Methods of treating ulcerative colitis

Abstract

To provide methods for the treatment of ulcerative colitis with an anti-IL-23pl9 antibody.SOLUTION: A method of treating ulcerative colitis (UC) comprises administering to a patient in need thereof an anti-IL-23p19 antibody, the method comprising: a) administering at least one induction dose of the anti-IL-23p19 antibody to the patient, wherein the induction dose comprises 50 mg to 1200 mg of the antibody; and b) administering at least one maintenance dose of the anti-IL-23p19 antibody to the patient after the last induction dose is administered, wherein the maintenance dose comprises 150 to 400 mg of the anti-IL-23p19 antibody.SELECTED DRAWING: Figure 5

Description

Detailed Description of the Invention

[0001] The present invention relates to a method for treating ulcerative colitis.

[0002] Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by inflammation of the colon. Patients have intermittent disease flares interspersed with periods of remission, and the main symptoms are bloody stools, diarrhea, and abdominal pain, which reduces the overall quality of life. Many patients with UC experience a severe clinical course, and approximately 30% require colectomy within 10 years of diagnosis (Ordas et al., Lancet, Vol. 380, No. 9853, pp 1606-1619, 2012). The goal of treatment in UC is the induction and maintenance of remission (including steroid-free remission). Conventional drugs used to treat UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressants such as azathioprine (AZA) and 6-mercaptopurine (6-MP). However, as many as 40% of UC patients fail or do not respond to conventional drugs, requiring secondary medical treatment or colectomy (Burger D et al., Gastroenterology, Vol. 140, No. 6, pp 1827-1837, 2011). As a result, various biologics targeting specific immunological pathways have been investigated as potential treatments for UC. Anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies and, more recently, vedolizumab, an integrin receptor antagonist, have been approved by the Food and Drug Administration and the European Medicines Agency.

[0003] Interleukin-23 (IL-23), a member of the interleukin-12 (IL-12) family of cytokines, is a heterodimeric protein composed of two subunits: the p40 subunit shared by IL-12, and the p19 subunit specific for IL-23. IL-23 is produced by antigen-presenting cells such as dendritic cells and macrophages and plays a critical role in the maintenance and amplification of T helper 17 (Th17) cells. Stimulation of these cells with IL-23 induces a unique inflammatory signature that includes interleukin-17A, interleukin-17F, interleukin-6, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, chemokine ligand 20, chemokine ligand 22, and the IL-23 receptor. In addition to Th17 cells, many innate immune cells respond to IL-23 and are important in both infection resistance and mediating pathology of many autoimmune / inflammatory diseases, including UC and Crohn's disease (CD). Treatment of several conditions with IL-23 targeted therapy is being pursued by several companies. The first such biologic to demonstrate clinical benefit in autoimmune disease was ustekinumab, a Food and Drug Administration approved monoclonal antibody for the treatment of psoriasis, psoriatic arthritis, and CD. Ustekinumab binds to the common p40 subunit of IL-12 and IL-23, and therefore specifically targets both cytokines, but not IL-23. Blockade of the IL-12 pathway would prevent interferon blockade of Th1 cell-induced Th17 cell development, potentially limiting the clinical activity of antibodies targeting p40. Agents that specifically target the IL-23p19 subunit have demonstrated clinical activity in psoriasis and CD (Kopp T et al., Nature, Volume 521, No. 7551, pages 222-226, 2015; Sands BE et al., Journal of Crohn's and Colitis, Volume 9, Issue Supplement 1, ppS15-S16, 2015).

[0004] The IL-23 / Th17 pathway is believed to play a role in UC (El-Bassat H et al, Journal of Molecular Biomarkers & Diagnosis, Vol. 5, No. 5, 100191, 2014). Nevertheless, clinical evaluation of IL-23 targeted therapy in UC has not yet been performed, and there remains a need for treatment options for ulcerative colitis that provide favorable outcomes for patients, for example, in terms of efficacy, safety, and / or tolerability of the treatment. In particular, there remains a need for treatment options in the form of dosing regimens that provide optimal efficacy.

[0005] Accordingly, in a first aspect of the present invention there is provided a method of treating ulcerative colitis (UC), comprising administering to a patient in need thereof an effective amount of an anti-IL-23p19 antibody, the method comprising: a) administering to the patient at least one induction dose of an anti-IL-23p19 antibody, the induction dose comprising between 50 mg and 1200 mg of antibody; b) administering to the patient at least one maintenance dose of an anti-IL-23p19 antibody after the final induction dose has been administered, wherein the maintenance dose comprises 150-400 mg of an anti-IL-23p19 antibody.

[0006] The method of the present invention comprises administering at least one induction dose of an anti-IL-23p19 antibody to a patient in need thereof during an induction period to induce a desired therapeutic effect, the desired therapeutic effect being clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission. If the patient achieves the desired therapeutic effect at the end of the induction period, the patient is then administered at least one maintenance dose to maintain at least one of the therapeutic effect(s) obtained during the induction period, the therapeutic effect(s) being clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission.

[0007] There is no minimum or maximum duration of the induction period, but typically the duration is 4, 8, or 12 weeks, and the end of the induction period is typically an end-of-induction evaluation that occurs 4 or 8 weeks after the last induction dose is administered. For example, a 4-week induction period may include administration of an induction dose at week 0 and an end-of-induction evaluation at week 4. An 8-week induction period may include administration of induction doses at weeks 0 and 4 and an end-of-induction evaluation at week 8. A 12-week induction period may include administration of induction doses at weeks 0, 4, and 8 and an end-of-induction evaluation at week 12.

[0008] In an embodiment of the invention, the ulcerative colitis is moderate to severe ulcerative colitis.

[0009] In a further embodiment of the method of the invention, the patient is biologic-naive. In an alternative embodiment of the method of the invention, the patient is biologic-experienced. In a further alternative embodiment of the method of the invention, the patient is biologic-failed or conventional-failed.

[0010] In yet a further embodiment of the method of the invention, at least one induction dose comprises between 200 mg and 1000 mg of anti-IL-23p19 antibody.

[0011] In yet a further embodiment of the method of the invention, at least one induction dose comprises between 200 mg and 600 mg of anti-IL-23p19 antibody.

[0012] In still further embodiments of the methods of the invention, at least one induction dose comprises 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0013] In a preferred embodiment of the method of the present invention, at least one induction dose comprises 300 mg of anti-IL-23p19 antibody.

[0014] In yet a further embodiment of the method of the present invention, one, two, or three induction doses are administered to the patient.

[0015] In yet a further embodiment of the method of the present invention, two or three induction doses are administered, four weeks apart.

[0016] In a preferred embodiment of the method of the present invention, three induction doses are administered, four weeks apart.

[0017] In yet a further embodiment of the method of the present invention, at least one induction dose is administered by intravenous infusion.

[0018] In yet a further embodiment of the method of the present invention, if the patient does not achieve a clinical response 4-12 weeks after the last induction dose is administered, one, two, or three extended induction doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extended induction dose is administered, at least one maintenance dose of an anti-IL-23p19 antibody is administered to the patient, where a clinical response is defined as achieving a reduction in rectal bleeding (RB) subscore of 1 or more, or a reduction in a 9-point Modified Mayo Score (MMS) subscore of 2 or more points and a reduction of 30-35% or more from baseline with an RB subscore of either 0 or 1.

[0019] This embodiment of the method of the present invention includes administration of one, two, or three additional induction doses, called "extended induction doses" to distinguish them from the first induction dose, if the patient does not achieve a clinical response at the end of the first induction period. The dose and dosing interval during the extended induction period are typically the same as those during the first induction period, but may be modified if the attending medical professional has reason to believe that the patient may benefit from a change, such as an increased dose or more frequent dosing of anti-IL-23p19. If the patient achieves a clinical response at the end of the extended induction period, at least one maintenance dose of anti-IL-23p19 antibody is administered to maintain the clinical response or other desired therapeutic effect(s), such as clinical remission, endoscopic remission, endoscopic cure, and / or symptomatic remission.

[0020] The first maintenance dose is administered 4-12 weeks after the last extended induction dose is administered to the patient. The 4-12 week period corresponds to a variation in the period between administration of the last extended induction dose and the extended induction end evaluation. The variation can result from a variation in the dosing frequency during the extended induction period. For example, the dosing frequency during the extended induction period is every 4 weeks, and the extended induction end evaluation is performed 4 weeks after the last extended induction dose is administered. If the patient achieves a clinical response, the first maintenance dose can be administered at the induction end evaluation visit (i.e., 4 weeks after administration of the last extended induction dose) or at the next visit scheduled shortly thereafter. Alternatively, the dosing frequency during the extended induction period is every 8 weeks, and the extended induction end evaluation is performed 8 weeks after the last extended induction dose is administered. If the patient achieves a clinical response, the first maintenance dose can be administered at the induction end evaluation visit (i.e., 8 weeks after administration of the last extended induction dose) or at the next visit scheduled shortly thereafter.

[0021] In yet a further embodiment of the method of the present invention, if the patient has not achieved a clinical response four weeks after the last induction dose was administered, one, two, or three extended induction doses are administered to the patient.

[0022] In yet a further embodiment of the method of the present invention, two or three extended induction doses are administered four weeks apart.

[0023] In a preferred embodiment of the method of the present invention, three extended induction doses are administered, four weeks apart.

[0024] In yet further embodiments of the methods of the invention, the one, two, or three extended induction doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0025] In a preferred embodiment of the method of the invention, the one, two, or three extended induction doses comprise 300 mg of anti-IL-23p19 antibody.

[0026] In yet a further embodiment of the method of the present invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0027] In still further embodiments of the methods of the invention, at least one maintenance dose comprises 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0028] In a preferred embodiment of the method of the invention, at least one maintenance dose comprises 200 mg of anti-IL-23p19 antibody.

[0029] In yet a further embodiment of the method of the present invention, multiple maintenance doses are administered to the patient, with the first maintenance dose being administered 2 to 8 weeks after the last induction dose or the last extended induction dose was administered.

[0030] Preferably, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose has been administered.

[0031] Alternatively, preferably, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last induction dose or the last extended induction dose is administered.

[0032] Even more preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose has been administered.

[0033] In still further embodiments of the methods of the present invention, the subsequent maintenance dose(s) are administered at 4 week, 8 week, or 12 week intervals following administration of the initial maintenance dose.

[0034] Preferably, subsequent maintenance dose(s) are administered at four week intervals.

[0035] Alternatively, preferably, subsequent maintenance dose(s) are administered at 8 week intervals.

[0036] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 12 week interval(s).

[0037] In yet a further embodiment of the method of the present invention, the maintenance dose(s) is administered by subcutaneous injection.

[0038] In yet a further embodiment of the method of the invention, if the patient experiences a loss of response during the maintenance period, one, two, or three extra-time doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extra-time dose is administered, one or more further maintenance doses of an anti-IL-23p19 antibody are administered to the patient, where loss of response is defined as (a) a 2 or more point increase from baseline in a combination of stool frequency (SF) and rectal bleeding (RB) scores, (b) a combination of SF and RB scores of 4 or greater on two consecutive visits, 7 days or more apart, with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3, and clinical response is defined as achieving a 2 or more point reduction in a 9-point modified Mayo score (MMS) subscore and a 30-35% or greater reduction from baseline, with a 1 or greater reduction in the rectal bleeding (RB) subscore or an RB subscore of either 0 or 1.

