Mirikizumab for use in method of treating crohn's disease

Abstract

To provide a method for treating Crohn's disease (CD).SOLUTION: A method comprising: a) administering to a patient at least one induction dose of mirikizumab of about 200 mg to about 1200 mg; and b) administering to the patient at least one maintenance dose of mirikizumab of about 100 mg to about 600 mg after the last induction dose is administered.SELECTED DRAWING: Figure 1

Description

Detailed Description of the Invention

[0001] The present invention relates generally to methods of treating Crohn's disease (CD) using antibodies that bind to the p19 subunit of human IL-23.

[0002] CD is a chronic disease of unknown etiology involving environmental, genetic, and immunological influences. Transmural inflammation, which can affect any part of the gastrointestinal tract from the mouth to the anus and usually manifests as discrete lesions, is a common feature of CD (Baumgart DC and Sandborn WJ, Lancet, Vol. 369, pp. 1641–57, 2007). Symptoms include chronic diarrhea (often bloody, containing pus, or mucus), abdominal pain, weight loss, fever, fatigue, anemia, rectal bleeding, and abdominal distension. Symptoms vary depending on the severity and location of the disease; the majority of patients experience abscesses, fistulas, strictures, or obstructions requiring surgical intervention. A relapsing-remitting syndrome, meaning that many patients have intermittent disease flares with periods of remission, is very common in CD (Lichtenstein GR et al., American Journal of Gastroenterology, Vol. 113, pages 481-517, 2018). In clinical practice, the treatment goals are symptom suppression and intestinal mucosal healing.

[0003] Treatment of autoimmune / inflammatory diseases with IL-23-targeted therapy is being pursued. The first such biologic to demonstrate clinical benefit in autoimmune diseases was ustekinumab, a monoclonal antibody approved by the Food and Drug Administration (FDA) for the treatment of psoriasis, psoriatic arthritis, and CD. Ustekinumab specifically targets both IL-12 and IL-23 cytokines, rather than IL-23, because it binds to the common p40 subunit of these cytokines. Blockade of the IL-12 pathway prevents interferon blockade of Th1 cell-induced Th17 cell development, potentially limiting the clinical activity of antibodies targeting p40. Experimental studies suggest that blocking the IL-23 / Th17 / IL-17 immune axis alone is sufficient to treat autoimmune inflammation (Monteleone G et al., Mediators of Inflammation, E-publication, 27 May 2009). Drugs that specifically target the IL-23 p19 subunit have shown clinical activity in psoriasis (Sofen H et al., J Allergy Clin Immunol. Vol. 133, No. 4, pages 1032-1040, 2014; Kopp T et al., Nature, Vol. 521, No. 7551, pages 222-226, 2015; Krueger JG et al., J Allergy Clin Immunol., Vol. 136, No. 1, pages 116-124 e7, 2015). IL-23 p19-specific antibodies have also shown clinical activity in CD (Sands BE et al., Gastroenterology, Vol. 148, No. 4, Supplement 1, S163-S164, Abstract 830, 2015; Feagan BG et al., Gastroenterology, Vol. 150, No. 4, Supplement 1, S1266, Abstract 812a, 2016).

[0004] Treatment regimens for CD with anti-IL-23p19 antibodies are disclosed in WO2014 / 143540A1 and WO2017 / 048901A1.

[0005] For example, there remains a need for treatment options for CD that provide favorable patient outcomes in terms of treatment efficacy, safety, and / or tolerability, particularly in the form of mirikizumab dosing regimens that provide optimal efficacy for the treatment of CD.

[0006] Accordingly, in a first aspect of the present invention there is provided a method for treating CD comprising administering mirikizumab to a patient, the method comprising: a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises between about 200 mg and about 1200 mg of mirikizumab; b) administering to the patient at least one maintenance dose of mirikizumab after the final induction dose has been administered, wherein the maintenance dose comprises between about 100 mg and about 600 mg of mirikizumab.

[0007] In a further embodiment of the method of the present invention, the CD is moderate to severe CD.

[0008] In yet a further embodiment of the method of the present invention, the patient is a conventional-failed patient.

[0009] In an alternative embodiment of the method of the present invention, the patient is biologic-experienced.

[0010] In an alternative further embodiment of the method of the present invention, the patient is a biologic-failed patient.

