Methods of treating ulcerative colitis

Abstract

Provided herein are methods for treating ulcerative colitis in pediatric patients, the use of anti-IL-23p19 antibodies, such as mirikizumab, and pharmaceutical compositions therefor. Also provided herein are doses and dosing regimens for methods for treating ulcerative colitis in pediatric patients, and the use of anti-IL-23p19 antibodies, such as mirikizumab, therefor.

Description

[Technical Field]

[0001] This invention relates to a method for treating ulcerative colitis in pediatric patients, the use of an antibody that binds to human IL-23p19 ("anti-IL-23p19 antibody") for the purpose of treating ulcerative colitis in pediatric patients, and dosages and drug regimens for the use of the anti-IL-23p19 antibody for the purpose of treating ulcerative colitis in pediatric patients. [Background technology]

[0002] Ulcerative colitis (UC) is a chronic disease of unknown cause characterized by inflammation of the colon. Patients experience intermittent disease relapses with periods of remission, and primary symptoms include blood in the stool, diarrhea, urgency to defecate, and abdominal pain. The incidence of UC in children is increasing globally, accounting for approximately 15-20% of all UC cases, with 60-80% of all pediatric cases showing widespread disease, and hospitalization for acute severe exacerbations (25-30% in 3-4 years) and colectomy for medically refractory disease (up to 30-40% in 10-year follow-up surveys) occurring twice as frequently as in adults (Sykora J., et al., World J Gastroenterol., 2018 Jul 7;24(25):2741-2763). The manifestation and spontaneous history of pediatric ulcerative colitis (UC) differ from those of adult UC in that the majority of pediatric UC cases present with widespread colitis affecting the entire colon, exhibiting atypical features including macroscopic rectal preservation (5-30%), reflux ileitis associated with severe pancolitis, and limited distal disease associated with mild fecal inflammation (otherwise with a normal right colon (cecal patch)) (Colman RJ., et al., Frontiers in Pediatrics 2021 Feb 17;9:634739). In addition to more severe colitis, children have unique age-related problems such as delayed growth and pubertal development, malnutrition, increased bone mineral density, and different psychosocial needs (Sykora J., et al., World J Gastroenterol. 2018).

[0003] Interleukin-23 (IL-23), a member of the interleukin-12 (IL-12) family of cytokines, is a heterodimeric protein composed of two subunits: the p40 subunit shared by IL-12 and the p19 subunit specific to IL-23. IL-23 receptor binding results in signal transduction converters and activators for JAKs (primarily TYK2 and JAK2) and transcription factors 3 and 4 (STAT3 and STAT4), inducing transcription of downstream target genes. IL-23 promotes the differentiation, maintenance, and stabilization of pathogenic T cell lineages, including populations that simultaneously produce multiple pro-inflammatory cytokines (e.g., interferon-γ, IL-17A, IL-17F, and IL-22), as well as the activation and induction of effector function in innate lymphoid cells. Therapeutic blockade of p40 has been found effective in treating UC, and drugs targeting p19 are being studied for the treatment of UC. To date, there are no anti-IL23p19 biological agents approved for the treatment of ulcerative colitis (UC) in children or adults.

[0004] The treatment goal in pediatric patients with ulcerative colitis (UC) is to induce and maintain remission (including steroid-free remission) with endoscopic cure. Conventional treatments such as corticosteroids, thiopurines (e.g., azathioprine (AZA), 6-mercaptopurine (6-MP)), tacrolimus, and immunomodulatory therapies such as methotrexate have limitations in terms of efficacy, safety, and tolerability. For example, while corticosteroids are effective in inducing clinical response or remission, they are not effective in maintaining remission and have been reported to cause steroid-related complications including osteopenia, acne, glaucoma, cataracts, and growth retardation. It has also been reported that 45% of patients develop corticosteroid dependence and require additional drug therapy to successfully discontinue corticosteroids (Turner D, et al., Journal of Pediatric Gastroenterology and Nutrition 2018 August 67(2):257-291). Immunomodulatory therapies such as thiopurines (e.g., azathioprine (AZA), 6-mercaptopurine (6-MP)) and tacrolimus are used to treat ulcerative colitis (UC) in pediatric patients, but require close monitoring for potential toxicities such as myelosuppression and other toxicities (Turner D, et al., Journal of Pediatric Gastroenterology and Nutrition 2018). Infliximab and adalimumab are anti-TNF biologics indicated for the treatment of moderate to severe UC in patients aged 5 years and older, but their drawbacks include, for example, the development of anti-drug antibodies and potential side effects.

[0005] Treatment of adult patients with mirikizumab has been reported in International Publication No. 2019191464. However, due to the clear and severe manifestation of pediatric UC, there remains an unmet medical need for safe and effective therapies and treatment regimens for moderate to severe active UC in pediatric patients. [Overview of the Initiative]

[0006] Methods for treating moderate to severe active ulcerative colitis in pediatric patients, the use of anti-IL-23p19 antibodies such as mirikizumab, and pharmaceutical compositions for this purpose are provided herein. Also provided herein are doses and dosing regimens for methods for treating moderate to severe ulcerative colitis in pediatric patients aged 2 to under 18 years who have an insufficient response to, have lost response to, or are intolerant to non-biological therapies for UC (biologic-naive or biologic not failed, as used interchangeably herein), and / or patients who have been exposed to at least one biologic and / or high-intensity therapy for UC (e.g., TNFα and / or JAK inhibitors), and for the use of anti-IL-23p19 antibodies such as mirikizumab for this purpose. Furthermore, the doses and drug regimens provided herein demonstrate clinical efficacy within approximately 4 to 12 weeks of treatment in such patients and / or sustain clinical efficacy for up to approximately 52 weeks of treatment (e.g., Modified Mayo Score (MMS) clinical remission, MMS clinical response, MMS alternative clinical remission, Pediatric Ulcerative Colitis Activity Index (PUCAI) clinical remission, PUCAI clinical response, endoscopic remission, and / or symptomatic remission). The doses and drug regimens provided herein further demonstrate histological endoscopic mucosal improvement, histological endoscopic mucosal remission, and / or corticosteroid-free remission within approximately 52 weeks of treatment. Furthermore, the doses and drug regimens of the present invention have an acceptable PK and immunogenicity profile.

[0007] Accordingly, in a first aspect, a method for treating a patient requiring treatment for moderate to severe active ulcerative colitis (UC) is provided herein, comprising administering an induction dose of mirikizumab to the patient at approximately 5 mg / kg to approximately 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight greater than 10 kilograms (kg).

[0008] Accordingly, a method for treating moderate to severe active ulcerative colitis (UC) in a patient who is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior therapy, comprising administering an induction dose of mirikizumab to the patient at about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight greater than 10 kilograms (kg). In such embodiments, the prior therapy may be a biologic, an advanced therapy, or a non-biological therapy such as an immunomodulator or corticosteroid.

[0009] In some embodiments of the methods of the present invention provided herein, which are used to treat patients requiring treatment for moderate to severe active ulcerative colitis, the methods include administering an induction dose of mirikizumab to a patient, the patient being between 2 and under 18 years of age and having a body weight greater than 10 kg but less than or equal to 40 kg, and the induction dose of mirikizumab being administered to the patient in a dose based on the patient's body weight. In such embodiments, the induction dose of mirikizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg (e.g., about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg). In further embodiments, the induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In another embodiment, the induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0010] In certain embodiments of the method of the present invention, one, two, or three induction doses of mirikizumab are administered to the patient. In even further embodiments of the method of the present invention, three induction doses of mirikizumab are administered to the patient. In certain embodiments, induction doses are administered to the patient at intervals of 4 to 8 weeks (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, and 8 weeks). In more specific embodiments, induction doses are administered to the patient at 4-week intervals. In certain embodiments, the induction period is a duration of 4, 8, or 12 weeks. In certain embodiments, the induction period is a duration of 12 weeks. In even more specific embodiments, induction doses are administered to the patient at 0, 4, and 8 weeks. Induction doses are delivered over the induction period.

[0011] In embodiments of the present invention, an induction dose of mirikizumab is administered to the patient by intravenous infusion.

[0012] In certain embodiments of the method of the present invention, if a patient has not achieved a clinical response 4 to 8 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, and the subjects are between 2 and under 18 years of age and have a body weight greater than 10 kilograms (kg). In further embodiments, if the patient has a body weight greater than 10 kg but not exceeding 40 kg, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In further embodiments, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. In another embodiment, an extension induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg.

[0013] In further embodiments, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In a more specific embodiment of the present invention, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 weeks.

[0014] In embodiments of the present invention, one, two, or three extended induction doses of mirikizumab are administered by intravenous infusion.

[0015] In a further embodiment of the present invention, if a clinical response is achieved at the end of the induction period or the end of the extended induction period, a maintenance dose of mirikizumab is administered to the patient. The extended dose is delivered over the extended induction period.

[0016] In certain embodiments of methods for treating patients with moderate to severe active ulcerative colitis, a maintenance dose of mirikizumab is administered to the patient at approximately 50 mg to approximately 100 mg, with the maintenance dose being administered after the last induction dose or last extension induction dose has been administered. In some embodiments, if the patient weighs more than 10 kg but no more than 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. In other embodiments, if the subject weighs more than 20 kg but no more than 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

[0017] In such embodiments of a method for treating moderate to severe active ulcerative colitis in patients requiring treatment, the initial maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks (e.g., 2, 3, 4, 5, 6, 7, 8 weeks) after the last induction dose or last extension induction dose has been administered. In preferred embodiments, the initial maintenance dose is administered 4 to 6 weeks after the last induction dose or last extension induction dose has been administered. More preferably, the initial maintenance dose is administered 4 weeks after the last induction dose or last extension induction dose has been administered. In further embodiments, additional maintenance doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks after the administration of the initial maintenance dose. Preferably, the maintenance doses are administered at 4-week intervals.

[0018] In embodiments of the present invention, the maintenance dose is administered by subcutaneous injection.

[0019] The duration of the 4-8 week maintenance dose corresponds to the variation in the period between the administration of the last extension induction dose and the extension induction end evaluation. This variation may arise from variations in the frequency of medication during the extension induction period. In some embodiments, the frequency of medication during the extension induction period is every 4 weeks, and the extension induction end evaluation is performed 4 weeks after the administration of the last extension induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 4 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. Alternatively, the frequency of medication during the extension induction period is every 8 weeks, and the extension induction end evaluation is performed 8 weeks after the administration of the last extension induction dose. If the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 8 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. In such embodiments, the maintenance dose of mirikizumab is administered after the patient has achieved a clinical response from one, two, or three extension induction doses.

[0020] In a further embodiment of a method for treating active ulcerative colitis in patients requiring treatment, if the patient loses response during the maintenance period, the maintenance dose is delivered over the maintenance period.

[0021] An ad-hoc escalator dose of mirikizumab is administered to the patient 2 to 8 weeks after the last maintenance dose. In such embodiments, if the patient has a body weight of more than 10 kg but no more than 40 kg, the ad-hoc escalator dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In some embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 5 mg / kg. In other embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 10 mg / kg.

[0022] In some embodiments of the present invention, one, two, or three additional doses of mirikizumab are administered to a patient at intervals of 4 to 8 weeks. In yet another embodiment, two or three additional doses of mirikizumab are administered to a patient at intervals of 4 to 8 weeks. In a preferred embodiment of the present invention, three additional doses of mirikizumab are administered to a patient at 4-week intervals. The additional doses are delivered over an additional dosing period.

[0023] In an embodiment of the present invention, the additional dose is administered by intravenous infusion.

[0024] In a further embodiment of the present invention, if a subject achieves a clinical response 4 to 12 weeks after one, two, or three additional doses (additional dosing period), a maintenance dose of mirikizumab is administered to the patient. In such embodiments, the maintenance dose is administered to the patient based on the weight and intervals as described above herein.

[0025] In such embodiments of a method of doing so in a patient who requires treatment of moderately to severely active ulcerative colitis, a maintenance dose of mirikizumab is administered to the patient at about 50 mg to about 100 mg. In some embodiments, if the patient has a body weight of more than 10 kg to 20 kg or less, a maintenance dose of mirikizumab is administered to the patient at about 50 mg. In other embodiments, if the subject has a body weight of more than 20 kg to 40 kg or less, a maintenance dose of mirikizumab is administered to the patient at about 100 mg.

[0026] In such embodiments of a method of doing so in a patient who requires treatment of moderately to severely active ulcerative colitis, the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last additional dose has been administered to the patient. In a preferred embodiment, the maintenance dose of mirikizumab is administered 2 to 6 weeks after the last additional dose has been administered. More preferably, the maintenance dose is administered 2 weeks or 4 weeks after the last additional dose has been administered. In still further embodiments, additional maintenance doses of mirikizumab are administered to the patient at 4 or 8-week intervals. Preferably, the maintenance dose is administered at 4-week intervals.

[0027] In certain embodiments of the method of treating patients with moderate to severe active ulcerative colitis, maintenance doses of mirikizumab are administered to the patient for up to approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 to up to approximately 152 weeks after the last induction dose, last extension induction dose, or last ad-hoc bolus dose has been administered. In certain embodiments, the maintenance dose is administered for up to approximately 1, 2, 3, or 4 years.

[0028] In embodiments of the method of the present invention, patients achieve at least one of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding. In such embodiments of the method of the present invention, at least one therapeutic effect is achieved within approximately 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab. Such therapeutic effects may be achieved during the induction period, extended induction period, and / or ad-hoc supplemental period. In certain embodiments, the therapeutic effect may be achieved during the maintenance period, which may be the maintenance period after the induction period, the maintenance period after the extended induction period, or the maintenance period after the ad-hoc supplemental period.

[0029] In embodiments of the present invention, patients achieve a reduction from baseline in fecal calprotectin and C-reactive protein within approximately 2 to 48 weeks of treatment with mirikizumab.

[0030] In further embodiments of the method of the present invention, the patient achieves at least one of the following therapeutic effects during the maintenance period: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of defecation frequency, and improvement of rectal bleeding. In such embodiments, the therapeutic effect is sustained for a maximum of approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to a maximum of approximately 152 weeks during the maintenance period after the end of the induction period, extended induction period, or ad-hoc supplementary period.

[0031] In further embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of mirikizumab treatment.

[0032] In such embodiments, the patient continues maintenance therapy with mirikizumab until they become unresponsive, have an insufficient response, lose their response, or become intolerant to mirikizumab.

[0033] In embodiments of the method of the present invention, the induction dose, extended induction, or temporary surcharge dose range of about 5 mg / kg to about 10 mg / kg may be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0034] In embodiments of the present invention, the patient is conventionally failed.

[0035] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0036] In some embodiments, the patient is biologic-experienced and / or advanced therapy experienced.