[0039] This embodiment of the invention includes administration of one, two, or three extra-boost doses of anti-IL-23p19 antibody if the patient experiences loss of response during the maintenance period. The extra-boost dose is a dose of anti-IL-23p19 antibody administered to the patient to re-induce / re-achieve the therapeutic effect achieved at the end of the induction period, the therapeutic effect being clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission. The extra-boost dose and dosing interval during the extra-boost dosing period are typically the same as the dose and dosing interval during the initial induction period, but may be modified if the attending medical professional has reason to believe that the patient could benefit from a change, such as an increased dose or more frequent dosing of anti-IL-23p19.

[0040] If the patient achieves a clinical response at the end of the extra-boost dosing period, maintenance therapy is resumed and one or more additional maintenance doses of anti-IL-23p19 antibody are administered to the patient. These maintenance doses are referred to as "additional maintenance dose(s)" to identify them as the doses that are the maintenance doses administered when maintenance therapy is resumed. The additional maintenance doses are a dose of anti-IL-23p19 antibody administered to the patient to maintain or continue the clinical response or other desired therapeutic effect(s), such as clinical remission, endoscopic remission, endoscopic cure, and / or symptomatic remission, achieved after administration of the extra-boost dose(s) during the extra-boost period. The additional maintenance dose(s) and dosing interval during the resumed maintenance therapy are typically the same as the maintenance dose and dosing interval during the initial maintenance period, but may be changed if the responsible medical professional has reason to believe that the patient may benefit from a change, such as an increased dose or more frequent dosing of anti-IL-23p19.

[0041] The first further maintenance dose is administered 4-12 weeks after the last extra-boost dose is administered to the patient. The 4-12 week period corresponds to a variation in the time between administration of the last extra-boost dose and the extra-boost end evaluation. The variation can result from a variation in the dosing frequency during the extra-boost period. For example, the dosing frequency during the extra-boost period is every 4 weeks, with the extended induction end evaluation occurring 4 weeks after the last extended induction dose is administered. If the patient achieves a clinical response, the first further maintenance dose can be administered at the extra-boost end evaluation visit (i.e., 4 weeks after administration of the last extra-boost dose) or at the next visit scheduled shortly thereafter. Alternatively, the dosing frequency during the extra-boost period is every 8 weeks, with the extra-boost end evaluation occurring 8 weeks after the last extra-boost dose is administered. If the patient achieves a clinical response, the first further maintenance dose may be administered at the end of induction evaluation visit (i.e., 8 weeks after administration of the last boost dose) or at the next scheduled visit shortly thereafter.

[0042] In yet a further embodiment of the method of the present invention, two or three boost doses are administered four weeks apart.

[0043] In a preferred embodiment of the method of the present invention, three boost doses are administered four weeks apart.

[0044] In still further embodiments of the methods of the invention, the one, two, or three boost doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0045] Preferably, one, two, or three boost doses contain 300 mg of anti-IL-23p19 antibody.

[0046] In yet a further embodiment of the method of the present invention, one, two, or three bolus doses are administered by intravenous infusion.

[0047] In still further embodiments of the methods of the invention, the one or more additional maintenance doses comprise 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0048] In a preferred embodiment of the method of the invention, the one or more further maintenance doses comprise 200 mg of anti-IL-23p19 antibody.

[0049] In yet a further embodiment of the method of the present invention, multiple additional maintenance doses are administered to the patient, with the first additional maintenance dose being administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last boost dose was administered.

[0050] Preferably, the first further maintenance dose is administered four weeks after the last boost dose is administered.

[0051] In still further embodiments of the methods of the present invention, the subsequent further maintenance dose(s) are administered at 4 week, 8 week, or 12 week interval(s) following administration of the first further maintenance dose.

[0052] Preferably, subsequent further maintenance dose(s) are administered at four week interval(s).

[0053] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 8 week interval(s).

[0054] Further alternatively, preferably, further maintenance dose(s) thereafter are administered at 12 week interval(s).

[0055] In yet a further embodiment of the method of the present invention, the further maintenance dose(s) is administered by subcutaneous injection.

[0056] In still further embodiments of the methods of the invention, the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

[0057] In a preferred embodiment of the methods of the present invention, the anti-IL-23p19 antibody is mirikizumab.

[0058] In yet a further embodiment of the method of the present invention, the method comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0059] In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered.

[0060] In a further preferred embodiment of the method of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0061] In an alternative preferred embodiment of the method of the present invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0062] In yet a further embodiment of the method of the present invention, the method comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0063] In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose is administered.

[0064] In a further preferred embodiment of the method of the invention, subsequent maintenance doses of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0065] In an alternative preferred embodiment of the method of the present invention, subsequent maintenance doses of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0066] In yet a further embodiment of the method of the present invention, the method comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experiences loss of response during the maintenance period, three extra doses of mirikizumab will be administered to the patient at 4-week intervals, each extra dose containing 300 mg of mirikizumab; If the patient achieves a clinical response 4 weeks after the last boost dose, an additional maintenance dose of mirikizumab is administered to the patient, and the first additional maintenance dose is administered 2 to 8 weeks after the last boost dose. Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose contains 200 mg of mirikizumab.

[0067] In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0068] In a further preferred embodiment of the method of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0069] In an alternative preferred embodiment of the method of the present invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose.

[0070] In yet a further embodiment of the method of the present invention, the method comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experiences loss of response during the maintenance period, three extra doses of mirikizumab will be administered to the patient at 4-week intervals, each extra dose containing 300 mg of mirikizumab; If the patient achieves a clinical response 4 weeks after the last boost dose is administered, then further maintenance dose(s) of mirikizumab are administered to the patient, and the first further maintenance dose(s) is administered 2 to 8 weeks after the last boost dose is administered; Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose and each further maintenance dose contains 200 mg of mirikizumab.

[0071] In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0072] In a further preferred embodiment of the method of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0073] In an alternative preferred embodiment of the method of the present invention, subsequent maintenance doses of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance doses of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose.

[0074] A further aspect of the invention provides an anti-IL-23p19 antibody for use in the treatment of UC, the treatment comprising: a) administering to the patient at least one induction dose of an anti-IL-23p19 antibody, the induction dose comprising between 50 mg and 1200 mg of antibody; and b) administering to the patient at least one maintenance dose of the anti-IL-23p19 antibody after the final induction dose has been administered, wherein the maintenance dose comprises 150 to 400 mg of the anti-IL-23p19 antibody.

[0075] In an embodiment of the invention, the UC is moderate to severe ulcerative colitis.

[0076] In a further embodiment of the invention, the patient is biologic naive. In an alternative embodiment of the invention, the patient is biologic experienced. In a further alternative embodiment of the invention, the patient is biologic failed or conventional failed.

[0077] In yet a further embodiment of the invention, at least one induction dose comprises between 200 mg and 1000 mg of anti-IL-23p19 antibody.

[0078] In yet a further embodiment of the invention, at least one induction dose comprises between 200 mg and 600 mg of anti-IL-23p19 antibody.

[0079] In still further embodiments of the invention, at least one induction dose comprises 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0080] In a preferred embodiment of the invention, at least one induction dose comprises 300 mg of anti-IL-23p19 antibody.

[0081] In yet a further embodiment of the invention, one, two, or three induction doses are administered to the patient.

[0082] In yet a further embodiment of the invention, two or three induction doses are administered four weeks apart.

[0083] In a preferred embodiment of the invention, three induction doses are administered, four weeks apart.

[0084] In yet a further embodiment of the invention, at least one induction dose is administered by intravenous infusion.

[0085] In yet a further embodiment of the invention, if the patient does not achieve a clinical response 4-12 weeks after the last induction dose is administered, one, two, or three extended induction doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extended induction dose is administered, at least one maintenance dose of an anti-IL-23p19 antibody is administered to the patient, where a clinical response is defined as achieving a reduction in rectal bleeding (RB) subscore of 1 or more, or a reduction in a 9-point Modified Mayo Score (MMS) subscore of 2 or more points and a reduction of 30-35% or more from baseline with an RB subscore of either 0 or 1.

[0086] In yet a further embodiment of the invention, one, two, or three extended induction doses are administered to a patient if the patient has not achieved a clinical response four weeks after the last induction dose was administered.

[0087] In yet a further embodiment of the invention, two or three extended induction doses are administered four weeks apart.

[0088] In a preferred embodiment of the invention, three extended induction doses are administered, four weeks apart.

[0089] In yet further embodiments of the invention, the one, two, or three extended induction doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0090] In a preferred embodiment of the invention, the one, two, or three extended induction doses comprise 300 mg of anti-IL-23p19 antibody.

[0091] In yet a further embodiment of the invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0092] In still further embodiments of the invention, at least one maintenance dose comprises 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0093] In a preferred embodiment of the invention, at least one maintenance dose comprises 200 mg of anti-IL-23p19 antibody.

[0094] In yet a further embodiment of the invention, multiple maintenance doses are administered to the patient, with the first maintenance dose being administered 2-8 weeks after the last induction dose or the last extended induction dose was administered.

[0095] Preferably, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose has been administered.

[0096] Alternatively, preferably, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last induction dose or the last extended induction dose is administered.

[0097] More preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose has been administered.

[0098] In yet a further embodiment of the invention, subsequent maintenance dose(s) are administered at 4 week, 8 week, or 12 week interval(s) following administration of the initial maintenance dose.

[0099] Preferably, subsequent maintenance dose(s) are administered at four week intervals.

[0100] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 8 week interval(s).

[0101] Further alternatively, preferably, subsequent maintenance dose(s) are administered at 12 week intervals.

[0102] In yet a further embodiment of the invention, the maintenance dose(s) are administered by subcutaneous injection.

[0103] In yet a further embodiment of the invention, if the patient experiences loss of response during the maintenance period, one, two, or three extra-time doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extra-time dose is administered, one or more further maintenance doses of an anti-IL-23p19 antibody are administered to the patient, where loss of response is defined as (a) a 2 or more point increase from baseline in a combination of stool frequency (SF) and rectal bleeding (RB) scores, (b) a combination of SF and RB scores of 4 or greater on two consecutive visits, 7 days or more apart, with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3, and clinical response is defined as achieving a 2 or more point reduction in a 9-point modified Mayo score (MMS) subscore and a 30-35% or greater reduction from baseline, with a 1 or greater reduction in the rectal bleeding (RB) subscore or an RB subscore of either 0 or 1.

[0104] In yet a further embodiment of the invention, two or three boost doses are administered four weeks apart.

[0105] In a preferred embodiment of the invention, three boost doses are administered four weeks apart.

[0106] In still further embodiments of the invention, the one, two, or three boost doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0107] In a preferred embodiment of the invention, one, two, or three boost doses comprise 300 mg of anti-IL-23p19 antibody.

[0108] In yet a further embodiment of the invention, one, two, or three bolus doses are administered by intravenous infusion.

[0109] In still further embodiments of the invention, the one or more additional maintenance doses comprise 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0110] In a preferred embodiment of the invention, the one or more further maintenance doses comprise 200 mg of anti-IL-23p19 antibody.

[0111] In a preferred embodiment of the invention, multiple further maintenance doses are administered to the patient, with the first further maintenance dose being administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last boost dose was administered.

[0112] Preferably, the first further maintenance dose is administered four weeks after the last boost dose is administered.

[0113] In yet a further embodiment of the invention, the subsequent further maintenance dose(s) are administered at 4 week, 8 week, or 12 week interval(s) following administration of the first further maintenance dose.