[0011] In still further embodiments of the methods of the present invention, the at least one induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0012] In a preferred embodiment of the method of the present invention, at least one induction dose comprises about 900 mg of mirikizumab.

[0013] In still further embodiments of the methods of the present invention, one, two, three, or four induction doses are administered to the patient.

[0014] In a preferred embodiment of the method of the present invention, three induction doses are administered to the patient about four weeks apart.

[0015] In yet a further embodiment of the method of the present invention, at least one induction dose is administered by intravenous infusion.

[0016] In still further embodiments of the methods of the present invention, if the patient has not achieved an endoscopic response about 4 weeks to about 12 weeks after the last induction dose was administered, at least one extended induction dose of mirikizumab is administered to the patient, and if the patient has achieved an endoscopic response about 4 weeks to about 12 weeks after the last extended induction dose was administered, at least one maintenance dose of mirikizumab is administered to the patient, where an endoscopic response is defined as a 50% reduction from baseline in the SES-CD score.

[0017] In yet a further embodiment of the method of the present invention, if the patient has not achieved an endoscopic response about four weeks after the last induction dose was administered, at least one extended induction dose is administered to the patient.

[0018] In yet a further embodiment of the method of the present invention, multiple extended induction doses are administered at intervals of about four weeks.

[0019] In a further preferred embodiment of the method of the present invention, three extended induction doses are administered about four weeks apart.

[0020] In still further embodiments of the methods of the invention, the extended induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0021] Preferably, the extended induction dose comprises about 200 mg, about 600 mg, about 900 mg, or about 1000 mg of mirikizumab.

[0022] More preferably, the extended induction dose comprises about 900 mg of mirikizumab.

[0023] In yet a further embodiment of the method of the present invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0024] In still further embodiments of the methods of the invention, at least one maintenance dose comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, or about 600 mg of mirikizumab.

[0025] In a further preferred embodiment of the method of the present invention, at least one maintenance dose comprises about 300 mg of mirikizumab.

[0026] In an alternative preferred embodiment of the method of the present invention, at least one maintenance dose comprises about 200 mg of mirikizumab.

[0027] In yet a further embodiment of the method of the present invention, at least one maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

[0028] In still further embodiments of the methods of the present invention, at least one maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0029] In yet a further embodiment of the method of the present invention, at least one maintenance dose is administered about four weeks after the final induction dose is administered.

[0030] In an alternative further preferred embodiment of the method of the present invention, at least one maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0031] 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 16 weeks after the last induction dose.

[0032] In still further embodiments of the methods of the present invention, the first maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0033] In yet a further embodiment of the method of the present invention, the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

[0034] In an alternative, more preferred embodiment of the method of the present invention, the first maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0035] In still further embodiments of the methods of the present invention, one or more additional maintenance doses are administered at intervals of about 4 weeks, about 8 weeks, or about 12 weeks after administration of the initial maintenance dose.

[0036] In yet a further preferred embodiment of the method of the present invention, one or more further maintenance doses are administered at about four week intervals following administration of the initial maintenance dose.

[0037] In yet a further preferred embodiment of the method of the present invention, one or more additional maintenance doses are administered at about eight week intervals following administration of the initial maintenance dose.

[0038] In yet a further preferred embodiment of the method of the present invention, the maintenance dose is administered by subcutaneous injection.

[0039] In yet a further preferred embodiment of the method of the present invention, the method comprises the steps of: a) administering to the patient three induction doses of mirikizumab by intravenous injection, each induction dose comprising about 900 mg of mirikizumab; b) administering to the patient by subcutaneous injection maintenance doses of mirikizumab at intervals of about 4 weeks or about 8 weeks, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered, and each maintenance dose comprises 200 mg or 300 mg of mirikizumab; Moderate to severe CD.

[0040] In yet a further embodiment of the invention, the patient is a conventional drug failure patient.

[0041] In an alternative embodiment of the invention, the patient is biologic experienced.

[0042] In a further alternative embodiment of the invention, the patient is a biologics failure patient.

[0043] In yet a further preferred embodiment of the method of the present invention, three induction doses of mirikizumab are administered about four weeks apart, with the first maintenance dose being administered about four weeks after the last induction dose.

[0044] In a further aspect of the invention there is provided mirikizumab for use in the treatment of CD, the treatment comprising: a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises between about 200 mg and about 1200 mg of mirikizumab; b) administering to the patient at least one maintenance dose of mirikizumab after the final induction dose has been administered, wherein the maintenance dose comprises between about 100 mg and about 600 mg of mirikizumab.