[0037] In some embodiments, the patient is a biologic-failed patient and / or an advanced therapy-failed patient.

[0038] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0039] In embodiments of the present invention, the biological agent or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0040] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0041] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors.

[0042] In a further embodiment of the method of the present invention, this method is The patient is administered three induction doses of mirikizumab at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals via intravenous infusion. This includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the last induction dose has been administered. The patient is between 2 and 18 years old and weighs between 10 kg and 40 kg.

[0043] In a further embodiment of the method of the present invention, this method is The patient is administered three induction doses of mirikizumab at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals via intravenous infusion. This includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection every four weeks, 2 to 8 weeks after the last induction dose has been administered. The patient is between 2 and 18 years old and weighs between 20 kg and 40 kg.

[0044] In such embodiments of the method of the present invention, if the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, three extension induction doses of mirikizumab are administered to the patient. If the patient has a body weight of more than 10 kg but no more than 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0045] In a further embodiment, if a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose.

[0046] In such embodiments, if the patient loses response during maintenance medication (maintenance period), one, two, or three ad-hoc surcharge doses of mirikizumab are administered to the patient. If the patient weighs between 10 kg and 40 kg, an additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. An additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0047] In such embodiments of the method of the present invention, if the patient achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalators, a maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals.

[0048] In further embodiments, patients achieve at least one of the following therapeutic effects within approximately 2 to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding.

[0049] In further embodiments of the method of the present invention, at least one therapeutic effect is achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirikizumab. In such embodiments, at least one therapeutic effect is achieved during the induction period or extended induction period.

[0050] In other embodiments, one or more of the therapeutic effects are sustained during the maintenance period.

[0051] In such embodiments, the therapeutic effect is sustained for up to approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to up to approximately 152 weeks during the maintenance period after the induction period, extended induction period, or temporary supplementary period.

[0052] In certain embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of mirikizumab treatment.

[0053] In such embodiments, the patient continues maintenance therapy with mirikizumab until they become unresponsive, have an insufficient response, lose their response, or become intolerant to mirikizumab.

[0054] In embodiments of the method of the present invention, the induction dose, extended induction, or temporary surcharge dose range of about 5 mg / kg to about 10 mg / kg may be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0055] In embodiments of the present invention, the patient is a patient who has previously failed to respond to conventional medications.

[0056] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0057] In some embodiments, the patient has experience with biologics and / or advanced therapy.

[0058] In some embodiments, the patient is a biologic-unsuccessful patient and / or a highly unsuccessful patient.

[0059] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0060] In some embodiments, the biologic or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0061] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0062] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors.

[0063] In one aspect of the present invention, a method is provided herein for use in the treatment of a patient requiring treatment for moderate to severe active ulcerative colitis (UC), comprising administering an induction dose of mirikizumab to the patient at a dose of about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years of age and under 18 years of age and has a body weight greater than 10 kilograms (kg).

[0064] In another embodiment, a method is provided herein for use in the treatment of a patient requiring treatment for moderate to severe active ulcerative colitis (UC) who is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior therapy, comprising administering an induction dose of mirikizumab to the patient at about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight greater than 10 kilograms (kg). In such embodiments, the prior therapy may be a biologic, an advanced therapy, or a non-biological therapy such as an immunomodulator or corticosteroid.

[0065] In some embodiments of the present invention provided herein, the patient is between 2 and under 18 years of age and has a body weight greater than 10 kg but less than or equal to 40 kg. In such embodiments, an induction dose of mirikizumab is administered to the patient in a dose based on the patient's body weight. In such embodiments, an induction dose of mirikizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg (e.g., about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg). In some embodiments, an induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In another embodiment, an induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0066] In certain embodiments of the present invention, one, two, or three induction doses of mirikizumab are administered to the patient. In even more specific embodiments of the present invention, three induction doses of mirikizumab are administered to the patient. In certain embodiments, induction doses are administered to the patient at intervals of 4 to 8 weeks (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, and 8 weeks). In more specific embodiments, induction doses are administered to the patient at 4-week intervals. In certain embodiments, the induction period is a duration of 4, 8, or 12 weeks. In certain embodiments, the induction period is a duration of 12 weeks. In even more specific embodiments, induction doses are administered to the patient at 0, 4, and 8 weeks.

[0067] In embodiments of the present invention, an induction dose of mirikizumab is administered to the patient by intravenous infusion.

[0068] In certain embodiments of the present invention, if a patient has not achieved a clinical response 4 to 8 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, and the subjects are between 2 and under 18 years of age and have a body weight greater than 10 kilograms (kg). In further embodiments, if the patient has a body weight greater than 10 kg but 40 kg or less, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In yet another embodiment, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg.

[0069] In further embodiments, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In a more specific embodiment of the present invention, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 weeks.

[0070] In embodiments of the present invention, one, two, or three extended induction doses of mirikizumab are administered by intravenous infusion.

[0071] In a further embodiment of the present invention, if a clinical response is achieved at the end of the induction period or the end of the extended induction period, a maintenance dose of mirikizumab is administered to the patient.

[0072] In certain embodiments, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg to 100 mg, and the maintenance dose is administered to the patient after the last induction dose or last extension induction dose has been administered. In some embodiments, if the patient has a body weight of more than 10 kg but no more than 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. In other embodiments, if the subject has a body weight of more than 20 kg but no more than 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

[0073] In such embodiments, the initial maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks (e.g., 2, 3, 4, 5, 6, 7, or 8 weeks) after the last induction dose or last extension induction dose has been administered. In preferred embodiments, the initial maintenance dose is administered 4 to 6 weeks after the last induction dose or last extension induction dose has been administered. More preferably, the initial maintenance dose is administered 4 weeks after the last induction dose or last extension induction dose has been administered. In further embodiments, additional maintenance doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks after the administration of the initial maintenance dose. Preferably, the maintenance doses are administered at 4-week intervals.

[0074] In embodiments of the present invention, the maintenance dose is administered by subcutaneous injection.

[0075] The duration of the 4-8 week maintenance dose corresponds to the variation in the period between the administration of the last extension induction dose and the extension induction end evaluation. This variation may arise from variations in the frequency of medication during the extension induction period. In some embodiments, the frequency of medication during the extension induction period is every 4 weeks, and the extension induction end evaluation is performed 4 weeks after the administration of the last extension induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 4 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. Alternatively, the frequency of medication during the extension induction period is every 8 weeks, and the extension induction end evaluation is performed 8 weeks after the administration of the last extension induction dose. If the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 8 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. In such embodiments, the maintenance dose of mirikizumab is administered after the patient has achieved a clinical response from one, two, or three extension induction doses.

[0076] In further embodiments of the present invention, if the subject loses response during maintenance therapy (maintenance period), an ad-hoc escalator dose of mirikizumab is administered to the patient 2 to 8 weeks after the last maintenance dose. In such embodiments, if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the ad-hoc escalator dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In some embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 5 mg / kg. In other embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 10 mg / kg.

[0077] In some embodiments of the present invention, one, two, or three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In yet another embodiment, two or three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In a preferred embodiment of the present invention, three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 weeks.

[0078] In the embodiments of the present invention, the temporary additional dose is administered by intravenous infusion.

[0079] In further embodiments of the present invention, if the subject achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalator doses (ad-hoc escalator period), a maintenance dose of mirikizumab is administered to the patient. In such embodiments, the maintenance dose is administered to the patient based on body weight and interval as described herein.

[0080] In such embodiments, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg to approximately 100 mg. In some embodiments, if the patient has a body weight of more than 10 kg but no more than 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. In other embodiments, if the subject has a body weight of more than 20 kg but no more than 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

[0081] In such embodiments, the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last emergency bolus dose. In preferred embodiments, the maintenance dose of mirikizumab is administered 2 to 6 weeks after the last emergency bolus dose. More preferably, the maintenance dose is administered 2 or 4 weeks after the last emergency bolus dose. In further embodiments, additional maintenance doses of mirikizumab are administered to the patient at intervals of 4 or 8 weeks. Preferably, the maintenance dose is administered at 4-week intervals.

[0082] In certain embodiments, the maintenance dose of mirikizumab is administered to the patient for up to approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 to approximately 152 weeks after the last induction dose, last extension induction dose, or last ad-hoc bolus dose has been administered. In certain embodiments, the maintenance dose is administered for up to approximately 1, 2, 3, or 4 years.

[0083] In embodiments of the present invention, patients achieve at least one of the following therapeutic effects within approximately 2 to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding. In such embodiments of the present invention, at least one therapeutic effect is achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirikizumab. Such therapeutic effects may be achieved during the induction period, extended induction period, and / or ad-hoc supplemental period. In certain embodiments, the therapeutic effect may be achieved during the maintenance period, which may be the maintenance period after the induction period, the maintenance period after the extended induction period, or the maintenance period after the ad-hoc supplemental period.

[0084] In a further embodiment of the present invention, one or more of the therapeutic effects are sustained during the maintenance period.

[0085] In such embodiments, the therapeutic effect is sustained for up to approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to up to approximately 152 weeks during the maintenance period after the induction period, extended induction period, or temporary supplementary period.

[0086] In further embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of mirikizumab treatment.

[0087] In such embodiments, the patient continues maintenance therapy with mirikizumab until they become unresponsive, have an insufficient response, lose their response, or become intolerant to mirikizumab.

[0088] In some embodiments of the present invention, patients achieve a reduction in fecal calprotectin and C-reactive protein within approximately 2 to 48 weeks of treatment with mirikizumab.

[0089] In embodiments of the present invention, the induction dose range of about 5 mg / kg to about 10 mg / kg may be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0090] In embodiments of the present invention, the patient is a patient who has not responded to conventional medications.

[0091] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0092] In some embodiments, the patient has experience with biologics and / or advanced therapy.

[0093] In some embodiments, the patient is a biologic-unsuccessful patient and / or a highly unsuccessful patient.

[0094] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0095] In embodiments of the present invention, the biological agent or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0096] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0097] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors.

[0098] In a further aspect of the present invention, mirikizumab, or a pharmaceutical composition comprising mirikizumab, for use in the treatment of patients requiring treatment for moderate to severe active ulcerative colitis, The patient is administered three induction doses of mirikizumab at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals via intravenous infusion. This includes, or, administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the last induction dose has been administered. This specification provides for mirikizumab or pharmaceutical compositions used in patients who are between 2 and 18 years of age and have a body weight of more than 10 kg but not exceeding 20 kg.

[0099] In a further aspect of the present invention, mirikizumab, or a pharmaceutical composition comprising mirikizumab, for use in the treatment of patients requiring treatment for moderate to severe active ulcerative colitis, The patient is administered three induction doses of mirikizumab at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals via intravenous infusion. This includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection every four weeks, 2 to 8 weeks after the last induction dose has been administered. This specification provides for mirikizumab or pharmaceutical compositions used in patients who are between 2 and 18 years of age and have a body weight of more than 20 kg but not exceeding 40 kg.

[0100] In such embodiments of the present invention, if the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose was administered, three extension induction doses of mirikizumab are administered to the patient. If the patient has a body weight of more than 10 kg but no more than 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0101] In a further embodiment, if a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose.

[0102] In such embodiments, if the patient loses response during maintenance medication (maintenance period), one, two, or three ad-hoc surcharge doses of mirikizumab are administered to the patient. If the patient weighs between 10 kg and 40 kg, an additional dose of mirikizumab may be administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg, or An additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0103] In such embodiments of the present invention, if the patient achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalator doses, a maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals.

[0104] In further embodiments, patients achieve at least one of the following therapeutic effects within approximately 2 to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding.

[0105] In further embodiments of the present invention, at least one therapeutic effect is achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirikizumab. In such embodiments, at least one therapeutic effect is achieved during the induction period or extended induction period.

[0106] In other embodiments, one or more therapeutic effects are sustained during the maintenance period. In such embodiments of the present invention, the therapeutic effect is sustained for a maximum of approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to a maximum of approximately 152 weeks during the maintenance period following the end of the induction period, extended induction period, or temporary supplementary period.

[0107] In certain embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of treatment with mirikizumab. In such embodiments, the patient continues maintenance treatment with mirikizumab until they become unresponsive, have an inadequate response, lose their response, or become intolerant to mirikizumab.

[0108] In embodiments of the present invention, the induction dose range of approximately 5 mg / kg to approximately 10 mg / kg may be 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[0109] In embodiments of the present invention, the patient is a patient who has not responded to conventional medications.

[0110] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0111] In some embodiments, the patient has experience with biologics and / or advanced therapy.

[0112] In some embodiments, the patient is a biologic-unsuccessful patient and / or a highly unsuccessful patient.

[0113] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0114] In some embodiments, the biologic or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0115] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0116] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors.

[0117] One aspect of the present invention provides for the use of mirikizumab in the manufacture of a medicament for treating a patient with moderate to severe active ulcerative colitis, comprising administering an induction dose of mirikizumab to the patient at about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight greater than 10 kilograms (kg), and such use is provided herein.

[0118] In another embodiment, the use of mirikizumab in the manufacture of a medicament for treating moderate to severe active ulcerative colitis in a patient who is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior therapy, comprising administering an induction dose of mirikizumab to the patient at about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight greater than 10 kilograms (kg), the use provided herein. In such embodiments, the prior therapy may be a biologic, an advanced therapy, or a non-biological therapy such as an immunomodulator or corticosteroid.

[0119] In some embodiments of the present invention provided herein, the patient is between 2 and under 18 years of age and has a body weight greater than 10 kg but less than or equal to 40 kg. In such embodiments, an induction dose of mirikizumab is administered to the patient in a dose based on the patient's body weight. In such embodiments, an induction dose of mirikizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg (e.g., about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, v9 mg / kg, or about 10 mg / kg). In some embodiments, an induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In another embodiment, an induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0120] In certain embodiments of the present invention, one, two, or three induction doses of mirikizumab are administered to the patient. In even more specific embodiments of the present invention, three induction doses of mirikizumab are administered to the patient. In certain embodiments, induction doses are administered to the patient at intervals of 4 to 8 weeks (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, and 8 weeks). In more specific embodiments, induction doses are administered to the patient at 4-week intervals. In certain embodiments, the induction period is a duration of 4, 8, or 12 weeks. In certain embodiments, the induction period is a duration of 12 weeks. In even more specific embodiments, induction doses are administered to the patient at 0, 4, and 8 weeks.

[0121] In embodiments of the present invention, an induction dose of mirikizumab is administered to the patient by intravenous infusion.

[0122] In certain embodiments of the present invention, if a patient has not achieved a clinical response 4 to 8 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, and the subjects are between 2 and under 18 years of age and have a body weight greater than 10 kilograms (kg). In further embodiments, if the patient has a body weight greater than 10 kg but 40 kg or less, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In yet another embodiment, an extension induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg.