[0114] Preferably, subsequent further maintenance dose(s) are administered at four week interval(s).

[0115] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 8 week interval(s).

[0116] Further alternatively, preferably, further maintenance dose(s) thereafter are administered at 12 week interval(s).

[0117] In yet a further embodiment of the invention, the further maintenance dose(s) are administered by subcutaneous injection.

[0118] In still further embodiments of the invention, the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

[0119] In a preferred embodiment of the invention, the anti-IL-23p19 antibody is mirikizumab.

[0120] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0121] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered.

[0122] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0123] In an alternative preferred embodiment of the invention, further maintenance dose(s) of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0124] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0125] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose has been administered.

[0126] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0127] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0128] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experienced loss of response during the maintenance period, three additional doses of mirikizumab were administered to the patient at 4-week intervals. Each boost dose contained 300 mg of mirikizumab. If the patient achieves a clinical response 4 weeks after the last boost dose is administered, an additional maintenance dose of mirikizumab is administered to the patient, with the first additional maintenance dose being administered 2 to 8 weeks after the last boost dose is administered. Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose and each further maintenance dose contains 200 mg of mirikizumab.

[0129] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0130] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0131] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose.

[0132] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose comprising 300 mg of mirikizumab; A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point Modified Mayo Score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experiences loss of response during the maintenance period, three extra doses of mirikizumab will be administered to the patient at 4-week intervals, each extra dose containing 300 mg of mirikizumab; If the patient achieves a clinical response 4 weeks after the last boost dose is administered, an additional maintenance dose of mirikizumab is administered to the patient, with the first additional maintenance dose being administered 2 to 8 weeks after the last boost dose is administered. Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose and each further maintenance dose contains 200 mg of mirikizumab.

[0133] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0134] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0135] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose.

[0136] A further aspect of the invention provides the use of an anti-IL-23p19 antibody in the manufacture of a medicament for use in the treatment of UC, the treatment comprising: a) administering to the patient at least one induction dose of an anti-IL-23p19 antibody, the induction dose comprising between 50 mg and 1200 mg of antibody; b) administering to the patient at least one maintenance dose of the anti-IL-23p19 antibody after the final induction dose has been administered, wherein the maintenance dose comprises 150-400 mg of the anti-IL-23p19 antibody.

[0137] In an embodiment of the invention, the UC is moderate to severe ulcerative colitis.

[0138] In a further embodiment of the invention, the patient is biologic naive. In an alternative embodiment of the invention, the patient is biologic experienced. In a further alternative embodiment of the invention, the patient is biologic failed or conventional failed.

[0139] In yet a further embodiment of the invention, at least one induction dose comprises between 200 mg and 1000 mg of anti-IL-23p19 antibody.

[0140] In yet a further embodiment of the invention, at least one induction dose comprises between 200 mg and 600 mg of anti-IL-23p19 antibody.

[0141] In still further embodiments of the invention, at least one induction dose comprises 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0142] In a preferred embodiment of the invention, at least one induction dose comprises 300 mg of anti-IL-23p19 antibody.

[0143] In yet a further embodiment of the invention, one, two, or three induction doses are administered to the patient.

[0144] In yet a further embodiment of the invention, two or three induction doses are administered four weeks apart.

[0145] In a preferred embodiment of the invention, three induction doses are administered, four weeks apart.

[0146] In yet a further embodiment of the invention, at least one induction dose is administered by intravenous infusion.

[0147] In yet a further embodiment of the invention, if the patient does not achieve a clinical response 4-12 weeks after the last induction dose is administered, one, two, or three extended induction doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extended induction dose is administered, at least one maintenance dose of an anti-IL-23p19 antibody is administered to the patient, where a clinical response is defined as achieving a reduction in rectal bleeding (RB) subscore of 1 or more, or a reduction in a 9-point Modified Mayo Score (MMS) subscore of 2 or more points and a reduction of 30-35% or more from baseline with an RB subscore of either 0 or 1.

[0148] In yet a further embodiment of the invention, one, two, or three extended induction doses are administered to a patient if the patient has not achieved a clinical response four weeks after the last induction dose was administered.

[0149] In yet a further embodiment of the invention, two or three extended induction doses are administered four weeks apart.

[0150] In a preferred embodiment of the invention, three extended induction doses are administered, four weeks apart.

[0151] In yet further embodiments of the invention, the one, two, or three extended induction doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0152] In a preferred embodiment of the invention, the one, two, or three extended induction doses comprise 300 mg of anti-IL-23p19 antibody.

[0153] In yet a further embodiment of the invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0154] In still further embodiments of the invention, at least one maintenance dose comprises 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0155] In a preferred embodiment of the invention, at least one maintenance dose comprises 200 mg of anti-IL-23p19 antibody.

[0156] In yet a further embodiment of the invention, multiple maintenance doses are administered to the patient, with the first maintenance dose being administered 2-8 weeks after the last induction dose or the last extended induction dose was administered.

[0157] Preferably, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose has been administered.

[0158] Alternatively, preferably, the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last induction dose or the last extended induction dose is administered.

[0159] More preferably, the first maintenance dose is administered 4 weeks after the last induction dose or the last extended induction dose has been administered.

[0160] In yet a further embodiment of the invention, subsequent maintenance dose(s) are administered at 4 week, 8 week, or 12 week interval(s) following administration of the initial maintenance dose.

[0161] Preferably, subsequent maintenance dose(s) are administered at four week intervals.

[0162] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 8 week interval(s).

[0163] Further alternatively, preferably, subsequent maintenance dose(s) are administered at 12 week intervals.

[0164] In yet a further embodiment of the invention, the maintenance dose(s) are administered by subcutaneous injection.

[0165] In yet a further embodiment of the invention, if the patient experiences loss of response during the maintenance period, one, two, or three extra-time doses of an anti-IL-23p19 antibody are administered to the patient, and if the patient achieves a clinical response 4-12 weeks after the last extra-time dose is administered, one or more further maintenance doses of an anti-IL-23p19 antibody are administered to the patient, where loss of response is defined as (a) a 2 or more point increase from baseline in a combination of stool frequency (SF) and rectal bleeding (RB) scores, (b) a combination of SF and RB scores of 4 or greater on two consecutive visits, 7 days or more apart, with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3, and clinical response is defined as achieving a 2 or more point reduction in a 9-point modified Mayo score (MMS) subscore and a 30-35% or greater reduction from baseline, with a 1 or greater reduction in the rectal bleeding (RB) subscore or an RB subscore of either 0 or 1.

[0166] In yet a further embodiment of the invention, two or three boost doses are administered four weeks apart.

[0167] In a preferred embodiment of the invention, three boost doses are administered four weeks apart.

[0168] In still further embodiments of the invention, the one, two, or three boost doses comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of anti-IL-23p19 antibody.

[0169] In a preferred embodiment of the invention, one, two, or three boost doses comprise 300 mg of anti-IL-23p19 antibody.

[0170] In yet a further embodiment of the invention, one, two, or three bolus doses are administered by intravenous infusion.

[0171] In still further embodiments of the invention, the one or more additional maintenance doses comprise 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-23p19 antibody.

[0172] In a preferred embodiment of the invention, the one or more further maintenance doses comprise 200 mg of anti-IL-23p19 antibody.

[0173] In a preferred embodiment of the invention, multiple further maintenance doses are administered to the patient, with the first further maintenance dose being administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last boost dose was administered.

[0174] Preferably, the first further maintenance dose is administered four weeks after the last boost dose is administered.

[0175] In yet a further embodiment of the invention, the subsequent further maintenance dose(s) are administered at 4 week, 8 week, or 12 week interval(s) following administration of the first further maintenance dose.

[0176] Preferably, subsequent further maintenance dose(s) are administered at four week interval(s).

[0177] Alternatively, preferably, further maintenance dose(s) thereafter are administered at 8 week interval(s).

[0178] Further alternatively, preferably, further maintenance dose(s) thereafter are administered at 12 week interval(s).

[0179] In yet a further embodiment of the invention, the further maintenance dose(s) are administered by subcutaneous injection.

[0180] In still further embodiments of the invention, the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

[0181] In a preferred embodiment of the invention, the anti-IL-23p19 antibody is mirikizumab.

[0182] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0183] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered.

[0184] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0185] In an alternative preferred embodiment of the invention, further maintenance dose(s) of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0186] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, where the first maintenance dose is administered 2-8 weeks after the last induction dose, and where each maintenance dose contains 200 mg of mirikizumab.

[0187] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose has been administered.

[0188] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals following administration of the first maintenance dose.

[0189] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals following administration of the first maintenance dose.

[0190] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, each induction dose containing 300 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experienced loss of response during the maintenance period, three additional doses of mirikizumab were administered to the patient at 4-week intervals. Each boost dose contained 300 mg of mirikizumab. If the patient achieves a clinical response 4 weeks after the last boost dose is administered, an additional maintenance dose of mirikizumab is administered to the patient, with the first additional maintenance dose being administered 2 to 8 weeks after the last boost dose is administered. Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose and each further maintenance dose contains 200 mg of mirikizumab.

[0191] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0192] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0193] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose.

[0194] In yet a further embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous infusion four weeks apart, where if the patient has not achieved a clinical response four weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, each induction dose and each extended induction dose comprising 300 mg of mirikizumab; A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point Modified Mayo Score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at 4-week or 12-week intervals, the first maintenance dose being administered 2-8 weeks after the last induction dose; If a patient experiences loss of response during the maintenance period, three extra doses of mirikizumab will be administered to the patient at 4-week intervals, each extra dose containing 300 mg of mirikizumab; If the patient achieves a clinical response 4 weeks after the last boost dose is administered, an additional maintenance dose of mirikizumab is administered to the patient, with the first additional maintenance dose being administered 2 to 8 weeks after the last boost dose is administered. Loss of response was defined as (a) a ≥2-point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of ≥4 on two consecutive visits ≥7 days apart with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3. A clinical response was defined as achieving a reduction of ≥1 in the rectal bleeding (RB) subscore or a reduction of ≥2 points in the 9-point modified Mayo score (MMS) subscore with an RB subscore of either 0 or 1 and a reduction of ≥30-35% from baseline. Each maintenance dose and each further maintenance dose contains 200 mg of mirikizumab.

[0195] In a preferred embodiment of the invention, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or the last extended induction dose is administered, and the first further maintenance dose is administered 4 to 6 weeks after the last boost dose is administered.

[0196] In a further preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at four week intervals after administration of the first further maintenance dose.

[0197] In an alternative preferred embodiment of the invention, subsequent maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose, and subsequent further maintenance dose(s) of mirikizumab are administered at 12 week intervals after administration of the first further maintenance dose. [Brief description of the drawings]

[0198] [Figure 1] Illustrates population PK model-estimated mean serum concentrations of mirikizumab in clinical studies. [Diagram 2] Illustrates week 12 rates of derived endpoints of interest compared with mean mirikizumab concentrations in each dose group. [Diagram 3] Model-estimated mean concentrations of mirikizumab during induction in patients based on clinical response (upper panel) or clinical remission (lower panel) status are plotted. [Figure 4] Observed week 12 concentrations of mirikizumab during induction in patients based on clinical response (upper panel) or clinical remission (lower panel) status are plotted. [Diagram 5] 13A plots model-simulated change in modified Mayo score (MMS) at week 12 versus mirikizumab concentration at week 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0199] UC is a form of colitis, an inflammatory disease of the intestine, usually the colon, that contains characteristic ulcers. Symptoms of active disease include diarrhea, usually mixed with blood, usually accompanied by abdominal pain of varying degrees, ranging from mild discomfort to severe, painful cramps.

