Methods of treating ulcerative colitis

Abstract

Provided herein are methods, uses, and pharmaceutical compositions of anti-IL-23p19, such as migerizumab, for the treatment of ulcerative colitis in pediatric patients. Also provided herein are doses and dosing regimens for methods and uses of an anti-IL-23p19 antibody, such as migerizumab, for the treatment of ulcerative colitis in a pediatric patient.

Description

[0001] Field of the invention

[0002] The present invention relates to antibodies that bind human IL-23p19 (“anti-IL-23p19 antibodies”), methods, uses and pharmaceutical compositions of, such as mirikizumab, for the treatment of ulcerative colitis in pediatric patients. The present invention also relates to dosage and dosing regimen of anti-IL-23p19 antibodies for methods and uses of treating ulcerative colitis in pediatric patients. BACKGROUND

[0004] Ulcerative colitis (UC) is a chronic disease of unknown cause characterized by inflammation in the colon. Patients have intermittent exacerbations of disease interspersed with periods of remission; major symptoms include blood in the stool, diarrhea, bowel urgency, and abdominal pain. The incidence of pediatric UC is reported to be rising worldwide, accounting for approximately 15% to 20% of all UC, and is characterized by extensive disease in 60%-80% of all pediatric cases, with a frequency of hospitalization for acute severe exacerbations (25%-30% in 3-4 years) and medically refractory disease colectomy (up to 30%-40% at 10-year follow-up) that is twice that of adults (Sykora J. et al., World J Gastroenterol., 2018 Jul 7;24(25):2741-2763). The presentation and natural history of pediatric UC differ from adult UC in that most pediatric-onset UC presents as extensive colitis affecting the entire colon, with atypical features including visualizable rectal sparing (5-30%), retrograde ileitis associated with severe pancolitis, and limited distal disease with other right colon normal (cecal patch) associated with mild fecal inflammation (Colman RJ. et al., Frontiers in Pediatrics 2021 Feb 17;9:634739). In addition to more severe colitis, children have unique age-related issues, such as growth and pubertal delay, nutritional deficiencies and increased bone mineral density, and different psychosocial needs (Sykora J. et al., World J Gastroenterol. 2018).

[0005] Interleukin-23 (IL-23), a member of the cytokine interleukin-12 (IL-12) family, is a heterodimeric protein composed of a p40 subunit shared with IL-12, and a p19 subunit specific to IL-23. Binding of IL-23 receptor leads to activation of JAKs (mainly TYK2 and JAK2) and signal transducer and activator of transcription 3 and 4 (STAT3 and STAT4), triggering transcription of downstream target genes. IL-23 promotes differentiation, maintenance and stabilization of pathogenic T cell lineages, including populations that simultaneously produce multiple pro-inflammatory cytokines such as interferon-gamma, IL-17A, IL-17F and IL-22, as well as activation and induction of effector functions of innate lymphoid cells in colitis. Therapeutic blockade of p40 has been found to be effective in treating UC, and drugs targeting p19 are being investigated for the treatment of UC. To date, no anti-IL23p19 biologic has been approved for the treatment of pediatric or adult UC.

[0006] The therapeutic goal in pediatric patients with UC is to induce and maintain remission, including steroid-free remission, with endoscopic healing. Conventional therapies such as corticosteroids, immunomodulatory therapies such as thiopurines (e.g. azathioprine (AZA), 6-mercaptopurine (6-MP)), tacrolimus and methotrexate have limitations in terms of efficacy, safety and tolerability. For example, corticosteroids, while effective in inducing clinical response or remission, are not effective in maintaining remission, and have been reported to have steroid-related complications, including osteopenia, acne, glaucoma, cataracts, growth suppression, with 45% of patients reporting development of corticosteroid dependence and requiring additional medical 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, while used to treat UC in pediatric patients, require close monitoring for potential toxicities such as myelosuppression and other toxicities (Turner D et al., Journal of Pediatric Gastroenterology and Nutrition 2018). In patients 5 years of age or older, anti-TNF biologies including infliximab and adalimumab are indicated for the treatment of moderate to severe UC, however, drawbacks to their application include, for example, development of anti-drug antibodies and potential side effects.

[0007] Treatment of adult patients with risutuximab has been reported in WO2019191464. However, due to the significant and severe manifestations 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. SUMMARY

[0009] Provided herein are methods, uses, and pharmaceutical compositions of an anti-IL-23p19 antibody, such as risutuximab, for treating moderate to severe active ulcerative colitis in pediatric patients. Further, provided herein are dosages and dosing regimens of an anti-IL-23p19 antibody, such as risutuximab, for methods and uses of treating moderate to severe ulcerative colitis in pediatric patients 2 years to less than 18 years of age who are inadequate responders to non-biologic therapy for UC, lost response, or intolerant to non-biologic therapy for UC (biologic naive or biologic treatment failure are used interchangeably herein), and / or have been exposed to at least 1 biologic and / or advanced therapy (e.g., TNFa and / or JAK inhibitor) for UC. Further, the dosages and dosing regimens provided herein demonstrate clinical efficacy through about week 4 to about week 12 of treatment in such patients, and / or maintain clinical efficacy through about week 52 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 symptom relief). The dosages and dosing regimens provided herein further demonstrate histological endoscopic mucosal improvement, histological endoscopic mucosal remission, and or corticosteroid-free remission through about week 52 of treatment. In addition, the dosages and dosing regimens of the invention have acceptable PK and immunogenicity profiles.

[0010] Thus, in a first aspect, provided herein is a method of treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof, the method comprising administering to the patient an induction dosage of risutuximab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kilograms (kg).

[0011] Accordingly, in a first aspect, provided herein are methods of treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof who is non-responsive, insufficiently responsive, lost response, or intolerant to at least one prior therapy, comprising administering to the patient an induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kilograms (kg). In such embodiments, the prior therapy can be a biologic, an advanced therapy, or a non-biologic therapy, such as an immunomodulator or a corticosteroid.

[0012] In some embodiments of the methods of the application as provided herein, the methods of treating moderate to severe active ulcerative colitis in a patient in need thereof comprise administering to the patient an induction dose of mirikizumab, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kg to less than or equal to 40 kg, administering to the patient an induction dose of mirikizumab at a dose that is based on the patient’s 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 other embodiments, the induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In alternative embodiments, the induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0013] In certain embodiments of the methods of the application, the induction dose of mirikizumab is administered to the patient once, twice, or three times. In further embodiments of the methods of the application, the induction dose of mirikizumab is administered to the patient three times. In particular embodiments, the induction dose is administered to the patient at intervals of 4-8 weeks (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks). In more particular embodiments, the induction dose is administered to the patient at intervals of 4 weeks. In certain embodiments, the induction dosing period (induction period) lasts for 4, 8, or 12 weeks. In particular embodiments, the induction period lasts for 12 weeks. In even more particular embodiments, the induction dose is administered to the patient at 0, 4, and 8 weeks. The induction dose is delivered during the induction dosing period.

[0014] In embodiments of the application, the induction dose of mirikizumab is administered to the patient by intravenous infusion.

[0015] In certain embodiments of the methods of the present application, if the patient has not achieved a clinical response 4-8 weeks after administration of the last induction dose, the patient is administered one, two, or three extended induction doses of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kilograms (kg). In other embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered an extended induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg. In other embodiments, the patient is administered an extended induction dose of mirikizumab at about 5 mg / kg. In alternative embodiments, the patient is administered an extended induction dose of mirikizumab at about 10 mg / kg.

[0016] In yet other embodiments, the patient is administered three extended induction doses of mirikizumab at 4-8 week intervals. In more particular embodiments of the present application, the patient is administered three extended induction doses of mirikizumab at 4 week intervals.

[0017] In embodiments of the present application, the one, two, or three extended induction doses of mirikizumab are administered by intravenous infusion.

[0018] In other embodiments of the present application, if the patient achieves a clinical response at the end of the induction period or at the end of the extended induction period, then the patient is administered a maintenance dose of mirikizumab. The extended doses are delivered over the extended induction dosing period.

[0019] In certain embodiments of the methods of treating moderate to severe active ulcerative colitis in a patient in need thereof, the patient is administered a maintenance dose of mirikizumab at about 50 mg to about 100 mg, wherein the maintenance dose is administered to the patient after administration of the last induction dose or the last extended induction dose. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the patient is administered a maintenance dose of mirikizumab at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the patient is administered a maintenance dose of mirikizumab at about 100 mg.

[0020] In such embodiments of the method of treating moderate to severe active ulcerative colitis in a patient in need thereof, the first maintenance dose of mirikizumab is administered to the patient 2-8 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks) after the last induction dose or the last extended induction dose is administered to the patient. In preferred embodiments, the first maintenance dose of mirikizumab is administered 4-6 weeks after the last induction dose or the last extended induction dose is administered. Further preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose is administered. In yet other embodiments, additional maintenance doses of mirikizumab are administered to the patient at 4 or 8 week intervals after the first maintenance dose is administered. Preferably, the maintenance doses are administered at 4 week intervals.

[0021] In embodiments of the application, the maintenance doses are administered by subcutaneous injection.

[0022] The 4-8 week period of time over which the maintenance doses are administered accommodates variation in the period between administration of the last extended induction dose and the extended induction end assessment. This variation can arise from variation in the frequency of dosing during the extended induction period. In some embodiments, the frequency of dosing during the extended induction period is once every 4 weeks, and the extended induction end assessment occurs 4 weeks after administration of the last extended induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose can be administered at the induction end assessment visit (i.e., 4 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. Alternatively, the frequency of dosing during the extended induction period is once every 8 weeks, and the extended induction end assessment occurs 8 weeks after administration of the last extended induction dose. If the patient achieves a clinical response, the first maintenance dose can be administered at the induction end assessment visit (i.e., 8 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. In such embodiments, the maintenance doses of mirikizumab are administered after the patient achieves a clinical response from one, two, or three extended induction doses.

[0023] In yet other embodiments of the method of treating moderate to severe active ulcerative colitis in a patient in need thereof, if the patient develops as a loss of response during maintenance dosing (the maintenance period), the maintenance doses are delivered during maintenance dosing.

[0024] Two to eight weeks after the last maintenance dose, the patient is administered a rescue dose of mirikizumab. In such embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered a rescue dose of mirikizumab at about 5 mg / kg to about 10 mg / kg. In some embodiments, the patient is administered a rescue dose of mirikizumab at about 5 mg / kg. In other embodiments, the patient is administered a rescue dose of mirikizumab at about 10 mg / kg.

[0025] In some embodiments of the application, the patient is administered one, two, or three rescue doses of mirikizumab at intervals of 4-8 weeks. In yet other embodiments, the patient is administered two or three rescue doses of mirikizumab at intervals of 4-8 weeks. In preferred embodiments of the application, the patient is administered three rescue doses of mirikizumab at intervals of 4 weeks. The rescue doses are delivered over a rescue dosing period.

[0026] In embodiments of the application, the rescue doses are administered by intravenous infusion.

[0027] In other embodiments of the application, if the patient achieves a clinical response 4-12 weeks (rescue dosing period) after one, two, or three rescue doses, the patient is administered maintenance doses of mirikizumab. In such embodiments, the patient is administered maintenance doses based on weight and intervals as described above.

[0028] In such embodiments of the method of treating moderate to severe active ulcerative colitis in a patient in need thereof, the patient is administered maintenance doses of mirikizumab at about 50 mg to about 100 mg. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the patient is administered maintenance doses of mirikizumab at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the patient is administered maintenance doses of mirikizumab at about 100 mg.

[0029] In such embodiments of the method of treating moderate to severe active ulcerative colitis in a patient in need thereof, the patient is administered maintenance doses of mirikizumab 2-8 weeks after the last rescue dose is administered to the patient. In preferred embodiments, the maintenance doses of mirikizumab are administered 2-6 weeks after the last rescue dose is administered. Further preferably, the maintenance doses are administered 2 weeks or 4 weeks after the last rescue dose is administered. In yet other embodiments, the patient is administered additional maintenance doses of mirikizumab at intervals of 4 or 8 weeks. Preferably, the maintenance doses are administered at intervals of 4 weeks.

[0030] In particular embodiments of the method of treating moderate to severe active ulcerative colitis in a patient in need thereof, the patient is administered a maintenance dose of mirikizumab for up to about 4 weeks, 8 weeks, week 12, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, week 52, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or 104 weeks up to about 152 weeks after administration of the last induction dose, the last extended induction dose, or the last rescue dose. In certain embodiments, the maintenance dose is administered for up to about 1 year, 2 years, 3 years, or about 4 years.

[0031] In embodiments of the methods of the present application, the patient achieves at least one or more of a therapeutic effect of clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptomatic relief, symptomatic response, clinical remission without surgery, corticosteroid free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, improvement in stool frequency, improvement in rectal bleeding within about 2 weeks to about 48 weeks of treatment with mirikizumab. In such embodiments of the methods of the present application, at least one or more of the therapeutic effects is achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, or 48 weeks of treatment with mirikizumab. Such therapeutic effects can be achieved during the induction period, the extended induction period, and / or the rescue period. In certain embodiments, the therapeutic effects can be achieved during the maintenance period, which can be a maintenance period following the induction period, a maintenance period following the extended induction period, or a maintenance period following the rescue period.

[0032] In embodiments of the methods of the present application, the patient achieves a reduction from baseline in fecal calprotectin and C-reactive protein within about 2 weeks to about 48 weeks of treatment with mirikizumab.

[0033] In other embodiments of the methods of the invention, the patient shows a sustained therapeutic effect in at least one or more of clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptomatic relief, symptomatic response, surgery-free clinical remission, corticosteroid-free clinical remission, histologic endoscopic mucosal remission, histologic endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, improvement in stool frequency, improvement in rectal bleeding during the maintenance period. In such embodiments, the therapeutic effect is sustained for up to about 4 weeks, 8 weeks, week 12, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, week 52, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 104 weeks up to about 152 weeks in the maintenance period after the end of the induction period, extended induction period, or rescue period.

[0034] In other embodiments, the patient has a surgery-free sustained clinical remission at week 52 and has not used steroids at least week 12 prior to week 52 of treatment with mirikizumab.

[0035] In such embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses response, or is intolerant to mirikizumab.

[0036] In embodiments of the methods of the invention, the induction dose, extended induction dose, or rescue dose ranging from about 5 mg / kg to about 10 mg / kg can be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg.

[0037] In embodiments of the methods of the invention, the patient is a conventional treatment failure.

[0038] In other embodiments, the patient is biologic naive and or advanced therapy naive.

[0039] In some embodiments, the patient has experienced biologic therapy and or experienced advanced therapy therapy.

[0040] In some embodiments, the patient is a biologic treatment failure and or advanced therapy failure.

[0041] In some embodiments, the patient is non-responsive, insufficiently responsive, loses response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0042] In embodiments of the invention, the biologic therapy or advanced therapy is an anti-TNF therapy and or anti-a4b7 therapy.

[0043] In some embodiments, the advanced therapy is a JAK inhibitor, a S1 P receptor modulator, or a TYK2 inhibitor.

[0044] In other embodiments, the patient is one or more of anti-TNF therapy-failed, anti-α4β7 therapy-failed, JAK inhibitor-failed, S1 P receptor modulator-failed, or TYK2 inhibitor-failed.

[0045] In other embodiments of the methods of the present application, the methods comprise,

[0046] administering to the patient three induction doses of mirikizumab at about 5 mg / kg or at about 10 mg / kg by intravenous infusion at 4-week intervals; and

[0047] two to eight weeks after the last induction dose administration, administering to the patient maintenance doses of mirikizumab at about 50 mg by subcutaneous injection at 4-week intervals,

[0048] wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kg to less than or equal to 40 kg.

[0049] In other embodiments of the methods of the present application, the methods comprise,

[0050] administering to the patient three induction doses of mirikizumab at about 5 mg / kg or at about 10 mg / kg by intravenous infusion at 4-week intervals; and

[0051] two to eight weeks after the last induction dose administration, administering to the patient maintenance doses of mirikizumab at about 100 mg by subcutaneous injection at 4-week intervals,

[0052] wherein the patient is 2 years to less than 18 years of age and weighs greater than 20 kg to less than or equal to 40 kg.