[0123] In further embodiments, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In a more specific embodiment of the present invention, three extension induction doses of mirikizumab are administered to the patient at intervals of 4 weeks.

[0124] In embodiments of the present invention, one, two, or three extended induction doses of mirikizumab are administered by intravenous infusion.

[0125] In a further embodiment of the present invention, if a clinical response is achieved at the end of the induction period or the end of the extended induction period, a maintenance dose of mirikizumab is administered to the patient.

[0126] In certain embodiments, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg to 100 mg, and the maintenance dose is administered to the patient after the last induction dose or last extension induction dose has been administered. In some embodiments, if the patient has a body weight of more than 10 kg but no more than 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. In other embodiments, if the subject has a body weight of more than 20 kg but no more than 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

[0127] In such embodiments, the initial maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks (e.g., 2, 3, 4, 5, 6, 7, or 8 weeks) after the last induction dose or last extension induction dose has been administered. In preferred embodiments, the initial maintenance dose is administered 4 to 6 weeks after the last induction dose or last extension induction dose has been administered. More preferably, the initial maintenance dose is administered 4 weeks after the last induction dose or last extension induction dose has been administered. In further embodiments, additional maintenance doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks after the administration of the initial maintenance dose. Preferably, the maintenance doses are administered at 4-week intervals.

[0128] In embodiments of the present invention, the maintenance dose is administered by subcutaneous injection.

[0129] The duration of the 4-8 week maintenance dose corresponds to the variation in the period between the administration of the last extension induction dose and the extension induction end evaluation. This variation may arise from variations in the frequency of medication during the extension induction period. In some embodiments, the frequency of medication during the extension induction period is every 4 weeks, and the extension induction end evaluation is performed 4 weeks after the administration of the last extension induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 4 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. Alternatively, the frequency of medication during the extension induction period is every 8 weeks, and the extension induction end evaluation is performed 8 weeks after the administration of the last extension induction dose. If the patient achieves a clinical response, the first maintenance dose may be administered at the induction end evaluation visit (i.e., 8 weeks after the administration of the last extension induction dose) or at the next visit scheduled to take place soon thereafter. In such embodiments, the maintenance dose of mirikizumab is administered after the patient has achieved a clinical response from one, two, or three extension induction doses.

[0130] In further embodiments of the present invention, if the subject loses response during maintenance therapy (maintenance period), an ad-hoc escalator dose of mirikizumab is administered to the patient 2 to 8 weeks after the last maintenance dose. In such embodiments, if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the ad-hoc escalator dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. In some embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 5 mg / kg. In other embodiments, the ad-hoc escalator dose of mirikizumab is administered at approximately 10 mg / kg.

[0131] In some embodiments of the present invention, one, two, or three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In yet another embodiment, two or three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 to 8 weeks. In a preferred embodiment of the present invention, three ad-hoc bolus doses of mirikizumab are administered to the patient at intervals of 4 weeks.

[0132] In the embodiments of the present invention, the temporary additional dose is administered by intravenous infusion.

[0133] In further embodiments of the present invention, if the subject achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalator doses (ad-hoc escalator period), a maintenance dose of mirikizumab is administered to the patient. In such embodiments, the maintenance dose is administered to the patient based on body weight and interval as described herein.

[0134] In such embodiments, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg to approximately 100 mg. In some embodiments, if the patient has a body weight of more than 10 kg but no more than 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. In other embodiments, if the subject has a body weight of more than 20 kg but no more than 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

[0135] In such embodiments, the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last emergency bolus dose. In preferred embodiments, the maintenance dose of mirikizumab is administered 2 to 6 weeks after the last emergency bolus dose. More preferably, the maintenance dose is administered 2 or 4 weeks after the last emergency bolus dose. In further embodiments, additional maintenance doses of mirikizumab are administered to the patient at intervals of 4 or 8 weeks. Preferably, the maintenance dose is administered at 4-week intervals.

[0136] In certain embodiments, the maintenance dose of mirikizumab is administered to the patient for up to approximately 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, or 104 to approximately 152 weeks after the last induction dose, last extension induction dose, or last ad-hoc bolus dose has been administered. In certain embodiments, the maintenance dose is administered for up to approximately 1, 2, 3, or 4 years.

[0137] In embodiments of the present invention, patients achieve at least one of the following therapeutic effects within approximately 2 to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding. In such embodiments of the present invention, at least one therapeutic effect is achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirikizumab. Such therapeutic effects may be achieved during the induction period, extended induction period, and / or ad-hoc supplemental period. In certain embodiments, the therapeutic effect may be achieved during the maintenance period, which may be the maintenance period after the induction period, the maintenance period after the extended induction period, or the maintenance period after the ad-hoc supplemental period.

[0138] In a further embodiment of the present invention, one or more of the therapeutic effects are sustained during the maintenance period.

[0139] In such embodiments, the therapeutic effect is sustained for up to approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to up to approximately 152 weeks during the maintenance period after the induction period, extended induction period, or temporary supplementary period.

[0140] In further embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of mirikizumab treatment.

[0141] In such embodiments, the patient continues maintenance therapy with mirikizumab until they become unresponsive, have an insufficient response, lose their response, or become intolerant to mirikizumab.

[0142] In embodiments of the present invention, the induction dose, extended induction, or temporary surcharge dose range of about 5 mg / kg to about 10 mg / kg may be about 5 mg / kg, 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0143] In embodiments of the present invention, the patient is a patient who has not responded to conventional medications.

[0144] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0145] In some embodiments, the patient has experience with biologics and / or advanced therapy.

[0146] In some embodiments, the patient is a biologic-unsuccessful patient and / or a highly unsuccessful patient.

[0147] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0148] In embodiments of the present invention, the biological agent or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0149] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0150] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors.

[0151] A further aspect of the present invention relates to the use of mirikizumab in the manufacture of a pharmaceutical product for treating patients who require treatment for moderate to severe active ulcerative colitis (UC), The patient is administered three induction doses of mirikizumab at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals via intravenous infusion. This includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the last induction dose has been administered. Use provided herein is for patients who are between 2 and 18 years of age and weigh between 10 kg and 20 kg.

[0152] A further aspect of the present invention relates to the use of mirikizumab in the manufacture of a pharmaceutical product for treating patients who require treatment for moderate to severe active ulcerative colitis (UC), Two to eight weeks after the last induction dose, a maintenance dose of approximately 100 mg of mirikizumab is administered. This includes administering the drug to the patient by subcutaneous injection at 4-week intervals, Use provided herein is for patients who are between 2 and 18 years of age and weigh between 20 kg and 40 kg.

[0153] In such embodiments of the present invention, if the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose was administered, three extension induction doses of mirikizumab are administered to the patient. If the patient has a body weight of more than 10 kg but no more than 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0154] In a further embodiment, if a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose.

[0155] In such embodiments, if the patient loses response during maintenance medication (maintenance period), one, two, or three ad-hoc surcharge doses of mirikizumab are administered to the patient. If the patient weighs between 10 kg and 40 kg, an additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. An additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

[0156] In such embodiments of the present invention, if the patient achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalator doses, a maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals.

[0157] In further embodiments, patients achieve at least one of the following therapeutic effects within approximately 2 to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, and improvement of rectal bleeding.

[0158] In further embodiments of the present invention, at least one therapeutic effect is achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirikizumab. In such embodiments, at least one therapeutic effect is achieved during the induction period or extended induction period.

[0159] In other embodiments, one or more therapeutic effects are sustained during the maintenance period. In such embodiments of the present invention, the therapeutic effect is sustained for a maximum of approximately 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks to a maximum of approximately 152 weeks during the maintenance period following the end of the induction period, extended induction period, or temporary supplementary period.

[0160] In certain embodiments, clinical remission is maintained without surgery at week 52 and without the use of steroids for at least 12 weeks prior to week 52 of mirikizumab treatment.

[0161] In some embodiments, the patient continues maintenance therapy with mirikizumab until they become unresponsive, have an insufficient response, lose their response, or become intolerant to mirikizumab.

[0162] In embodiments of the present invention, the induction dose range of about 5 mg / kg to about 10 mg / kg may be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0163] In embodiments of the present invention, the patient is a patient who has not responded to conventional medications.

[0164] In other embodiments, the patient is biologic-free and / or hypnotherapy-free.

[0165] In some embodiments, the patient has experience with biologics and / or advanced therapy.

[0166] In some embodiments, the patient is a biologic-unsuccessful patient and / or a highly unsuccessful patient.

[0167] In some embodiments, the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0168] In some embodiments, the biologic or advanced therapy is an anti-TNF agent and / or an anti-α4β7 agent.

[0169] In some embodiments, the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

[0170] In further embodiments, the patient is one or more of the following: unsuccessful treatment with anti-TNF drugs, unsuccessful treatment with anti-α4β7 drugs, unsuccessful treatment with JAK inhibitors, unsuccessful treatment with S1P receptor modulators, or unsuccessful treatment with TYK2 inhibitors. [Modes for carrying out the invention]

[0171] This specification provides methods, uses of anti-IL-23p19 antibodies, and pharmaceutical compositions for the treatment of moderate to severe active ulcerative colitis. Also provided are methods, doses, and drug regimens for the use of IL-23p19 antibodies for the treatment of moderate to severe active ulcerative colitis in pediatric patients. UC is a form of colitis, an inflammatory disease of the intestines, usually the colon, characterized by distinctive ulcers. Symptoms of active disease typically include diarrhea with blood, usually accompanied by varying degrees of abdominal pain, ranging from mild discomfort to severe cramps. A feeling of urgency to defecate is also a common and destructive symptom of ulcerative colitis (UC), distinct from stool frequency (SF) and rectal bleeding (RB).

[0172] There are several methods for assessing disease severity / clinical indicators, including the Mayo score, modified Mayo score (MMS), pediatric ulcerative colitis disease activity index (PUCAI), total Mayo score, Mayo endoscopic subscore, total score of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Geboes score, Roberts Histopathology Index (RHI), and combinations thereof.

[0173] The Mayo score is a composite measurement method consisting of the following four subscores.

[0174] Bowel Movement Frequency (SF): The SF subscore is a patient-reported measurement. This item reports the number of bowel movements in a 24-hour period on a 4-point scale, compared to the patient's normal number of bowel movements over the same period. Bowel movement is defined as going to the toilet when the patient has a bowel movement, or when they excrete only blood, blood and mucus, or only mucus. For younger children, this includes changing diapers each time there is a bowel movement. The total number of bowel movements excreted within a 24-hour period is recorded by the patient. The patient's reference "normal" SF is typically recorded at the start of the study or during the observation period. The patient's normal SF is based on the SF reported when the patient was in remission, or, if the patient has never achieved remission, on the SF reported before the first onset of signs and symptoms of UC.

[0175] [Table 1]

[0176] Rectal bleeding: The RB subscore is a patient-reported measurement. This item reports the most severe amount of blood rectally expelled on a given day, on a 4-point scale.

[0177] [Table 2]

[0178] Endoscopic Subscore (ES): ES is a physician-reported measurement that describes the worst mucosal appearance during flexible sigmoidoscopy or colonoscopy, on a 4-point scale. In line with current clinical practice, fragility is excluded from the definition of ES 1.

[0179] [Table 3]

[0180] Physician's Global Assessment (PGA): The PGA is a physician-reported measure that summarizes the patient's UC disease activity on a 4-point scale.

[0181] [Table 4]

[0182] Each subscore is scored on a 4-point scale ranging from 0 to 3, with a maximum Mayo score of 12.

[0183] The Modified Mayo Score, or MMS, is a modification made to the original Mayo index reference (Schroeder et al., New Eng J Med, 317(26):1625-1629, 1987) and includes three of the four subscores of the Mayo score. The physician's overall assessment is not included. The MMS evaluates three subscores, each on a scale of 0 to 3, with a maximum total score of 9. Patients with a Mayo score of 6 to 12 or an MMS of 4 to 9, with an ES of 2 or higher in each category, are defined as having moderate to severe active ulcerative colitis.

[0184] The Mayo score ranges from 0 to 12, with higher scores indicating greater severity. The partial Mayo score excludes endoscopy and ranges from 0 to 9, while the modified Mayo score excludes physician's overall assessment and also ranges from 0 to 9. The initial description of the Mayo score included lithotripsy in the definition of the endoscopic subscore 1.

[0185] As used herein, “clinical remission” using MMS is defined as an RB subscore of 0, an SF subscore of 0 or 1, and an ES of 0 or 1 (excluding pulverization).

[0186] As used herein, “clinical response” using MMS is defined as achieving a decrease of 2 points or more and 30% or more from baseline in an MMS subscore, and a decrease of 1 or more in an RB subscore, or an RB subscore of 0 or 1.

[0187] As used herein, “endoscopic remission” using MMS is defined as achieving a Mayo ES of 0. It may also be defined as achieving a Mayo ES of 0 or 1 (excluding lithotripsy).

[0188] As used herein, “endoscopic improvement” using MMS is defined as achieving a Mayo ES of 0 or 1.

[0189] "Histological-endoscopic mucosal improvement (HEMI)" is defined as achieving both endoscopic improvement (endoscopic subscores read centrally as 0 or 1, excluding lithotripsy) and histological improvement (neutrophil infiltration in less than 5% of crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue, based on the Geboes scoring system).

[0190] Histologic endoscopic mucosal remission (HEMR) is defined as achieving both endoscopic and histological remission (defined as a Geboes histological subscore of 0 for neutrophils in the lamina propria, neutrophils in the epithelium, and erosion or ulcer formation parameters, or as an RHI score of 2 or less).

[0191] As used herein, “symptom remission” using MMS is defined as achieving an SF subscore of 0, or an SF subscore of 1 with a decrease of 1 point or more from baseline, and an RB subscore of 0.

[0192] As used herein, “symptom response” is defined as a 30% or greater reduction from baseline in the composite clinical endpoint of the sum of the SF subscore and RB subscore.

[0193] As used herein, “loss of response” using MMS is defined as follows: an increase of 2 or more points from the end of the partial Mayo score at two consecutive visits at least 5 days apart, accompanied by confirmation of a negative Clostridium difficile test; or

[0194] An alternative definition of “loss of response” is a PGA subscore of 2 or higher for moderate to severe disease at two consecutive visits at least 5 days apart, accompanied by (a) a total partial Mayo score of 4 or higher, and (b) confirmation of a negative Clostridium difficile test.

[0195] As used herein, “corticosteroid-free remission” is defined as clinical remission at week 52, achieved without surgery or steroid use for at least 12 weeks prior to week 52.