[0200] There are several methods for assessing disease severity, including the Mayo score, the modified Mayo score (MMS), and the Ulcerative Colitis Disease Activity Index (UCDAI).

[0201] The Mayo score is a composite measure consisting of four subscores: (i) Bowel Frequency (SF): The SF subscore is a patient-reported measure. This item reports the number of bowel movements in a 24-hour period on a 4-point scale compared to the patient's usual number of bowel movements for the same period. A bowel movement is defined as going to the toilet either when the patient has a bowel movement or when passing blood only, blood and mucus, or mucus only. The total number of bowel movements passed within a 24-hour period is recorded by the patient. The patient's reference "normal" SF is typically recorded at the beginning of the study or observation period. The patient's normal SF is the SF reported when the patient was in remission or, if the patient has never achieved remission, the SF reported before the first onset of signs and symptoms of UC. [Table 1] [Table 2] [Table 3] [Table 4]

[0202] Each subscore is scored on a 4-point scale ranging from 0 to 3, resulting in a maximum Mayo score of 12.

[0203] The MMS is a modification of the original Mayo Index scale (Schroeder et al., New Eng J Med, 317(26):1625-1629, 1987) and includes three of the four subscores of the Mayo score. The physician global assessment is not included. The MMS assesses three subscores, each on a scale of 0 to 3, with a maximum total score of 9. The following table summarizes each MMS subscale for scoring purposes. [Table 5]

[0204] Patients with a Mayo score of 6-12 or an MMS of 4-9, each with an ES of 2 or greater, are defined as having moderately to severely active ulcerative colitis.

[0205] As used herein, the term "biologic experienced" refers to a patient who has been administered a biologic, e.g., an anti-TNF-α antibody, for the treatment of UC, particularly for the treatment of moderate to severe UC. Such patients may or may not have been administered conventional drugs for the treatment of UC. Conventional drugs for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressants such as azathioprine (AZA) and 6-mercaptopurine (6-MP).

[0206] As used herein, the term "biologic failure" refers to a patient who has been administered a biologic, e.g., an anti-TNF-α antibody, for the treatment of UC, particularly for the treatment of moderate to severe UC. Such patients may or may not have been administered conventional drugs for the treatment of UC. Conventional drugs for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressants such as azathioprine (AZA) and 6-mercaptopurine (6-MP). Such patients have an inadequate response, loss of response, or intolerance to biologic therapy for UC (such as anti-TNF or anti-integrin antibodies) or Janus kinase (JAK) inhibitors (such as tofacitinib). In the context of the term "biologic failure," an inadequate response means showing signs and symptoms of persistent active disease despite induction treatment with approved induction dosing as indicated on the product label at the time of use. In the context of the term "biologic failure," loss of response is defined as a recurrence of signs and symptoms of active disease on approved maintenance medication following previous clinical benefit (discontinuation despite clinical benefit is not evidence of failure or intolerance to UC biologic therapy). In the context of the term "biologic failure," intolerance means a history of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, or other approved biologics or JAK inhibitors (including, but not limited to, infusion-related events, demyelination, congestive heart failure, or any other drug-related AE that led to dose reduction or discontinuation).

[0207] As used herein, the term "biologic naive" refers to a patient who has not received a biologic, e.g., an anti-TNF-α antibody, for the treatment of UC, particularly for the treatment of moderate to severe UC. Such patients may or may not have received conventional drugs for the treatment of UC. Conventional drugs for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressants such as azathioprine (AZA) and 6-mercaptopurine (6-MP).

[0208] As used herein, the term "conventional drug failure" refers to patients who have an inadequate response, loss of response, or intolerance to at least one of the following medications: (i) Corticosteroids -Corticosteroid-refractory colitis is defined as the presence of signs and / or symptoms of active UC despite treatment with oral prednisone (or equivalent) at a dose of at least 30 mg / day for at least 2 weeks. - Corticosteroid-dependent colitis is defined as (a) the inability to reduce corticosteroids to below 10 mg prednisone equivalent per day within 3 months of initiating corticosteroids without recurrence of signs and / or symptoms of active UC, and (b) recurrence within 3 months of completing a course of corticosteroids. - History of corticosteroid intolerance including, but not limited to, Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, or neuropsychiatric side effects, including insomnia, associated with corticosteroid treatment. (ii) Immunomodulators: - Have signs and / or symptoms of persistent active disease despite at least 3 months of treatment with one of the following: (a) oral AZA (≥1.5 mg / kg / day) or 6-MP (≥0.75 mg / kg / day), or (b) oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or (c) combinations of thiopurine and allopurinol within the therapeutic range as determined by thioguanine metabolite testing - History of intolerance to at least one immunomodulatory agent, including but not limited to nausea / vomiting, abdominal pain, pancreatitis, abnormal liver function tests, and lymphopenia

[0209] Patients with prior drug failure had failed or had never demonstrated intolerance to a biologic medication (anti-TNF antibody or anti-integrin antibody) indicated for the treatment of UC.

[0210] As used herein, "clinical remission" using MMS is defined as an RB subscore of 0, an SF subscore of 0 or 1 (a reduction of 1 or more points from baseline), and an ES of 0 or 1 (excluding frailty). As used herein, clinical response using MMS is defined as achieving a reduction of 2 or more points in the 9-point MMS subscore and a reduction of 30-35% or more from baseline, with a reduction of 1 or more points in the RB subscore or with an RB subscore of either 0 or 1. As used herein, "endoscopic remission" using MMS is defined as achieving a Mayo ES of 0. As used herein, "endoscopic cure" using MMS is defined as achieving a Mayo ES of 0 or 1. As used herein, "symptomatic remission" using MMS is defined as achieving an SF=0 or SF=1, and RB=0, with a reduction of 1 or more points from baseline. As used herein, using the MMS, "loss of response" is defined as (a) a 2-point or greater increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores, (b) a combined SF and RB score of 4 or greater on two consecutive visits, 7 days or more apart, with confirmation of a negative Clostridium difficile test, and (c) an endoscopic subscore (ES) of 2 or 3.

[0211] As used herein, "dose" or "dosing" refers to the administration of a substance (eg, an anti-IL-23p19 antibody) to achieve a therapeutic objective (eg, treatment of ulcerative colitis).

[0212] As used herein, "induction period" refers to the period of treatment of a patient, including administration of an anti-IL-23p19 antibody to the patient to induce clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of these terms being as defined above. There is no minimum or maximum duration of the "induction period", but it is typically 4 weeks, 8 weeks, or 12 weeks in duration. The end of the induction period is typically the end-of-induction evaluation, which is performed 4 weeks or 8 weeks after the last induction dose is administered.

[0213] As used herein, "induction dose" refers to the first dose of anti-IL-23p19 antibody administered to a patient to induce clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of these terms being as defined above. An "induction dose" can be a single dose, or alternatively, a set of doses. An "induction dose" is administered during an induction period.

[0214] As used herein, an "extended induction period" refers to a period of treatment of a patient, including administration of an anti-IL-23p19 antibody to the patient, required to induce clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, because such was not achieved during the initial induction period, each of these terms being as defined above. An "extended induction period" can be 4 weeks, 8 weeks, or 12 weeks in duration.

[0215] As used herein, an "extended induction dose" refers to an additional induction dose of an anti-IL-23p19 antibody administered to a patient to induce clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission because clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission was not achieved during the initial induction period, each of these terms being as defined above. An "extended induction dose" can be a single dose, or alternatively, a set of doses. There is no minimum or maximum duration of the "extended induction period", but it is typically 4 weeks, 8 weeks, or 12 weeks in duration. The end of the extended induction period is typically the extended induction end evaluation, which is performed 4 weeks or 8 weeks after the last extended induction dose is administered. An "extended induction dose" is administered during the extended induction period.

[0216] As used herein, a "maintenance period" refers to a period of treatment that includes administration of an anti-IL-23p19 antibody to a patient to maintain a desired therapeutic effect, be it clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of which is as defined above. A "maintenance period" follows an induction period or extended induction period and thus begins once the desired therapeutic effect - clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission - has been achieved.

[0217] As used herein, a "maintenance dose" refers to a subsequent dose of an anti-IL-23p19 antibody administered to a patient to maintain or continue a desired therapeutic effect, i.e., clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of these terms being as defined above. A "maintenance dose" is administered following an induction dose. A "maintenance dose" can be a single dose, or alternatively, a set of doses.

[0218] In the situation where a patient experiences loss of response during the maintenance period and achieves the desired therapeutic effect again after administration of one or more extra doses, and maintenance therapy is resumed, the maintenance dose is referred to as a "further maintenance dose." A "maintenance dose" or "further maintenance dose" is administered during the maintenance period of treatment. The further maintenance dose and dosing interval during the resumed maintenance therapy are typically the same as the dose and dosing interval during the initial maintenance period, but may be changed if the responsible medical professional has reason to believe that the patient may benefit from a change, such as an increase in the dose of anti-IL-23p19 or more frequent dosing.

[0219] As used herein, the term "spike dose" refers to a dose of anti-IL-23p19 antibody administered to a patient who has experienced loss of response to re-induce / re-achieve the therapeutic effect achieved at the end of the induction period, the therapeutic effect being clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of which is as defined above.

[0220] As used herein, the term "charter boost period" refers to a period of treatment of a patient that includes administration of an anti-IL-23p19 antibody to the patient to re-induce clinical remission, where a therapeutic benefit is achieved at the end of the induction period, the therapeutic benefit being clinical remission, clinical response, endoscopic remission, endoscopic cure, and / or symptomatic remission, each of which terms are as defined above. A "charter boost period" can be 4 weeks, 8 weeks, or 12 weeks in duration.

[0221] The extra-boost dose and dosing interval during the extra-boost period will typically be the same as the dose and dosing interval during the initial induction period, but may be modified if the attending medical professional has reason to believe that the patient could benefit from a change, such as an increased dose or more frequent dosing of the anti-IL-23p19.

[0222] As used herein, the terms "treating", "treat" or "treatment" refer to inhibiting, slowing, attenuating, reducing or reversing the progression or severity of an existing symptom, disorder, condition or disease, or relieving the clinical symptoms and / or signs of a condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of a disease or disorder, stabilization of a disease or disorder (i.e., where the disease or disorder is not worsening), delaying or slowing the progression of a disease or disorder, amelioration or alleviation of a disease or disorder, and remission of a disease or disorder (whether partial or total). Those in need of treatment include those already suffering from the disease.

[0223] As used herein, the term "antibody" is further intended to encompass antibodies, digest fragments, specified portions, and variants thereof, including antibody mimetics or portions of antibodies that mimic the structure and / or function of an antibody or specified fragments or portions thereof, including single chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to human IL-23. For example, antibody fragments capable of binding to IL-12 / 23 or a portion thereof, including, but not limited to, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments are encompassed by the present invention (see, e.g., Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, NY, (1994-2001)).

[0224] Such fragments can be produced by enzymatic cleavage, synthesis, or recombinant techniques, as known in the art and / or described herein. Antibodies can also be produced in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination gene encoding a F(ab')2 heavy chain portion can be designed to include DNA sequences encoding the CH1 domain and / or hinge region of the heavy chain. The various portions of the antibody can be joined chemically by conventional techniques or prepared as a contiguous protein using genetic engineering techniques.