[0053] In such embodiments of the methods of the present application, wherein if the patient has not achieved a clinical response four to twelve weeks after the last induction dose administration, administering to the patient three extended induction doses of mirikizumab,

[0054] wherein, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the extended induction doses of mirikizumab are administered to the patient at about 5 mg / kg or at about 10 mg / kg; and

[0055] wherein the extended induction doses of mirikizumab are administered to the patient by intravenous infusion at 4-week intervals.

[0056] In other embodiments, wherein the patient achieves a clinical response 4 to 12 weeks after the last extended induction dose is administered, the patient is administered a maintenance dose of mirikizumab 2-8 weeks after the last extended induction dose.

[0057] In such embodiments, wherein the patient develops loss of response during the maintenance dosing (maintenance period), the patient is administered one, two, or three rescue doses of mirikizumab,

[0058] wherein, if the patient weighs 10 kg to less than or equal to 40 kg, the patient is administered the rescue dose of mirikizumab at about 5 mg / kg or at about 10 mg / kg;

[0059] wherein the rescue dose of mirikizumab is administered to the patient by intravenous infusion at 4 week intervals.

[0060] In such embodiments of the methods of the present application, if the patient achieves a clinical response 4-12 weeks after the one, two, or three rescue doses, the patient is administered a maintenance dose of mirikizumab by subcutaneous injection at 4 week intervals.

[0061] In other embodiments, the patient achieves at least one or more therapeutic effects within about 2 weeks to about 48 weeks of treatment with mirikizumab, the therapeutic effects being at least one or more of a clinical response, a clinical remission, an endoscopic remission, an endoscopic improvement, a symptomatic remission, a symptomatic response, a surgery-free clinical remission, a corticosteroid-free clinical remission, a histological endoscopic mucosal remission, a histological endoscopic mucosal improvement, a bowel urgency relief, a bowel urgency improvement, an improvement in stool frequency, an improvement in rectal bleeding.

[0062] In still further embodiments of the methods of the present application, at least one or more therapeutic effects are achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, or week 48 of treatment with mirikizumab. In such embodiments, the at least one or more therapeutic effects are achieved during an induction period or an extended induction period.

[0063] In other embodiments, the one or more therapeutic effects persist during the maintenance period.

[0064] In such embodiments, the therapeutic effects persist during the maintenance period for up to about 4 weeks, 8 weeks, week 12, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, week 104 to up to about week 152 after the end of the induction period, the extended induction period, or the rescue period.

[0065] In particular embodiments, the patient has a surgery-free sustained clinical remission at week 52 and has not used steroids at least week 12 prior to week 52 of treatment with mirikizumab.

[0066] In such embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses response, or is intolerant to mirikizumab.

[0067] In embodiments of the methods of the application, the induction dose, the extended induction dose, or the rescue dose ranging from about 5 mg / kg to about 10 mg / kg can be about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg.

[0068] In embodiments of the methods of the application, the patient is a conventional therapy failure.

[0069] In other embodiments, the patient is a biologic naive and or an advanced therapy naive.

[0070] In some embodiments, the patient has experienced biologic therapy and or has experienced advanced therapy therapy.

[0071] In some embodiments, the patient is a biologic therapy failure and or an advanced therapy failure.

[0072] In some embodiments, the patient is non-responsive, insufficiently responsive, loses response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0073] In some embodiments, the biologic therapy or advanced therapy is an anti-TNF therapy and or an anti-a4b7 therapy.

[0074] In some embodiments, the advanced therapy is a JAK inhibitor, a S1P receptor modulator, or a TYK2 inhibitor.

[0075] In other embodiments, the patient is one or more of an anti-TNF therapy failure, an anti-a4b7 therapy failure, a JAK inhibitor failure, a S1P receptor modulator failure, or a TYK2 inhibitor failure.

[0076] In one aspect of the application, provided herein is mirikizumab or a pharmaceutical composition comprising mirikizumab for use in treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof, comprising administering to the patient an induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years to less than 18 years of age and weighs more than 10 kilograms (kg).

[0077] In another aspect, provided herein is margetuximab or a pharmaceutical composition comprising margetuximab for use in treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof who is non-responsive, insufficiently responsive, lost response, or intolerant to at least one prior therapy, comprising administering to the patient an induction dose of margetuximab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kilograms (kg). In such embodiments, the prior therapy can be a biologic therapy, an advanced therapy, or a non-biologic therapy, such as an immunomodulator or a corticosteroid.

[0078] In some embodiments of the application provided herein, if the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kg to less than or equal to 40 kg. In such embodiments, the induction dose of margetuximab is administered to the patient at a dose based on the patient’s body weight. In such embodiments, the induction dose of margetuximab 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, the induction dose of margetuximab is administered to the patient at about 5 mg / kg. In alternative embodiments, the induction dose of margetuximab is administered to the patient at about 10 mg / kg.

[0079] In certain embodiments of the application, the induction dose of margetuximab is administered to the patient once, twice, or three times. In still further embodiments of the application, the induction dose of margetuximab is administered to the patient three times. In particular embodiments, the induction dose is administered to the patient at intervals of 4-8 weeks (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks). In more particular embodiments, the induction dose is administered to the patient at intervals of 4 weeks. In certain embodiments, the induction dosing period (induction period) lasts for 4, 8, or 12 weeks. In particular embodiments, the induction period lasts for 12 weeks. In even more particular embodiments, the induction dose is administered to the patient at 0, 4, and 8 weeks.

[0080] In embodiments of the application, the induction dose of margetuximab is administered to the patient by intravenous infusion.

[0081] In certain embodiments of the application, if the patient has not achieved a clinical response 4-8 weeks after the last induction dose administration, the patient is administered one, two, or three extended induction doses of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kilograms (kg). In other embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered an extended induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg. In other embodiments, the patient is administered an extended induction dose of mirikizumab at about 5 mg / kg. In alternative embodiments, the patient is administered an extended induction dose of mirikizumab at about 10 mg / kg.

[0082] In yet other embodiments, the patient is administered three extended induction doses of mirikizumab at 4-8 week intervals. In more particular embodiments of the application, the patient is administered three extended induction doses of mirikizumab at 4 week intervals.

[0083] In embodiments of the application, the one, two, or three extended induction doses of mirikizumab are administered by intravenous infusion.

[0084] In other embodiments of the application, if the patient achieves a clinical response at the end of the induction period or at the end of the extended induction period, the patient is administered a maintenance dose of mirikizumab.

[0085] In certain embodiments, the patient is administered a maintenance dose of mirikizumab at about 50 mg to about 100 mg, wherein the maintenance dose is administered to the patient after the last induction dose or the last extended induction dose administration. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the patient is administered a maintenance dose of mirikizumab at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the patient is administered a maintenance dose of mirikizumab at about 100 mg.

[0086] In such embodiments, the first maintenance dose of mirikizumab is administered to the patient 2-8 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks) after the last induction dose or the last extended induction dose is administered to the patient. In preferred embodiments, the first maintenance dose of mirikizumab is administered 4-6 weeks after the last induction dose or the last extended induction dose is administered. Further preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose is administered. In yet other embodiments, additional maintenance doses of mirikizumab are administered to the patient at 4 or 8 week intervals after the first maintenance dose is administered. Preferably, the maintenance doses are administered at 4 week intervals.

[0087] In embodiments of the application, the maintenance doses are administered by subcutaneous injection.

[0088] The 4-8 week period of administration of maintenance doses accommodates variation in the period between administration of the last extended induction dose and the extended induction end assessment. This variation can arise from variation in the frequency of dosing during the extended induction period. In some embodiments, the frequency of dosing during the extended induction period is once every 4 weeks, and the extended induction end assessment occurs 4 weeks after administration of the last extended induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose can be administered at the induction end assessment visit (i.e., 4 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. Alternatively, the frequency of dosing during the extended induction period is once every 8 weeks, and the extended induction end assessment occurs 8 weeks after administration of the last extended induction dose. If the patient achieves a clinical response, the first maintenance dose can be administered at the induction end assessment visit (i.e., 8 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. In such embodiments, the maintenance doses of mirikizumab are administered after the patient achieves a clinical response from one, two, or three extended induction doses.

[0089] In yet other embodiments of the application, if the patient develops loss of response during maintenance dosing (the maintenance period), a rescue dose of mirikizumab is administered to the patient 2-8 weeks after the last maintenance dose. In such embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the rescue dose of mirikizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg. In some embodiments, the rescue dose of mirikizumab is administered at about 5 mg / kg. In other embodiments, the rescue dose of mirikizumab is administered at about 10 mg / kg.

[0090] In some embodiments of the application, one, two or three supplemental doses of mirikizumab are administered to the patient at 4-8 week intervals. In yet other embodiments, two or three supplemental doses of mirikizumab are administered to the patient at 4-8 week intervals. In preferred embodiments of the application, three supplemental doses of mirikizumab are administered to the patient at 4 week intervals.

[0091] In embodiments of the application, the supplemental doses are administered by intravenous infusion.

[0092] In other embodiments of the application, if the patient achieves a clinical response 4-12 weeks (supplemental dosing period) after one, two or three supplemental doses, the patient is administered a maintenance dose of mirikizumab. In such embodiments, the maintenance dose is administered to the patient based on body weight and at intervals as described above.

[0093] In such embodiments, the maintenance dose of mirikizumab is administered to the patient at about 50 mg to about 100 mg. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the maintenance dose of mirikizumab is administered to the patient at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the maintenance dose of mirikizumab is administered to the patient at about 100 mg.

[0094] In such embodiments, the maintenance dose of mirikizumab is administered to the patient 2-8 weeks after the last supplemental dose is administered to the patient. In preferred embodiments, the maintenance dose of mirikizumab is administered 2-6 weeks after the last supplemental dose is administered. Further preferably, the maintenance dose is administered 2 weeks or 4 weeks after the last supplemental dose is administered. In yet other embodiments, additional maintenance doses of mirikizumab are administered to the patient at 4 or 8 week intervals. Preferably, the maintenance doses are administered at 4 week intervals.

[0095] In particular embodiments, the maintenance dose of mirikizumab is administered to the patient for up to about 4 weeks, 8 weeks, week 12, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, week 52, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, or 104 weeks up to about 152 weeks after administration of the last induction dose, the last extended induction dose, or the last supplemental dose. In certain embodiments, the maintenance dose is administered for up to about 1 year, 2 years, 3 years, or about 4 years.

[0096] In embodiments of the application, the patient achieves at least one or more of the therapeutic effects of clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptomatic relief, symptomatic response, surgery-free clinical remission, corticosteroid-free clinical remission, histologic endoscopic mucosal remission, histologic endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, improvement in stool frequency, improvement in rectal bleeding within about 2 weeks to about 48 weeks of treatment with mirikizumab. In such embodiments of the application, at least one or more of the therapeutic effects is achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, or week 48 of treatment with mirikizumab. The therapeutic effects can be achieved during the induction period, the extended induction period, and / or the rescue period. In certain embodiments, the therapeutic effects can be achieved during the maintenance period, which can be a maintenance period following the induction period, a maintenance period following the extended induction period, or a maintenance period following the rescue period.

[0097] In other embodiments of the application, one or more of the therapeutic effects persist in the maintenance period.

[0098] In such embodiments, the therapeutic effects persist for up to about 4 weeks, 8 weeks, week 12, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, week 104 to up to about week 152 in the maintenance period following the end of the induction period, the extended induction period, or the rescue period.

[0099] In other embodiments, the patient has a surgery-free sustained clinical remission at week 52 and has not used steroids at least week 12 prior to week 52 of treatment with mirikizumab.

[0100] In such embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses response, or is intolerant to mirikizumab.

[0101] In some embodiments of the application, the patient achieves a reduction in fecal calprotectin and C-reactive protein from baseline within about 2 weeks to about 48 weeks of treatment with mirikizumab.

[0102] In embodiments of the application, the induction dose, the extended induction dose, or the rescue dose ranges from about 5 mg / kg to about 10 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg.

[0103] In embodiments of the application, the patient is treatment-experienced.

[0104] In other embodiments, the patient is biologic naive and or advanced therapy naive.

[0105] In some embodiments, the patient has experienced biologic therapy and or advanced therapy therapy.

[0106] In some embodiments, the patient is biologic therapy failure and or advanced therapy failure.

[0107] In some embodiments, the patient is non-responsive, insufficiently responsive, lost response, or intolerant to at least one prior treatment for ulcerative colitis.

[0108] In embodiments of the application, the biologic therapy or advanced therapy is anti-TNF therapy and or anti-a4b7 therapy.

[0109] In some embodiments, the advanced therapy is a JAK inhibitor, a S1 P receptor modulator, or a TYK2 inhibitor.

[0110] In other embodiments, the patient is one or more of anti-TNF therapy failure, anti-a4b7 therapy failure, JAK inhibitor failure, S1 P receptor modulator failure, or TYK2 inhibitor failure.

[0111] In other aspects of the application, provided herein is mirikizumab or a pharmaceutical composition comprising mirikizumab for use in treating moderate to severe active ulcerative colitis in a patient in need thereof, comprising,

[0112] administering to the patient three induction doses of mirikizumab at about 5 mg / kg or at about 10 mg / kg via intravenous infusion at 4-week intervals; and

[0113] two to eight weeks after the last induction dose administration, administering to the patient a maintenance dose of mirikizumab at about 50 mg via subcutaneous injection at 4-week intervals, or

[0114] wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kg to less than or equal to 20 kg.

[0115] In other aspects of the application, provided herein is mirikizumab or a pharmaceutical composition comprising mirikizumab for use in treating moderate to severe active ulcerative colitis in a patient in need thereof, comprising

[0116] administering to the patient three induction doses of mirikizumab at about 5 mg / kg or at about 10 mg / kg via intravenous infusion at 4-week intervals; and

[0117] about 100 mg, at 4-week intervals, to the patient by subcutaneous injection,

[0118] wherein the patient is 2 years to less than 18 years of age and weighs greater than 20 kg to less than or equal to 40 kg.

[0119] In such embodiments of the application, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the last induction dose administration, the patient is administered three extended induction doses of mirikizumab,

[0120] wherein, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered an extended induction dose of mirikizumab at about 5 mg / kg or at about 10 mg / kg;

[0121] wherein the extended induction doses of mirikizumab are administered to the patient by intravenous infusion at 4-week intervals.

[0122] In other embodiments, wherein if the patient achieves a clinical response 4 to 12 weeks after the last extended induction dose administration, the patient is administered a maintenance dose of mirikizumab 2-8 weeks after the last extended induction dose.

[0123] In such embodiments, wherein if the patient develops loss of response during maintenance dosing (maintenance phase), the patient is administered one, two, or three rescue doses of mirikizumab,

[0124] wherein, if the patient weighs 10 kg to less than or equal to 40 kg, the patient is administered a rescue dose of mirikizumab at about 5 mg / kg or at about 10 mg / kg; or

[0125] wherein the rescue doses of mirikizumab are administered to the patient by intravenous infusion at 4-week intervals.

[0126] In such embodiments of the application, if the patient achieves a clinical response 4-12 weeks after the one, two, or three rescue doses, the patient is administered a maintenance dose of mirikizumab by subcutaneous injection at 4-week intervals.

[0127] In other embodiments, within about 2 weeks to about 48 weeks of treatment with mirikizumab, the patient achieves at least one or more of a therapeutic effect of a clinical response, a clinical remission, an endoscopic remission, an endoscopic improvement, a symptomatic remission, a symptomatic response, a surgery-free clinical remission, a corticosteroid-free clinical remission, a histological endoscopic mucosal remission, a histological endoscopic mucosal improvement, a bowel urgency relief, a bowel urgency improvement, an improvement in stool frequency, an improvement in rectal bleeding.

[0128] In still further embodiments of the application, at least one or more therapeutic effects are achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, or week 48 of treatment with mirikizumab. In such embodiments, at least one or more therapeutic effects are achieved in the induction period or the extended induction period.

[0129] In other embodiments, one or more therapeutic effects persist in the maintenance period. In such embodiments of the application, therapeutic effects persist in the maintenance period for up to about 4 weeks, 8 weeks, week 12, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, week 104 to up to about week 152 following the end of the induction period, the extended induction period, or the rescue period.