[0196] The Pediatric Ulcerative Colitis Activity Index (PUCAI) (Turner et al., 2007) is a six-item disease activity index intended for use in pediatric UC clinical trials. It measures abdominal pain, rectal bleeding, stool consistency (mostly), number of bowel movements per 24 hours, nocturnal bowel movements (any diarrhea episode causing waking), and activity level. All items are reported as the average over the "past two days." The total PUCAI disease activity score is calculated on a scale of 0 to 85. For the definition of disease severity according to PUCAI, see Section 10.10:

[0197] [Table 5]

[0198] Using the PUCAI framework, "clinical remission" is defined as a decrease of 20 points or more from the baseline PUCAI score. "Clinical response" is defined as a PUCAI score of less than 10 points. Mild disease activity is defined as a PUCAI score of 10–30, moderate disease activity as a PUCAI score of 35–60, and severe disease activity as a PUCAI score of 65–85.

[0199] The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a central-reader-reported measure of endoscopic disease activity of UC during colonoscopy, comprising three descriptors (scored for the most severe lesions): vascular pattern, bleeding, and erosion and ulceration. The central-reader determines the UCEIS for each endoscopy in a blinded manner, as detailed in the Endoscopy Image Review charter.

[0200] Bowel urgency is measured using the Uniform Numeric Rating Score (UNRS) to assess the mean change in the severity of bowel urgency. Bowel urgency, a sudden or immediate urge to defecate, is a common and troublesome symptom for patients with ulcerative colitis. The UNRS is a patient-reported measure of bowel urgency over the past 24 hours, using an 11-point scale from 0 (no urgency) to 10 (worst possible urgency). The UNRS score is recorded daily by the patient in an eDiary. The change in UNRS from baseline is measured over 12, 28, 52, or up to approximately 104 weeks of treatment. A clinically meaningful “improvement in bowel urgency” or a clinically meaningful change in the severity of bowel urgency is defined as the percentage of patients who achieve both a clinical response, based on an improvement of 3 points or more from baseline in both the MMS and UNRS scores. "Remission of defecation urgency" is defined as minimal to absent defecation urgency as assessed at 12 weeks, 28 weeks, and subsequent maintenance points in patients with a baseline UNRS of 3 or higher: UNRS[0, 1].

[0201] Other measures of improvement include abdominal pain NRS, fatigue NRS, nocturnal bowel movements, Patient's Global Impression of Change (PGI-C), and Patient's Global Rating of Severity (PGR-S). Such measures are assessed based on outcomes reported by participants and / or caregivers.

[0202] Changes in health outcomes and quality of life are assessed by changes from baseline at weeks 12 and 52 in the IMPACT-III score, TUMMY-UC, and / or WPAI+CIQ:UC score.

[0203] As used herein, IMPACT-III is a validated questionnaire that assesses disease-related health quality of life and well-being in participants aged 9 years or older with IBD. The questionnaire is self-administered and consists of 35 questions covering the following areas: bowel symptoms (7 items); systemic symptoms (3 items); emotional functioning (7 items); social functioning (12 items); physical imaging (3 items); and tests and treatments (3 items). The recall period is two weeks, and the questionnaire takes approximately 10 minutes to complete. Scores range from 35 to 175, with higher scores indicating better quality of life (Otley et al. 2002, Otley et al. 2006).

[0204] As used herein, the TUMMY-UC is a set of questions designed to identify important disease symptoms in pediatric patients with ulcerative colitis (UC). There are two versions of the TUMMY-UC: one for children aged 8–18 years and another for caregivers of children aged 2–7 years. Instead of directly scoring subjective concepts, the TUMMY-UC scores behaviors that demonstrate subjective concepts (for example, caregivers are asked to score pain-related behaviors rather than scoring the degree of their own pain). Both the version for children aged 8–18 and the version for caregivers include eight items that measure the following symptoms over a 24-hour recall period: Abdominal pain, frequency of bowel movements, maximum amount of rectal bleeding, frequency of rectal bleeding, Bristol Stool consistency chart, weakness, nocturnal bowel movements, and urgency.

[0205] The WPAI+CIQ:UC used herein is a patient-reported measure developed to measure the impact of specific health problems during the past 7 days on work productivity and activity / classroom impairment in patients aged 12 years and older. It includes nine measures: The score includes the percentage of working hours lost due to UC (absenteeism), the percentage of work-related impairment due to UC (presenteeism), the percentage of total work impairment due to UC (loss of labor productivity), the percentage of class time lost due to UC, the percentage of classroom impairment due to UC, and the percentage of impairment in normal activities (outside of work or class) due to UC (activity impairment). The score is calculated as an impairment percentage (Reilly et al. 1993; 2008), and a higher number indicates greater impairment and lower productivity, i.e., a worse outcome.

[0206] The Geboes score used herein consists of seven categories (or grades), each describing a histological feature, including "Structural (Structural Change)" (Grade 0), "Chronic Inflammatory Infiltration" (Grade 1), "Lamina Propriubilism Eosinophils" (Grade 2A), "Lamina Propriubilism Neutrophils" (Grade 2B), "Neutrophils in Epithelium" (Grade 3), "Cryptal Destruction" (Grade 4), and "Surface Epithelial Damage" (Grade 5). Each grade includes a subscore indicating the degree of abnormality observed in its histological feature, with a subscore of 0 indicating a normal appearance and higher subscores indicating an increase in abnormal appearance. The RHI uses weighted results from four Geboes score categories ("Chronic Inflammatory Infiltration," "Lamina Propriubilism Neutrophils," "Neutrophils in Epithelium," and "Surface Epithelial Damage") to derive a continuous score ranging from 0 (no disease activity) to 33 (severe disease activity). The RHI was developed as a response tool to detect therapeutic effects in early drug development.

[0207] Therefore, as used herein, “therapeutic effect” or response to treatment may be any one or more of the following: clinical response, clinical remission, endoscopic remission, histological-endoscopic mucosal remission, symptomatic remission, histological-endoscopic mucosal improvement, corticosteroid-free remission, remission of defecation urgency, improvement of defecation urgency, improvement of bowel movement frequency, reduction of nocturnal bowel movements, improvement of fatigue, improvement of abdominal pain, improvement of rectal bleeding, and / or improvement of other symptoms associated with ulcerative colitis.

[0208] As used herein, “sustained response” refers to the percentage of patients who achieved a therapeutic effect during the induction period and who achieved a therapeutic effect during the maintenance period. For example, as used herein, sustained response may refer to the percentage of patients who achieved clinical remission at week 52 and who achieved clinical remission at week 12.

[0209] As used herein, “extended induction dose” is a term used to distinguish the extended induction dose from the initial induction dose when the patient does not achieve a clinical response at the end of the initial induction period. The extended induction dose is delivered during the extended induction period. The dose and dosing interval during the extended induction period may be the same as those during the initial induction period, but may be changed if the healthcare professional in charge has reason to believe that the patient may benefit from changes such as an increased dose of anti-IL-23p19 or more frequent dosing. For example, the dose-dosing interval may be increased to the following dose level and / or administered at more frequent dosing intervals for a particular patient weight group.

[0210] As used herein, “add-on dose” refers to the dose of anti-IL-23p19 administered to re-induce / re-achieve the clinical response and / or other therapeutic effect achieved at the end of the induction period. Add-on doses are delivered during the add-on period. Add-on doses and dosing intervals during the add-on period are typically the same as those during the initial induction period, but may be modified if the healthcare professional in charge has reason to believe that the patient may benefit from changes such as an increased dose of anti-IL-23p19 or more frequent dosing.

[0211] As used herein, the term “insufficient response” refers to the failure to achieve good disease control of ulcerative colitis after using the treatment for the period recommended by the product prescription information (which may occur during treatment).

[0212] As used herein, the term "intolerance" refers to unacceptable toxicity or / or improvement of other symptoms associated with ulcerative colitis.

[0213] As used herein, the terms “bio-not failed” or “bio-successful” and / or “high-therapy-not failed” refer to patients who have not received biologics or high-therapy, e.g., anti-TNFα antibodies (e.g., adalimumab, golimumab, infliximab), anti-integrin antibodies (e.g., vedolizumab), JAK inhibitors (e.g., tofacitinib, upadacitinib), TYK2 inhibitors, or S1P receptor modulators (e.g., ozanimod), for the treatment of UC, particularly for moderate to severe UC. Biologic-not failed or high-therapy-not failed patients also include patients who have an inadequate response, loss of response, or intolerance to at least one of the corticosteroids or immunomodulators. Intolerance to immunomodulators includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia.

[0214] As used herein, the terms “experienced with a biologic” and / or “experienced with advanced therapy” refer to patients who have received at least one prior biologic or advanced therapy for the treatment of UC, other than an anti-IL23p19 antibody, and who have had, lost, or become intolerant to a biologic therapy, such as an anti-TNFα antibody (e.g., adalimumab, golimumab, infliximab), an anti-integrin antibody (e.g., vedolizumab), a JAK inhibitor (e.g., tofacitinib, upadacitinib), a TYK2 inhibitor, or an S1P receptor modulator (e.g., ozanimod), particularly for the treatment of moderate to severe active UC. Such patients may or may not have received conventional medications for the treatment of UC. An inadequate response includes signs and symptoms of disease that persist despite prescribed induction therapy.

[0215] As used herein, the terms “biological agent failure” and / or “highly therapy failure” refer to patients who have received at least one prior biological agent or highly therapy for the treatment of UC, e.g., anti-TNFα antibodies (e.g., adalimumab, golimumab, infliximab), anti-integrin antibodies (e.g., vedolizumab), JAK inhibitors (e.g., tofacitinib, upadacitinib), TYK2 inhibitors, or S1P receptor modulators (e.g., ozanimod), particularly for the treatment of moderate to severe active UC. Such patients may or may not have received conventional therapy for the treatment of UC. Such patients have an inadequate response to, have lost their response to, or are intolerant of, a biological agent or highly therapy for UC that is not an anti-IL23p19 antibody. In the context of the terms biological agent failure or highly therapy failure, inadequate response means showing signs and symptoms of persistent active disease despite induction therapy with the approved induction dosing regimen indicated on the product label at the time of use. In the context of the terms biologic failure patient or highly unsuccessful therapy patient, loss of response is defined as a recurrence of signs and symptoms of active disease during maintenance therapy following prior clinical benefit (discontinuation despite clinical benefit is not evidence of being unsuccessful or intolerant to UC biologic therapy). In the context of the terms biologic failure patient or highly unsuccessful therapy patient, intolerance means a history of intolerance to, for example, anti-TNF-α antibodies, anti-integrin antibodies, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, etc. Examples include infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, tofacitinib, upadacitinib, duklavacitinib, ozanimod, or other such approved therapies.

[0216] As used herein, “loss of response” includes the recurrence of signs and symptoms of active disease between prescribed maintenance medications following a prior clinical benefit. Intolerance includes, but is not limited to, a history of intolerance to a biologic or high-intensity therapy, including infusion-related events, demyelination, congestive heart failure, or any other drug-related AE that resulted in dose reduction or discontinuation of the biologic, or discontinuation of the biologic for any other reason.

[0217] As used herein, the term “conventionally unsuccessful” means a patient who has not been previously treated with a biologic and who has an inadequate response, loss of response, or intolerance to at least one of the following drugs:

[0218] corticosteroids ● Corticosteroid-refractory colitis is defined as the presence of signs or symptoms of active ulcerative colitis despite taking oral prednisone or an equivalent oral corticosteroid at a dose of 30 mg / day or more for two weeks or more. ● Corticosteroid-dependent colitis is defined as (a) the inability to gradually reduce or decrease the corticosteroid dose to less than the equivalent of 10 mg / kg / day of prednisone within 3 months of initiating corticosteroids without a recurrence of signs or symptoms of active UC, or (b) a relapse within 3 months of completing the course of corticosteroids. A history of corticosteroid intolerance includes, but is not limited to, cataracts, Cushing's syndrome, hyperglycemia, hypertension, osteopenia / osteoporosis, or neuropsychiatric side effects including insomnia.

[0219] Immunomodulators: ● Having signs and / or symptoms of persistent active disease despite treatment for three months or more with one of the following: ○ Oral AZA (1.5 mg / kg / day or more) or 6-MP (0.75 mg / kg / day or more) ○ Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or ○ A combination of thiopurine and allopurinol within the therapeutic range, as determined by thioguanine metabolite testing. A history of intolerance to at least one immunomodulatory agent includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia.

[0220] Patients who have previously failed to treat UC have either failed to treat or have never demonstrated intolerance to biological agents (anti-TNF antibodies or anti-integrin antibodies) or JAK, S1P, or TYK2 inhibitors indicated for the treatment of UC.

[0221] When used herein, the term "approximately" means a figure that is sufficiently close to the stated figure, for example, within ±10% of the stated figure.

[0222] As used herein, the term “antibody” refers to an immunoglobulin molecule that binds to an antigen. Embodiments of an antibody include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugate antibodies. Antibodies may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0223] An exemplary antibody is an immunoglobulin G (IgG) type antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) crosslinked via interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains contains a variable region of approximately 100 to 125 or more amino acids, primarily involved in antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region, primarily involved in effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (VL) and a light chain constant region. IgG isotypes may be further divided into subclasses (e.g., IgG1, IgG2, IgG3, and IgG4).

[0224] The VH and VL regions can be further subdivided into hypervariable regions called Complementarity Determining Regions (CDRs), which contain scattered, more conserved regions called Framework Regions (FRs). CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen-binding specificity. Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Hereinafter, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain the majority of the residues that form specific interactions with the antigen.The assignment of amino acid residues to CDRs is attributed to Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins," Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins," Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations," Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics The assignment of amino acid residues to the CDR may be carried out according to existing schemes, including those described in the database (available at www.imgt.org, see Lefranc et al., Nucleic Acids Res. 1999;27:209-212). The assignment of amino acid residues to the CDR may be carried out according to a combination of the above schemes.

[0225] Embodiments of the present disclosure also include antibody fragments or antigen-binding fragments, which, as used herein, include at least a portion of an antibody that retains the ability to specifically interact with an antigen or an antigenic epitope, such as Fab, Fab', F(ab')2, Fv fragment, scFv antibody fragment, scFab, disulfide-bound Fv(sdFv), and Fd fragment.

[0226] As used herein, “anti-IL-23p19 antibody” refers to an antibody that binds to the p19 subunit of human IL-23 but not to the p40 subunit of human IL-23. Therefore, an anti-IL-23p19 antibody binds to human IL-23 but not to human IL-12. Examples of anti-IL-23p19 antibodies include mirikizumab, guselkumab, tildrakizumab, risankizumab, and brazicumab.