[0225] As used herein, an "anti-IL-23p19 antibody" refers to an antibody that binds to the p19 subunit of human IL-23 but not to the p40 subunit of human IL-23. Thus, an anti-IL-23p19 antibody binds to human IL-23 but not to human IL-12.

[0226] Examples of anti-IL-23p19 antibodies that can be used in the methods of the invention include guselkumab, tildrakizumab, risankizumab, mirikizumab, and brazikumab.

[0227] Guselkumab, CAS Registry Number 1350289-85-8, is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of human IL-23. The antibody and methods for making it are described in U.S. Patent No. 7,935,344.

[0228] Tildrakizumab, CAS Registry Number 1326244-10-3, is a humanized IgG1 kappa monoclonal antibody that targets the p19 subunit of human IL-23. The antibody and methods for making it are described in U.S. Patent No. 8,293,883.

[0229] Risankizumab, CAS Registry Number 1612838-76-2, is a humanized IgG1 kappa monoclonal antibody that targets the p19 subunit of human IL-23. The antibody and methods for making it are described in U.S. Patent No. 8,778,346.

[0230] Mirikizumab, CAS Registry Number 1884201-71-1, is a humanized IgG4 kappa monoclonal antibody that targets the p19 subunit of human IL-23. The antibody and methods for making it are described in U.S. Patent No. 9,023,358.

[0231] Brazikumab, CAS Registry Number 1610353-18-8, is a humanized IgG2 lambda monoclonal antibody that targets the p19 subunit of human IL-23. The antibody and methods for making it are described in U.S. Patent No. 8,722,033.

[0232] The anti-IL-23p19 antibody, or a pharmaceutical composition comprising same, may be administered by a parenteral route (eg, subcutaneously, intravenously, intraperitoneally, intramuscularly, or transdermally).

[0233] The term "intravenous infusion" refers to the introduction of an agent into the veins of an animal or human patient over a period of more than about 15 minutes, typically about 30 to 90 minutes.

[0234] The term "subcutaneous injection" refers to the introduction of a drug into an animal or human patient under the skin, preferably into a pocket between the skin and the underlying tissue, by relatively slow, sustained delivery from a drug reservoir. The pocket can be created by pinching or lifting the skin away from the underlying tissue.

[0235] Pharmaceutical compositions containing anti-IL-23p19 antibodies for use in the methods of the present invention can be prepared using methods well known in the art (e.g., those described in Remington: The Science and Practice a / Pharmacy, 1999). thedition (1995), A. Gennaro et al., Mack Publishing Co.), and comprises an antibody disclosed herein and one or more pharma- ceutically acceptable carriers, diluents, or excipients. EXAMPLES

[0236] Example 1: Clinical Study overview This study is a phase 2, multicentric, randomized, double-blind, parallel, placebo-controlled study of mirikizumab in patients with moderate-to-severe ulcerative colitis (UC). Moderate-to-severe UC is defined as an MMS of 6-12 with an endoscopic subscore of ≥ 2. The study consists of a screening period of up to 28 days, a 12-week blinded intravenous treatment period, a 92-week subcutaneous treatment period for responders at week 12, and a 92-week intravenous and subcutaneous extension for non-responders at week 12.

[0237] the purpose The primary objective was to test the hypothesis that treatment with mirikizumab is superior to placebo in inducing clinical remission after 12 weeks of treatment (week 12). Secondary objectives included the following: - evaluating the safety and tolerability of treatment with mirikizumab; - To evaluate the efficacy of mirikizumab in inducing a clinical response at week 12; - Assessment of endoscopic remission at weeks 12 and 52; - To assess the effect of maintenance therapy with mirikizumab on clinical remission, endoscopic remission, and durability of clinical response at 52 weeks; and • Characterization of the pharmacokinetic (PK) profile of mirikizumab.

[0238] End points were defined using the MMS, a 9-point Mayo score excluding Physician Global Assessment (PGA). Endoscopies will be centrally read. Endoscopic cure rates will also be assessed at weeks 12 and 52. End point definitions are as follows: ● Clinical remission: Achievement of the following Mayo subscores: rectal bleeding (RB) subscore 0, stool frequency (SF) subscore 0 or 1 (≥1 point reduction from baseline), and endoscopic subscore 0 or 1. ● Clinical response: Achieved a reduction of ≥1 in the RB subscore or a reduction of ≥2 points in the 9-point Mayo subscore with either an RB subscore of 0 or 1 and a reduction of ≥35% from baseline. ●Endoscopic remission: Mayo ES achieved 0. ●Endoscopic cure: Mayo ES achieved 0 or 1.

[0239] method The study includes a screening period, two treatment periods for responders at week 12 (a 12-week blinded intravenous induction period and a 92-week subcutaneous maintenance period), and two treatment periods for non-responders at week 12 who wish to continue in the study (a 12-week blinded intravenous induction period and a 92-week intravenous and subcutaneous extension period). Approximately two-thirds of patients randomized to study treatment had previously received at least one biologic therapy (TNF antagonist or vedolizumab), and approximately one-third of patients were biologic-naive.

[0240] a) Screening Period Patients will be assessed for study eligibility no later than 28 days prior to the baseline visit. At the baseline visit, patients who meet the eligibility criteria will be equally randomized to one of four induction treatment arms.

[0241] Eligible patients were male or female patients aged 18-75 years at the time of initial screening who had moderately to severely active UC, as defined by a Mayo score of 6-12 (or MMS of 4-9) with an endoscopic subscore of ≥2 within 14 days prior to the first dose of study treatment, and evidence of UC extending proximally to the rectum (≥15 cm of involved colon). Patients must be either: (a) naïve to biologic therapy (e.g., TNF antagonist or vedolizumab) and have at least one of the following: - Inadequate response or failure to tolerate current treatment with oral or intravenous corticosteroids or immunomodulators (6-MP or AZA), or - History of corticosteroid dependence (inability to successfully taper corticosteroids without recurrence of UC) or (b) One or more biologic agents, at doses approved for the treatment of UC, with or without a history of non-response to or intolerance to such treatment. They have also been treated with an antagonist, or vedolizumab, or an experimental UC treatment, such as a biologic or oral kinase inhibitor.

[0242] Patients may be receiving therapeutic doses of the following medications: (a) Oral 5-ASA compounds: if the prescribed dose is stable for at least 2 weeks prior to baseline, (b) Oral corticosteroid therapy (≤20 mg / day prednisone or equivalent): if the prescribed dose was stable for at least 2 weeks prior to baseline; (c) AZA or 6-MP: if the prescribed dose was stable for at least 8 weeks prior to baseline.

[0243] b) induction period A 12-week induction period will be designed to establish the efficacy and safety of mirikizumab administered intravenously at weeks 0, 4, and 8 compared to placebo. At week 0 (baseline), patients will be enrolled into four induction treatment arms (placebo, 50 mg mirikizumab, 200 mg mirikizumab, or 600 mg mirikizumab) to adequately assess clinical response and remission endpoints. Patients enrolled in the study will be stratified across treatment arms based on prior exposure to biologic therapy for the treatment of UC. Blinded investigational product (mirikizumab or placebo) will be administered at weeks 0, 4, and 8.

[0244] Exposure-based dose adjustments were used for the two mirikizumab dose groups based on mirikizumab plasma concentrations. Dose levels in patients in the 50 mg mirikizumab and 200 mg mirikizumab groups could be increased at the week 4 and week 8 visits if predicted trough concentrations for these visits fell below prespecified thresholds. Patients in the 600 mg mirikizumab dose group maintained a stable dose throughout the induction period.

[0245] c) Maintenance period The maintenance period is designed to investigate the safety and durability of clinical response and remission to treatment with 200 mg mirikizumab administered SC Q4W or Q12W. Patients who achieve a response with mirikizumab induction-blind dosing will be re-randomized to one of two mirikizumab maintenance arms (200 mg subcutaneously (SC) every 4 weeks [Q4W] or 200 mg SC every 12 weeks [Q12W]). Patients in the placebo arm who achieve a clinical response will be maintained on placebo. Patients with a clinical response at week 12 will continue to participate in the study in the maintenance period up to week 52. Patients entering the mirikizumab maintenance dosing period will be stratified according to remission status at week 12.

[0246] d) Extension period Patients who are randomized into the induction period but do not have a clinical response at week 12 can choose to continue in the study extension period or to discontinue the study. The extension period consists of an induction and a maintenance portion, which are modified versions of the induction and maintenance periods in the main study design. During induction in the extension period, patients receive 600 mg or 1000 mg of mirikizumab intravenously at weeks 0, 4, and 8 of the extension. Patients with a clinical response to the induction dosing in the extension period have the opportunity to continue with maintenance therapy in the extension period, while non-responders in the extension period will discontinue the study. Patients who continue with maintenance treatment in the extension period will receive 200 mg of mirikizumab, administered SC Q4W (open label).

[0247] Summary of the Study There were a total of 249 patients in the intention-to-treat (ITT) population. Demographic characteristics were balanced between mirikizumab groups (total) and placebo (total). Of the 249 randomized patients, 100 patients were female. Mean age (± standard deviation) was 42.6 years (± 13.9 years).

[0248] Disease characteristics were balanced across mirikizumab-treated groups and placebo. Approximately 42% of patients had moderately active disease at baseline (Mayo score 6-8: placebo 42.9%, total mirikizumab 41.8%), whereas approximately 58% had severely active disease at baseline (Mayo score 9-12: placebo 57.1%, total mirikizumab 58.2%). In MMS, baseline fecal calprotectin and C-reactive protein (CRP) were all balanced between groups.

[0249] There were no significant differences between the total mirikizumab groups and placebo with regard to the proportion of patients receiving oral corticosteroids or 5-aminosalicylate at baseline.A greater proportion of patients in the placebo group received thiopurine therapy at baseline compared with the total mirikizumab group (total mirikizumab 23.1%, placebo 39.7%).

[0250] Results: Summary Endoscopic films were centrally read by experts blinded to treatment allocation and time points. Logistic regression analysis was used to compare rates of clinical remission (primary outcome), clinical response, endoscopic cure, endoscopic remission, and symptomatic remission. Baseline characteristics were similar between treatment groups. Most patients (63%) had previously been treated with biologics or had previously failed treatment.

[0251] At week 12, clinical remission rates were higher in patients treated with 200 mg mirikizumab compared with placebo-treated patients (p<0.01), but not with 50 mg or 600 mg mirikizumab (Table). Clinical response rates at week 12 were higher in all mirikizumab groups compared with placebo (p<0.05). Endoscopic cure rates were higher in the 50 mg and 200 mg mirikizumab groups compared with placebo-treated patients (p<0.05). Endoscopic remission rates were similar between all groups. Symptomatic remission rates were higher in the 200 mg and 600 mg mirikizumab groups compared with placebo-treated patients (p<0.01). Exposure to mirikizumab increased with dose, but efficacy did not follow the typical plateauing dose or exposure response. The incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) was similar across treatment groups.

[0252] In summary, the week 12 outcome data indicate that patients in the 200 mg mirikizumab group responded better to treatment at week 12 than patients in the placebo or 50 mg mirikizumab groups. Additionally, patients in the 200 mg mirikizumab group responded better to treatment at week 12 than patients in the 600 mg mirikizumab group.