[0130] In particular embodiments, the patient has a surgery-free sustained clinical remission at week 52 and has not used steroids at least week 12 prior to week 52 of treatment with mirikizumab. In such embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses response, or is intolerant to mirikizumab.

[0131] In embodiments of the application, the induction dose, the extended induction dose, or the rescue dose ranging from about 5 mg / kg to about 10 mg / kg can be 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg.

[0132] In embodiments of the application, the patient is a conventional treatment failure.

[0133] In other embodiments, the patient is a biologic naive and or an advanced therapy naive.

[0134] In some embodiments, the patient has experienced biologic therapy and or has experienced advanced therapy.

[0135] In some embodiments, the patient is a biologic treatment failure and or an advanced therapy failure.

[0136] In some embodiments, the patient is non-responsive, insufficiently responsive, loses response, or is intolerant to at least one prior treatment for ulcerative colitis.

[0137] In some embodiments, the biologic therapy or advanced therapy is an anti-TNF therapy and or an anti-a4b7 therapy.

[0138] In some embodiments, the advanced therapy is a JAK inhibitor, a S1P receptor modulator, or a TYK2 inhibitor.

[0139] In other embodiments, the patient is one or more of anti-TNF therapy-failed, anti-α4β7 therapy-failed, JAK inhibitor-failed, S1P receptor modulator-failed, or TYK2 inhibitor-failed.

[0140] In one aspect of the application provided herein is the use of mirikizumab in the manufacture of a medicament for treating moderate to severe active ulcerative colitis in a patient in need thereof, comprising administering to the patient an induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kilograms (kg).

[0141] In another aspect, provided herein is the use of mirikizumab in the manufacture of a medicament for treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof who is non-responsive, not adequately responsive, lost response, or intolerant to at least one prior therapy, comprising administering to the patient an induction dose of mirikizumab at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kilograms (kg). In such embodiments, the prior therapy can be a biologic therapy, an advanced therapy, or a non-biologic therapy, such as an immunomodulator or a corticosteroid.

[0142] In some embodiments of the application provided herein, if the patient is 2 years to less than 18 years of age and weighs greater than 10 kg to less than or equal to 40 kg. In such embodiments, the induction dose of mirikizumab is administered to the patient at 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 some embodiments, the induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In alternative embodiments, the induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0143] In certain embodiments of the application, one, two, or three induction doses of mirikizumab are administered to the patient. In still further embodiments of the application, three induction doses of mirikizumab are administered to the patient. In particular embodiments, the induction doses are administered to the patient at 4-8 week (e.g., 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks) intervals. In more particular embodiments, the induction doses are administered to the patient at 4 week intervals. In certain embodiments, the induction dosing period (induction period) lasts for 4, 8, or 12 weeks. In particular embodiments, the induction period lasts for 12 weeks. In even more particular embodiments, the induction doses are administered to the patient at 0, 4, and 8 weeks.

[0144] In embodiments of the application, the induction doses of mirikizumab are administered to the patient by intravenous infusion.

[0145] In certain embodiments of the application, if the patient has not achieved a clinical response 4-8 weeks after the last induction dose administration, one, two, or three extended induction doses of mirikizumab are administered to the patient at about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs greater than 10 kilograms (kg). In other embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, an extended induction dose of mirikizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg. In other embodiments, an extended induction dose of mirikizumab is administered to the patient at about 5 mg / kg. In alternative embodiments, an extended induction dose of mirikizumab is administered to the patient at about 10 mg / kg.

[0146] In yet other embodiments, three extended induction doses of mirikizumab are administered to the patient at 4-8 week intervals. In more particular embodiments of the application, three extended induction doses of mirikizumab are administered to the patient at 4 week intervals.

[0147] In embodiments of the application, the extended induction doses of mirikizumab are administered by intravenous infusion.

[0148] In other embodiments of the application, if the patient achieves a clinical response at the end of the induction period or at the end of the extended induction period, a maintenance dose of mirikizumab is administered to the patient.

[0149] In certain embodiments, the maintenance dose of mirikizumab is administered to the patient at about 50 mg to about 100 mg, wherein the maintenance dose is administered to the patient after the last induction dose or the last extended induction dose administration. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the maintenance dose of mirikizumab is administered to the patient at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the maintenance dose of mirikizumab is administered to the patient at about 100 mg.

[0150] In such embodiments, the first maintenance dose of mirikizumab is administered to the patient 2-8 weeks (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks) after the last induction dose or the last extended induction dose is administered to the patient. In preferred embodiments, the first maintenance dose of mirikizumab is administered 4-6 weeks after the last induction dose or the last extended induction dose is administered. Further preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose is administered. In yet other embodiments, additional maintenance doses of mirikizumab are administered to the patient at 4 or 8 week intervals after the first maintenance dose is administered. Preferably, the maintenance doses are administered at 4 week intervals.

[0151] In embodiments of the application, the maintenance doses are administered by subcutaneous injection.

[0152] The 4-8 week period of administration of maintenance doses accommodates variation in the period between administration of the last extended induction dose and the end of induction assessment. This variation can arise from variation in the frequency of dosing during the extended induction period. In some embodiments, the frequency of dosing during the extended induction period is once every 4 weeks, and the end of induction assessment occurs 4 weeks after administration of the last extended induction dose. In such embodiments, if the patient achieves a clinical response, the first maintenance dose can be administered at the end of induction assessment visit (i.e., 4 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. Alternatively, the frequency of dosing during the extended induction period is once every 8 weeks, and the end of induction assessment occurs 8 weeks after administration of the last extended induction dose. If the patient achieves a clinical response, the first maintenance dose can be administered at the end of induction assessment visit (i.e., 8 weeks after administration of the last extended induction dose), or at a subsequent visit scheduled to occur shortly thereafter. In such embodiments, the maintenance dose of mirikizumab is administered after the patient achieves a clinical response from one, two, or three extended induction doses.

[0153] In still further embodiments of the application, if the patient develops loss of response during the maintenance dosing (maintenance phase), the patient is administered a rescue dose of mirikizumab 2-8 weeks after the last maintenance dose. In such embodiments, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered a rescue dose of mirikizumab at about 5 mg / kg to about 10 mg / kg. In some embodiments, the rescue dose of mirikizumab is administered at about 5 mg / kg. In other embodiments, the rescue dose of mirikizumab is administered at about 10 mg / kg.

[0154] In some embodiments of the application, the patient is administered one, two, or three rescue doses of mirikizumab at intervals of 4-8 weeks. In yet other embodiments, the patient is administered two or three rescue doses of mirikizumab at intervals of 4-8 weeks. In preferred embodiments of the application, the patient is administered three rescue doses of mirikizumab at intervals of 4 weeks.

[0155] In embodiments of the application, the rescue dose is administered by intravenous infusion.

[0156] In other embodiments of the application, if the patient achieves a clinical response 4-12 weeks after the one, two, or three rescue doses (rescue dosing phase), the patient is administered a maintenance dose of mirikizumab. In such embodiments, the maintenance dose is administered to the patient based on weight and at intervals as described above.

[0157] In such embodiments, the patient is administered a maintenance dose of mirikizumab at about 50 mg to about 100 mg. In some embodiments, if the patient weighs greater than 10 kg to less than or equal to 20 kg, the patient is administered a maintenance dose of mirikizumab at about 50 mg. In other embodiments, if the patient weighs greater than 20 kg to less than or equal to 40 kg, the patient is administered a maintenance dose of mirikizumab at about 100 mg.

[0158] In such embodiments, the patient is administered a maintenance dose of mirikizumab 2-8 weeks after the last rescue dose is administered to the patient. In preferred embodiments, the maintenance dose of mirikizumab is administered 2-6 weeks after the last rescue dose is administered. Further preferably, the maintenance dose is administered 2 weeks or 4 weeks after the last rescue dose is administered. In yet other embodiments, the patient is administered additional maintenance doses of mirikizumab at intervals of 4 or 8 weeks. Preferably, the maintenance doses are administered at intervals of 4 weeks.

[0159] In particular embodiments, the patient is administered a maintenance dose of mirikizumab for up to about 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, or week 104 up to about week 152 after administration of the last induction dose, the last extended induction dose, or the last rescue dose. In certain embodiments, the maintenance dose is administered for up to about 1 year, 2 years, 3 years, or about 4 years.

[0160] In embodiments of the application, the patient achieves at least one or more of a therapeutic effect of clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptomatic relief, symptomatic response, surgery-free clinical remission, corticosteroid-free clinical remission, histologic endoscopic mucosal remission, histologic endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, improvement in stool frequency, improvement in rectal bleeding, within about 2 weeks to about 48 weeks of treatment with mirikizumab. In such embodiments of the application, at least one or more of the therapeutic effects is achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, or week 48 of treatment with mirikizumab. The therapeutic effects can be achieved during the induction period, the extended induction period, and / or the rescue period. In certain embodiments, the therapeutic effects can be achieved during the maintenance period, which can be a maintenance period following the induction period, a maintenance period following the extended induction period, or a maintenance period following the rescue period.

[0161] In other embodiments of the application, one or more of the therapeutic effects persist during the maintenance period.

[0162] In such embodiments, the therapeutic effects persist for up to about 4 weeks, 8 weeks, week 12, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, week 104 up to about week 152 during the maintenance period following the end of the induction period, the extended induction period, or the rescue period.

[0163] In other embodiments, the patient has a surgery-free, sustained clinical remission at week 52 and did not use steroids at least week 12 prior to week 52 of treatment with mirikizumab.

[0164] In such embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses responsiveness, or is intolerant to mirikizumab.

[0165] In embodiments of the application, the induction dose, the extended induction dose, or the salvage dose ranges from about 5 mg / kg to about 10 mg / kg, about 5 mg / kg, 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg.

[0166] In embodiments of the application, the patient is treatment- experienced.

[0167] In other embodiments, the patient is biologic naive and or advanced therapy naive.

[0168] In some embodiments, the patient is biologic experienced and or advanced therapy experienced.

[0169] In some embodiments, the patient is biologic treatment- failed and or advanced therapy- failed.

[0170] In some embodiments, the patient is non-responsive, insufficiently responsive, lost response, or intolerant to at least one prior treatment for ulcerative colitis.

[0171] In embodiments of the application, the biologic therapy or advanced therapy is an anti-TNF therapy and or an anti-a4b7 therapy.

[0172] In some embodiments, the advanced therapy is a JAK inhibitor, a S1P receptor modulator, or a TYK2 inhibitor.

[0173] In other embodiments, the patient is one or more of anti-TNF treatment- failed, anti-a4b7 treatment- failed, JAK inhibitor- failed, S1P receptor modulator- failed, or TYK2 inhibitor- failed.

[0174] In other aspects of the application, provided herein is the use of mirikizumab in the manufacture of a medicament for treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof, comprising,

[0175] administering to the patient three induction doses of mirikizumab at about 5 mg / kg or at about 10 mg / kg, at 4-week intervals, by intravenous infusion; and

[0176] administering to the patient a maintenance dose of mirikizumab at about 50 mg, at 4-week intervals, by subcutaneous injection,

[0177] wherein the patient is 2 years to less than 18 years of age and weighs greater than 10 kg to less than or equal to 20 kg.

[0178] In other aspects of the application, provided herein is the use of mirikizumab in the manufacture of a medicament for treating moderate to severe active ulcerative colitis (UC) in a patient in need thereof, comprising,

[0179] administering to the patient a maintenance dose of mirikizumab about 100 mg by subcutaneous injection at 4-week intervals 2-8 weeks after the last induction dose administration,

[0180] wherein the patient is 2 years to less than 18 years of age and weighs greater than 20 kg to less than or equal to 40 kg.

[0181] In such embodiments of the application, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the last induction dose administration, the patient is administered three extended induction doses of mirikizumab,

[0182] wherein, if the patient weighs greater than 10 kg to less than or equal to 40 kg, the patient is administered an extended induction dose of mirikizumab about 5 mg / kg or about 10 mg / kg;

[0183] wherein the patient is administered the extended induction dose of mirikizumab by intravenous infusion at 4-week intervals.

[0184] In other embodiments, wherein if the patient achieves a clinical response 4 to 12 weeks after the last extended induction dose administration, the patient is administered a maintenance dose of mirikizumab 2-8 weeks after the last extended induction dose.

[0185] In such embodiments, wherein if the patient develops loss of response during maintenance dosing (the maintenance phase), the patient is administered one, two, or three rescue doses of mirikizumab,

[0186] wherein, if the patient weighs 10 kg to less than or equal to 40 kg, the patient is administered a rescue dose of mirikizumab about 5 mg / kg or about 10 mg / kg;

[0187] wherein the patient is administered the rescue dose of mirikizumab by intravenous infusion at 4-week intervals.

[0188] In such embodiments of the application, if the patient achieves a clinical response 4-12 weeks after the one, two, or three rescue doses, the patient is administered a maintenance dose of mirikizumab by subcutaneous injection at 4-week intervals.

[0189] In other embodiments, the patient achieves at least one or more of the therapeutic effects of clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptomatic relief, symptomatic response, surgery-free clinical remission, corticosteroid-free clinical remission, histologic endoscopic mucosal remission, histologic endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, improvement in stool frequency, improvement in rectal bleeding, within about 2 weeks to about 48 weeks of treatment with mirikizumab.

[0190] In still further embodiments of the application, at least one or more of the therapeutic effects are achieved within about 2 weeks, 4 weeks, 8 weeks, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, or week 48 of treatment with mirikizumab. In such embodiments, at least one or more of the therapeutic effects are achieved in an induction period or an extended induction period.

[0191] In other embodiments, one or more of the therapeutic effects persist in the maintenance period. In such embodiments of the application, the therapeutic effects persist in the maintenance period following the end of the induction period, extended induction period, or rescue period, for up to about 4 weeks, 8 weeks, week 12, week 24, week 28, week 32, week 36, week 40, week 44, week 48, week 52, week 56, week 60, week 64, week 68, week 72, week 76, week 80, week 84, week 88, week 92, week 96, week 104, to up to about week 152.

[0192] In particular embodiments, the patient has a surgery-free sustained clinical remission at week 52 and has not used steroids at least week 12 prior to week 52 of treatment with mirikizumab.

[0193] In some embodiments, the patient continues maintenance treatment with mirikizumab until the patient becomes non-responsive, insufficiently responsive, loses responsiveness, or is intolerant to mirikizumab.

[0194] In embodiments of the application, the induction dose, extended induction dose, or rescue dose ranges from about 5 mg / kg to about 10 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg.

[0195] In embodiments of the application, the patient is treatment-experienced.

[0196] In other embodiments, the patient is biologic naive and or advanced therapy naive.

[0197] In some embodiments, the patient has experienced biologic therapy and or advanced therapy.

[0198] In some embodiments, the patient is a biologic therapy failure and or an advanced therapy failure.

[0199] In some embodiments, the patient is non-responsive, insufficiently responsive, lost response, or intolerant to at least one prior treatment for ulcerative colitis.

[0200] In some embodiments, the biologic therapy or advanced therapy is an anti-TNF therapy and or an anti-a4b7 therapy.

[0201] In some embodiments, the advanced therapy is a JAK inhibitor, a S1P receptor modulator, or a TYK2 inhibitor.

[0202] In other embodiments, the patient is one or more of an anti-TNF therapy failure, an anti-a4b7 therapy failure, a JAK inhibitor failure, a S1P receptor modulator failure, or a TYK2 inhibitor failure. DETAILED DESCRIPTION

[0204] Provided herein are methods, uses, and pharmaceutical compositions of an anti-IL23p19 antibody for the treatment of moderate to severe active ulcerative colitis. Also provided herein are methods and uses of doses and dosing regimens 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) that includes characteristic ulcers. Symptoms of active disease usually include diarrhea mixed with blood, often accompanied by varying degrees of abdominal pain, from mild discomfort to severe cramping. Bowel urgency is also a common and disruptive symptom of ulcerative colitis (UC) and is distinct from stool frequency (SF) and rectal bleeding (RB).