[0227] Millikizumab, CAS Registry No. 1884201-71-1, is a humanized IgG4 kappa (κ) monoclonal antibody that targets the p19 subunit of human IL-23. This antibody and a method for producing it are described in U.S. Patent No. 9,023,358. Millikizumab contains the following heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain (HC), and light chain (LC) amino acid sequences: ●HCVR-Sequence No. 1 ●LCVR-Sequence No. 2 ●HC-Sequence No. 3 ●LC-SEQ ID NO: 4

[0228] Mirikizumab is particularly suitable for use in many aspects of the present invention.

[0229] As used herein, the terms “bind” and “binds” mean, unless otherwise specified, the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, resulting in proximity of two proteins or molecules as determined by common methods known in the art.

[0230] As used herein, “treatment” or “treating” refers to all processes that may slow, control, delay, or halt the progression of a disorder or disease disclosed herein, or improve the symptoms of a disorder or disease, but does not necessarily imply the complete elimination of all symptoms of a disorder or disease. Treatment includes the administration of proteins, nucleic acids, vectors, or compositions for the treatment of a patient, in particular a disease or condition in a human. Various embodiments of the present invention are shown below. 1. A method for treating a patient who requires treatment for moderate to severe active ulcerative colitis (UC), comprising administering at least one induction dose of mirikizumab to the patient at approximately 5 mg / kg to approximately 10 mg / kg, wherein the patient is between 2 years of age and under 18 years of age and has a body weight greater than 10 kilograms (kg). 2. The method according to claim 1, wherein the patient has a body weight of more than 10 kg but not exceeding 40 kg, and an induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. 3. The method according to 1 or 2 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 4. The method according to 1 or 2 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 5. The method according to any one of 1 to 4 above, wherein mirikizumab is administered to the patient in three induction doses. 6. The method according to any one of items 1 to 5 above, wherein the induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 7. The method according to any one of items 1 to 6 above, wherein the induction dose of mirikizumab is administered to the patient at 4-week intervals. 8. The method according to any one of items 1 to 7 above, wherein the induction dose of mirikizumab is administered to the patient at 0, 4, and 8 weeks. 9. The method according to any one of items 1 to 8 above, wherein the induction dose is delivered over a 12-week induction period. 10. The method according to any one of items 1 to 9 above, wherein if the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. 11. The method according to 10 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, an extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. 12. The method according to 10 or 11 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, an extended induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 13. The method according to 10 or 11 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, an extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 14. The method according to any one of items 10 to 13 above, wherein at least one extension induction dose is administered to the patient 4 to 8 weeks after the last maintenance dose. The method according to any one of items 10 to 14 above, wherein 15.3 extended induction doses of mirikizumab are administered to the patient. 16. The method according to any one of items 10 to 15 above, wherein the extended induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 17. The method according to any one of items 10 to 16 above, wherein the extended induction dose of mirikizumab is administered to the patient at 4-week intervals. 18. The method according to any one of items 1 to 17 above, further comprising administering to the patient at least one maintenance dose of mirikizumab in an amount of about 50 mg to about 100 mg, wherein the maintenance dose is administered after the last induction dose or the last extension induction dose. 19. The method according to 18 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 20 kg, a maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. 20. The method according to 18 above, wherein if the patient has a body weight of more than 20 kg but not exceeding 40 kg, a maintenance dose of mirikizumab is administered to the patient at approximately 100 mg. 21. The method according to any one of items 18 to 20 above, wherein if the patient achieves a clinical response from the last induction or extended induction dose administered to the patient, the maintenance dose of mirikizumab is administered to the patient. 22. The method according to any one of items 18 to 21 above, wherein if the patient loses response during maintenance therapy, one, two, or three ad-hoc escalator doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. 23. The method according to 22 above, wherein if the patient has a body weight of 10 kg to 20 kg or less, an additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 24. The method according to 22 above, wherein if the patient has a weight of more than 20 kg but not exceeding 40 kg, an additional dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 25. The method according to any one of 22 to 24 above, wherein the temporary supplemental dose is administered to the patient 4 to 8 weeks after the last maintenance dose. 26. The method according to any one of the above 22 to 25, wherein the temporary supplemental dose is administered to the patient at intervals of 4 to 8 weeks. 27. The method according to any one of the above 22 to 26, wherein the temporary supplemental dose is administered to the patient at 4-week intervals. 28. The method according to any one of 22 to 27 above, wherein if the patient achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalators, a maintenance dose of mirikizumab is administered to the patient at approximately 50 mg or approximately 100 mg. 29. The method according to any one of 18-21 or 28 above, wherein the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 30. The method according to any one of items 18-21 or 28-29 above, wherein the maintenance dose of mirikizumab is administered to the patient four weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 31. The method according to any one of items 18-21 or 28-30 above, wherein the maintenance dose of mirikizumab is administered to the patient at intervals of 4-8 weeks. 32. The method according to any one of items 18-21 or 28-31 above, wherein the maintenance dose of mirikizumab is administered to the patient at 4-week intervals. 33. The method according to any one of items 18-21 or 28-32 above, wherein the maintenance dose of mirikizumab is administered to the patient by subcutaneous injection. 34. Administer 34.3 induction doses of mirikizumab to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals, and thereafter, The procedure includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The method according to item 1, wherein the patient is between 2 and 18 years of age and has a weight of more than 10 kg but not exceeding 20 kg. 35. Administer 35.3 induction doses of mirikizumab to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals, and thereafter, The procedure includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The method according to item 1, wherein the patient is between 2 and 18 years of age and has a weight of more than 20 kg but not exceeding 40 kg. 36. If the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, three extension induction doses of mirikizumab will be administered to the patient. If the patient has a body weight of more than 10 kg but no more than 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The method according to 34 or 35, wherein the extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 37. The method according to 36, wherein if a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose. 38. If the patient loses response during maintenance therapy, one, two, or three ad-hoc surcharge doses of mirikizumab may be administered to the patient. If the patient has a body weight of 10 kg to 40 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The method according to any one of the above 34 to 37, wherein the aforementioned temporary additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 39. The method according to 38, wherein if the patient achieves a clinical response 4 to 12 weeks after the first, second, or third ad-hoc escalator doses, a further maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals. 40. The method according to any one of items 1 to 39 above, wherein the patient achieves at least one of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of mirikizumab administration: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of defecation frequency, or improvement of rectal bleeding. 41. The method according to 46 above, wherein at least one therapeutic effect is achieved within approximately 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab. 42. The method according to 40 or 41 above, wherein at least one therapeutic effect is achieved during induction or extended induction. 43. The method according to any one of the above 40 to 42, wherein one or more of the therapeutic effects are sustained during the maintenance period. The method described in 43 above, wherein clinical remission is maintained without surgery at 44.52 weeks and without the use of steroids for at least 12 weeks prior to the 52nd week of mirikizumab administration. 45. The method according to any one of items 1 to 44 above, wherein the patient has not used any biological agents and / or has not used any advanced therapy. 46. ​​The method described in any of items 1 to 45 above, wherein the patient is a patient who has not responded to conventional drug treatment. 47. The method according to any one of items 1 to 44 or 46 above, wherein the patient has experienced biological agents and / or advanced therapy. 48. The method according to any one of items 1 to 44, 46, or 47 above, wherein the patient is a biologics failure patient and / or a highly unsuccessful patient. 49. The method according to any one of items 1-44 or 46-48 above, wherein the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis. 50. The method according to any one of the above 47 to 49, wherein the biological agent is an anti-TNF drug and / or an anti-α4β7 drug. 51. The method according to any one of the above 47 to 49, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. 52. Millikizumab for use in the treatment of a patient with moderate to severe active ulcerative colitis (UC), wherein an induction dose of millikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, and the patient is between 2 years of age and under 18 years of age and has a body weight greater than 10 kilograms (kg). 53. The mirikizumab for use as described in 52 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. 54. The mirikizumab for use as described in 52 or 53 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 55. The mirikizumab for use as described in 52 or 53 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 56. Millikizumab for use according to any one of 52 to 55 above, wherein 3 induction doses of mirikizumab are administered to the patient. 57. Millikizumab for use according to any one of 52 to 56 above, wherein the induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 58. Millikizumab for use according to any one of 52 to 57 above, wherein the induction dose of mirikizumab is administered to the patient at 4-week intervals. 59. Millikizumab for use according to any one of 52 to 58 above, wherein the induction dose of mirikizumab is administered to the patient at intervals of 0, 4, and 8 weeks. 60. Myrikizumab for use according to any one of 52 to 59 above, wherein the induction dose is delivered over a 12-week induction period. 61. If the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, as described in any of paragraphs 52 to 60 above. 62. The mirikizumab for use as described in 61 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, an extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. 63. If the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg, as described in 61 or 62 above. 64. If the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg, as described in 61 or 62 above. 65. Myrikizumab for use according to any one of 61 to 64 above, wherein the extended induction dose is administered to the patient 4 to 8 weeks after the last maintenance dose. 66. Millikizumab for use according to any one of 61 to 65 above, wherein 66.3 extended induction doses of mirikizumab are administered to the patient. 67. Millikizumab for use according to any one of 61 to 66 above, wherein the extended induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 68. Millikizumab for use according to any one of 61 to 67 above, wherein the extended induction dose of mirikizumab is administered to the patient at 4-week intervals. 69. Millikizumab for use according to any one of 61 to 68 above, comprising administering a maintenance dose of approximately 50 mg to approximately 100 mg to the patient, wherein the maintenance dose is administered after the last induction dose or the last extended induction dose has been administered. 70. The mirikizumab for use as described in 69 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. 71. The mirikizumab for use as described in 69 above, wherein if the patient has a body weight of more than 20 kg but not exceeding 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg. 72. If the patient achieves a clinical response from the last induction or extended induction dose administered to the patient, the maintenance dose of mirikizumab is administered to the patient, as described in any of paragraphs 69 to 71 above. 73. If the patient loses response during maintenance therapy, one, two, or three ad-hoc escalators of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, as described in any of paragraphs 69 to 72 above. 74. The mirikizumab for use as described in 73 above, wherein if the patient has a body weight of 10 kg to 20 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 75. If the patient has a body weight of more than 20 kg but not exceeding 40 kg, an additional dose of mirikizumab is administered to the patient at 10 mg / kg, as described in 73 above. 76. Myrikizumab for use according to any one of 73 to 75 above, wherein the ad-hoc supplemental dose is administered to the patient 4 to 8 weeks after the last maintenance dose. 77. Myrikizumab for use according to any one of 73 to 76 above, wherein the aforementioned temporary supplemental dose is administered to the patient at intervals of 4 to 8 weeks. 78. Myrikizumab for use according to any one of the above 73 to 77, wherein the temporary supplemental dose is administered to the patient at 4-week intervals. 79. If the patient achieves a clinical response 4 to 12 weeks after one, two, or three adjunct escalators, the maintenance dose administered to the patient is approximately 50 mg or approximately 100 mg, as described in any of 73 to 78 above. 80. Millikizumab for use according to any one of 69-72 or 79 above, wherein the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 81. Millikizumab for use according to any one of 69-72, 79, or 80, wherein the maintenance dose of mirikizumab is administered to the patient four weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 82. Millikizumab for use according to any one of 69-72 or 79-81 above, wherein the maintenance dose of mirikizumab is administered to the patient at intervals of 4-8 weeks. 83. Millikizumab for use according to any one of 69-72 or 79-82, wherein the maintenance dose of mirikizumab is administered to the patient at 4-week intervals. 84. Millikizumab for use according to any one of 69-72 or 79-83, wherein the maintenance dose of mirikizumab is administered to the patient by subcutaneous injection. 85.3 induction doses of mirikizumab are administered to the aforementioned patients by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals. The procedure includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The mirikizumab for use described in item 52 above, wherein the patient is between 2 and 18 years of age and has a body weight of more than 10 kg but not exceeding 20 kg. 86. Administer mirikizumab in induction doses of approximately 5 mg / kg or approximately 10 mg / kg to the patient by intravenous infusion at 4-week intervals. The procedure includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The mirikizumab for use described in item 52 above, wherein the patient is between 2 and 18 years of age and has a body weight of more than 20 kg but not exceeding 40 kg. 87. If the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, three extension induction doses of mirikizumab will be administered to the patient. If the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The mirikizumab for use according to 85 or 86 above, wherein the extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 88. If a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose, as described in 87 above. 89. If the patient loses response during maintenance therapy, one, two, or three ad-hoc surcharge doses of mirikizumab may be administered to the patient. If the patient has a body weight of 10 kg to 40 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. Millikizumab for use according to any one of items 85 to 102 above, wherein the aforementioned temporary additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 90. If the patient achieves a clinical response 4 to 12 weeks after the first, second, or third ad-hoc escalator doses, a maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals, as described in 89 above. 91. Millikizumab for use as described in any of paragraphs 52 to 90 above, wherein the patient achieves at least one of the following therapeutic effects within approximately 2 weeks to 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, endoscopic histological improvement of inflammation, remission of defecation urgency, improvement of defecation urgency, remission of defecation frequency, improvement of defecation frequency, or improvement of rectal bleeding. 92. Millikizumab for use as described in 91 above, wherein at least one therapeutic effect is achieved within approximately 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab. 93. Millikizumab for use as described in 91 or 92 above, wherein at least one therapeutic effect is achieved during the induction period or extended induction period. 94. A mirikizumab for use according to any one of the above 91 to 93, wherein one or more of the therapeutic effects described above are sustained during the maintenance period. 95. Millikizumab for use as described in 94 above, in patients who have maintained clinical remission for 52 weeks without surgery and without the use of steroids for at least 12 weeks prior to the 52nd week of treatment with mirikizumab. 96. Millikizumab for use as described in any of items 52 to 95 above, wherein the patient is a first-time user of biological agents and / or a first-time user of advanced therapy. 97. Myrikizumab for use as described in any of items 52 to 96 above, for patients who have previously failed conventional drug treatments. 98. Millikizumab for use as described in any of 52-95 or 97 above, in which the patient has experienced biological agents and / or advanced therapy. 99. Millikizumab for use as described in any of items 52-95, 97, or 98 above, wherein the patient is a biological agent failure patient and / or a high-level therapy failure patient. 100. Millikizumab for use according to any one of the above 52-95 or 97-99, wherein the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis. 101. Myrikizumab for use according to any one of paragraphs 98 to 100, wherein the biological agent is an anti-TNF agent and / or an anti-α4β7 agent. 102. Myrikizumab for use according to any one of paragraphs 98 to 100 above, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. 103. Use of mirikizumab in the manufacture of a pharmaceutical product for treating moderate to severe active ulcerative colitis (UC) in a patient requiring treatment, wherein an induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, and the patient is between 2 years of age and under 18 years of age and has a body weight greater than 10 kilograms (kg). 104. The use described in 103 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg. 105. The use described in 103 or 104 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 106. The use described in 103 or 104 above, wherein the induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 107. The use described in any of 103 to 106 above, wherein mirikizumab is administered to the patient in an induction dose of 103. 108. The use according to any one of items 103 to 107 above, wherein the induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 109. The use according to any one of items 103 to 108 above, wherein the induction dose of mirikizumab is administered to the patient at 4-week intervals. 110. The use according to any one of paragraphs 103 to 109, wherein the induction dose of mirikizumab is administered to the patient at intervals of 0, 4, and 8 weeks. 111. The use according to any one of paragraphs 103 to 110 above, wherein the induction dose is delivered over a 12-week induction period. 112. If the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at a dose of 5 mg / kg to approximately 10 mg / kg, as described in any of paragraphs 103 to 111 above. 113. The use described in 112 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. 114. The use described in 112 or 113 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg. 115. The use described in 112 or 113 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 116. The use according to any one of items 112 to 115, wherein the extended induction dose of mirikizumab is administered to the patient 4 to 8 weeks after the last maintenance dose. 117. The use described in any of 112 to 116 above, wherein mirikizumab is administered to the patient in an extended induction dose of 117. 118. The use according to any one of paragraphs 112 to 117, wherein the extended induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks. 119. The use according to any one of 112 to 118, wherein the extended induction dose of mirikizumab is administered to the patient at 4-week intervals. 120. The use according to any one of paragraphs 112 to 119, further comprising administering a maintenance dose of mirikizumab to the patient in an amount of approximately 50 mg to approximately 100 mg, wherein the maintenance dose is administered after the last induction dose or the last extended induction dose has been administered. 121. The use described in paragraph 120 above, wherein if the patient has a body weight of more than 10 kg but not exceeding 20 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 50 mg. 122. The use described in paragraph 120 above, wherein if the patient has a body weight of more than 20 kg but not exceeding 40 kg, the maintenance dose of mirikizumab is administered to the patient at approximately 100 mg. 123. The use according to any one of 120 to 122 above, wherein if the patient achieves a clinical response from the last induction or extended induction dose administered to the patient, the maintenance dose of mirikizumab is administered to the patient. 124. If the patient loses response during maintenance therapy, one, two, or three ad-hoc escalators of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg, as described in any of paragraphs 120 to 123 above. 125. The use described in 124 above, wherein if the patient has a body weight of 10 kg to 20 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg. 126. If the patient has a weight of more than 20 kg but not exceeding 40 kg, the temporary additional dose is administered to the patient at 10 mg / kg, as described in 124 above. 127. The use according to any one of paragraphs 124 to 126 above, wherein the temporary supplemental dose is administered to the patient 4 to 8 weeks after the last maintenance dose. 128. The use described in any of paragraphs 124 to 127 above, wherein the temporary supplemental dose is administered to the patient at intervals of 4 to 8 weeks. 129. The use described in any of 124 to 128 above, wherein the temporary additional dose is administered to the patient at 4-week intervals. 130. If the patient achieves a clinical response 4 to 12 weeks after one, two, or three ad-hoc escalators, the maintenance dose administered to the patient is approximately 50 mg or approximately 100 mg, as described in any of paragraphs 124 to 129 above. 131. The use described in any of paragraphs 120-123 or 130 above, wherein a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 132. The use described in any of paragraphs 120-123, 130, or 131 above, wherein the maintenance dose of mirikizumab is administered to the patient four weeks after the last induction dose, an ad-hoc escalator dose, or an extension induction dose. 133. The use according to any one of paragraphs 120-123 or 130-132 above, wherein the maintenance dose of mirikizumab is administered to the patient at intervals of 4-8 weeks. 134. The use according to any one of paragraphs 120-123 or 130-133, wherein the maintenance dose of mirikizumab is administered to the patient at 4-week intervals. 135. The use described in any of paragraphs 120-123 or 130-134 above, wherein the maintenance dose of mirikizumab is administered to the patient by subcutaneous injection. 136.3 induction doses of mirikizumab are administered to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals, and thereafter, The procedure includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The use described in item 103 above, wherein the patient is between 2 years of age and under 18 years of age and has a weight of more than 10 kg but not exceeding 20 kg. 137.3 induction doses of mirikizumab are administered to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals, and thereafter, The procedure includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the administration of the last induction dose. The use described in item 103 above, wherein the patient is between 2 years of age and under 18 years of age and has a weight of more than 20 kg but not exceeding 40 kg. 138. If the patient has not achieved a clinical response 4 to 12 weeks after the last induction dose was administered, three extension induction doses of mirikizumab are administered to the patient. If the patient has a body weight of more than 10 kg but no more than 40 kg, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The use according to 136 or 137, wherein the extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 139. The use described in 138 above, wherein if a clinical response is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose. 140. If the patient loses response during maintenance therapy, one, two, or three ad-hoc surcharge doses of mirikizumab may be administered to the patient. If the patient has a body weight of 10 kg to 40 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The use described in any of paragraphs 136 to 139 above, wherein the aforementioned temporary additional dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals. 141. The use described in paragraph 140, wherein if the patient achieves a clinical response 4 to 12 weeks after the first, second, or third ad-hoc escalator doses, a maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals. 142. Use according to any of items 103 to 141 above, wherein the patient achieves at least one of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of treatment with mirikizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, improvement of endoscopic histological inflammation, remission of defecation urgency, improvement of defecation urgency, remission of defecation frequency, improvement of defecation frequency, or improvement of rectal bleeding. 143. The use described in 142 above, wherein at least one therapeutic effect is achieved within approximately 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab. 144. The use described in 142 or 143 above, wherein at least one therapeutic effect is achieved during the induction period or extended induction period. 145. The use described in 142 or 143 above, wherein one or more of the therapeutic effects are sustained during the maintenance period. 146. Use as described in 145 above, in which clinical remission is maintained without surgery for 52 weeks and without the use of steroids for at least 12 weeks prior to 52 weeks of mirikizumab treatment. 147. Use according to any of items 103 to 146 above, wherein the patient has not used any biological agents and / or has not used any advanced therapy. 148. Use of any of the methods described in 103 to 147 above, provided that the patient is a patient who has previously failed to respond to conventional medication. 149. Use as described in any of paragraphs 103-146 or 148 above, in which the patient has had experience with biological agents and / or advanced therapy. 150. Use according to any of the above 103-146, 148, or 149, in which the patient is a biological agent failure patient and / or a highly unsuccessful patient. 151. The use according to any one of paragraphs 103-146 or 148-150 above, wherein the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis. 152. The use according to any one of paragraphs 149 to 151 above, wherein the biological agent is an anti-TNF drug and / or an anti-α4β7 drug. 153. The use described in any of paragraphs 149 to 151 above, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor. [Examples]