[0253] Based on the efficacy data available for the maintenance period of this study, the two mirikizumab SC dosing regimens, 200 mg Q4W and 200 mg Q12W, were observed to have similar clinical remission, clinical response, and endoscopic cure rates at week 52. Baseline (BL) characteristics of patients entering the maintenance period were similar between groups. At BL, 52.7% had received a previous biologic agent. At week 52, 46.8% (Q4W) and 37.0% (Q12W) were in clinical remission. Additionally, 80.9% (Q4W) and 76.1% (Q12W) had a clinical response, and 57.4% (Q4W) and 47.8% (Q12W) had an ES=0 / 1. Of patients in clinical remission at week 12, 61.1% (Q4W) and 38.5% (Q12W) remained in clinical remission at week 52. Of those with clinical responders (but not in remission) at week 12, 37.9% (Q4W) and 36.4% (Q12W) achieved clinical remission at week 52. One patient discontinued the study due to an adverse event (AE) during the maintenance period, and similar frequencies of treatment-emergent and serious AEs were reported across both treatment groups. Thus, mirikizumab demonstrated durable efficacy (assessed by multiple measures) with no unexpected safety signals and few discontinuations due to AEs throughout the maintenance period.

[0254] Analysis of mirikizumab concentration data showed that exposure increased proportionally with dose. Exposure was a significant predictor of change from baseline in MMS at week 12, but there was no strong relationship between exposure and clinical response or remission for individual patients.

[0255] During maintenance, the Q12W regimen produced a more intermittent mirikizumab concentration profile, whereas the Q4W regimen was more consistent. The Q4W regimen also produced trough concentrations at week 12 similar to those produced in the 200 mg induction cohort.

[0256] Mirikizumab was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no clinically significant safety findings and no dose-related associations were observed during the induction or maintenance periods. Across all groups, treatment-emergent adverse events (TEAEs) were generally mild or moderate in severity. There were no deaths.

[0257] Results: Week 12 - Efficacy Endoscopic films were centrally read by experts blinded to treatment allocation and time points. Logistic regression analysis was used to compare rates of clinical remission (primary outcome), clinical response, endoscopic cure, endoscopic remission, and symptomatic remission.

[0258] Primary, secondary, and key exploratory endpoint data at week 12 (non-responders, imputation [NRI], and ITT populations) are summarized in Table 2. [Table 6-1] [Table 6-2]

[0259] At week 12, clinical remission rates were higher in patients treated with 200 mg mirikizumab compared with placebo-treated patients (p<0.01), but not with 50 mg or 600 mg mirikizumab. Clinical response rates at week 12 were higher in all mirikizumab groups compared with placebo groups (p<0.05). Endoscopic cure rates were higher in the 50 mg and 200 mg mirikizumab groups compared with placebo-treated patients (p<0.05). Endoscopic remission rates were similar between all groups. Symptomatic remission rates were higher in the 200 mg and 600 mg mirikizumab groups compared with placebo-treated patients (p<0.01).

[0260] Overall, significant efficacy compared with placebo was observed at week 12 in the 50 mg and 200 mg IV Q4W groups in the study, with the greatest efficacy observed in the 200 mg IV Q4W group. Due to the application of exposure-based dose adjustments, the overall mean induction doses received by patients in the 50 mg and 200 mg cohorts were 100 mg and 250 mg, respectively. Mirikizumab exposure increased proportionally with dose, but patients in the 600 mg mirikizumab group responded less favorably to treatment at week 12 than patients in the 200 mg mirikizumab group.

[0261] Results: Week 12 - Efficacy with prior biologic therapy To determine whether patients who were biologic therapy naïve had better clinical outcomes than previously biologic-experienced patients, clinical remission, clinical response, and endoscopic cure data were examined by previous biologic subgroup (biologic-experienced vs. biologic-naïve).

[0262] Clinical remission, clinical response, and endoscopic cure rates at week 12 were higher in biologic-naive patients compared with biologic-experienced patients (see Tables 3–5 ).

[0263] Clinical remission rates in the biologic-naive 200 mg mirikizumab group were higher than placebo (36.4% vs. 8.7%, p = 0.035, Table 3).

[0264] Clinical response rates were higher with 200 mg mirikizumab than with placebo in biologic-naive patients (72.7% vs. 34.8%, p=0.017) and in biologic-experienced patients with 200 mg mirikizumab (52.5% vs. 12.5%, p<0.001) and 600 mg mirikizumab (42.1% vs. 12.5%, p=0.005) (Table 4).

[0265] Endoscopic cure rates were higher in the biologic-naive 50 mg mirikizumab (37.5% vs. 8.7%, p = 0.036) and 200 mg mirikizumab groups (50.0% vs. 8.7%, p = 0.003; Table 5) compared with placebo. [Table 7] [Table 8] [Table 9]

[0266] Rates of clinical remission, clinical response, and endoscopic cure were higher in biologic-naive patients who received mirikizumab compared with biologic-experienced patients.

[0267] Results: Maintenance Period - Week 52 Patients with a clinical response at week 12 were randomized to receive either 200 mg mirikizumab SC Q4W or 200 mg mirikizumab SC Q12W. There were no randomized treatment discontinuations to the placebo group during maintenance. Interim primary, secondary, and key exploratory endpoint data at week 52 are summarized in Tables 6a and 6b. Final primary, secondary, and key exploratory endpoint data at week 52 are summarized in Table 7.

[0268] The rates of each efficacy measure at the week 52 interim readout shown in Tables 6a and 6b were similar between the mirikizumab Q4W and Q12W maintenance groups, except for endoscopic remission, which was numerically higher in the Q12W group. [Table 10] [Table 11] [Table 12-1] [Table 12-2]

[0269] At the final readout at week 52, of patients in clinical remission at week 12, 61.1% (Q4W) and 38.5% (Q12W) remained in clinical remission at week 52. Of those who had clinical responders (not in remission) at week 12, 37.9% (Q4W) and 36.4% (Q12W) achieved clinical remission at week 52. Mirikizumab has therefore demonstrated durable efficacy.

[0270] Results: Extension Period - Week 12 Patients randomized to either placebo or mirikizumab induction treatment who did not experience a clinical response at week 12 were eligible to enter an extension period that included two parts: a 12-week extended induction period followed by a 28-week extended maintenance period. In the extended induction period, patients received continuous induction treatment with a fixed dose of 600 mg mirikizumab IV Q4W at weeks 0, 4, and 8, and efficacy was assessed at extension week 12. To investigate whether a higher extended induction dose could be associated with improved outcomes, the dose was increased to 1000 mg mirikizumab IV Q4W.

[0271] Of patients who received extended induction treatment with mirikizumab, 50.0% treated with 600 mg mirikizumab IV Q4W and 43.8% treated with 1000 mg mirikizumab IV Q12W, respectively, achieved a clinical response, 15.0% and 9.4% achieved clinical remission, 20.0% and 15.6% achieved an endoscopic score of 0 / 1, and 0 and 3.0% had an endoscopic score of 0 at the end of the extended induction period (week 24). Among placebo nonresponders, 58.0% and 71.9% receiving mirikizumab 600 mg or 1000 mg IV Q4W for 12 weeks, respectively, achieved a clinical response, 25.0% and 25.0% achieved clinical remission, 25.0% and 37.5% achieved an endoscopic score of 0 / 1, and 0 and 9.4% achieved an endoscopic score of 0 at the end of extended induction (week 24). Treatment-emergent adverse events (AEs), discontinuations due to AEs, and serious AEs were similar between treatment groups during the extended induction period. [Table 13]

[0272] Extended induction and maintenance dosing with mirikizumab demonstrated efficacy (assessed by multiple measures) through week 52 of the maximum study. Importantly, an additional 12 weeks of extended induction with mirikizumab enabled 43.8-50.0% of induction mirikizumab non-responders to achieve a clinical response. 65.8% of these patients demonstrated a clinical response at week 52 with mirikizumab 200 mg SC Q4W.

[0273] Result: Safe Mirikizumab was well tolerated, with few discontinuations due to adverse events (AEs). The incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) was similar between placebo and mirikizumab treatment groups, and no dose-related relationship was observed in the induction or maintenance periods. There were no deaths during the study. A summary of AEs by induction, maintenance, and extension study periods is shown in Tables 9–11. [Table 14] [Table 15] [Table 16]

[0274] Results: Pharmacokinetic (PK) and exposure / response modelling i) Summary of population PK analysis A total of 2828 serum mirikizumab concentration samples were collected from 229 patients during the induction, maintenance, and extension periods and used in the PK analysis. Concentration data were analyzed using population PK methods. A two-compartment model with first-order absorption for the SC maintenance dose was found to best represent the PK of mirikizumab. The estimated typical population clearance was 0.023 L / h (2.8% SD of estimate (SEE)) and the random interpatient variability in apparent clearance was 32% (%CV). The estimated SC bioavailability was 42%.

[0275] Estimated typical population values ​​for central and peripheral volumes of distribution and intercompartmental clearance were 3.5 L, 1.4 L, and 0.0064 L / h, respectively. A total of 303 samples (9%) were below the lower limit of quantification (100 ng / mL) of the mirikizumab assay. These samples were excluded from PK modeling compared to standard imputation or conditional estimation models, and no impact on estimated PK parameters was observed.

[0276] Figure 1 shows the mean serum concentrations of mirikizumab calculated using individual patient clearance values ​​estimated by the PK model, with a reference line indicating where the median mean concentration is expected for a 300 mg IV fixed dose.

[0277] A population PK model was used to evaluate the influence of the following covariates: age, sex, BMI, weight, ethnic origin, dose level, smoking status, injection site, previous biological status, baseline albumin, time-varying albumin, baseline CRP, baseline fecal calprotectin, baseline MMS, baseline RB subscore, extent of disease, immunogenicity (ADA+ / -, TE-ADA+ / -, ADA titer, neutralizing ADA+ / -). The only factors found to have a statistically significant effect were time-varying albumin on clearance and weight on central volume of distribution.

[0278] ii) A summary of concentrations observed during maintenance In the 200 mg mirikizumab SC Q4W group, the first sample was collected 2–10 days after the first dose, and all subsequent samples were collected before dosing and therefore represent trough concentrations. The Q4W regimen resulted in consistent trough concentrations throughout the maintenance period. These trough concentrations were similar to those observed in the 200 mg mirikizumab IV induction group at week 12 of the induction period.

[0279] In the 200 mg mirikizumab SC Q12W group, the first sample was also collected 2–10 days after the first dose, and subsequent samples were collected 4, 8, or 12 weeks after the dose. Samples collected at weeks 24, 48, and 72 were taken before dose administration and represent trough concentrations. Most patients in this dose group had concentrations below the limit of quantification (BQL) at the trough; this was expected based on the long interval between doses. The SC Q12W schedule resulted in a more intermittent concentration profile than the Q4W schedule.

[0280] iii) A summary of the observed exposure-response data Figure 2 shows the observed clinical responses, clinical remissions, endoscopic responses, and symptomatic responses versus the median mean concentrations in each induction group. Exposure increased proportionally with dose. The mean exposure-response relationships for the plotted endpoints followed the same general pattern, with rates increasing between the placebo and 50 mg groups and between the 50 mg and 200 mg groups, but then decreasing between the 200 mg and 600 mg groups.