[0205] There are numerous methods of assessing disease / clinical indicator severity, including the Mayo score, the modified Mayo score (MMS), the Pediatric Ulcerative Colitis Activity Index (PUCAI), the Total Mayo Score, the Mayo Endoscopic Subscore, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) total score, the Geboes score, the Robarts Histopathology Index (RHI), and combinations thereof.

[0206] The Mayo score is a composite tool comprising the following 4 subscores:

[0207] Stool Frequency (SF): SF subscore is a patient-reported measure. This item reports the number of bowel movements in a 24-hour period relative to the patient's normal bowel movement frequency during the same time period. A bowel movement is defined as a trip to the bathroom by the patient when he or she has a bowel movement or evacuates only blood, blood and mucus, or only mucus. For younger children, this includes each diaper change in the presence of stool. The patient records the total number of bowel movements passed during a 24-hour period. The patient's reference "normal" SF is generally recorded at the beginning of the study or observation phase. When the patient is in remission, the patient's normal SF is based on the reported SF, or if the patient never achieves remission, the SF reported prior to the initial onset of signs and symptoms of UC.

[0208]

[0209] Rectal Bleeding: RB subscore is a patient-reported measure. This item reports the most severe amount of blood per rectal evacuation on a given day on a 4-point scale.

[0210]

[0211] Endoscopic Subscore (ES): ES is a physician-reported measure that reports the worst appearance of the mucosa on flexible sigmoidoscopy or colonoscopy on a 4-point scale. In keeping with current clinical practice, friability is excluded from the definition of ES = 1.

[0212]

[0213] Physician Global Assessment (PGA): PGA is a physician-reported measure that summarizes the assessment of the patient's UC disease activity on a 4-point scale.

[0214]

[0215] Each subscore is rated on a 4-point scale, ranging from 0 to 3, to yield a maximum Mayo score of 12.

[0216] 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 3 of the 4 subscores in the Mayo score. It does not include the physician global assessment. The MMS evaluates three subscores, each scored from 0 to 3, with a maximum total score of 9. Patients with a Mayo score of 6-12 or MMS of 4-9, each with an ES > 2, are defined as having moderate to severely active ulcerative colitis.

[0217] The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. The partial Mayo score does not include endoscopy and ranges from 0 to 9, while the modified Mayo score does not include the physician's global assessment and also ranges from 0 to 9. The original description of the Mayo score includes friability as a definition of an endoscopic subscore of 1.

[0218] Using the MMS, "clinical remission" is defined as an RB subscore of 0, an SF subscore of 0 or 1, and an ES of 0 or 1 (excluding friability), as used herein.

[0219] Using the MMS, "clinical response" is defined as a decrease of >2 points in MMS subscores and a decrease of >30% from baseline, and a decrease of >1 in RB subscore or an RB subscore of 0 or 1, as used herein.

[0220] Using the MMS, "endoscopic remission" is defined as achieving a Mayo ES of 0. It can also be defined as achieving a Mayo ES of 0 or 1 (excluding friability), as used herein.

[0221] Using the MMS, "endoscopic improvement" is defined as achieving a Mayo ES of 0 or 1, as used herein.

[0222] "Histologic endoscopic mucosal improvement (HEMI)" is defined as achieving both endoscopic improvement (a centrally read endoscopy subscore of 0 or 1, excluding friability) and histologic improvement (neutrophil infiltration <5% crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue based on the Geboes scoring system).

[0223] "Histologic endoscopic mucosal remission (HEMR)" is defined as achieving both endoscopic remission and histologic remission (defined as a Geboes histology subscore of 0 for neutrophils in the lamina propria, neutrophils in the epithelium, and erosion or ulcer parameters, or defined as an RHI score of <2).

[0224] Using the MMS, "symptomatic remission" is defined as achieving an SF subscore = 0 or an SF subscore = 1, a decrease of >1 point from baseline, and an RB subscore = 0, as used herein.

[0225] "Symptomatic response" is defined as a composite clinical endpoint of a decrease of >30% in the sum of SF and RB subscores from baseline, as used herein.

[0226] Using the MMS, "loss of response" is defined as an increase of >2 -point in the partial Mayo score based on 2 consecutive visits separated by >5 days from the end of induction / extended induction, confirmed negative test for C. difficile.

[0227] An alternative definition of 'loss of response' is: (a) total partial Mayo score >4, and (b) moderate disease or worse (>2) on the PGA subscore at 2 consecutive visits separated by >5 days, confirmed negative for C. difficile testing.

[0228] As used herein, "corticosteroid-free remission" is defined as surgical-free clinical remission at Week 52 and no use of steroids from > Week 12 to Week 52.

[0229] The Pediatric Ulcerative Colitis Activity Index (PUCAI) (Turner et al., 2007) is a 6-item disease activity index designed for use in pediatric UC clinical trials that measures: abdominal pain, rectal bleeding, stool consistency of most stools, number of stools per 24 hours, nocturnal stool (any episode of diarrhea that results in waking) and activity level. All items are answered as an average over the "past 2 days." A total PUCAI disease activity score of 0 to 85 is calculated. See Section 10.10 for Disease Severity Definitions According to PUCAI:

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] Using the PUCAI, "clinical remission" is defined as a reduction of >20 points from baseline PUCAI score; "clinical response" is defined as a PUCAI score of <10 points; mild disease activity is defined as PUCAI 10-30: moderate disease activity is defined as PUCAI 35-60: and severe disease activity is defined as PUCAI 65-85.

[0237] The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a central reader reporting tool for measuring endoscopic disease activity of UC at colonoscopy, which includes 3 descriptors (scored for the most severe lesion): blood vessels, bleeding, and erosion and ulceration. The central reader will determine the UCEIS for each endoscopy in a blinded fashion, as detailed in the Endoscopy Chart.

[0238] The mean change in urgency severity was assessed by the Unified Numerical Rating Score (UNRS) measure of bowel urgency. Urgency, a sudden or immediate need to have a bowel movement, is a common and bothersome symptom in patients with ulcerative colitis. The UNRS is a patient-reported measure of urgency over the past 24 hours using an 11-point scale, from 0 (no urgency) to 10 (most severe possible urgency). UNRS scores were recorded by patients daily in the eDiary. The change from baseline in UNRS was measured at Week 12, Week 28, Week 52, or up to about Week 104 of treatment. A clinically meaningful "improvement in urgency" or change in severity of urgency was defined as the proportion of patients achieving a clinical response based on both a >3-point improvement from baseline in MMS and UNRS scores. "Relief of urgency" was defined as minimal to no urgency: UNRS [0,1] as assessed in patients with a >3-point improvement from baseline UNRS at Week 12, Week 28, and subsequent time points (maintenance).

[0239] Other measures of improvement include abdominal pain NRS, fatigue NRS, nocturnal bowel movements, Patient's Change Global Impression (PGI-C), Patient's Global Rating of Severity (PGR-S). Such measures are assessed from participant- and / or caregiver-reported outcomes.

[0240] Changes in health outcomes and quality of life measures were assessed by changes from baseline in Week 12 and Week 52 IMPACT-III scores, TUMMY-UC, and or WPAI+CIQ:UC scores.

[0241] IMPACT-III, as used herein, is a validated questionnaire that assesses disease-related health quality of life measures and health status in participants >9 years of age with IBD. The questionnaire is self-administered and includes 35 questions covering the following domains: bowel symptoms (7 items); systemic symptoms (3 items); emotional functioning (7 items); social functioning (12 items); body image (3 items); tests and treatments (3 items). The recall period is 2 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).

[0242] TUMMY-UC, as used herein, is a series of questions designed to capture disease symptoms important to pediatric patients with UC. There are 2 versions of the TUMMY-UC: one for children 8 to 18 years of age and one for caregivers of children 2 to 7 years of age, in which behaviors that reflect subjective concepts are scored rather than the concepts themselves (e.g., caregivers are asked to score behaviors associated with pain rather than their own rating of the degree of pain). Both the version for children 8 to 18 years of age and the version for caregivers of children contain 8 items that measure the following symptoms over a 24-hour recall period:

[0243] Abdominal pain, bowel frequency, rectal bleeding mass, rectal bleeding frequency, Bristol Stool Form Scale, weakness, nocturnal bowel movements, and urgency.

[0244] WPAI+CIQ:UC as used herein is a patient-reported instrument developed to measure the impact on work productivity and activity / classroom loss attributed to a specific health problem in patients >12 years of age over the past 7 days of study. It contains 9 measures:

[0245] Percent of work time missed (absenteeism) due to UC, percent of work time lost due to UC (presenteeism), percent of overall work loss due to UC (work productivity loss), percent of school time missed due to UC, percent of classroom loss due to UC, percent of regular activities (other than work or school) lost due to UC (activity impairment). Scores are calculated as impairment percentages (Reilly et al 1993; 2008) with higher numbers indicating greater impairment and lower productivity; that is, worse outcomes.

[0246] The Geboes Score as used herein consists of seven categories (or grades), with each category describing a histological item, including "architecture (changes in architecture)" (grade 0), "chronic inflammatory infiltrate" (grade 1), "infiltrate of eosinophils in the lamina propria" (grade 2A), "infiltrate of neutrophils in the lamina propria" (grade 2B), "epithelial neutrophil" (grade 3), "crypt destruction" (grade 4), and "surface epithelial damage" (grade 5). Each grade includes a subscore indicating the degree of abnormality seen for that histological feature, with a subscore of 0 indicating a normal appearance, and higher subscores indicating an increasingly abnormal appearance. The RHI uses the weighted results of 4 Geboes Score categories ("chronic inflammatory infiltrate", "infiltrate of neutrophils in the lamina propria", "epithelial neutrophil", 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 responsive instrument to detect therapeutic effects in early drug development.

[0247] As used herein, "therapeutic effect" or response to treatment can be any one or more of clinical response, clinical remission, endoscopic remission, histological-endoscopic mucosal remission, symptom remission, histological-endoscopic mucosal improvement, corticosteroid-free remission, bowel urgency remission, bowel urgency improvement, bowel frequency improvement, nocturnal bowel movement reduction, fatigue improvement, abdominal pain improvement, rectal bleeding improvement, and / or improvement in other symptoms associated with ulcerative colitis.

[0248] As used herein, "sustained response" is the percentage of patients achieving a therapeutic effect during the maintenance phase who were achieving a therapeutic effect during the induction phase. For example, a sustained response as used herein can be the percentage of patients achieving clinical remission at week 52 who were achieving clinical remission at week 12.

[0249] As used herein, an "extended induction dose" is referred to distinguish from the initial induction dose if a patient does not achieve a clinical response at the end of the initial induction period. The extended induction dose is delivered during an extended induction period. The dose and dosing interval during the extended induction period can be the same as the dose and dosing interval of the initial induction period, but can be changed if the attending healthcare professional has reason to believe that the patient can benefit from a change, such as an increase in the dose of the anti-IL-23p19 antibody or more frequent dosing. For example, the dose and dosing interval can be increased to the next dose level for a particular patient weight group, and / or can be administered at a more frequent dosing interval.

[0250] As used herein, a "rescue dose" is a dose of the anti-IL-23p19 antibody administered to a patient in order to re-induce / re-achieve a clinical response and / or other therapeutic effect obtained at the end of the induction period. The rescue dose is delivered during a rescue period. The rescue dose and dosing interval during the rescue dosing period are generally the same as the dose and dosing interval during the initial induction period, but can be changed if the attending healthcare professional has reason to believe that the patient can benefit from a change, such as an increase in the dose of the anti-IL-23p19 antibody or more frequent dosing.

[0251] As used herein, the term "inadequate response" means that good disease control of ulcerative colitis did not occur after treatment for the duration recommended using the product's prescribing information.

[0252] As used herein, the term "intolerance" means unacceptable toxicity, or worsening of other symptoms associated with ulcerative colitis.

[0253] The terms "biologic naive" or "biologic treatment non-failed," used interchangeably, and / or "advanced therapy naive," as used herein, refer to a patient who has not been administered a biologic or advanced therapy, e.g., an anti-TNFa antibody (e.g., adalimumab, golimumab, infliximab), an anti-integrin antibody (e.g., vedolizumab), a JAK inhibitor (e.g., tofacitinib, upadacitinib), a TYK2 inhibitor, a S1 P receptor modulator (e.g., ozanimod), which are used to treat UC, particularly to treat moderate to severe UC. A biologic naive or advanced therapy naive patient also includes a patient who has had an inadequate response, has lost response, or is intolerant to at least one corticosteroid or immunomodulator. Intolerance to an immunomodulator includes, but is not limited to, nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia.

[0254] The terms "biologic experienced" and or "advanced therapy experienced," as used herein, refer to a patient who has previously been administered at least one biologic or advanced therapy other than an anti-IL23p19 antibody for the treatment of UC, particularly for the treatment of moderate to severe active UC, who has had an inadequate response, has lost response, or is intolerant to a biologic therapy, e.g., an anti-TNFa antibody (e.g., adalimumab, golimumab, infliximab), an anti-integrin antibody (e.g., vedolizumab), a JAK inhibitor (e.g., tofacitinib, upadacitinib), a TYK2 inhibitor, a S1 P receptor modulator (e.g., ozanimod). The patient can or can not have been administered a conventional drug for the treatment of UC. An inadequate response includes signs and symptoms of active disease that persist despite a prescription for induction therapy.

[0255] As used herein, the terms "biologic therapy failure" and or "advanced therapy failure" refer to a patient who has been administered at least one prior biologic or advanced therapy for the treatment of UC, particularly for the treatment of moderate to severe active UC, such as an anti-TNFa antibody (e.g., adalimumab, golimumab, infliximab), an anti-integrin antibody (e.g., vedolizumab), a JAK inhibitor (e.g., tofacitinib, upadacitinib), a TYK2 inhibitor, a S1 P receptor modulator (e.g., ozanimod). The patient can or can not have been administered a conventional medication for the treatment of UC. These patients have had an inadequate response, lost response, or were intolerant to a biologic or advanced therapy for UC that is not an anti-IL23p19 antibody. In the context of the term experienced biologic therapy failure or advanced therapy failure, inadequate response means that there are signs and symptoms of active disease despite induction dosing with the approved induction dosing as indicated in the product label. In the context of the term experienced biologic therapy failure or advanced therapy failure, lost response is defined as the recurrence of signs and symptoms of active disease during maintenance dosing after a prior clinical benefit (discontinuation despite clinical benefit does not qualify as a failure of or intolerance to a biologic therapy for UC). In the context of the term experienced biologic therapy failure or advanced therapy failure, intolerance refers to a history of intolerance to a treatment such as an anti-TNF-a antibody, an anti-integrin antibody, a JAK inhibitor, a TYK2 inhibitor, a S1 P receptor modulator, examples of which include infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, tofacitinib, upadacitinib, deucravacitinib, ozanimod, or other such approved treatments.

[0256] As used herein, "lost response" includes the recurrence of signs and symptoms of active disease during prescribed maintenance dosing after a prior clinical benefit. Intolerance includes a history of intolerance to a biologic therapy or advanced therapy, which includes, but is not limited to, infusion-related events, demyelination, congestive heart failure, or any other drug-related AE that resulted in a dose reduction or drug discontinuation or discontinuation of the biologic for any other reason.

[0257] As used herein, the term "conventional therapy failure" refers to a patient who has not been treated with a biologic and who has had an inadequate response, lost response, or was intolerant to at least one of the following medications:

[0258] Corticosteroids

[0259] Corticosteroid-refractory colitis is defined as having signs or symptoms of active UC despite oral prednisone or equivalent oral corticosteroids at a dose of >30 mg / day for >2 weeks.

[0260] Corticosteroid-dependent colitis is defined as (a) an inability to taper corticosteroid dose or reduce corticosteroid dose below the equivalent of 10 mg / kg / day of prednisone without recurrence of active signs or symptoms of UC within 3 months of starting corticosteroid therapy, or (b) a relapse within < 3 months of completing a course of corticosteroid therapy.

[0261] History of intolerance to corticosteroids, including but not limited to cataracts, Cushing's syndrome, hyperglycemia, hypertension, osteopenia / osteoporosis, or neuropsychiatric side effects, including insomnia.