[0231] Example 1: A multicenter, open-label pharmacokinetic study of mirikizumab in pediatric patients with moderate to severe active ulcerative colitis. Study AMBU is an open-label study to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical response of mirikizumab in children and adolescents with ulcerative colitis aged 2 to under 18 years to establish induction and maintenance doses for evaluation in Phase 3. The study population includes pediatric patients with moderate to severe active UC who have had an inadequate response to, lost response to, or are intolerant of non-biologic therapy for UC (biologic-unused), and / or have been exposed to at least one biologic and / or JAK inhibitor therapy for UC (biologic / JAK inhibitor-experienced). Mirikizumab is also abbreviated as "Miri" herein.

[0232] Objectives and evaluation criteria: The following primary, secondary, and exploratory objectives and outcome measures will be evaluated for this study. Statistical analysis will be performed on the primary and main secondary outcome measures.

[0233] [Table 6-1]

[0234] [Table 6-2]

[0235] [Table 6-3] Abbreviations: NRS - Numerical Rating Scale; PGI - Patient's Overall Impression of Change; PGRS = Patient's Overall Severity Assessment; PUCAI = Pediatric Ulcerative Colitis Activity Index; SAP = Statistical Analysis Plan; UC = Ulcerative Colitis.

[0236] Research design: At weeks 0, 4, and 8, patients weighing less than 40 kg will receive a 300 mg induction dose of mirikizumab via IV infusion, while patients weighing 40 kg or more will receive a 5 mg / kg or 10 mg / kg induction dose via IV infusion. Enrollment will begin with the 300 mg and 5 mg / kg dose cohorts. Five patients in the 5 mg / kg dose cohort will receive mirikizumab for 4 weeks, and the available pharmacokinetics in the 5 mg / kg cohort will be evaluated. After enrollment in the 5 mg / kg dose cohort is complete, patients in the 10 mg / kg cohort will be enrolled.

[0237] Patients who achieve a modified Mayo score (MMS) clinical response at week 12 proceed to the maintenance phase and receive the standard dose (Q4W) of mirikizumab at 200 mg (over 40 kg), 100 mg (over 20 kg to 40 kg), or 50 mg (under 20 kg) until week 48.

[0238] Patients who do not meet the MMS clinical response definition at week 12 may receive an additional 12 weeks of extended IV induction (at the same dose, or gradually increased to 10 mg / kg for the 5 mg / kg dose cohort) or discontinue the treatment. After completion of IV administration at week 24, if the investigator determines that the patient has improved, the patient proceeds to the maintenance phase and receives the Q4W SC dose based on body weight class until week 48. If the investigator determines that sufficient improvement has not been achieved, the patient will discontinue the study drug and undergo procedures for early termination of the study drug (including post-treatment follow-up as described in the Schedule of Activities).

[0239] Upon completion of the maintenance period (week 52), all patients will have the option to either enter the 3-year extended study I6T-MC-AMAZ (AMAZ) or enter a post-treatment follow-up period (12 weeks if the last dose was administered via SC, or 16 weeks if the last dose was administered via IV).

[0240] [Table 7]

[0241] Inclusion criteria: Patients eligible for inclusion in this trial must meet all of the following criteria: 1. Male or female patients who weigh more than 10 kg at the time of informed consent and are between 2 years of age and 18 years of age. 2. Having an established diagnosis of UC with a pre-baseline period of 3 months or more, including endoscopic evidence of UC confirmed by a histopathological report. 3. Having moderate to severe active ulcerative colitis (UC) defined by an ES of 2 or higher and an MMS of 4-9 within 14 days prior to the first dose (baseline) of the study treatment. 4. Having evidence of ulcerative colitis (UC) extending proximal to the rectum, including the distal sigmoid colon. 5. Criteria for previous drug failure: The patient must have had an inadequate response, loss of response, or intolerance to at least one of the listed drugs. Documentation of the dose, frequency, route of administration, and duration of treatment for previous failures is required. [A] Patients who have failed with biologics: Patients who have an inadequate response, loss of response, or intolerance to at least one of the following drugs: ■ Corticosteroids Corticosteroid-refractory colitis, defined as signs and / or symptoms of active UC despite a two-week course of oral prednisone at a dose of 0.75 mg / kg / day or more or its equivalent, or a two-week course of oral prednisone at a dose of 40 mg / day or more, or ○Corticosteroid-dependent colitis is defined as follows: a. Inability to gradually reduce corticosteroids without recurrence of signs and / or symptoms of active UC, or b. Relapse within 3 months of completing the corticosteroid course, ○ A history of corticosteroid intolerance (including, but not limited to, evidence of severe side effects that interfere with continued treatment with corticosteroids, including, but not limited to, Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, growth retardation, or neuropsychiatric side effects associated with corticosteroid treatment, such as insomnia). ■Immunomodulators: ○ Despite treatment for at least three months with one of the following, the person has signs and / or symptoms of persistent active disease. ○ Oral AZA (1 mg / kg / day or more) or 6-MP (0.5 mg / kg / day or more), ○ Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or ○ A combination of thiopurine and allopurinol within the therapeutic range, as determined by thioguanine metabolite testing. ○MTX, either alone or in combination with another therapy. A history of intolerance to at least one immunomodulatory agent includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia. If treatment is discontinued despite clinical benefit, the patient is not considered unsuccessful or intolerant to non-biological therapies for UC. b. Patients with a history of biologics / JAK inhibitors: Patients who have had an inadequate response, lost response, or are intolerant to biologic therapy for UC (such as anti-TNF antibodies or anti-integrin antibodies) and / or JAK inhibitors (such as tofacitinib), as described below. The principal investigator must document an appropriate trial of the drug. Patients must meet at least one of the following criteria: ○ Inadequate response: persistent active signs and symptoms of the disease despite prescribed induction therapy, or ○ Loss of response: Recurrence of signs and symptoms of active disease during prescribed maintenance medication, following previous clinical benefit, or ○ Intolerance: A history of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or other biological agents, or to JAK inhibitors (including, but not limited to, fluid-related events, demyelination, congestive heart failure, or any other drug-related adverse events resulting in dose reduction or discontinuation of the medication). ○Discontinued taking the biological agent for any other reason. If discontinuation occurs despite clinical benefit, the patient is not considered to have an inadequate response to or intolerance to biologic or JAK inhibitor therapy for UC. 6. Inclusion Criteria for Dose Stabilization: Taking a stable dose of the following approved medications: ○ Oral 5-ASA compound: If the prescribed dose was stable for at least two weeks prior to the screening endoscopy. ○ Oral corticosteroid therapy (prednisone 0.5 mg / kg / day to a maximum of 30 mg / day or equivalent): If the prescribed dose was stable for at least one week prior to the screening endoscopy. ○AZA, 6-MP, and MTX: If these immunomodulators have been prescribed at stable doses for at least 8 weeks prior to screening endoscopy.

[0242] Results: Interim analysis of AMBU after a 12-week induction period and a 40-week maintenance period. PK, efficacy, and safety analyses were performed after a 12-week induction period in 26 pediatric participants (≤40 kg (n=15) and ≥40 kg (n=11)) with moderate to severe ulcerative colitis from the Phase 2 AMBU trial. Participants were evaluated for clinical response, clinical remission, and endoscopic remission at weeks 12 and / or 52, and safety was monitored throughout the trial. For pediatric patients ≥40 kg, observed exposure and estimated exposure in the PK model were similar to those in adults treated with 300 mg mirikizumab IV Q4W. No new safety findings were identified compared to the previous induction study (AMAN) conducted in adult patients with moderate to severe ulcerative colitis.

[0243] Intermediate data cutoff: ●20 participants are currently undergoing treatment or have completed treatment, of which: ○11 people completed the 52-week treatment, and ○Nine people were undergoing ongoing treatment, and ●Six participants discontinued treatment during the maintenance period. This included the following: ○One participant in the 300 mg mirikizumab group weighing over 40 kg experienced an adverse event due to worsening of UC. ○One participant in the 5 mg / kg mirikizumab group weighing 40 kg or less due to lack of efficacy, and ○Four participants in the 300 mg mirikizumab group weighing over 40 kg experienced a lack of efficacy.

[0244] Table 3. Summarizes the baseline characteristics of the patients.