[0281] Figures 3 and 4 show the mean concentrations or concentrations observed at week 12 for individual patients grouped by whether the patient achieved a clinical response or remission. These plots show that there was significant overlap in individual patient concentrations for patients who achieved a response or remission versus those who did not achieve these endpoints. The plots also show that the lower efficacy observed in the 600 mg group in some patients was not due to lower exposure, as patients in the 50 mg and 200 mg cohorts achieved clinical response and remission at exposures similar to or lower than the lowest individual patient in the 600 mg group. Patients in the 600 mg group who did not achieve remission had the lowest concentrations observed at week 12 in tertile 1 and tertile 2, similar to those of patients who achieved remission in the 50 mg and 200 mg groups.

[0282] iv) Summary of model-based analysis The relationship between exposure and efficacy was explored using the MMS. Direct assessment of the MMS resolves the relationship between exposure and efficacy as it is an index with more levels compared to binary clinical response and remission endpoints. The MMS is assessed by assessing the change from baseline to week 12 in MMS, with patients with the greatest reduction from baseline in MMS being interpreted as achieving the best efficacy. The following covariates were assessed in the model: baseline albumin, baseline CRP, baseline fecal calprotectin, prior biologic treatment status, extent of disease, baseline MMS, baseline SF subscore, baseline RB subscore, baseline ES, smoking status, weight, and whether the patient underwent exposure-based dose adjustment.

[0283] The relationship between mirikizumab exposure and reduction in MMS at week 12 indicates that efficacy may be reduced at doses below 300 mg, with the 300 mg dose providing 91% of the maximum efficacy possible with mirikizumab. Furthermore, the 300 mg dose is expected to produce median mean concentrations that cover the majority of individual patient exposures observed in the 200 mg cohort in the study (see Figure 5).

[0284] During the maintenance period, a more consistent concentration profile was observed with the Q4W dose schedule compared with the Q12W schedule, which produced a more intermittent concentration profile. The Q4W schedule also produced trough concentrations similar to those at week 12 produced in the 200 mg induction group, which achieved the best efficacy. Patients who achieved clinical response or clinical remission at week 52 also tended to have higher maintenance concentrations. These results suggest that the 200 mg SC Q4W schedule is likely to provide better maintenance efficacy than the 200 mg Q12W schedule.

[0285] Example 2: Clinical Study Part A overview The study is a multicentric, randomized, double-blind, parallel-arm, placebo-controlled study designed to evaluate the safety and efficacy of mirikizumab compared to placebo over a 12-week induction period. The study population includes patients with moderately to severely active UC who have an inadequate response, loss of response, or intolerance to corticosteroids or immunomodulatory therapy for UC (referred to as "conventional failure" in this study) and patients who have an inadequate response, loss of response, or intolerance to biologic therapy for UC (referred to as "biologic failure" in this study). Patients who complete Part A through week 12 will be eligible to complete post-treatment follow-up in Part A or enter Part B.

[0286] Patients who discontinue treatment before the week 12 assessment or who are unable or unwilling to participate in Part B will complete post-treatment follow-up 16 weeks after their last visit. The study consists of a screening period of up to 28 days and a 12-week blinded intravenous therapy period.

[0287] the purpose The primary objective was to test the hypothesis that mirikizumab is superior to placebo in inducing clinical remission at week 12 in patients with moderately to severely active ulcerative colitis (UC).

[0288] Secondary objectives include: To evaluate the efficacy of treatment with mirikizumab compared to placebo in inducing a clinical response at week 12; To evaluate the efficacy of treatment with mirikizumab compared with placebo in inducing endoscopic remission at week 12; To evaluate the efficacy of treatment with mirikizumab compared to placebo in inducing symptomatic remission at weeks 4 and 12; To evaluate the efficacy of treatment with mirikizumab compared to placebo in inducing a clinical response in the biologic failure population at week 12; • To assess time to symptomatic response and time to symptomatic remission.

[0289] Endpoints were defined using the MMS. Endoscopies will be centrally read. Endoscopic cure rates will also be assessed at week 12. Endpoint definitions are as follows: ● Clinical remission: Achievement of the following MMS subscores: rectal bleeding (RB) subscore 0, stool frequency (SF) subscore 0 or 1 (≥1 point reduction from baseline), and endoscopy subscore (ES) 0 or 1 (excluding frailty). ● Clinical response: Achieved a reduction of ≥1 in the RB subscore or a reduction of ≥2 points in the 9-point Mayo subscore with either an RB subscore of 0 or 1 and a reduction of ≥30% from baseline. ●Endoscopic remission: Mayo ES achieved 0. ●Endoscopic cure: Mayo ES achieved 0 or 1. ● Symptomatic remission: SF=0, or SF=1, and RB=0, with a reduction of 1 point or more from baseline. • Symptomatic response: at least 30% reduction from baseline in composite SF and RB.

[0290] method The study consisted of a screening period and a 12-week blinded intravenous induction period.

[0291] a) Screening Period Patients will be assessed for study eligibility no later than 28 days prior to the baseline visit. At the baseline visit, patients who meet the eligibility criteria will be equally randomized to one of four induction treatment arms.

[0292] Eligible patients are male or female patients aged 18-80 years at the time of initial screening. Patients must have the following: i) Established diagnosis of UC of ≥3 months duration prior to baseline (week 0), including endoscopic evidence of UC and histopathological reports supporting the diagnosis of UC. ii) moderately to severely active UC as defined by a modified Mayo score (MMS) of 4–9 with an endoscopic subscore (ES) ≥2 on endoscopy performed within 10 days prior to baseline. iii) evidence of UC extending into the proximal rectum (distal to the rectosigmoid junction, approximately 10–15 cm from the anal verge). iv) The following documents: a) Surveillance colonoscopy (per local standards) within 12 months prior to baseline for: - Patients with pancreatitis of >8 years duration, or - Patients with left-sided colitis of more than 12 years duration, or - Patients with primary sclerosing cholangitis. or b) Updated colorectal cancer surveillance (performed according to local standards) in patients not covered under a). At the investigator's discretion, colonoscopy (instead of flexible sigmoidoscopy) may be performed as the screening endoscopy for this study. Patients without a colonoscopy report available in the source documentation will undergo colonoscopy at screening.

[0293] Patients may be receiving therapeutic doses of the following medications: (a) Oral 5-ASA compounds: if the prescribed dose is stable for at least 2 weeks prior to baseline, (b) oral corticosteroid therapy ≤20 mg / day prednisone or 9 mg / day budesonide extended-release tablets [budesonide MMX], if the prescribed dose has been stable for at least 2 weeks prior to the screening endoscopy, or (c) AZA, 6-MP, and methotrexate: if these immunomodulators have been prescribed at stable doses for at least 8 weeks prior to the screening endoscopy.

[0294] b) induction period The study involves a comparison of IV administration of mirikizumab versus placebo during a 12-week induction period. [Table 17] IV infusion of mirikizumab or placebo will be administered over at least 30 minutes.

[0295] The primary endpoint is clinical remission at week 12 (mirikizumab vs. placebo). Clinical remission is based on MMS.

[0296] The MMS and composite SF and RB scores derived from assessment of the Mayo score will be used to determine key secondary endpoints.

[0297] Part B overview Part B is a multicentric, randomized, double-blind, placebo-controlled, parallel-arm study evaluating the safety and efficacy of 200 mg mirikizumab Q4W SC in maintaining treatment response at week 40 (i.e., in combination with Part A, 52 weeks of continued treatment). The study population includes patients with moderately to severely active UC who completed Part A. Part A includes patients with an inadequate response, loss of response, or intolerance to conventional (non-biologic) therapy for UC ("conventional failure") and patients with an inadequate response, loss of response, or intolerance to biologic therapy for UC ("biologic failure").

[0298] Patients who achieve a clinical response to blinded mirikizumab treatment during Part A will be randomized 2:1 to blinded 200 mg mirikizumab Q4W SC or blinded placebo. Patients who respond to blinded placebo in the induction study will remain on blinded placebo in Part B. If patients lose response, they will receive open-label break-in therapy with mirikizumab 300 mg Q4W intravenous infusion (IV) for three doses.

[0299] Patients who do not achieve a clinical response with either blinded mirikizumab or blinded placebo during Part A will receive open-label extended induction therapy with mirikizumab 300 mg Q4W IV for three doses. Patients who achieve a delayed clinical response (defined using induction study baseline) will receive open-label 200 mg mirikizumab Q4W SC. Non-responders in the extension induction study who do not achieve a clinical response at Week 12 of Part A will be discontinued.

[0300] the purpose The primary objective is to test the hypothesis that in patients induced into clinical remission with mirikizumab, mirikizumab is superior to placebo in maintaining clinical remission at week 40 (52 weeks of continued treatment). This includes determining the proportion of patients who are in clinical remission at week 12 of Part A and in clinical remission, i.e., durable clinical remission, at week 40.

[0301] Secondary objectives include: To evaluate the efficacy of mirikizumab compared with placebo in achieving clinical remission at week 40 in patients with mirikizumab-induced clinical response. To evaluate the efficacy of mirikizumab compared with placebo in achieving endoscopic remission at week 40 in patients with mirikizumab-induced clinical response. To evaluate the efficacy of mirikizumab compared with placebo in achieving corticosteroid-free remission without surgery in patients who were guided by a clinical response to mirikizumab and received corticosteroids at induction baseline. • To evaluate clinical remission at week 40 in patients induced by mirikizumab in the subgroup of patients for whom biologics had failed or caused intolerance. • To evaluate endoscopic remission at week 40 in patients with mirikizumab-induced clinical response in the subgroup of patients in whom biologics had failed or caused intolerance. • To evaluate clinical remission at week 40 in patients induced into clinical remission with mirikizumab in the subgroup of patients in whom biologics had failed or caused intolerance. To evaluate the efficacy of mirikizumab compared with placebo in achieving corticosteroid-free remission without surgery in patients induced into clinical remission with mirikizumab and who received corticosteroids at induction baseline.

[0302] Endpoints will be defined using the MMS. Endoscopies will be centrally read. Endoscopic cure rates will also be assessed at week 52. Endpoint definitions are as follows: ● Clinical remission: Achievement of the following MMS subscores: rectal bleeding (RB) subscore 0, stool frequency (SF) subscore 0 or 1 (≥1 point reduction from baseline), and endoscopy subscore (ES) 0 or 1 (excluding frailty). ● Clinical response: Achieved a reduction of ≥1 in the RB subscore or a reduction of ≥2 points in the 9-point Mayo subscore with either an RB subscore of 0 or 1 and a reduction of ≥30% from baseline. ●Endoscopic remission: Mayo ES achieved 0. ●Endoscopic cure: Mayo ES achieved 0 or 1. ● Symptomatic remission: SF=0, or SF=1, and RB=0, with a reduction of 1 point or more from baseline. • Symptomatic response: at least 30% reduction from baseline in composite SF and RB. Non-surgical, corticosteroid-free remission is defined as follows: - Clinical remission, and - No corticosteroid use for ≥12 weeks prior to evaluation

[0303] method Patient population Patients with moderately to severely active UC who complete Part A and meet the eligibility requirements will be enrolled in the study. The study will enroll patients who achieve a clinical response or clinical remission with blinded mirikizumab or placebo dosing in Part A, as well as patients who do not achieve a clinical response with blinded mirikizumab or placebo during Part A.