[0262] Immunomodulators

[0263] Signs and / or symptoms of persistent active disease despite treatment with one of the following for > 3 months:

[0264] Oral AZA (> 1.5 mg / kg / day) or 6-MP (> 0.75 mg / kg / day)

[0265] Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or

[0266] Combination therapy with mercaptopurine and allopurinol within the therapeutic range as determined by thioguanine metabolite testing;

[0267] History of intolerance to at least one immunomodulator, including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia.

[0268] Patients who have failed conventional therapy have never failed or demonstrated intolerance to a biologic (anti-TNF antibody or anti-integrin antibody) or JAK, S1P, or TYK2 inhibitor suitable for the treatment of UC.

[0269] As used herein, the term "about" means in reasonable proximity to the stated value, e.g., plus or minus 10% of the stated value.

[0270] As used herein, the term "antibody" refers to an immunoglobulin molecule that binds an antigen. Embodiments of antibodies include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or conjugated antibodies. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgGl, IgG2, IgG3, IgG4).

[0271] ​An exemplary antibody is an immunoglobulin G (IgG) type antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC), which are cross-linked via interchain disulfide bonds. The amino-terminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids, which is primarily responsible for antigen recognition. The carboxy-terminal portion of each of the four polypeptide chains contains a constant region that is primarily responsible for effector functions. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is composed of a light chain variable region (VL) and a light chain constant region. IgG isotypes can be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).

[0272] The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). The CDRs are exposed on the protein surface and are important for the antigen-binding specificity of an antibody. Each of VHand VLis composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2 and HCDR3”, while the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specific interactions with the antigen. Amino acid residues can be assigned to CDRs according to well-known schemes, including those described in 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 database available on at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27: 209-212). Assignment of amino acid residues to CDRs can be made according to a combination of the above schemes.

[0273] As used herein, embodiments of the disclosure also include antibody fragments or antigen-binding fragments comprising at least a portion of an antibody that retains the ability to specifically interact with an antigen or an epitope of an antigen, such as a Fab, Fab', F(ab')2, Fv fragment, scFv antibody fragment, scFab, disulfide bonded Fvs (sdFv), Fd fragment.

[0274] As used herein, an "anti-IL-23p19 antibody" refers to an antibody that binds to the pl9 subunit of human IL-23, but not to the p40 subunit of human IL-23. Anti-IL-23p19 antibodies thus bind to human IL-23, but not to human IL-12. Examples of anti-IL23p19 antibodies include Mirikizumab, Guselkumab, Tildrakizumab, Risankizumab, and Brazikumab.

[0275] Mirikizumab, CAS Registry Number 1884201-71-1, is a humanized IgG2-lambda monoclonal antibody that targets the pl9 subunit of human IL-23. The antibody and methods of making it are described in U.S. Patent No. 9,023.358. Mirikizumab comprises the following heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain (HC), and light chain (LC) amino acid sequences:

[0276] HCVR - SEQ ID NO: 1

[0277] LCVR - SEQ ID NO: 2

[0278] HC - SEQ ID NO: 3

[0279] LC - SEQ ID NO: 4

[0280] Mirikizumab is particularly suitable for use in many aspects of the present application.

[0281] The term "binds" as used herein, unless otherwise indicated, refers to the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule resulting in the proximity of the two proteins or molecules, as determined by routine methods known in the art.

[0282] As used herein, "treatment" refers to all processes wherein there can be a slowing, control, delay or stopping of the progress of a disorder or disease disclosed herein, or amelioration of symptoms of a disorder or disease, but does not necessarily indicate a total elimination of all disorder or disease symptoms. Treatment includes administration of a protein or nucleic acid or vector or composition to treat a disease or condition in a patient, particularly a human.

[0283] Examples

[0284] Example 1 : A multicenter, open-label, Phase 3 study of milatuzumab in pediatric patients with moderate to severe active ulcerative colitisPK study of milatuzumab in pediatric patients with moderate to severe active ulcerative colitis

[0285] The AMBU study is an open-label study to evaluate the safety, PK, pharmacodynamics, and clinical response to mirikizumab to establish induction and maintenance doses for evaluation in Phase 3 clinical trials in children and adolescents 2 years of age to less than 18 years of age with ulcerative colitis. The study population includes pediatric patients with moderate to severe active UC who are inadequate responders to, have lost response to, or are intolerant to non-biologic therapy for UC (biologic naive), and / or those who have been exposed to at least 1 biologic and / or JAK inhibitor therapy for UC (biologic / JAK inhibitor experienced). Mirikizumab is also abbreviated herein as “Miri.”

[0286] Objectives and Endpoints:

[0287] The following primary, secondary, and exploratory objectives and endpoints were evaluated for this study. Statistical analyses were performed for the primary and key secondary endpoints.

[0288] Table 1: Shows the objectives and endpoints for AMBU

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] Abbreviations: NRS = Numerical Rating Scale; PGI-C = Patient's Global Impression of Change; PGRS = Patient's Global Rating of Severity (PGR-S); PUCAI = Pediatric Ulcerative Colitis Activity Index; SAP = Statistical Analysis Plan; UC = Ulcerative Colitis.

[0304] Study Design:

[0305] At Weeks 0, 4, and 8, patients weighing > 40 kg will receive a 300 mg induction dose of mirikizumab via IV infusion, and patients weighing < 40 kg will receive an induction dose of 5 mg / kg or 10 mg / kg via IV infusion. Enrollment will begin with the 300 mg and 5 mg / kg dose groups. Five patients in the 5 mg / kg dose group received 4 weeks of mirikizumab, completing the effective PK evaluation in the 5 mg / kg group, and upon meeting the post-enrollment criteria for the 5 mg / kg dose group, patients in the 10 mg / kg group will be enrolled.

[0306] Patients achieving a modified Mayo score (MMS) clinical response at Week 12 will continue on to the maintenance phase and receive a dose of 200 mg (for patients weighing > 40 kg), or 100 mg (for patients weighing > 20 kg to < 40 kg), or 50 mg (for patients weighing < 20 kg) of mirikizumab Q4W via SC through Week 48.

[0307] Patients not meeting the definition of a Week 12 MMS clinical response can receive extended IV induction dosing (at the same dose as the 5 mg / kg dose group or escalated to the 10 mg / kg dose) for an additional 12 weeks or discontinued. Upon completion of Week 24 IV dosing, if the investigator determines that the patient has improved, the patient will continue on to the maintenance phase and receive a Q4W SC dose based on body weight through Week 48, and if the investigator determines that there has not been adequate improvement, the patient will be discontinued from study drug and undergo the early termination procedure for study drug, including post-treatment follow-up as outlined in the activity schedule.

[0308] Upon completion of the maintenance phase (Week 52), all patients will have the option to enter a 3-year long-term extension study, I6T-MC-AMAZ (AMAZ), or enter a post-treatment follow-up period (Week 12 if the last dose was administered SC or Week 16 if the last dose was administered IV).

[0309] Table 2: Mirikizumab Dose Based on Participant Body Weight

[0310]

[0311] Inclusion Criteria:

[0312] Patients eligible for this trial must meet all of the following criteria:

[0313] 1. Male or female patients weighing > 10 kg, aged > 2 and < 18 years at the time of informed consent.

[0314] 2. Have a confirmed diagnosis of UC for at least 3 months prior to baseline, which includes endoscopic evidence of UC confirmed by histopathology report.

[0315] 3. Have moderate to severe active UC, as defined by MMS, of 4 to 9, ES > 2, at baseline within 14 days prior to the first dose of study treatment.

[0316] 4. Have evidence of UC extending to the proximal rectum and involving the distal sigmoid colon.

[0317] 5. Prior medication failure criteria: Patients must have been inadequately responsive to, lost response to, or intolerant of at least 1 of the following medications. The dose, frequency, route of administration, and duration of the previous failed treatment(s) need to be documented.

[0318] a. Biologic naive patients: Patients who were inadequately responsive to, lost response to, or intolerant of at least 1 of the following medications:

[0319] Corticosteroids

[0320] Corticosteroid-refractory colitis, defined as having signs and / or symptoms of active UC despite a 2-week course of oral prednisone at a dose of > 0.75 mg / kg / day or equivalent dose or a 2-week course of oral prednisone at a dose of > 40 mg / day; or

[0321] Corticosteroid-dependent colitis, defined as:

[0322] a. Inability to taper corticosteroids without recurrence of signs and / or symptoms of active UC; or

[0323] b. Recurrence within 3 months of completion of a course of corticosteroids; or

[0324] History of intolerance to corticosteroids, which includes evidence of side effects severe enough to preclude continued treatment with corticosteroids, including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, growth retardation, or neuropsychiatric side effects, including insomnia, associated with corticosteroid therapy.

[0325] Immunomodulators :

[0326] Despite treatment with one of the following for at least 3 months, there are signs and / or symptoms of persistently active disease:

[0327] oral AZA (>1 mg / kg / day) or 6-MP (>0.5 mg / kg / day), or

[0328] oral AZA or 6-MP within the therapeutic range as judged by thioguanine metabolite testing, or

[0329] combination of mercaptopurine and allopurinol within the therapeutic range as judged by thioguanine metabolite testing, or

[0330] MTX, alone or in combination with another therapy.

[0331] History of intolerance to at least one immunomodulator (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia).

[0332] Discontinuation despite clinical benefit that does not meet the criteria for UC biologic therapy failure or intolerance.

[0333] b. Patients who have experienced biologic / JAK inhibitor therapy: Patients who have had an inadequate response, have lost response, or are intolerant to biologic therapy for UC (such as an anti-TNF antibody or an anti-integrin antibody) and / or to a JAK inhibitor (e.g., tofacitinib), as described below. The Investigator must document a sufficient trial of the medication. Patients should meet at least one of the following criteria:

[0334] Inadequate response: Despite a prescribed induction therapy, there are signs and symptoms of persistently active disease, or

[0335] Loss of response: Recurrence of signs and symptoms of active disease during a prescribed maintenance dosing after a prior clinical benefit, or

[0336] Intolerance: History of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or other biologic or JAK inhibitor (including but not limited to infusion-related events, demyelination, congestive heart failure, or any other drug-related AE that resulted in dose reduction or discontinuation of medication), or

[0337] Discontinuation of biologic for any other reason.

[0338] Despite clinical benefit, discontinuation did not meet conditions for inadequate response to UC biologic or JAK inhibitor therapy or intolerance.

[0339] 6. Dose stable inclusion criteria: Stable dose of the following permitted medications:

[0340] Oral 5-ASA compounds: If the prescribed dose has been stable for at least 2 weeks prior to the screening endoscopy.

[0341] Oral corticosteroid therapy (prednisone 0.5 mg / kg / day up to 30 mg / day or equivalent): If the prescribed dose has been stable for at least 1 week prior to the screening endoscopy.

[0342] AZA, 6-MP, and MTX: If these immunomodulators have been prescribed at a stable dose for at least 8 weeks prior to the screening endoscopy.

[0343] Results: Interim analysis of AMBU after the 12-week induction period and 40-week maintenance period

[0344] Following the conduct of the Week 12 induction period, PK, efficacy, and safety analyses were performed on 26 pediatric participants (≤ 40 kg (n = 15) and > 40 kg (n = 11)) with moderate to severe active UC from Phase 2 study AMBU. Participants were evaluated for clinical response, clinical remission, and endoscopic remission at Week 12 and / or Week 52, and safety was monitored throughout the trial. For pediatric patients > 40 kg, observed and PK model-estimated exposures were similar to those in adults treated with 300 mg mirikizumab IV Q4W. No new safety findings were identified compared to the prior induction study (AMAN) in adult patients with moderate to severe ulcerative colitis.

[0345] At interim data cut-off:

[0346] 20 participants were on-going or had completed treatment, including:

[0347] 11 had completed Week 52 treatment, and

[0348] 9 were on-going treatment, and

[0349] 6 participants had treatment interrupted during the maintenance period, including

[0350] 1 participant in the > 40 kg 300 mg mirikizumab group due to an adverse event of worsening UC;

[0351] 1 participant in the 5 mg / kg mirikizumab cohort who was < 40 kg due to lack of efficacy, and

[0352] 4 participants in the 300 mg mirikizumab cohort who were > 40 kg due to lack of efficacy.

[0353] Table 3 summarizes the baseline characteristics of the patients.

[0354] Table 3: Summary of baseline demographics at interim analysis (Week 12)

[0355]

[0356]

[0357] 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.

[0358] Efficacy endpoint analyses

[0359] As shown in Table 4, the interim analysis at Week 12 of the induction efficacy endpoints showed clinically meaningful improvements in clinical response, clinical remission, and endoscopic remission among pediatric patients across each body weight and dose range, as measured by MMS and PUCAI. Although maintenance efficacy data at Week 52 was available for less than half of the patients due to the interim data cut-off, the 9 patients summarized in Table 5 also demonstrated clinically meaningful improvements in clinical response, clinical remission, and endoscopic remission, as measured by MMS and PUCAI. In addition, no significant new safety findings were observed. The benefit-risk balance was considered favorable.

[0360] Table 4: Study AMBU efficacy endpoints at Week 12

[0361]

[0362]

[0363]

[0364] 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.

[0365] a. Response confidence intervals were constructed using the Wilson method without continuity correction.

[0366] b. Endoscopic remission was defined as MMS endoscopic subscore = 0 or 1 (excluding friability)

[0367] c. Alternative MMS clinical remission was defined as SF subscore = 0, or SF = 1, reduction from baseline of > 1 -point, and RB subscore = 0, ES subscore = 0 or 1 (excluding friability.

[0368] Table 5 Study AMBU efficacy endpoints at Week 52 (limited data set available at interim analysis)

[0369]

[0370] 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.

[0371] a. Response confidence intervals were constructed using the Wilson method without continuity correction.

[0372] b. Endoscopic remission was defined as MMS endoscopic subscore = 0 or 1 (excluding friability).

[0373] Results: Final analysis of AMBU at Week 52

[0374] Table 6 summarizes key demographics and baseline disease characteristics for the mITT population collected at AMBU baseline. Overall, demographics and disease characteristics were well balanced between treatment groups and were consistent with a 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.

[0375] Table 6: Summary of study AMBU demographics and other baseline characteristics (mITT population)

[0376]

[0377]

[0378] 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 the specified category; PUCAI = Pediatric Ulcerative Colitis Activity Index; SD = standard deviation; UC = ulcerative colitis.

[0379] ​a.Study inclusion criteria classified moderate disease severity as MMS 4-6; whereas the current criteria have been modified to MMS 5 to 6, in this study, 1 of 26 participants had a baseline MMS of 4, and all other participants (96%) had a baseline MMS of 5 or greater.

[0380] Table 7 provides efficacy data for Week 52 of the study AMBU. Consistent with the induction data for clinically meaningful changes in the Week 12 efficacy endpoints, additional improvements in the Week 52 efficacy endpoints of clinical remission, clinical response, endoscopic remission, and symptom remission were observed. Of the Week 12 responders, 10 / 18 (55.6%) patients achieved clinical remission (by MMS), endoscopic remission, and off corticosteroid remission at Week 52. In addition, at Week 52, the PUCAI response and remission rates were 77.8 and 72.2%, respectively. Finally, of the Week 12 clinical responders, 50% of the pediatric participants met the histology-endoscopy mucosal remission criteria at Week 52.

[0381] Table 7: Efficacy data for Week 52 study AMBU in Week 12 clinical responders

[0382]

[0383] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; IV = intravenous; Miri = miliciguimab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; PUCAI = Pediatric Ulcerative Colitis Activity Index.

[0384] Note: Patients who experienced loss of response during the maintenance phase and received rescue dosing were defined and evaluated as non-responders at Week 52.

[0385] a. Percent response is n / N x 100% 100% calculation

[0386] b. Clinical remission was defined as: SF subscore = 0, or SF = 1, RB subscore = 0; and ES = 0 or 1 (excluding fragile)

[0387] c. Clinical response was defined as: MMS reduction of >2 points and reduction of >30% from baseline, RB subscore reduction of >1 point from baseline, or RB score of 0 or 1

[0388] d. PUCAI clinical remission was defined as: PUCAI score <10 points

[0389] e. PUCAI clinical response was defined as: reduction of >20 points from baseline PUCAI score

[0390] f. Clinical remission off corticosteroids was defined as MMS clinical remission at Week 52 and no use of corticosteroids or UC-related surgery from > Week 12 prior to Week 52

[0391] g. Endoscopic remission was defined as ES = 0 or 1 (excluding friability)

[0392] h. Symptomatic remission was defined as SF = 0, or SF = 1 with > 1 -point reduction from baseline, and RB = 0

[0393] i. Histologic endoscopic mucosal improvement was defined as simultaneous achievement of histologic improvement and endoscopic improvement.