[0245] [Table 8] Abbreviations: BMI = Body Mass Index; IV = Intravenous; miri = Mirikizumab; N = Number of participants in the analysis population; n = Number of participants in each specific category; SD = Standard deviation.

[0246] Analysis of effectiveness evaluation items As shown in Table 4, the interim analysis-inducing efficacy endpoint at week 12 demonstrated that pediatric patients across weight and dose ranges achieved clinically meaningful improvements in clinical response, clinical remission, and endoscopic remission, as measured by MMS and PUCAI. Due to a provisional data cut, maintenance efficacy data is available for less than half of the patients at week 52; however, the nine patients summarized in Table 5 also demonstrated clinically meaningful improvements in clinical response, clinical remission, and endoscopic remission, as measured by MMS and PUCAI. Furthermore, no significant new safety findings were observed. The benefit-risk balance was considered favorable.

[0247] [Table 9] Abbreviations: IV = intravenous; miri = mirikizumab; MMS = modified Mayo score; N = number of participants in the analysis population; n = number of participants in each specific category; PUCAI = Pediatric Ulcerative Colitis Activity Index. a. The response confidence interval is constructed using Wilson's method without continuity correction. b Endoscopic remission defined as MMS endoscopic subscore = 0 or 1 (excluding lithotripsy) c. Alternative MMS clinical remission is defined as SF=1 with a decrease of 1 point or more from baseline, RB subscore=0, and ES subscore=0 or 1 (excluding fragmentation).

[0248] [Table 10] Abbreviations: IV = intravenous; miri = mirikizumab; MMS = modified Mayo score; N = number of participants in the analysis population; n = number of participants in each specific category; PUCAI = Pediatric Ulcerative Colitis Activity Index. a. The response confidence interval is constructed using Wilson's method without continuity correction. b Endoscopic remission defined as MMS endoscopic subscore = 0 or 1 (excluding lithotripsy)

[0249] Results: Final analysis of AMBU at week 52 Table 6 summarizes the key demographic and baseline disease characteristics collected at AMBU baseline for the mITT population. Overall, demographic and disease characteristics were well-balanced across treatment groups and consistent with the population with moderate to severe active UC (Walsh et al. 2014; Peyrin-Biroulet et al. 2016). Note that the safety population in the study AMBU was the same as the mITT population.

[0250] [Table 11] Abbreviations: IV = intravenous; Kg = kilogram; mg = milligram; miri = mirikizumab; MMS = modified Mayo score; N = number of patients in the analysis population; n = number of patients in a specific category; PUCAI = pediatric ulcerative colitis activity index; SD = standard deviation; UC = ulcerative colitis. a. The study inclusion criteria classified moderate disease severity as MMS 4–6. However, the criteria have now been revised to MMS 5–6. In this study, one of the 26 participants had a baseline MMS of 4, while all others (96%) had a baseline MMS of 5 or higher.

[0251] Table 7 provides efficacy data from the AMBU study at week 52. Consistent with inductive data showing clinically meaningful changes in efficacy endpoints at week 12, further improvements in the efficacy endpoints of clinical remission, clinical response, endoscopic remission, and symptomatic remission were observed at week 52. At week 52, 10 / 18 (55.6%) of the week 12 responders were in clinical remission, endoscopic remission, and corticosteroid-free remission with MMS. Furthermore, the PUCAI response rate and remission rate were 77.8% and 72.2%, respectively, at week 52. Finally, of the week 12 clinical responders, 50% of pediatric participants met the criteria for histological-endoscopic mucosal remission at week 52.

[0252] [Table 12] Abbreviations: CI = Confidence Interval; mITT = Modified Intention to Treat; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; PUCAI = Pediatric Ulcerative Colitis Disease Activity Index. Note: Patients who experience loss of response and receive ad-hoc supplemental medication during the maintenance period are defined as non-responders at week 52 and are supplemented. a. The percentage of responses is n / Nx * It is calculated as 100%. Clinical remission is defined as follows: SF subscore = 0 or SF = 1, RB subscore = 0, and ES = 0 or 1 (excluding lithotripsy). c. Clinical response is defined as follows: a decrease of 2 points or more and a decrease of 30% or more in the MMS from baseline, and a decrease of 1 point or more in the RB subscore from baseline or an RB score of 0 or 1. d. PUCAI clinical remission is defined as follows: PUCAI score less than 10 points e.PUCAI clinical response is defined as follows: a decrease of 20 points or more in the baseline PUCAI score. f. Corticosteroid-free clinical remission is defined as follows: MMS clinical remission at week 52 and no corticosteroid use or UC-related surgery for at least 12 weeks prior to week 52. g. Endoscopic remission is defined as follows: ES = 0 or 1 (excluding lithotripsy) h. Symptom remission is defined as follows: SF=0, or SF=1 and RB=0, with a decrease of 1 point or more from baseline. i. Histological-endoscopic mucosal improvement is defined as achieving both histological and endoscopic improvement. j. Histological-endoscopic mucosal remission is defined as: achieving both histological and endoscopic remission. k. Alternative MMS clinical remission is defined as follows: SF subscore = 0, or SF = 1 with a decrease of 1 point or more from baseline, and RB subscore = 0, and ES subscore = 0 or 1 (excluding fragmentation).

[0253] Tables 8-25 provide subgroup analyses of key efficacy endpoints at week 52 between pediatric participants with previous biologic failures and those with biologic successes.

[0254] Clinical remission of modified Mayo score at week 52: Clinical remission by subgroup (previous biologic failure category) A total of 29.4% of participants in the biologic treatment failure subgroup and 55.6% of participants in the biologic treatment success subgroup achieved clinical remission at week 52 (Table 8).

[0255] [Table 13] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Millikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup. a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0256] Clinical remission at week 52 among induced clinical responders by subgroup (previous biologic failure category) Among the induced clinical responders (n=18), a total of 45.5% of participants in the biologic failure subgroup and 71.4% of participants in the biologic success subgroup achieved clinical remission at week 52 (Table 9).

[0257] [Table 14] Abbreviations: kg = kilogram; miri = mirikizumab; mg = milligram; SC = subcutaneous; CI = confidence interval; N = number of patients in the analysis population; n = number of patients in a specific subgroup; NRI = non-responder complementation; Ns = number of patients in each subgroup. a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0258] Clinical response by MMS subgroup (previous biologic failure category) at week 52 A total of 41.2% of participants in the biologics failure subgroup and 77.8% of participants in the biologics success subgroup achieved a clinical response at week 52 (see Table 10).

[0259] [Table 15] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated at 100%. b. The response confidence interval is constructed using Wilson's method without continuity correction.

[0260] Clinical response at week 52 among induced clinical responders by subgroup (previous biologic failure category) Of the induced clinical responders (n=18), a total of 63.6% of participants in the biologic failure subgroup and 100.0% of participants in the biologic success subgroup achieved a clinical response at week 52 (see Table 11).

[0261] [Table 16] Abbreviations: kg = kilogram; miri = mirikizumab; mg = milligram; SC = subcutaneous; CI = confidence interval; N = number of patients in the analysis population; n = number of patients in a specific subgroup; NRI = non-responder complementation; Ns = number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0262] PUCAI clinical remission at 52 weeks by subgroup (previous biologic treatment failure category) A total of 35.3% of participants in the biologic treatment failure subgroup and 77.8% of participants in the biologic treatment success subgroup achieved clinical remission at week 52 (see Table 12).

[0263] [Table 17] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0264] PUCAI clinical response by subgroup (previous biologics failure category) A total of 41.2% of participants in the biologics failure subgroup and 77.8% of participants in the biologics success subgroup achieved a PUCAI clinical response at week 52 (see Table 13).

[0265] [Table 18] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0266] Corticosteroid-free remission by subgroup (previous biologic failure category) A total of 29.4% of participants in the biologic treatment failure subgroup and 55.6% of participants in the biologic treatment success subgroup achieved corticosteroid-free clinical remission at week 52 (see Table 14).

[0267] [Table 19] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0268] Endoscopic remission at 52 weeks in a subgroup (previously classified as unsuccessful with biologics). A total of 29.4% of participants in the biologic treatment failure subgroup and 55.6% of participants in the biologic treatment success subgroup achieved endoscopic remission at week 52 (see Table 15).

[0269] [Table 20] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of response is calculated as n / Ns * at 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0270] Endoscopic remission at week 52 among subgroup (previous biological agent non-responders subgroup) of induced endoscopic remitters Among the 14 induced endoscopic remitters, a total of 55.6% of the participants in the biological agent non-responder subgroup and 80.0% of the participants in the biological agent responder subgroup achieved endoscopic remission at week 52 (see Table 16).

[0271] [Table 21] Abbreviations: kg = kilogram; miri = mirikizumab; mg = milligram; SC = subcutaneous; CI = confidence interval; N = number of patients in the analysis population; n = number of patients within a specific subgroup; NRI = non-responder imputation; Ns = number of patients in each subgroup a. The percentage of response is calculated as n / Ns * at 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0272] Endoscopic subscore (ES) = 0 at week 52 by subgroup (previous biological agent non-responders subgroup) A total of 17.6% of the participants in the biological agent non-responder subgroup and 33.3% of the participants in the biological agent responder subgroup achieved an endoscopic subscore of 0 at week 52 (Table 17).

[0273] [Table 22] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0274] Symptom remission during the maintenance period at weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. The proportion of patients in symptom remission at the relevant study visit increased from baseline at all relevant visits during the maintenance period. NRI analysis showed that a total of 14 participants (53.8%) were in symptom remission at week 20, and the proportion of patients achieving symptom remission remained relatively stable at all subsequent relevant visits. A total of 12 participants (46.2%) were in symptom remission at week 52 (Table 18).

[0275] [Table 23] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific segment; NRI = Non-responder Complementary; SC = Subcutaneous. a. The response confidence interval is constructed using the Wilson method without continuity correction.

[0276] Symptom remission at weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 by subgroup (previous biologics failure category). The proportion of participants in the biologics-unsuccessful subgroup in achieving symptom remission increased from baseline at all relevant visits and remained relatively stable from week 16 to week 52 (n=6 [35.3%]). The proportion of participants in the biologics-successful subgroup in achieving symptom remission increased from baseline at all relevant visits and remained relatively stable from week 16 to week 52 (n=6 [66.7%]) (Table 19).

[0277] [Table 24-1]

[0278] [Table 24-2] (Continued from Table 19)

[0279] [Table 24-3] (Continued from Table 19) Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup; SC = Subcutaneous. a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0280] Histological and endoscopic mucosal improvement at 52 weeks by subgroup (previous biologic failure category). Five participants (29.4%) in the biologics unsuccessful subgroup and four participants (44.4%) in the successful subgroup achieved histological-endoscopic mucosal improvement at week 52 (Table 20).

[0281] [Table 25] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup; SC = Subcutaneous. a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0282] Histological and endoscopic mucosal remission at 52 weeks by subgroup (previous biologic failure category) A total of 29.4% of participants in the biologic treatment failure subgroup and 44.4% of participants in the biologic treatment success subgroup achieved histological-endoscopic mucosal remission at week 52 (Table 1).

[0283] [Table 26] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0284] Alternative modified Mayo clinical remission at week 52: Clinical remission by subgroup (previous biologic failure category) A total of 29.4% of participants in the biologic treatment failure subgroup and 44.4% of participants in the biologic treatment success subgroup achieved surrogate MMS clinical remission at week 52 (Table 22).

[0285] [Table 27] Abbreviations: CI = Confidence Interval; mITT = Modified Treatment Intent; SC = Subcutaneous; IV = Intravenous; Miri = Mirikizumab; N = Number of patients in the mITT population; n = Number of patients in each specific subgroup; NRI = Non-responder Complementary; Kg = Kilogram; mg = Milligram; Ns = Number of patients in each subgroup a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0286] Surrogate MMS clinical remission at 52 weeks among induced clinical responders by subgroup (previous biologic failure category) Among the induced clinical responders (n=18), a total of 45.5% of participants in the biologic failure subgroup and 57.1% of participants in the biologic success subgroup achieved clinical remission at week 52 (Table 23).

[0287] [Table 28] Abbreviations: kg = kilogram; miri = mirikizumab; mg = milligram; SC = subcutaneous; CI = confidence interval; N = number of patients in the analysis population; n = number of patients in a specific subgroup; NRI = non-responder complementation; Ns = number of patients in each subgroup. a. The percentage of responses is n / Ns * It is calculated as 100%. b. The response confidence interval is constructed using the Wilson method without continuity correction.

[0288] Calprotectin in feces at 52 weeks Table 24 provides a summary of fecal calprotectin (change from baseline) at week 52. After maintenance with mirikizumab, participants had a mean decrease of -3447.54 from baseline in fecal calprotectin.

[0289] [Table 29] Abbreviations: IV = intravenous; Kg = kilogram; miri = mirikizumab; mBOCF = modified baseline rollover; mg = milligram; N = number of patients in the analysis population; Q4W = every 4 weeks; SC = subcutaneous; SD = standard deviation; mITT = modified treatment intent

[0290] CRP at 52 weeks Table 25 provides a summary of serum C-reactive protein (change from baseline) at week 52. After maintenance with mirikizumab, participants had a mean reduction of CRP from baseline of -2.65.

[0291] [Table 30] Abbreviations: IV = intravenous; Kg = kilogram; miri = mirikizumab; mBOCF = modified baseline rollover; mg = milligram; N = number of patients in the analysis population; Q4W = every 4 weeks; SC = subcutaneous; SD = standard deviation; mITT = modified treatment intent

[0292] Example 2. A multicenter, open-label phase 3 study to investigate the efficacy, pharmacokinetics, and safety of mirikizumab in participants aged 2 to under 18 years with moderate to severe active ulcerative colitis. The AMBA study is a multicenter, open-label phase 3 study to investigate the efficacy, pharmacokinetics, and safety of mirikizumab in male and female children and adolescents aged 2 to under 18 years with moderate to severe active ulcerative colitis, defined as having an endoscopic subscore of 2 or higher and an MMS of 5–9 within 28 days prior to the first dose.

[0293] Primary evaluation: The proportion of children and adolescents with moderate to severe active UC who achieved a clinical response at 12 weeks after mirikizumab induction therapy and achieved MMS clinical remission at 52 weeks, compared to the proportion of adults in Study AMBG who achieved a clinical response at 12 weeks and were re-randomized to placebo treatment after achieving a clinical response at 12 weeks in Study AMAN, without discontinuing the study intervention or receiving ad-hoc add-ons before 52 weeks.

[0294] Objectives and evaluation criteria: The following primary, secondary, and exploratory objectives and outcome measures will be evaluated for this study. Statistical analysis will be performed on the primary and main secondary outcome measures.