[0304] Treatment issues The maintenance study treatment assignment depends on whether the patient responded to the study drug dosing in Part A and whether they experienced a loss of response (LOR) during the study as follows: i) Mirikizumab responders from Part A Patients who achieve a clinical response with blinded mirikizumab in Part A will be randomized in a 2:1 ratio to receive blinded 200 mg mirikizumab SC Q4W or blinded placebo SC Q4W (randomized treatment discontinuation). Randomization will be stratified to achieve comparability between groups based on biologic failure status (yes or no), induced remission status (yes or no), corticosteroid use (yes or no), and region (North America / Europe / other). Patients will continue on the randomized treatment assignment for the remainder of Part B unless they experience a secondary LOR.

[0305] Loss of response (LOR) is defined as: - SF+RB total score increase of ≥2 points from baseline in Part B; - A combined SF+RB score of 4 or greater on two consecutive visits (≥7 days apart and confirmed with negative C. difficile tests); - Confirmed by a centrally read endoscopic subscore (ES) of 2 or 3

[0306] SC dosing will continue according to the dosing schedule until endoscopy determines whether LOR is confirmed. If LOR is confirmed based on endoscopy after week 12 (and Clostridium difficile fecal toxin test is negative), patients will be spiked with open-label mirikizumab 300 mg Q4W IV for three doses. The first IV spike dose may be administered as soon as LOR is confirmed by centrally read endoscopy if it is ≥7 days since the most recent SC dose. Subsequent doses will be administered every 4 weeks for a total of three doses.

[0307] If endoscopy does not identify secondary LOR, patients will continue SC study medication and maintain scheduled dosing intervals. If study medication is continued, an additional endoscopy will be performed at the early discontinuation visit (ETV) or unscheduled visit (UV) at Week 40.

[0308] Patients who, in the opinion of the investigator, receive clinical benefit after completion of LOR bailout therapy (12 weeks after the first IV bailout dose) will be considered for enrollment in the long-term extension study, Part C, to receive additional SC dosing. Once LOR IV bailout therapy is initiated, no additional SC dosing will be available in Part B.

[0309] ii) Placebo responders from Part A Patients who achieve a clinical response with blinded placebo in Part A will continue to receive blinded placebo for the remainder of the maintenance study. Placebo SC injections will be administered Q4W to maintain the study blind. If LOR is confirmed based on endoscopy after Week 12 (and Clostridium difficile fecal toxin test is negative), patients will be spiked with open-label 300 mg mirikizumab Q4W IV for three doses. The same LOR assessments and procedures should be performed as described for mirikizumab responders from Part A.

[0310] iii) Mirikizumab and placebo non-responders from Part A Patients who do not achieve a clinical response to blinded mirikizumab or blinded placebo during Part A will receive open-label extended induction therapy with 300 mg mirikizumab IV at weeks 0, 4, and 8, followed by endoscopy at week 12.

[0311] Patients who achieve a delayed clinical response (compared to induction study baseline) with extended mirikizumab induction therapy at week 12 will then receive open-label 200 mg mirikizumab Q4W SC starting at week 12. Patients will continue on this dosing regimen and undergo endoscopy at week 40.

[0312] Patients who, in the opinion of the investigator, receive clinical benefit may be considered for enrollment in the long-term extension study, Part C, to receive additional SC dosing.

[0313] Patients who do not achieve a clinical response to mirikizumab IV extended induction therapy at week 12 compared to induction baseline will discontinue study drug and undergo procedures for early discontinuation of study drug, including post-treatment follow-up.

[0314] iv) Follow-up period after treatment Patients will have a follow-up period of up to 16 weeks after treatment. -Patients who discontinue the final dose of IV study drug will return for post-treatment follow-up visits 4 and 16 weeks after the End of Treatment visit. - Patients who discontinue the final dose of study drug administered SC will return for post-treatment follow-up visits 4 and 12 weeks after the End of Treatment visit. -Patients who subsequently enter the long-term extension study, Part C, are not required to complete the post-treatment follow-up period.

[0315] Part C overview Part C is a single-arm, outpatient, open-label, multicentric, long-term extension study evaluating the efficacy and safety of mirikizumab in patients with moderately to severely active UC who participated in the original mirikizumab UC studies, including but not limited to the studies described in Example 1 and Part B.

[0316] the purpose The primary objective is to evaluate the long-term efficacy of mirikizumab. The secondary objective is to evaluate the effect of long-term mirikizumab therapy on histological response (mucosal healing).

[0317] method Patients in the study of Example 1 and Part B are eligible to enroll in Part C.

[0318] Patient population The Example 1 study is a randomized, double-blind, placebo-controlled study investigating the efficacy and safety of mirikizumab in patients with moderate to severe UC. The study consists of a 12-week double-blind induction period followed by either a maintenance period (up to 144 weeks) or an extension period (12-week extended induction, up to 132 weeks extended maintenance) for a total of up to 156 weeks. Study patients eligible for consideration for enrollment in Part C include: Patients who completed the maintenance week 52 endoscopy visit and end-of-study / early discontinuation visit evaluations, or Patients who completed the extension week 40 endoscopy visit and the end-of-study / early discontinuation visit assessments.

[0319] At the final Example 1 study visit, patients may receive blinded mirikizumab 200 mg SC Q4W, blinded mirikizumab 200 mg SC Q12W, blinded placebo SC Q4W, or open-label (open-label) mirikizumab 200 mg SC Q4W. Patients who received blinded placebo SC at the final visit in the Example 1 study will receive mirikizumab for the first time in Part C.

[0320] Part B is a randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of 200 mg mirikizumab SC Q4W in maintaining treatment response at week 40 (52 weeks of continued treatment) in patients with moderately-to-severely active UC who have completed 12 weeks of induction treatment. Part B patients eligible to be considered for enrollment in AMAP include: Patients who completed the Week 40 visit on blinded SC mirikizumab or placebo treatment without experiencing loss of response (LOR) during Part B Patients who completed the Week 40 visit on open-label SC mirikizumab after responding to re-induction with IV mirikizumab Patients who received IV contingency for LOR, completed the Part B early discontinuation visit, and had clinical benefit at their last Part B visit

[0321] Patients may have received blinded mirikizumab 200 mg SC Q4W, blinded placebo SC Q4W, open-label (open-label) mirikizumab 300 mg IV, or open-label mirikizumab 200 mg SC Q4W. Patients who received blinded placebo SC at their last visit in Part B will receive mirikizumab for the first time in Part C.

[0322] research treatment Mirikizumab 200 mg is given subcutaneously every 4 weeks. Patients will receive open-label mirikizumab in Part C regardless of whether they were receiving blinded or open-label (open-label) mirikizumab or blinded placebo when participation in the original study ended. Run-in with mirikizumab is not available during Part C.

[0323] Endoscopies will be performed at weeks 52 (year 1), 100 (year 2), and 160 (year 3) of Part C. The last endoscopy performed in the original study may be used as the baseline for Part C. Patients from Part C who have not had an endoscopy within 8 months of week 0 of Part C will have an endoscopy at week 0. Patients with pancreatitis of more than 8 years duration, left-sided colitis of more than 12 years duration, or primary sclerosing cholangitis require colorectal cancer surveillance colonoscopy for UC-associated dysplasia and malignancy. Patients with a family history of colorectal cancer, a personal history of increased risk of colorectal cancer, age >50 years, or other known risk factors also require colonoscopy for colorectal cancer surveillance.

Claims

1. A pharmaceutical composition comprising an anti-IL-23p19 antibody for use in a method for treating ulcerative colitis (UC) comprising administering said anti-IL-23p19 antibody to a patient in need of treatment, said method comprising: a) administering to said patient at least one induction dose of said anti-IL-23p19 antibody, wherein each induction dose comprises 50-1200 mg of said antibody; and b) administering to said patient at least one maintenance dose of said anti-IL-23p19 antibody after the final induction dose has been administered, wherein each maintenance dose comprises 150-400 mg of said anti-IL-23p19 antibody.

13. A pharmaceutical composition comprising:

2. The pharmaceutical composition described in claim 1, wherein the patient is inexperienced with biological agents.

3. The pharmaceutical composition described in claim 1, wherein the patient has experience with biological agents.

4. The pharmaceutical composition described in claim 1, wherein the patient is a patient who has failed biological agents or conventional drugs.

5. The pharmaceutical composition described in any one of claims 1 to 4, wherein one, two, or three induction doses are administered to the patient.

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein each induction dose is administered by intravenous infusion.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein one, two, or three extended induction doses of the anti-IL-23p19 antibody are administered to the patient if the patient does not achieve a therapeutic benefit 4 to 12 weeks after the final induction dose is administered, and wherein at least one maintenance dose of the anti-IL-23p19 antibody is administered to the patient if the patient achieves a therapeutic benefit 4 to 12 weeks after the final extended induction dose is administered.

8. The pharmaceutical composition described in claim 7, wherein one, two, or three extended induction doses are administered to the patient if the patient does not achieve a therapeutic effect four weeks after the final induction dose is administered.

9. The pharmaceutical composition of claim 7 or 8, wherein three extended induction doses are administered four weeks apart.

10. The pharmaceutical composition of claim 7, wherein each extension-inducing dose comprises 200 to 1000 mg of the anti-IL-23p19 antibody.

11. A pharmaceutical composition described in any one of claims 7 to 10, wherein each extension-inducing dose is administered by intravenous infusion.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein each maintenance dose comprises 150 mg, 200 mg, 250 mg, or 300 mg of the anti-IL-23p19 antibody.

13. The pharmaceutical composition described in any one of claims 7 to 12, wherein multiple maintenance doses are administered to the patient, wherein a first maintenance dose is administered 2 to 8 weeks after the final induction dose or the final extended induction dose is administered.

14. The pharmaceutical composition described in any one of claims 7 to 13, wherein the first maintenance dose is administered 4 to 6 weeks after the final induction dose or the final extended induction dose is administered.

15. The pharmaceutical composition of any one of claims 7 to 13, wherein the first maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the final induction dose or the final extended induction dose is administered.

16. The pharmaceutical composition of any one of claims 7 to 15, wherein subsequent maintenance doses are administered at 4-week, 8-week, or 12-week intervals following administration of the initial maintenance dose.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein each maintenance dose is administered by subcutaneous injection.

18. The pharmaceutical composition of any one of claims 1 to 17, wherein one, two, or three extra boost doses of the anti-IL-23p19 antibody are administered to the patient if the patient experiences loss of therapeutic benefit during the maintenance period, and wherein one or more further maintenance doses of the anti-IL-23p19 antibody are administered to the patient if the patient achieves therapeutic benefit 4 to 12 weeks after the last extra boost dose is administered.

19. The pharmaceutical composition of claim 18, wherein two or three extra doses are administered at four week intervals.

20. The pharmaceutical composition of claim 18 or 19, wherein each extra dose comprises 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, or 600 mg of the anti-IL-23p19 antibody.

21. A pharmaceutical composition described in any one of claims 18 to 20, wherein each extra dose is administered by intravenous infusion.

22. The pharmaceutical composition of any one of claims 18 to 21, wherein each further maintenance dose comprises 150 mg, 200 mg, 250 mg, or 300 mg of the anti-IL-23p19 antibody.

23. The pharmaceutical composition of any one of claims 18 to 22, wherein multiple further maintenance doses are administered to the patient, wherein the first further maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last extra boost dose was administered.

24. The pharmaceutical composition of claim 23, wherein after administration of the first further maintenance dose, subsequent further maintenance doses are administered at 4 week, 8 week, or 12 week intervals.

25. A pharmaceutical composition described in any one of claims 18 to 24, wherein each further maintenance dose is administered by subcutaneous injection.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

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