[0045] In one embodiment of the present invention, the CD is moderate to severe CD.

[0046] In yet a further embodiment of the invention, the patient is a conventional drug failure patient.

[0047] In an alternative embodiment of the invention, the patient is biologic experienced.

[0048] In a further alternative embodiment of the invention, the patient is a biologics failure patient.

[0049] In still further embodiments of the invention, the at least one induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0050] In a preferred embodiment of the invention, at least one induction dose comprises about 900 mg of mirikizumab.

[0051] In still further embodiments of the invention, one, two, three, or four induction doses are administered to the patient.

[0052] In a more preferred embodiment of the invention, three induction doses are administered to the patient about four weeks apart.

[0053] In an alternative further embodiment of the invention, at least one induction dose is administered by intravenous infusion.

[0054] In a further embodiment of the invention, if the patient does not achieve an endoscopic response about 4 weeks to about 12 weeks after the last induction dose is administered, at least one extended induction dose of mirikizumab is administered to the patient, and if the patient achieves an endoscopic response about 4 weeks to about 12 weeks after the last extended induction dose is administered, at least one maintenance dose of mirikizumab is administered to the patient, where an endoscopic response is defined as a 50% reduction from baseline in the SES-CD score.

[0055] In yet a further preferred embodiment of the method of the present invention, if the patient has not achieved an endoscopic response about four weeks after the last induction dose was administered, at least one extended induction dose is administered to the patient.

[0056] In yet a further embodiment of the invention, multiple extended induction doses are administered at intervals of about four weeks.

[0057] In yet a further preferred embodiment of the invention, three extended induction doses are administered about four weeks apart.

[0058] In still further embodiments of the invention, the extended induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0059] Preferably, the extended induction dose comprises about 200 mg, about 600 mg, about 900 mg, or about 1000 mg of mirikizumab.

[0060] More preferably, the extended induction dose comprises about 900 mg of mirikizumab.

[0061] In yet a further preferred embodiment of the invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0062] In still further embodiments of the invention, at least one maintenance dose comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, or about 600 mg of mirikizumab.

[0063] In yet a further preferred embodiment of the invention, at least one maintenance dose comprises about 300 mg of mirikizumab.

[0064] In an alternative preferred embodiment of the invention, at least one maintenance dose comprises about 200 mg of mirikizumab.

[0065] In yet a further embodiment of the invention, at least one maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

[0066] In still further embodiments of the invention, at least one maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0067] In yet a further preferred embodiment of the present invention, at least one maintenance dose is administered about four weeks after the last induction dose is administered.

[0068] In an alternative more preferred embodiment of the present invention, at least one maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0069] In yet a further embodiment of the invention, multiple maintenance doses are administered to the patient, with the first maintenance dose being administered 2 to 16 weeks after the last induction dose.

[0070] In still further embodiments of the invention, the first maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0071] In yet a further preferred embodiment of the present invention, the first maintenance dose is administered about four weeks after the last induction dose is administered.

[0072] In an alternative more preferred embodiment of the present invention, the first maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0073] In still further embodiments of the invention, one or more additional maintenance doses are administered at intervals of about 4 weeks, about 8 weeks, or about 12 weeks after administration of the initial maintenance dose.

[0074] In yet a further preferred embodiment of the invention, one or more further maintenance doses are administered at about four week intervals following administration of the initial maintenance dose.

[0075] In an alternative further preferred embodiment of the present invention, one or more further maintenance doses are administered at about eight week intervals following administration of the initial maintenance dose.

[0076] In yet a further embodiment of the invention, the maintenance dose is administered by subcutaneous injection.

[0077] In yet a further preferred embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous injection, each induction dose comprising about 900 mg of mirikizumab; b) administering to the patient maintenance doses of mirikizumab by subcutaneous injection at intervals of about 4 weeks or about 8 weeks, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered, and each maintenance dose comprises 200 mg or 300 mg of mirikizumab; Moderate to severe CD.

[0078] In yet a further embodiment of the invention, the patient is a conventional drug failure patient.

[0079] In an alternative embodiment of the invention, the patient is biologic experienced.

[0080] In a further alternative embodiment of the invention, the patient is a biologics failure patient.