[0295] [Table 31-1]

[0296] [Table 31-2] Abbreviation: AUC = area under the curve; C max = Peak concentration of drug in the blood after dose administration; CRP = C-reactive protein; MMS = Modified Mayo score; NRS = Numerical Rating Scale; PGI-C = Patient's overall impression of change; PGR-S = Patient's overall severity assessment; PK = Pharmacokinetics; PUCAI = Pediatric Ulcerative Colitis Activity Index; TEADA = Anti-drug antibodies present during treatment; UC = Ulcerative Colitis; UCEIS = Endoscopic Severity Index of Ulcerative Colitis; WPAI+CIQ:UC = Work Productivity and Activity Impairment Questionnaire + Classroom Impairment Questionnaire for Ulcerative Colitis.

[0297] Research design: The exam has four examination periods. Period I Screening Period II - Milikizumab open-label induction Induction period from weeks 2-6 and 0-12: Participants receive three induction doses according to their body weight at each medication visit.

[0298] Period III - Open-label maintenance with mirikizumab Maintenance period from weeks 7-17 and 12-52: Participants receive either an extended induction dose or a maintenance dose of mirikizumab at each medication visit, according to their body weight, up to week 52.

[0299] Period II - Milikizumab open-label induction Induction period from weeks 2-6 and 0-12: Participants receive three induction doses according to their body weight at each medication visit.

[0300] Period III - Open-label maintenance with mirikizumab Maintenance period from weeks 7-17 and 12-52 - Participants receive either a prolongation induction dose or a maintenance dose of mirikizumab at each medication visit, according to their body weight, up to week 52.

[0301] After the 17th and 52nd week visits, all participants will have the option of either joining the AMAZ study or entering a post-procedure follow-up period.

[0302] With the approval of the study sponsor, additional medication may be administered at week 52 and UV may be administered after week 52, if necessary, to eligible participants for enrollment in the AMAZ study, for which the clinical trial site is not yet open.

[0303] Participants must complete all procedures by visit 16, and any additional medication should be administered at a 4-week interval (±7 days) from the previous dose.

[0304] Period IV: Safety follow-up for approximately 16 weeks after the last treatment visit. This trial will also evaluate the safety and efficacy of extension induction for participants who did not have a clinical response at week 12, and the effectiveness of ad-hoc additional treatments for participants who lost a clinical response during the maintenance phase.

[0305] In the opinion of the principal investigator, participants who have received a clinical benefit may proceed to a 3-year extended study (I6T-MC-AMAZ) instead of safety follow-up.

[0306] [Table 32]

[0307] Inclusion criteria: Patients eligible for inclusion in this trial must meet all of the following criteria: 1. Male or female patients who weigh more than 10 kg at the time of informed consent and are between 2 years of age and 18 years of age. 2. Having an established diagnosis of UC with a pre-baseline period of 3 months or more, including endoscopic evidence of UC confirmed by a histopathological report. 3. Having moderate to severe active ulcerative colitis (UC) defined by an ES of 2 or higher and a MMS of 5-9 within 28 days prior to the first dose (baseline) of the study treatment. 4. Having evidence of ulcerative colitis (UC) extending proximal to the rectum, including the distal sigmoid colon. 5. Criteria for previous drug failure: The patient must have had an inadequate response, loss of response, or intolerance to at least one of the listed drugs. Documentation of the dose, frequency, route of administration, and duration of treatment for previous failures is required. [A] Patients who have failed with biologics: Patients who have an inadequate response, loss of response, or intolerance to at least one of the following drugs: ■ Corticosteroids ○ Corticosteroid-refractory colitis, defined as signs and / or symptoms of active UC despite a two-week course of oral prednisone at a dose of 0.75 mg / kg / day or higher or its equivalent, or a two-week course of oral prednisone at a dose of 40 mg / day or higher, or an eight-week course of budesonide MMX at 9 mg / day. ○Corticosteroid-dependent colitis is defined as follows: a. Inability to gradually reduce corticosteroids without recurrence of signs and / or symptoms of active UC, or b. Relapse within 3 months of completing the corticosteroid course, ○ Corticosteroid intolerance (including, but not limited to, evidence of a serious adverse event that interferes with continued treatment with corticosteroids, including, but not limited to, Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, growth retardation, or neuropsychiatric side effects such as insomnia associated with corticosteroid treatment). ■Immunomodulators: ○ Despite treatment for at least three months with one of the following, the person has signs and / or symptoms of persistent active disease. ○ Oral AZA (1 mg / kg / day or more) or 6-MP (0.5 mg / kg / day or more), ○ Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or ○ A combination of thiopurine and allopurinol within the therapeutic range, as determined by thioguanine metabolite testing. ○MTX, either alone or in combination with another therapy. A history of intolerance to at least one immunomodulatory agent includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia. If selective discontinuation occurs despite clinical benefit, the patient is not considered unsuccessful or intolerant to non-biological therapy for UC. b. Patients with a history of biologics / JAK inhibitors: Patients who have had an inadequate response, lost response, or are intolerant to biologic therapy for UC (such as anti-TNF antibodies or anti-integrin antibodies) and / or JAK inhibitors (such as tofacitinib), as described below. The principal investigator must document an appropriate trial of the drug. Patients must meet at least one of the following criteria: ○ Inadequate response: persistent active signs and symptoms of the disease despite prescribed induction therapy, or ○ Loss of response: Recurrence of signs and symptoms of active disease during prescribed maintenance medication, following previous clinical benefit, or ○ Intolerance: A history of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, upadacitinib, or other biological agents, or to JAK inhibitors (including, but not limited to, fluid-related events, demyelination, congestive heart failure, or any other drug-related adverse events resulting in dose reduction or discontinuation of the medication). ○Discontinued taking the biological agent for any other reason. If discontinuation occurs despite clinical benefit, the patient is not considered to have an inadequate response to or intolerance to biologic or JAK inhibitor therapy for UC. 6. Inclusion Criteria for Dose Stabilization: Taking a stable dose of the following approved medications: ○ Oral 5-ASA compound: If the prescribed dose was stable for at least two weeks prior to the screening endoscopy. ○ Oral corticosteroid therapy (prednisone 1.5 mg / kg / day or less to a maximum of 40 mg / day or equivalent): If the prescribed dose was stable for at least one week prior to the screening endoscopy. ○AZA, 6-MP, and MTX: At least 8 weeks before screening endoscopy.

[0308] array Sequence ID 1: Millikizumab heavy chain variable region (HCVR) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

[0309] Sequence ID 2: Milikizumab light chain variable region (LCVR) DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK

[0310] Sequence ID 3: Millikizumab heavy chain (HC) QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0311] Sequence ID 4: milikizumab light chain (LC) DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Claims

1. A composition comprising mirikizumab for use in a method of treating a patient requiring treatment for moderate to severe active ulcerative colitis (UC), wherein the method comprises administering at least one induction dose of mirikizumab to the patient at a dose of about 5 mg / kg to about 10 mg / kg, wherein the patient is between 2 years and under 18 years of age and has a body weight of about 10 kilograms (kg) to 40 kg or less.

2. The composition according to claim 1, wherein the induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg.

3. The composition according to claim 1, wherein the induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg.

4. The composition according to any one of claims 1 to 3, wherein three induction doses of mirikizumab are administered to the patient.

5. The composition according to claim 1, wherein the induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks.

6. The composition according to claim 1, wherein the induction dose of mirikizumab is administered to the patient at 4-week intervals.

7. The composition according to claim 1, wherein the induction dose of mirikizumab is administered to the patient at 0, 4, and 8 weeks.

8. The composition according to claim 1, wherein the induction dose is delivered over a 12-week induction period.

9. The composition according to claim 1, wherein if the patient has not achieved a therapeutic response 4 to 12 weeks after the last induction dose has been administered, one, two, or three extension induction doses of mirikizumab are administered to the patient at approximately 5 mg / kg to approximately 10 mg / kg.

10. The composition according to claim 9, wherein if the patient has a body weight of approximately 10 kg to 40 kg or less, an extended induction dose of mirikizumab is administered to the patient at approximately 10 mg / kg.

11. The composition according to claim 9, wherein if the patient has a body weight of approximately 10 kg to 40 kg or less, an extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg.

12. The composition according to claim 9, wherein at least one extension induction dose is administered to the patient 4 to 8 weeks after the last induction dose.

13. The composition according to claim 9, wherein three prolongation induction doses of mirikizumab are administered to the patient.

14. The composition according to claim 9, wherein the extended induction dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks.

15. The composition according to claim 9, wherein the extended induction dose of mirikizumab is administered to the patient at 4-week intervals.

16. The composition according to claim 1, wherein the method further comprises administering at least one maintenance dose of mirikizumab to the patient in an amount of about 50 mg to about 100 mg, the maintenance dose being administered after the last induction dose or the last extension induction dose.

17. The composition according to claim 16, wherein if the patient has a body weight of about 10 kg to 20 kg or less, a maintenance dose of mirikizumab is administered to the patient at about 50 mg.

18. The composition according to claim 16, wherein if the patient has a body weight of more than 20 kg but not exceeding 40 kg, a maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

19. The composition according to claim 16, wherein if the patient achieves a therapeutic effect from the last induction or extended induction dose administered to the patient, the maintenance dose of mirikizumab is administered to the patient.

20. The composition according to claim 16, wherein if the patient loses the therapeutic effect during maintenance therapy, one, two, or three ad-hoc surcharge doses of mirikizumab are administered to the patient at a dose of approximately 5 mg / kg to approximately 10 mg / kg.

21. The composition according to claim 20, wherein if the patient has a body weight of approximately 10 kg to 20 kg or less, an additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg.

22. The composition according to claim 20, wherein if the patient has a body weight of more than 20 kg but not exceeding 40 kg, an additional dose of mirikizumab is administered to the patient at approximately 10 mg / kg.

23. The composition according to claim 20, wherein the temporary additional dose is administered to the patient 4 to 8 weeks after the last maintenance dose.

24. The composition according to claim 20, wherein the aforementioned temporary additional dose is administered to the patient at intervals of 4 to 8 weeks.

25. The composition according to claim 20, wherein the aforementioned temporary additional dose is administered to the patient at four-week intervals.

26. The composition according to claim 20, wherein if the patient achieves a therapeutic effect 4 to 12 weeks after one, two, or three ad-hoc supplemental doses, a maintenance dose of mirikizumab is administered to the patient at approximately 50 mg or approximately 100 mg.

27. The composition according to claim 26, wherein if the patient has a body weight of about 10 kg to 20 kg or less, a maintenance dose of mirikizumab is administered to the patient at about 50 mg.

28. The composition according to claim 26, wherein if the patient has a body weight of approximately 20 kg to 40 kg or less, a maintenance dose of mirikizumab is administered to the patient at approximately 100 mg.

29. The composition according to claim 16 or 26, wherein the maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last induction dose, extension induction dose, or temporary escalator dose.

30. The composition according to claim 29, wherein the maintenance dose of mirikizumab is administered to the patient four weeks after the last induction dose, extension induction dose, or extra dose.

31. The composition according to claim 16 or 26, wherein the maintenance dose of mirikizumab is administered to the patient at intervals of 4 to 8 weeks.

32. The composition according to claim 31, wherein the maintenance dose of mirikizumab is administered to the patient at four-week intervals.

33. The composition according to claim 16 or 26, wherein the maintenance dose of mirikizumab is administered to the patient by subcutaneous injection.

34. The composition according to claim 1 or 9, wherein the induction dose of mirikizumab is administered to the patient by intravenous infusion.

35. The aforementioned method involves administering three induction doses of mirikizumab to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at 4-week intervals. This includes administering a maintenance dose of approximately 50 mg of mirikizumab to the patient by subcutaneous injection at 4-week intervals, 2 to 8 weeks after the last induction dose has been administered. The composition according to claim 1, wherein the patient is between 2 years of age and under 18 years of age and has a body weight of approximately 10 kg to 20 kg or less.

36. The method involves administering three induction doses of mirikizumab to the patient by intravenous infusion at approximately 5 mg / kg or approximately 10 mg / kg at intervals of approximately 4 weeks, and thereafter, This includes administering a maintenance dose of approximately 100 mg of mirikizumab to the patient by subcutaneous injection at intervals of approximately 4 weeks, 2 to 8 weeks after the last induction dose has been administered. The composition according to claim 1, wherein the patient is between 2 years of age and under 18 years of age and has a body weight of 20 kg to 40 kg or less.

37. If the patient has not achieved a therapeutic effect 4 to 12 weeks after the administration of the last induction dose, three extension induction doses of mirikizumab are administered to the patient. If the patient has a body weight of approximately 10 kg to 40 kg or less, the extended induction dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The composition according to claim 35, wherein the extended induction dose of mirikizumab is administered to the patient by intravenous infusion at 4-week intervals.

38. The composition according to claim 37, wherein if the therapeutic effect is achieved 4 to 12 weeks after the last extension induction dose is administered, a maintenance dose of mirikizumab is administered to the patient 2 to 8 weeks after the last extension induction dose.

39. If the patient loses the therapeutic effect during maintenance therapy, one, two, or three ad-hoc surcharge doses of mirikizumab may be administered to the patient. If the patient has a body weight of approximately 10 kg to 40 kg or less, the temporary additional dose of mirikizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The composition according to claim 35, wherein the aforementioned temporary additional dose of mirikizumab is administered to the patient by intravenous infusion at four-week intervals.

40. The composition according to claim 39, wherein if the patient achieves a therapeutic effect 4 to 12 weeks after the first, second, or third ad-hoc supplemental doses, a further maintenance dose of mirikizumab is administered to the patient by subcutaneous injection at 4-week intervals.

41. The composition according to claim 1, wherein the patient achieves at least one of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of mirikizumab administration: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom remission, symptom response, clinical remission without surgery, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, remission of defecation urgency, improvement of defecation urgency, improvement of defecation frequency, and improvement of rectal bleeding.

42. The composition according to claim 40, wherein at least one therapeutic effect is achieved within approximately 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab.

43. The composition according to claim 40, wherein one or more of the aforementioned therapeutic effects are sustained during the maintenance period.

44. The composition according to claim 43, wherein the patient has maintained clinical remission without surgery for 52 weeks and without using steroids for at least 12 weeks prior to the 52nd week of mirikizumab administration.

45. The composition according to claim 1, wherein the patient has not used any biological agents and / or has not used any advanced therapy.

46. The composition according to claim 1, wherein the patient is a patient who has not responded to conventional medications.

47. The composition according to claim 1, wherein the patient has experienced biological agents and / or advanced therapy.

48. The composition according to claim 1, wherein the patient is a patient who has failed biological agents and / or a patient who has failed advanced therapy.

49. The composition according to claim 1, wherein the patient is unresponsive, has an insufficient response, has lost response, or is intolerant to at least one prior treatment for ulcerative colitis.

Images