 59, wherein the buffer is selected from the group consisting of citrate, phosphate, tartrate, succinate, formate, acetate, and combinations thereof.

63. The stable oral pharmaceutical solution according to claim 59, wherein the pH adjuster is selected from the group consisting of citric acid, phosphoric acid, tartaric acid, succinic acid, formic acid, acetic acid, and combinations thereof.

64. The stable oral pharmaceutical solution according to claim 59, wherein the preservative is selected from the group consisting of sodium benzoate, benzoic acid, propylparaben, sodium metabisulfite, potassium sorbate, parabens, paraben esters, and combinations thereof.

65. The stable oral pharmaceutical solution according to claim 59, wherein the sweetener is selected from the group consisting of sucralose, acesulfame potassium, sodium saccharin, neotame, sucrose, maltitol, xylitol, and combinations thereof.

66. The stable oral drug solution according to claim 59, wherein the stable oral drug solution comprises anhydrous free base utpatinib, citric acid, sodium citrate, sodium benzoate, sucralose and water.

67. The stable oral drug solution according to claim 59, wherein the stable oral drug solution has a pH in the range of about 2 to about 5.

68. The stable oral drug solution according to claim 59, wherein the stable oral drug solution has a pH in the range of about 3 to about 4.

69. The stable oral medication solution according to claim 59, wherein the stable oral medication solution has a pH in the range of about 2.5 to about 3.

5.

70. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 30 response 24 weeks after the first daily administration.

71. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 50 response 24 weeks after the first daily administration.

72. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 70 response 24 weeks after the first daily administration.

73. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 90 response 24 weeks after the first daily administration.

74. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 30 response 48 weeks after the first daily administration.

75. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 50 response 48 weeks after the first daily administration.

76. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 70 response 48 weeks after the first daily administration.

77. The method according to any one of claims 1 to 4, wherein the pediatric patient achieves a JIA ACR Pediatric 90 response 48 weeks after the first daily administration.

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