[0081] In a more preferred embodiment of the invention, three induction doses of mirikizumab are administered about four weeks apart, with the first maintenance dose being administered about four weeks after the last induction dose.

[0082] In a still further aspect of the invention there is provided the use of mirikizumab in the manufacture of a medicament for use in the treatment of CD, the treatment comprising: a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises between about 200 mg and about 1200 mg of mirikizumab; b) administering to the patient at least one maintenance dose of mirikizumab after the final induction dose has been administered, wherein the maintenance dose comprises between about 100 mg and about 600 mg of mirikizumab.

[0083] In one embodiment of the present invention, the CD is moderate to severe CD.

[0084] In yet a further embodiment of the invention, the patient is a conventional drug failure patient.

[0085] In an alternative embodiment of the invention, the patient is biologic experienced.

[0086] In an alternative further embodiment of the invention, the patient is a biologics failure patient.

[0087] In still further embodiments of the invention, the at least one induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0088] In a preferred embodiment of the invention, at least one induction dose comprises about 900 mg of mirikizumab.

[0089] In still further embodiments of the invention, one, two, three, or four induction doses are administered to the patient.

[0090] In a more preferred embodiment of the invention, three induction doses are administered to the patient about four weeks apart.

[0091] In an alternative further embodiment of the invention, at least one induction dose is administered by intravenous infusion.

[0092] In a further embodiment of the invention, if the patient does not achieve an endoscopic response about 4 weeks to about 12 weeks after the last induction dose is administered, at least one extended induction dose of mirikizumab is administered to the patient, and if the patient achieves an endoscopic response about 4 weeks to about 12 weeks after the last extended induction dose is administered, at least one maintenance dose of mirikizumab is administered to the patient, where an endoscopic response is defined as a 50% reduction from baseline in the SES-CD score.

[0093] In yet a further preferred embodiment of the method of the present invention, if the patient has not achieved an endoscopic response about four weeks after the last induction dose was administered, at least one extended induction dose is administered to the patient.

[0094] In yet a further embodiment of the invention, multiple extended induction doses are administered at intervals of about four weeks.

[0095] In yet a further preferred embodiment of the invention, three extended induction doses are administered about four weeks apart.

[0096] In still further embodiments of the invention, the extended induction dose comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg of mirikizumab.

[0097] Preferably, the extended induction dose comprises about 200 mg, about 600 mg, about 900 mg, or about 1000 mg of mirikizumab.

[0098] More preferably, the extended induction dose comprises about 900 mg of mirikizumab.

[0099] In yet a further preferred embodiment of the invention, one, two, or three extended induction doses are administered by intravenous infusion.

[0100] In still further embodiments of the invention, at least one maintenance dose comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, or about 600 mg of mirikizumab.

[0101] In yet a further preferred embodiment of the invention, at least one maintenance dose comprises about 300 mg of mirikizumab.

[0102] In an alternative preferred embodiment of the invention, at least one maintenance dose comprises about 200 mg of mirikizumab.

[0103] In yet a further embodiment of the invention, at least one maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

[0104] In still further embodiments of the invention, at least one maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0105] In yet a further preferred embodiment of the present invention, at least one maintenance dose is administered about four weeks after the last induction dose is administered.

[0106] In an alternative more preferred embodiment of the present invention, at least one maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0107] In yet a further embodiment of the invention, multiple maintenance doses are administered to the patient, with the first maintenance dose being administered 2 to 16 weeks after the last induction dose.

[0108] In still further embodiments of the invention, the first maintenance dose is administered about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 12 weeks, or about 16 weeks after the last induction dose is administered.

[0109] In yet a further preferred embodiment of the present invention, the first maintenance dose is administered about four weeks after the last induction dose is administered.

[0110] In an alternative more preferred embodiment of the present invention, the first maintenance dose is administered about 8 weeks after the last induction dose is administered.

[0111] In still further embodiments of the invention, one or more additional maintenance doses are administered at intervals of about 4 weeks, about 8 weeks, or about 12 weeks after administration of the initial maintenance dose.

[0112] In yet a further preferred embodiment of the invention, one or more further maintenance doses are administered at about four week intervals following administration of the initial maintenance dose.

[0113] In an alternative further preferred embodiment of the present invention, one or more further maintenance doses are administered at about eight week intervals following administration of the initial maintenance dose.

[0114] In yet a further embodiment of the invention, the maintenance dose is administered by subcutaneous injection.