[0394] j. Histologic-endoscopic mucosal remission was defined as simultaneous achievement of histologic remission and endoscopic remission.

[0395] k. Alternative MMS clinical remission was defined as SF subscore = 0, or SF = 1 with > 1 -point reduction from baseline, and RB subscore = 0, and ES subscore = 0 or 1 (excluding friability).

[0396] Tables 8 through 25 provide subgroup analyses of key efficacy endpoints at Week 52 for pediatric participants who previously failed biologic therapy and those who did not fail biologic therapy.

[0397] Week 52 modified Mayo score clinical remission: Clinical remission by subgroup (prior biologic therapy failure classification) Week 52 MMS clinical response by subgroup clinical response (prior biologic therapy failure classification)

[0398] Overall, 29.4% of participants in the biologic therapy failure subgroup and 55.6% of participants in the biologic therapy non-failure subgroup achieved clinical remission at Week 52 (Table 8).

[0399] Table 8. Week 52 clinical remission by subgroup (NRI; mITT population)

[0400]

[0401] Abbreviations: CI = confidence interval; mITT = modified intention-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup.

[0402] a. Percent response by n / N x 100% 100% calculated.

[0403] b. Response confidence intervals constructed using Wilson method, no continuity correction.

[0404] Week 52 clinical remission in subgroup of participants who induced a clinical response (prior biologic therapy failure category)

[0405] Of the participants in the total biologic treatment failure subgroup, 45.5% achieved clinical remission at Week 52 and of the participants in the biologic treatment non-failure subgroup, 71.4% achieved clinical remission at Week 52 (Table 9).

[0406] Table 9. Clinical remission at Week 52 by subgroup (NRI; mITT population clinical responders)

[0407]

[0408] 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 the specified category; NRI = non-responder imputation; Ns = number of patients in each subgroup.

[0409] a. Response percentages are calculated as n / Nx 100% calculated.

[0410] b. Response confidence intervals constructed using Wilson method, no continuity correction.

[0411] Week 52 PUCAI clinical remission by subgroup (prior biologic therapy failure classification)

[0412] Of the participants in the total biologic treatment failure subgroup, 41.2% responded and of the participants in the biologic treatment non-failure subgroup, 77.8% responded (see Table 10).

[0413] Table 10. Clinical response at Week 52 by subgroup (NRI; mITT population)

[0414]

[0415] Abbreviations: CI = confidence interval; mITT = modified intention-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0416] a. By n / Ns Response percentages are calculated as 100%

[0417] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0418] Clinical response at Week 52 by subgroup in clinical responders (prior biologic treatment failure category)

[0419] Of the participants in the total biologic treatment failure subgroup, 63.6% achieved a clinical response at Week 52 and of the participants in the biologic treatment non-failure subgroup, 100.0% achieved a clinical response at Week 52 (see Table 11).

[0420] Table 11. Clinical response at Week 52 by subgroup (NRI; mITT population clinical responders)

[0421]

[0422] 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 the specified category; NRI = non-responder imputation; Ns = number of patients in each subgroup

[0423] a. by n / Ns 100% response percentage calculated

[0424] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0425] Table 12. Week 52 AMBU PUCAI clinical remission by subgroup (NRI; mITT population)

[0426] Of the participants in the total biologic treatment failure subgroup, 35.3% achieved a clinical remission at Week 52 and of the participants in the biologic treatment non-failure subgroup, 77.8% achieved a clinical remission at Week 52 (see Table 12).

[0427] PUCAI clinical response by subgroup (prior biologic therapy failure classification)

[0428]

[0429] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0430] a. by n / Ns 100% response percentage calculated

[0431] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0432] Corticosteroid-free remission by subgroup (prior biologic therapy failure classification)

[0433] Of the participants in the total biologic treatment failure subgroup, 41.2% achieved a PUCAI clinical response at Week 52 and of the participants in the biologic treatment non-failure subgroup, 77.8% achieved a PUCAI clinical response at Week 52 (see Table 13).

[0434] Table 13: Week 52 AMBU PUCAI clinical response by subgroup (NRI; mITT population)

[0435]

[0436] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = milicicitab, N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0437] a. by n / Ns 100% response percentage calculated

[0438] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0439] Endoscopic remission at Week 52 by subgroup (prior biologic therapy failure classification)

[0440] A total of 29.4% of participants in the biologic treatment failure subgroup and 55.6% of participants in the biologic treatment non-failure subgroup achieved endoscopic remission at Week 52 (see Table 15).

[0441] Table 14: Week 52 corticosteroid-free remission by subgroup (NRI; mITT population)

[0442]

[0443] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = milicicitab, N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0444] a. by n / Ns 100% response percentage calculated

[0445] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0446] Endoscopic remission at Week 52 by subgroup in those who achieved induction endoscopic remission (prior biologic therapy failure classification)

[0447] A total of 29.4% of participants in the biologic treatment failure subgroup and 55.6% of participants in the biologic treatment non-failure subgroup achieved endoscopic remission at Week 52 (see Table 15).

[0448] Table 15. Week 52 Endoscopic Remission by Subgroup (NRI; mITT Population)

[0449]

[0450] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0451] a. by n / Ns 100% response percentage calculated

[0452] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0453] Endoscopic subscore (ES) = 0 at Week 52 by subgroup (prior biologic therapy failure classification) Symptom relief during the maintenance period at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52

[0454] Among the participants in the overall biologic treatment failure subgroup, 55.6% achieved Week 52 endoscopic remission, and among the participants in the overall biologic treatment non-failure subgroup, 80.0% achieved Week 52 endoscopic remission (see Table 16).

[0455] Table 16. Week 52 Endoscopic Remission by Subgroup (NRI; mITT Population - Induction Endoscopic Remission)

[0456]

[0457] 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 the specified category; NRI = non-responder imputation; Ns = number of patients in each subgroup

[0458] a. by n / Ns 100% response percentage calculated

[0459] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0460] Histological endoscopic mucosal improvement at Week 52 by subgroup (prior biologic therapy failure classification)

[0461] Among the participants in the overall biologic treatment failure subgroup, 17.6% achieved Week 52 endoscopic subscore of 0, and among the participants in the overall biologic treatment non-failure subgroup, 33.3% achieved Week 52 endoscopic subscore of 0 (Table 17).

[0462] Table 17. Week 52 Endoscopic Subscore of 0 by Subgroup (NRI; mITT Population)

[0463]

[0464] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0465] a. By n / Ns 100% calculated response percentage

[0466] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0467] Histological-endoscopic mucosal remission at Week 52 by subgroup (prior biologic therapy failure classification)

[0468] The proportion of patients with symptom relief at applicable study visits during the maintenance period increased from baseline. NRI analysis showed that a total of 14 (53.8%) participants achieved symptom relief at Week 20, and the proportion of patients with symptom relief remained relatively stable at all of the following applicable visits. A total of 12 (46.2%) participants achieved symptom relief at Week 52 (Table 18).

[0469] Table 18. Symptom relief by maintenance period visit (NRI; mITT population)

[0470]

[0471]

[0472]

[0473]

[0474] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; SC = subcutaneous.

[0475] a. Response confidence intervals constructed using Wilson method, no continuity correction

[0476] Symptom relief by Week 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 in subgroups (prior biologic treatment failure category)

[0477] In the biologic treatment failure subgroup, the proportion of participants with symptom relief increased from baseline at all applicable visits and remained relatively stable from Week 16 to Week 52 (n=6 [35.3%]). In the biologic treatment non-failure subgroup, the proportion of participants with symptom relief increased from baseline at all applicable visits and remained relatively stable from Week 16 to Week 52 (n=6 [66.7%]) (Table 19).

[0478] Table 19: Symptom relief at each visit by subgroup, biologic treatment failure subgroup (NRI; mITT population)

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup; SC = subcutaneous.

[0490] a. By n / Ns 100% calculated response percentage

[0491] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0492] Alternative modified Mayo clinical remission at Week 52: Clinical remission by subgroup (prior biologic therapy failure classification)

[0493] Five (29.4%) participants in the biologic treatment failure subgroup and four (44.4%) participants in the non-failure subgroup achieved histological endoscopic mucosal improvement at Week 52 (Table 20).

[0494] Table 20: Week 52 histologic endoscopic mucosal improvement (NRI; mITT population) by subgroup

[0495]

[0496] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup; SC = subcutaneous.

[0497] a. by n / Ns 100% response percentage was calculated.

[0498] b. Response confidence intervals were constructed using the Wilson method without continuity correction.

[0499] Alternative MMS clinical remission at Week 52 by subgroup in those who achieved induction clinical response (prior biologic therapy failure classification)

[0500] Overall, 29.4% of participants in the biologic treatment failure subgroup and 44.4% of participants in the biologic treatment non-failure subgroup achieved histologic-endoscopic mucosal remission at Week 52 (Table 1).

[0501] Table 21: Week 52 histologic-endoscopic mucosal remission (NRI; mITT population) by subgroup

[0502]

[0503] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = mirikizumab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0504] a. by n / Ns 100% response percentage was calculated.

[0505] b. Response confidence intervals were constructed using the Wilson method without continuity correction

[0506] Fecal calprotectin at Week 52 CRP at Week 52

[0507] Overall, 29.4% of participants in the biologic treatment failure subgroup and 44.4% of participants in the biologic treatment non-failure subgroup achieved alternative MMS clinical remission at Week 52 (Table 22).

[0508] Table 22: Week 52 Substitutional Modified Mayo Clinical Remission by Subgroup (mITT Population)

[0509]

[0510] Abbreviations: CI = confidence interval; mITT = modified intent-to-treat; SC = subcutaneous; IV = intravenous; Miri = miliciguimab; N = number of patients in the mITT population; n = number of patients in each specified category; NRI = non-responder imputation; kg = kilogram; mg = milligram; Ns = number of patients in each subgroup

[0511] a. by n / Ns 100% response percentage calculated

[0512] b. Response confidence intervals constructed using Wilson method, no continuity correction

[0513] Example 2. A multicenter, Phase 3, open-label study to investigate the efficacy, pharmacokinetics, and safety of milatuzumab in participants aged 2 years to less than 18 years with moderate to severe active ulcerative colitis Primary assessment

[0514] Of the participants in the total biologic treatment failure subgroup, 45.5% achieved clinical remission at Week 52, and of the participants in the biologic treatment non-failure subgroup, 57.1% achieved clinical remission at Week 52 (Table 23).

[0515] Table 23. Week 52 Clinical Remission by Subgroup (mITT Population Induction Clinical Responders)

[0516]

[0517] Abbreviations: kg = kilogram; miri = miliciguimab; mg = milligram; SC = subcutaneous; CI = confidence interval; N = number of patients in the analysis population; n = number of patients in the specified category; NRI = non-responder imputation; Ns = number of patients in each subgroup.

[0518] a. by n / Ns 100% response percentage calculated

[0519] b. Response confidence intervals constructed using Wilson method, no continuity correction.

[0520] Corticosteroids

[0521] Table 24 provides a summary of fecal calprotectin at Week 52 (change from baseline). Participants had an average decrease of -3447.54 in fecal calprotectin from baseline following maintenance with miliciguimab.

[0522] Table 24. Fecal calprotectin at Week 52 (change from baseline; mBOCF) (mITT population)

[0523]

[0524] Abbreviations: IV = intravenous; kg = kilogram; miri = mirikizumab; mBOCF = modified baseline carry forward; mg = milligram; N = number of patients in the analysis population; Q4W = every 4 weeks; SC = subcutaneous; SD = standard deviation; mITT = modified intent-to-treat

[0525] Immunomodulators

[0526] Table 25 provides a summary of serum C-reactive protein at Week 52 (change from baseline). After maintenance with mirikizumab, participants’ CRP decreased on average by -2.65 from baseline.

[0527] Table 25. CRP at Week 52 (change from baseline; mBOCF) (mITT population)

[0528]

[0529] Abbreviations: IV = intravenous; kg = kilogram; miri = mirikizumab; mBOCF = modified baseline carry forward; mg = milligram; N = number of patients in the analysis population; Q4W = every 4 weeks; SC = subcutaneous; SD = standard deviation; mITT = modified intent-to-treat

[0530] Results: Interim analysis of AMBU after the 12-week induction period and 40-week maintenance period At interim data cut-off:

[0531] Study AMBA was a multicenter, open-label, Phase 3 study to investigate the efficacy, pharmacokinetics, and safety of mirikizumab in male and female children and adolescents 2 years of age to less than 18 years of age with moderate to severe active UC (defined as MMS 5 to 9 with an endoscopic subscore > 2 within 28 days prior to first dose).

[0532] Table 3: Summary of baseline demographics at interim analysis (Week 12) What is the proportion of children and adolescents with moderate to severe active UC who achieve clinical remission in MMS at Week 52 after having achieved clinical response at Week 12 following induction treatment with mirikizumab compared to the proportion of adults in Study AMBG who were re-randomized to placebo treatment after having achieved clinical response at Week 12 in Study AMAN while receiving induction treatment with mirikizumab, who did not discontinue study intervention prior to Week 52, or who received rescue medication.

[0533] Objectives and endpoints:

[0534] The following primary, secondary, and exploratory objectives and endpoints were evaluated in this study. Statistical analyses were performed on the primary and key secondary endpoints.

[0535] Table 26: Objectives and Endpoints for AMBA

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545] Abbreviations: AUC = area under the curve; C max = maximum concentration of drug in the blood after dosing; CRP = C-reactive protein; MMS = modified Mayo score; NRS = Numerical Rating Scale; PGI-C = Patient's Global Impression of Change; PGR-S = Patient's Global Rating of Severity (PGR-S); PK = pharmacokinetics; PUCAI = Pediatric Ulcerative Colitis Activity Index; TEADA = treatment-emergent anti-drug antibodies; UC = ulcerative colitis; UCEIS = Ulcerative Colitis Endoscopic Index of Severity; WPAI+CIQ:UC = Work Productivity and Activity Impairment Questionnaire + Classroom Impairment Questionnaire Ulcerative Colitis.

[0546] Study Design:

[0547] The study will have 4 study periods

[0548] Period I Screening

[0549] Period II - Open-label induction of mirikizumab

[0550] Visits 2 through 6, Weeks 0 through 12 Induction Phase - Participants will receive 3 induction doses based on their weight at each dosing visit.

[0551] Period III - Open-label maintenance of mirikizumab

[0552] Visits 7 through 17, Weeks 12 through 52 Maintenance Period = Participants will receive either an extended induction dose or maintenance dose of mirikizumab based on their body weight at each dosing visit through Week 52.

[0553] Cycle II - Mirikizumab Open-Label Induction

[0554] Visits 2 through 6, Weeks 0 through 12 Induction Period - Participants will receive 3 induction doses based on their body weight at each dosing visit.

[0555] Cycle III - Mirikizumab Open-Label Maintenance

[0556] Visits 7 through 17, Weeks 12 through 52 Maintenance Period = Participants will receive either an extended induction dose or maintenance dose of mirikizumab based on their body weight at each dosing visit through Week 52.

[0557] Visit 17, Week 52 - After Week 52, all participants will have the option to enter Study AMAZ or enter the Post-Treatment Follow-Up Period.

[0558] At the Sponsor's discretion, participants who are eligible for the AMAZ study for which a clinical trial site has not yet opened can be dosed as needed at Week 52 and beyond Week 52 UV.

[0559] Participants must complete all procedures at Visit 16 and should have an additional dose at 4-week intervals (7 days) after the previous dose.

[0560] Cycle IV: Safety Follow-Up Approximately 16 Weeks After the Last Treatment Visit

[0561] The study will also evaluate the safety and efficacy of extended induction in participants who have no clinical response at Week 12 and rescue therapy in participants who lose clinical response during the maintenance period.

[0562] Participants who the investigator believes are deriving clinical benefit can continue in the 3-year long-term extension study (I6T-MC-AMAZ) instead of the safety follow-up.