[0115] In yet a further preferred embodiment of the invention, the treatment comprises: a) administering to the patient three induction doses of mirikizumab by intravenous injection, each induction dose comprising about 900 mg of mirikizumab; b) administering to the patient by subcutaneous injection maintenance doses of mirikizumab at intervals of about 4 weeks or about 8 weeks, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered, and each maintenance dose comprises 200 mg or 300 mg of mirikizumab; Moderate to severe CD.

[0116] In yet a further embodiment of the invention, the patient is a conventional drug failure patient.

[0117] In an alternative embodiment of the invention, the patient is biologic experienced.

[0118] In a further alternative embodiment of the invention, the patient is a biologics failure patient.

[0119] In yet a further preferred embodiment of the invention, three induction doses of mirikizumab are administered about four weeks apart, with the first maintenance dose being administered about four weeks after the last induction dose. [Brief explanation of the drawings]

[0120] [Figure 1] 1 illustrates the mean serum concentrations of mirikizumab during the induction period in the study described in Example 1. Mean concentrations were estimated based on a population PK analysis using individual subject clearance values ​​and the total dose received during the induction period. Subjects with low outlier concentrations are primarily the result of subjects who discontinued the study and did not receive all planned mirikizumab doses. [Figure 2]1 illustrates the mean serum concentrations of mirikizumab during the maintenance period in the study described in Example 1. Mean concentrations estimated based on population PK analysis using individual subject clearance values ​​and doses received during the maintenance period. [Figure 3] 1 shows the population pharmacokinetic model-estimated clearance versus body weight for the study of Example 1. [Figure 4] 1 shows the population pharmacokinetic model—estimated central volume of distribution versus body weight for the study of Example 1. [Figure 5] 1 shows a visual predictive check of the model fit for endoscopic response at 12 weeks in the study of Example 1. [Figure 6] 1 shows a visual predictive check of the model fit for endoscopic remission at week 12 in the study of Example 1. [Figure 7] 1 illustrates simulated endoscopic response and endoscopic remission rates at week 12 for mirikizumab doses and exposures of interest in the study of Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0121] There are various measures of CD disease activity levels, including but not limited to the Simple Endoscopic Score for Crohn's Disease (SES-CD) (Daperno M et al., Gastrointest Endosc., Vol. 60, No. 4, pages 505-512, 2004) and the Crohn's Disease Activity Index (CDAI).

[0122] The SES-CD is an endoscopic scoring system for CD based on four endoscopic variables (presence and size of ulcers, percentage of surface covered by ulcers, percentage of surface affected by disease, and presence and severity of strictures) assessed in five ileocolonic bowel segments (ileum; right, transverse, and left colon; and rectum). Each of the four endoscopic variables is scored from 0 to 3: presence and size of ulcers (none = score 0, 0.1 cm to 0.5 cm diameter = score 1, 0.5 cm to 2 cm = score 2, >2 cm = score 3), extent of ulcerated surface (none = 0, <10% = 1, 10% to 30% = 2, >30% = 3), extent of affected surface (none = 0, <50% = 1, 50% to 75% = 2, >75% = 3), and presence and type of strictures (none = 0, only one, passable = 1, multiple, passable = 2, non-passable = 3). A total score is obtained as the sum of all endoscopic scores across all bowel segments. Scores range from 0 to 56, with higher scores indicating greater severity.

[0123] The Crohn's Disease Activity Index (CDAI) is an 8-item disease activity measure consisting of a composite of three patient-reported items and five physician-reported / laboratory items (physical signs and laboratory parameters [hematocrit]). Patient responses are summed over a 7-day period, and then all items are weighted to obtain a total score range of 0 to 600 points. For additional details on patient-reported outcomes (PROs) (e.g., CDAI-SF, CDAI-AP, and CDAI-Well-Being), see Supplementary Note 10.8.

[0124] PRO includes: -Bowel Movement Count (BMC) -Crohn's Disease Activity Index-Stool Frequency (CDAI-SF) NOTE: The Bristol Stool Form Scale is used as a reference for completing the CDAI-SF. -Crohn's Disease Activity Index - Abdominal Pain (CDAI-AP) - Crohn's Disease Activity Index-Well-being (CDAI-Well-being) -Abdominal pain NRS -UrgencyNRS -Patient Global Rating Scale (PGRS) -Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) -Inflammatory Bowel Disease Questionnaire (IBDQ)

[0125] 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 CD, particularly for the treatment of moderate to severe CD. Such patients may or may not have been administered conventional medications for the treatment of CD. Conventional medications for the treatment of CD include aminosalisates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA), and steroids.

[0126] As used herein, the term "biologic failure" refers to a patient who has been receiving a biologic, e.g., an anti-TNF-α antibody, for the treatment of CD, particularly moderate to severe CD. Such patients may or may not be receiving conventional medications for the treatment of CD. Conventional medications for the treatment of CD include aminosalisates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA), and steroids. Such patients have an inadequate response, loss of response, or intolerance to biologic therapy for CD (e.g., an anti-TNF antibody). In terms of the term "biologic failure," an inadequate response means exhibiting signs and symptoms of persistent active disease despite induction treatment with the approved induction medication indicated in the product label at the time of use. In terms of the term "biologic failure," loss of response is defined as a recurrence of signs and symptoms of active disease while on approved maintenance medication following previous clinical benefit (discontinuation despite clinical benefit does not qualify as failure or intolerance to CD biologic therapy). In terms of the term "biologic failure," intolerance means a history of intolerance to infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, or other approved biologics (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).

[0127] 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 CD, particularly for the treatment of moderate to severe CD. Such patients may or may not be receiving conventional medications for the treatment of CD. Conventional medications for the treatment of CD include aminosalisates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA), and steroids.

[0128] As used herein, the term "conventional drug failure" refers to a patient who has had an inadequate response, loss of response, or intolerance to at least one of the following medications: 5-aminosalicylic acid (5-ASA) compounds; corticosteroids; AZA, 6-MP, or methotrexate (MTX) or CD-specific antibiotics. Patients who are conventional drug failures have never failed or demonstrated intolerance to biologic medications (anti-TNF antibodies or anti-integrin antibodies) indicated for the treatment of CD.

[0129] As used herein, "moderate to severe CD" refers to: > For subjects with active CD, defined as a diagnosis of CD within 3 months, and ileocolonic disease within 14 days prior to the first dose of study treatment > 7 (centrally read), or for subjects with isolated ileal disease > Has an SES-CD score of 4.

[0130] As used herein, "clinical benefit" is defined as having an endoscopic response (50% reduction from baseline in SES-CD score) or having a 25% reduction from baseline in SES-CD score combined with a 40% reduction from baseline in stool frequency (SF) or abdominal pain (AP) score.

[0131] As used herein, "endoscopic response" is defined as a 50% reduction from baseline in SES-CD score.

[0132] As used herein, "endoscopic remission of SES-CD" < 4" means that the total SES-CD score is < 4, defined as a reduction of at least 2 points versus baseline and no subscore >1.

[0133] As used herein, "endoscopic remission SES-CD 0-2" means < Defined as a total SES-CD score of 2.

[0134] As used herein, "clinical remission by PRO" refers to the unweighted mean daily SF < 2.5 or < 3 (number of liquid or very soft stools [obtained from the Crohn's Disease Activity Index, CDAI], i.e., liquid or watery stools, defined using the Bristol Stool Form Scale category 6 or 7 [Lewis and Heaton 1997]) and unweighted mean daily AP < 1 (AP [4-point scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe]), and defined as both SF and AP not worse than baseline.

[0135] As used herein, a "clinical response by PRO" is defined as at least a 30% reduction in SF and / or AP and no worse than baseline.

[0136] As used herein, "clinical remission by CDAI" is defined as a CDAI score <150.

[0137] As used herein, "clinical response by CDAI" refers to a clinical response compared to baseline. > Defined as a 100-point CDAI score reduction and / or clinical remission according to the CDAI.

[0138] As used herein, "dose" or "dosing" refers to the administration of a substance (e.g., mirikizumab) to achieve a therapeutic objective (e.g., treatment of CD).

[0139] As used herein, the "induction period" refers to the period from the time of endoscopic response, endoscopic remission, or SES-CD < 4. Endoscopic remission refers to the period of treatment for a patient that includes the administration of mirikizumab to induce clinical remission by SES-CD 0-2, clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI, as defined above. There is no minimum or maximum duration for the "induction period," but it is typically approximately 4 weeks, 8 weeks, or 12 weeks in duration. The end of the induction period is typically the end-of-induction assessment, which occurs approximately 4 weeks or 8 weeks after the last induction dose is administered.