[0563] Table 2. Mirikizumab Doses Based on Participant Body Weight.

[0564]

[0565] Inclusion Criteria:

[0566] Patients eligible for this trial must meet all of the following criteria:

[0567] ​1. Male or female patients weighing > 10 kg, aged > 2 and < 18 years at the time of informed consent.

[0568] 2. Have a confirmed diagnosis of UC for at least 3 months prior to baseline, which includes endoscopic evidence of UC confirmed by histopathology report.

[0569] 3. Have moderate to severe active UC, as defined by MMS, of 5 to 9, ES > 2, at 14 days prior to the first dose of study treatment (baseline).

[0570] 4. Have evidence of UC extending to the proximal rectum and involving the distal sigmoid colon.

[0571] 5. Prior medication failure criteria: Patients must have had an inadequate response to, lost response to, or were intolerant to at least 1 of the following medications. The dose, frequency, route of administration, and duration of the previous failed treatment must be documented.

[0572] a. Biologic naive patients: Patients who have had an inadequate response to, lost response to, or were intolerant to at least 1 of the following medications:

[0573] Table 4: Study AMBU efficacy endpoints at Week 12

[0574] Corticosteroid-refractory colitis, defined as having signs and / or symptoms of active UC despite a 2-week course of oral prednisone at a dose of > 0.75 mg / kg / day or equivalent dose or a 2-week course of oral prednisone at a dose of > 40 mg / day or a 8-week course of budesonide MMX at a dose of 9 mg / day; or

[0575] Corticosteroid-dependent colitis, defined as:

[0576] a. Inability to taper corticosteroids without relapse of signs and / or symptoms of active UC; or

[0577] b. Relapse within 3 months of completion of a course of corticosteroids; or

[0578] Intolerance to corticosteroids (which includes evidence of side effects severe enough to preclude continued treatment with corticosteroids, including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, growth retardation, or neuropsychiatric side effects including insomnia associated with corticosteroid therapy).

[0579] Table 5 Study AMBU efficacy endpoints at Week 52 (limited data set available at interim analysis) Results: Final analysis of AMBU at Week 52 Week 52 modified Mayo score clinical remission: Clinical remission by subgroup (prior biologic therapy failure classification) Week 52 MMS clinical response by subgroup clinical response (prior biologic therapy failure classification) Week 52 PUCAI clinical remission by subgroup (prior biologic therapy failure classification) Table 12. Week 52 AMBU PUCAI clinical remission by subgroup (NRI; mITT population) PUCAI clinical response by subgroup (prior biologic therapy failure classification) Corticosteroid-free remission by subgroup (prior biologic therapy failure classification) Endoscopic remission at Week 52 by subgroup (prior biologic therapy failure classification) Endoscopic remission at Week 52 by subgroup in those who achieved induction endoscopic remission (prior biologic therapy failure classification) Endoscopic subscore (ES) = 0 at Week 52 by subgroup (prior biologic therapy failure classification) Symptom relief during the maintenance period at Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 Histological endoscopic mucosal improvement at Week 52 by subgroup (prior biologic therapy failure classification) Histological-endoscopic mucosal remission at Week 52 by subgroup (prior biologic therapy failure classification) Alternative modified Mayo clinical remission at Week 52: Clinical remission by subgroup (prior biologic therapy failure classification) Alternative MMS clinical remission at Week 52 by subgroup in those who achieved induction clinical response (prior biologic therapy failure classification) Fecal calprotectin at Week 52 CRP at Week 52 Example 2. A multicenter, Phase 3, open-label study to investigate the efficacy, pharmacokinetics, and safety of milatuzumab in participants aged 2 years to less than 18 years with moderate to severe active ulcerative colitis Primary assessment Corticosteroids Immunomodulators :

[0580] Despite treatment with 1 of the following medications for at least 3 months, have signs and / or symptoms of persistent active disease:

[0581] oral AZA (>1 mg / kg / day) or 6-MP (>0.5 mg / kg / day), or

[0582] oral AZA or 6-MP within the therapeutic range as judged by thioguanine metabolite testing, or

[0583] combination of mercaptopurine and allopurinol within the therapeutic range as judged by thioguanine metabolite testing, or

[0584] MTX, alone or in combination with another therapy.

[0585] History of intolerance to at least one immunomodulator (including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia).

[0586] Discontinuation despite clinical benefit does not meet criteria for failure or intolerance of UC biologic therapy.

[0587] b. Patients who have experienced biologic / JAK inhibitor therapy: Patients who have had an inadequate response, lost response, or were intolerant to a biologic therapy for UC (such as an anti-TNF antibody or an anti-integrin antibody) and / or to a JAK inhibitor (e.g., tofacitinib), as described below. The Investigator must document a sufficient trial of medication. Patients should meet at least one of the following criteria:

[0588] Inadequate response: despite a prescribed induction therapy, there are signs and symptoms of active disease persisting, or

[0589] Lost response: recurrence of signs and symptoms of active disease during a prescribed maintenance dosing period following prior clinical benefit, or

[0590] Intolerance: history of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or other biologic or JAK inhibitor (including but not limited to infusion-related events, demyelination, congestive heart failure, or any other drug-related AE that resulted in dose reduction or discontinuation of medication), or

[0591] Discontinuation of biologic for any other reason.

[0592] Discontinuation despite clinical benefit does not meet criteria for inadequate response or intolerance to a biologic or JAK inhibitor therapy for UC.

[0593] 6. Dose-stable inclusion criteria: Is on a stable dose of the following permitted medications:

[0594] Oral 5-ASA compound: If the prescribed dose has been stable for at least 2 weeks prior to the screening endoscopy.

[0595] Oral corticosteroid therapy (prednisone 0.5 mg / kg / day up to 30 mg / day or equivalent): If the prescribed dose has been stable for at least 1 week prior to the screening endoscopy.

[0596] AZA, 6-MP, and MTX: Stable for at least 8 weeks prior to the screening endoscopy.

[0597] Sequence

[0598] SEQ ID NO: 1 Mrgnifiumab heavy chain variable region (HCVR)

[0599] QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSS

[0600] SEQ ID NO: 2 Mrgnifiumab light chain variable region (LCVR)

[0601] DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK

[0602] SEQ ID NO: 3 Mrgnifiumab heavy chain (HC)

[0603] QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYNDGTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[0604] SEQ ID NO: 4 Margetuximab light chain (LC)

[0605] DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

Claims

1. A method for treating patients with moderate to severe active ulcerative colitis (UC) in need, the method comprising administering at least one induction dose of mijicillinumab to the patient at a dose of about 5 mg / kg to about 10 mg / kg, wherein the patient is 2 years of age to less than 18 years of age and weighs more than 10 kg.

2. The method of claim 1, wherein the patient weighs more than 10 kg and less than or equal to 40 kg, and an induction dose of migilizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg.

3. The method of any one of claims 1-2, wherein an induction dose of mijicillinumab is administered to the patient at about 5 mg / kg.

4. The method of any one of claims 1-2, wherein an induction dose of mijicillinumab is administered to the patient at about 10 mg / kg.

5. The method of any one of claims 1-4, wherein the patient is given three induction doses of mijicillinumab.

6. The method of any one of claims 1-5, wherein an induction dose of mijicillinumab is administered to the patient at intervals of 4-8 weeks.

7. The method of any one of claims 1-6, wherein an induction dose of mijicillinumab is administered to the patient at 4-week intervals.

8. The method of any one of claims 1-7, wherein an induction dose of mijicillinumab is administered to the patient at weeks 0, 4, and 8.

9. The method of any one of claims 1-8, wherein the induction dose is delivered during a 12-week induction dosing period.

10. The method of any one of claims 1-9, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the last induction dose, the patient is given one, two, or three extended induction doses of migilizumab at about 5 mg / kg to about 10 mg / kg.

11. The method of claim 10, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, an extended induction dose of migiliterumab is administered to the patient at about 5 mg / kg or about 10 mg / kg.

12. The method of claims 10-11, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, an extended induction dose of migiliterumab is administered to the patient at about 10 mg / kg.

13. The method of claims 10-11, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, an extended induction dose of migiliterumab is administered to the patient at about 5 mg / kg.

14. The method of any one of claims 10-13, wherein at least one extended induction dose is administered to the patient 4-8 weeks after the final maintenance dose.

15. The method of any one of claims 10-14, wherein the patient is administered three extended induction doses of mijicillinab.

16. The method of any one of claims 10-15, wherein an extended induction dose of mijicillinumab is administered to the patient at intervals of 4-8 weeks.

17. The method of any one of claims 10-16, wherein the patient is given an extended induction dose of mijicillin at 4-week intervals.

18. The method of any one of claims 1-17, further comprising administering at least one maintenance dose of mijicillinab to the patient at a dose of about 50 mg to about 100 mg, wherein the maintenance dose is administered after the final induction dose or the final extended induction dose.

19. The method of claim 18, wherein if the patient's weight is greater than 10 kg and less than or equal to 20 kg, a maintenance dose of migilizumab is administered to the patient at about 50 mg.

20. The method of claim 18, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a maintenance dose of migilizumab is administered to the patient at about 100 mg.

21. The method of any one of claims 18-20, wherein if the patient achieves a clinical response from the last induction or extended induction dose administered to the patient, a maintenance dose of mijicillinumab is administered to the patient.

22. The method of any one of claims 18-21, wherein, If a patient develops a loss of response during maintenance dosing, a rescue dose of mijicillinumab may be administered to the patient once, twice, or three times at a dose of about 5 mg / kg to about 10 mg / kg.

23. The method of claim 22, wherein if the patient's weight is 10 kg to less than or equal to 20 kg, a rescue dose of mijicillinumab is administered to the patient at about 5 mg / kg.

24. The method of claim 22, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a rescue dose of migiliterumab is administered to the patient at about 10 mg / kg.

25. The method of any one of claims 22-24, wherein the rescue dose is administered to the patient 4-8 weeks after the last maintenance dose.

26. The method of any one of claims 22-25, wherein the rescue dose is administered to the patient at intervals of 4-8 weeks.

27. The method of any one of claims 22-26, wherein the rescue dose is administered to the patient at 4-week intervals.

28. The method of any one of claims 22-27, wherein if a clinical response is achieved in the patient 4-12 weeks after one, two, or three rescue doses, a maintenance dose of mijicillinab is administered to the patient at about 50 mg or about 100 mg.

29. The method of any one of claims 18-21 or 28, wherein a maintenance dose of mijicillinumab is administered to the patient 2-8 weeks after the final induction dose, rescue dose, or extended induction dose.

30. The method of any one of claims 18-21 or 28-29, wherein a maintenance dose of mijizumab is administered to the patient 4 weeks after the final induction dose, rescue dose, or extended induction dose.

31. The method of any one of claims 18-21 or 28-30, wherein a maintenance dose of mijicillinumab is administered to the patient at intervals of 4 to 8 weeks.

32. The method of any one of claims 18-21 or 28-31, wherein a maintenance dose of mijicillinumab is administered to the patient at 4-week intervals.

33. The method of any one of claims 18-21 or 28-32, wherein a maintenance dose of mijizumab is administered to the patient via subcutaneous injection.

34. The method of claim 1, comprising: Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; then Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 4-week intervals. The patients were between 2 and 18 years old and weighed between 10 kg and 20 kg or less.

35. The method of claim 1, comprising: Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; then Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 100 mg intervals of four weeks. The patients were between 2 and 18 years old and weighed between 20 kg and 40 kg or less.

36. The method of any one of claims 34-35, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the final induction dose, the patient is given three extended induction doses of mijicillinab. in, If the patient's weight is greater than 10 kg but less than or equal to 40 kg, administer an extended induction dose of mijicillinab at approximately 5 mg / kg or approximately 10 mg / kg. In this case, patients were given an extended induction dose of mijicillinumab via intravenous infusion at 4-week intervals.

37. The method of claim 36, wherein if the patient achieves a clinical response 4 to 12 weeks after the last extended induction dose, a maintenance dose of mijizumab is administered to the patient 2 to 8 weeks after the last extended induction dose.

38. The method of any one of claims 34-37, wherein, If a patient develops a loss of response during maintenance therapy, administer one, two, or three rescue doses of mijizumab. Specifically, if the patient weighs 10 kg to less than or equal to 40 kg, a rescue dose of mijizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg; and The rescue dose of mijizumab was administered to the patient via intravenous infusion at 4-week intervals.

39. The method of claim 38, wherein if a clinical response is achieved in the patient 4-12 weeks after one, two, or three rescue doses, an additional maintenance dose of mijizumab is administered to the patient subcutaneously at 4-week intervals.

40. The method of any one of claims 1-39, wherein, within about 2 weeks to about 48 weeks of administration of mijizumab, the patient achieves at least one or more of the following therapeutic effects: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom relief, symptom response, surgical-free clinical remission, corticosteroid-free clinical remission, histological endoscopic mucosal remission, histological endoscopic mucosal improvement, bowel urgency relief, bowel urgency improvement, defecation frequency improvement, and rectal bleeding improvement.

41. The method of claim 46, wherein at least one or more therapeutic effects are achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mirgizumab.

42. The method of claims 40-41, wherein at least one or more therapeutic effects are achieved during induction administration or prolonged induction administration.

43. The method of any one of claims 40-42, wherein one or more therapeutic effects persist during the maintenance period.

44. The method of claim 43, wherein the patient has a surgical-free sustained clinical remission at week 52 and has not used steroids for at least 12 weeks prior to week 52 of administration of mijizumab.

45. The method of any one of claims 1-44, wherein the patient is biologic-naïve and / or advanced therapy-naïve.

46. ​​The method of any one of claims 1-45, wherein the patient has failed conventional treatment.

47. The method of any one of claims 1-44 or 46, wherein the patient has received biologic therapy and / or advanced therapy.

48. The method of any one of claims 1-44 or 46-47, wherein the patient is a patient who has failed biologic therapy and / or advanced therapy.

49. The method of any one of claims 1-44 or 46-48, wherein the patient is unresponsive, poorly responsive, loses response, or is intolerant to at least one prior treatment for ulcerative colitis.

50. The method of any one of claims 47-49, wherein the biological agent is an anti-TNF therapy and / or an anti-α4β7 therapy.

51. The method of any one of claims 47-49, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

52. Mijizizumab for the treatment of patients with moderate to severe active ulcerative colitis (UC) in need, wherein the patient is given an induction dose of mijizizumab at a dose of about 5 mg / kg to about 10 mg / kg, and wherein the patient is 2 years of age or younger than 18 years of age and weighs more than 10 kg.

53. Mijicillinumab for the said use according to any one of claims 52, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, an induction dose of mijicillinumab is administered to the patient at about 5 mg / kg to about 10 mg / kg.

54. Mijicillinumab for the said use according to any one of claims 52-53, wherein an induction dose of mijicillinumab is administered to the patient at about 5 mg / kg.

55. Mijicillinumab for the purpose according to any one of claims 52-53, wherein an induction dose of mijicillinumab is administered to the patient at about 10 mg / kg.

56. Mijicillinumab for the purpose according to any one of claims 52-55, wherein the patient is given three induction doses of mijicillinumab.

57. Mijicillinumab for the stated purpose according to any one of claims 52-56, wherein an induction dose of mijicillinumab is administered to the patient at intervals of 4-8 weeks.

58. Mijicillinumab for the stated purpose according to any one of claims 52-57, wherein an induction dose of mijicillinumab is administered to the patient at 4-week intervals.

59. Mijicillinumab for the said use according to any one of claims 52-58, wherein an induction dose of mijicillinumab is administered to the patient at weeks 0, 4, and 8.

60. Mijicillinumab for the said use according to any one of claims 52-59, wherein the induction dose is delivered during a 12-week induction dosing period.

61. Mijicillinumab for the stated purpose according to any one of claims 52-60, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the last induction dose, the patient is given one, two, or three extended induction doses of mijicillinumab at about 5 mg / kg to about 10 mg / kg.

62. The mijicillinumab for the said use according to claim 61, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of mijicillinumab is administered to the patient at about 5 mg / kg or about 10 mg / kg.

63. Mijicillinumab for the purpose according to any one of claims 61-62, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of mijicillinumab is administered to the patient at about 10 mg / kg.

64. Mijicillinumab for the purpose according to any one of claims 61-62, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of mijicillinumab is administered to the patient at about 5 mg / kg.

65. Mijicillinumab for the stated purpose according to any one of claims 61-64, wherein an extended induction dose is administered to the patient 4-8 weeks after the final maintenance dose.

66. Mijicillinumab for the said use according to any one of claims 61-65, wherein the patient is given three extended induction doses of mijicillinumab.

67. Mijicillinumab for the stated purpose according to any one of claims 61-66, wherein an extended induction dose of mijicillinumab is administered to the patient at intervals of 4-8 weeks.

68. Mijicillinumab for the stated purpose according to any one of claims 61-67, wherein the patient is given an extended induction dose of mijicillinumab at 4-week intervals.

69. Mijicillinumab for the stated purpose according to any one of claims 61-68, comprising administering a maintenance dose of mijicillinumab to a patient at a dose of about 50 mg to about 100 mg, wherein the maintenance dose is administered after the last induction dose or the last extended induction dose.

70. The mijicillinumab for the said use according to claim 69, wherein if the patient's weight is greater than 10 kg and less than or equal to 20 kg, a maintenance dose of mijicillinumab is administered to the patient at about 50 mg.

71. The mijicillinumab for the said use according to claim 69, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a maintenance dose of mijicillinumab is administered to the patient at about 100 mg.

72. Mijicillinumab for the said use according to any one of claims 69-71, wherein a maintenance dose of mijicillinumab is administered to the patient if the patient achieves a clinical response from the last induction or extended induction dose administered to the patient.

73. The migiliterumab for the said use according to any one of claims 69-72, wherein, If a patient develops a loss of response during maintenance dosing, a rescue dose of mijicillinumab may be administered to the patient once, twice, or three times at a dose of about 5 mg / kg to about 10 mg / kg.

74. The mijicillinumab for the said use according to claim 73, wherein if the patient's weight is 10 kg to less than or equal to 20 kg, a rescue dose of mijicillinumab is administered to the patient at about 5 mg / kg.

75. Mijicillinumab for the stated purpose according to claim 73, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a rescue dose of mijicillinumab is administered to the patient at 10 mg / kg.

76. Mijicillinumab for the stated purpose according to any one of claims 73-75, wherein the rescue dose is administered to the patient 4-8 weeks after the final maintenance dose.

77. Mijicillinumab for the purpose according to any one of claims 73-76, wherein the rescue dose is administered to the patient at intervals of 4-8 weeks.

78. Mijicillinumab for the stated purpose according to any one of claims 73-77, wherein the rescue dose is administered to the patient at 4-week intervals.

79. Mijicillinumab for the stated purpose according to any one of claims 73-78, wherein if a clinical response is achieved in the patient 4-12 weeks after one, two, or three rescue doses, a maintenance dose is administered to the patient at about 50 mg or about 100 mg.

80. Mijicillinumab for the said use according to any one of claims 69-72 or 79, wherein a maintenance dose of mijicillinumab is administered to the patient 2-8 weeks after the last induction dose, rescue dose, or extended induction dose.

81. Mijicillinumab for the stated purpose according to any one of claims 69-72 or 79-80, wherein a maintenance dose of mijicillinumab is administered to the patient 4 weeks after the final induction dose, rescue dose, or extended induction dose.

82. Mijicillinumab for the stated purpose according to any one of claims 69-72 or 79-81, wherein a maintenance dose of mijicillinumab is administered to the patient at intervals of 4 to 8 weeks.

83. Mijicillinumab for the stated purpose according to any one of claims 69-72 or 79-82, wherein a maintenance dose of mijicillinumab is administered to the patient at 4-week intervals.

84. Mijicillinumab for the said use according to any one of claims 69-72 or 79-83, wherein a maintenance dose of mijicillinumab is administered to the patient via subcutaneous injection.

85. The migelizumab for the said use according to claim 52, comprising, Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; and Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 4-week intervals. The patients were between 2 and 18 years old and weighed between 10 kg and 20 kg or less.

86. The migiliterumab for said use according to any one of claims 52, comprising: Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; and Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 100 mg intervals of four weeks. The patients were between 2 and 18 years old and weighed between 20 kg and 40 kg or less.

87. Mijicillinumab for the stated purpose according to any one of claims 85-86, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the final induction dose, the patient is given three extended induction doses of mijicillinumab. in, If the patient's weight is greater than 10 kg but less than or equal to 40 kg, administer an extended induction dose of migiliterumab at approximately 5 mg / kg or approximately 10 mg / kg. The extended induction dose of mijicillinumab is administered to the patient via intravenous infusion at 4-week intervals.

88. Mijicillinumab for the said use according to any one of claims 87, wherein if a clinical response is achieved in the patient 4 to 12 weeks after the last extended induction dose, a maintenance dose of mijicillinumab is administered to the patient 2 to 8 weeks after the last extended induction dose.

89. The migiliterumab for said use according to any one of claims 85-102, wherein, If a patient develops a loss of response during maintenance therapy, administer one, two, or three rescue doses of mijizumab. If the patient weighs between 10 kg and less than or equal to 40 kg, a rescue dose of migizumab is administered to the patient at approximately 5 mg / kg or approximately 10 mg / kg. The rescue dose of mijizumab was administered to the patient via intravenous infusion at 4-week intervals.

90. Mijicillinumab for the stated purpose according to claim 89, wherein if a patient achieves a clinical response 4-12 weeks after one, two, or three rescue doses, a maintenance dose of mijicillinumab is administered to the patient subcutaneously at 4-week intervals.

91. Mijizumab for the purpose according to any one of claims 52-90, wherein the patient achieves at least one or more of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of treatment with mijizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom relief, symptom response, surgical-free clinical remission, corticosteroid-free clinical remission, histological endoscopic mucosal remission, improvement of endoscopic histological inflammation, relief of bowel urgency, improvement of bowel urgency, relief of defecation frequency, improvement of defecation frequency, and improvement of rectal bleeding.

92. The mijizumab for the said use according to claim 91, wherein at least one or more therapeutic effects are achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, or 48 weeks of treatment with mijizumab.

93. Mijicillinumab for the purpose according to any one of 91-92, wherein at least one or more therapeutic effects are achieved during the induction phase or the prolonged induction phase.

94. Mijicillinumab according to 91-93 for the stated purpose, wherein one or more therapeutic effects persist during the maintenance period.

95. Mijicillinumab for the stated purpose according to claim 94, wherein the patient has a surgical-free sustained clinical response at week 52 and has not used steroids for at least 12 weeks prior to week 52 of treatment with mijicillinumab.

96. Mijicillinumab for the purpose of any one of claims 52-95, wherein the patient is biologic-naïve and / or advanced therapy-naïve.

97. Mijicillinumab for the purpose of any one of claims 52-96, wherein the patient has failed conventional treatment.

98. Mijicillinumab for the purpose of said use according to any one of claims 52-95 or 97, wherein said patient has received biologic therapy and / or advanced therapy.

99. Mijicillinumab for the purpose of said use according to any one of claims 52-95 or 97-98, wherein said patient is a patient who has failed biologic therapy and / or advanced therapy.

100. Mijizumab for the purpose of any one of claims 52-95 or 97-99, wherein the patient has no response, inadequate response, loss of response, or intolerance to at least one prior treatment for ulcerative colitis.

101. Mijicillinumab for the purpose according to any one of claims 98-100, wherein the biological agent is an anti-TNF therapy and / or an anti-α4β7 therapy.

102. Mijicillina for the use of any one of claims 98-100, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

103. Use of mijizumab in the preparation of an agent for the treatment of patients in need of moderate to severe active ulcerative colitis (UC), wherein an induction dose of mijizumab is administered to a patient at a dose of about 5 mg / kg to about 10 mg / kg, and wherein the patient is 2 years of age or younger than 18 years of age and weighs more than 10 kg.

104. The use according to any one of claims 103, wherein if the patient's weight is greater than 10 kg to less than or equal to 40 kg, an induction dose of migilizumab is administered to the patient at about 5 mg / kg to about 10 mg / kg.

105. The use according to any one of claims 103-104, wherein an induction dose of mijizumab is administered to a patient at about 5 mg / kg.

106. The use according to any one of claims 103-104, wherein an induction dose of mijicillinumab is administered to a patient at about 10 mg / kg.

107. The use according to any one of claims 103-106, wherein the patient is given three induction doses of mijicillinumab.

108. The use according to any one of claims 103-107, wherein an induction dose of mijizumab is administered to the patient at intervals of 4-8 weeks.

109. The use according to any one of claims 103-108, wherein an induction dose of mijicillinumab is administered to the patient at 4-week intervals.

110. The use according to any one of claims 103-109, wherein an induction dose of mijizumab is administered to the patient at weeks 0, 4 and 8.

111. The use according to any one of claims 103-110, wherein the induction dose is delivered during a 12-week induction dosing period.

112. The use according to any one of claims 103-111, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the last induction dose, the patient is given one, two, or three extended induction doses of migilizumab at a dose of 5 mg / kg to about 10 mg / kg.

113. The use according to claim 112, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of migiliterumab is administered to the patient at about 5 mg / kg or about 10 mg / kg.

114. The use according to any one of claims 112-113, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of migiliterumab is administered to the patient at about 10 mg / kg.

115. The use according to any one of claims 112-113, wherein if the patient's weight is greater than 10 kg and less than or equal to 40 kg, the extended induction dose of migilizumab is administered to the patient at about 5 mg / kg.

116. The use according to any one of claims 112-115, wherein an extended induction dose of mijicillinumab is administered to the patient 4-8 weeks after the final maintenance dose.

117. The use according to any one of claims 112-116, wherein the patient is given three extended induction doses of mijicillinab.

118. The use according to any one of claims 112-117, wherein an extended induction dose of mijicillinumab is administered to the patient at intervals of 4-8 weeks.

119. The use according to any one of claims 112-118, wherein the patient is given an extended induction dose of mijicillin at 4-week intervals.

120. The use according to any one of claims 112-119, further comprising administering a maintenance dose of mijizumab to the patient at a dose of about 50 mg to about 100 mg, wherein the maintenance dose is administered after the last induction dose or the last extended induction dose.

121. The use according to claim 120, wherein if the patient's weight is greater than 10 kg and less than or equal to 20 kg, a maintenance dose of migilizumab is administered to the patient at about 50 mg.

122. The use according to claim 120, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a maintenance dose of migilizumab is administered to the patient at about 100 mg.

123. The use according to any one of claims 120-122, wherein if the patient achieves a clinical response from the last induction or extended induction dose administered to the patient, a maintenance dose of mijicillinumab is administered to the patient.

124. The use according to any one of claims 120-123, wherein, If a patient develops a loss of response during maintenance dosing, a rescue dose of mijicillinumab may be administered to the patient once, twice, or three times at a dose of about 5 mg / kg to about 10 mg / kg.

125. The use according to claim 124, wherein if the patient weighs 10 kg to less than or equal to 20 kg, a rescue dose of mijicillinumab is administered to the patient at about 5 mg / kg.

126. The use according to claim 124, wherein if the patient's weight is greater than 20 kg and less than or equal to 40 kg, a rescue dose of 10 mg / kg is administered to the patient.

127. The use according to any one of claims 124-126, wherein the rescue dose is administered to the patient 4-8 weeks after the last maintenance dose.

128. The use according to any one of claims 124-127, wherein the rescue dose is administered to the patient at intervals of 4-8 weeks.

129. The use according to any one of claims 124-128, wherein the rescue dose is administered to the patient at 4-week intervals.

130. The use according to any one of claims 124-129, wherein if a clinical response is achieved in the patient 4-12 weeks after one, two, or three rescue doses, a maintenance dose of about 50 mg or about 100 mg is administered to the patient.

131. The use according to any one of claims 120-123 or 130, wherein a maintenance dose of mijizumab is administered to the patient 2-8 weeks after the final induction dose, rescue dose, or extended induction dose.

132. The use according to any one of claims 120-123 or 130-131, wherein a maintenance dose of mijizumab is administered to the patient 4 weeks after the final induction dose, rescue dose, or extended induction dose.

133. The use according to any one of claims 120-123 or 130-132, wherein a maintenance dose of mijicillinumab is administered to the patient at intervals of 4 to 8 weeks.

134. The use according to any one of claims 120-123 or 130-133, wherein a maintenance dose of mijizumab is administered to the patient at 4-week intervals.

135. The use according to any one of claims 120-123 or 130-134, wherein a maintenance dose of mijizumab is administered to the patient via subcutaneous injection.

136. The use according to claim 103, comprising: Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; then Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 4-week intervals. The patients were between 2 and 18 years old and weighed between 10 kg and 20 kg or less.

137. The use according to claim 103, comprising: Mijicillinumab was administered to the patient three times via intravenous infusion at intervals of approximately 5 mg / kg or approximately 10 mg / kg, over a period of 4 weeks; then Two to eight weeks after the final induction dose, a maintenance dose of mijizumab is administered subcutaneously at 100 mg intervals of four weeks. The patients were between 2 and 18 years old and weighed between 20 kg and 40 kg or less.

138. The use according to any one of claims 136-137, wherein if the patient does not achieve a clinical response 4 to 12 weeks after the final induction dose, the patient is given three extended induction doses of mijicillinab. in, If the patient weighs more than 10 kg but less than or equal to 40 kg, administer an extended induction dose of mijicillinab at approximately 5 mg / kg or approximately 10 mg / kg; and In this case, patients were given an extended induction dose of mijicillinumab via intravenous infusion at 4-week intervals.

139. The use according to claim 138, wherein if the patient achieves a clinical response 4 to 12 weeks after the last extended induction dose, a maintenance dose of mijizumab is administered to the patient 2 to 8 weeks after the last extended induction dose.

140. The use according to any one of claims 136-139, wherein, If a patient develops a loss of response during maintenance therapy, administer one, two, or three rescue doses of mijizumab. Specifically, if the patient weighs between 10 kg and 40 kg, a rescue dose of mijizumab is administered at approximately 5 mg / kg or approximately 10 mg / kg. The rescue dose of mijizumab was administered to the patient via intravenous infusion at 4-week intervals.

141. The use according to claim 140, wherein if the patient achieves a clinical response 4-12 weeks after one, two, or three rescue doses, a maintenance dose of mijizumab is administered to the patient subcutaneously at 4-week intervals.

142. The use according to any one of claims 103-141, wherein the patient achieves at least one or more of the following therapeutic effects within approximately 2 weeks to approximately 48 weeks of treatment with mirgiizumab: clinical response, clinical remission, endoscopic remission, endoscopic improvement, symptom relief, symptom response, surgical-free clinical remission, corticosteroid-free clinical remission, histological endoscopic mucosal remission, improvement of endoscopic histological inflammation, relief of bowel urgency, improvement of bowel urgency, relief of defecation frequency, improvement of defecation frequency, and improvement of rectal bleeding.

143. The use according to claim 142, wherein at least one or more therapeutic effects are achieved within approximately 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 or 48 weeks of treatment with mirgicillinumab.

144. The use according to any one of 142-143, wherein at least one or more therapeutic effects are achieved during the induction period or a prolonged induction period.

145. The use according to any one of claims 142-143, wherein one or more therapeutic effects persist during the maintenance period.

146. The use according to claim 145, wherein the patient has a surgical-free sustained clinical remission at week 52 and has not used steroids for at least week 12 prior to week 52 of treatment with mijizumab.

147. The use according to any one of claims 103-146, wherein the patient is biologic-naïve and / or advanced therapy-naïve.

148. The use according to any one of claims 103-147, wherein the patient is a patient who has failed conventional treatment.

149. The use according to any one of claims 103-146 or 148, wherein the patient has received biologic therapy and / or advanced therapy.

150. The use according to any one of claims 103-146 or 148-149, wherein the patient is a patient who has failed biologic therapy and / or advanced therapy.

151. The use according to any one of claims 103-146 or 148-150, wherein the patient is unresponsive, poorly responsive, loses response, or is intolerant to at least one prior treatment for ulcerative colitis.

152. The use according to any one of claims 149-151, wherein the biological agent is an anti-TNF therapy and / or an anti-α4β7 therapy.

153. The use according to any one of claims 149-151, wherein the advanced therapy is a JAK inhibitor, an S1P receptor modulator, or a TYK2 inhibitor.

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