[0140] As used herein, an "induction dose" refers to a dose that induces an endoscopic response, endoscopic remission, or SES-CD. < 4. Endoscopic remission (SES-CD 0-2), clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI, as defined above. An "induction dose" may be a single dose or, alternatively, a set of doses. An "induction dose" is administered during the induction period.

[0141] As used herein, an "extended induction period" refers to the period during which endoscopic response, endoscopic remission, or SES-CD is achieved. < 4. Endoscopic remission SES-CD 0-2, clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI was not achieved during the first induction period, so endoscopic response and endoscopic remission SES-CD were not achieved. <4. An "extended induction period" refers to the period of treatment required to induce endoscopic remission (SES-CD 0-2), clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI, as each of these terms is defined above. An "extended induction period" can be about 4 weeks, about 8 weeks, or about 12 weeks in duration.

[0142] As used herein, an "extended induction dose" refers to a dose that induces endoscopic response, endoscopic remission, or SES-CD. < 4. Endoscopic remission SES-CD 0-2, clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI was not achieved during the first induction period, so endoscopic response, endoscopic remission SES-CD < 4. Endoscopic remission (SES-CD 0-2), clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI refers to an additional induction dose of mirikizumab administered to a patient to induce endoscopic remission (SES-CD 0-2), clinical remission by PRO, clinical response by CDAI, or clinical response by CDAI, 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 for the "extended induction period," but it is typically about 4 weeks, about 8 weeks, or about 12 weeks in duration. The end of the extended induction period is typically the end-of-extension evaluation, which occurs about 4 weeks or about 8 weeks after the last extended induction dose is administered. An "extended induction dose" is administered during the extended induction period.

[0143] As used herein, the "maintenance period" refers to the period during which the desired therapeutic effect, endoscopic response of the desired therapeutic effect, endoscopic remission of SES-CD, < 4. Endoscopic remission SES-CD 0-2. This refers to a treatment period that involves administering mirikizumab to patients to maintain clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI, as each of these terms is defined above. A "maintenance period" follows an induction period or extended induction period and is intended to maintain the desired therapeutic effect—endoscopic response, endoscopic remission SES-CD. <4. Endoscopic remission is initiated when SES-CD 0-2, clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI is achieved.

[0144] As used herein, a "maintenance dose" refers to a dose that is sufficient to achieve the desired therapeutic effect, i.e., endoscopic response, endoscopic remission, or SES-CD. < 4. Endoscopic remission (SES-CD 0-2), clinical remission by PRO, clinical response by PRO, clinical remission by CDAI, or clinical response by CDAI refers to subsequent doses of mirikizumab administered to a patient to maintain or continue the induction dose. A "maintenance dose" is administered following the induction dose. A "maintenance dose" may be a single dose or, alternatively, a set of doses.

[0145] As used herein, the terms "treating," "treat," or "treatment" refer to suppressing, slowing, attenuating, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease, or alleviating 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 the disease or disorder, stabilization of the disease or disorder (i.e., where the disease or disorder is not worsening), delaying or slowing the progression of the disease or disorder, improvement or alleviation of the disease or disorder, and remission of the disease or disorder (whether partial or total). Those in need of treatment include those already suffering from the disease.

[0146] As used herein, "anti-IL-23p19 antibody" refers to an antibody or fragment thereof 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.

[0147] 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.

[0148] Mirikizumab, or a pharmaceutical composition comprising it, can be administered by a parenteral route (e.g., subcutaneously, intravenously, intraperitoneally, intramuscularly, or transdermally).

[0149] The term "intravenous infusion" refers to the introduction of a drug into the veins of an animal or human patient over a period of more than about 15 minutes, generally about 30 to 90 minutes.

[0150] The term "subcutaneous injection" refers to the introduction of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow, sustained delivery from a drug reservoir. The pocket may be created by pinching or pulling the skin up and away from the underlying tissue.

[0151] Pharmaceutical compositions containing mirikizumab for use in the methods of the present invention can be prepared by methods well known in the art (e.g., Remington: The Science and Practice a / Pharmacy, 19th edition (1995), (A. Gennaro et al., Mack Publishing Co.)) and comprise an antibody as disclosed herein and one or more pharmaceutically acceptable carriers, diluents, or excipients. [Example]

[0152] Example 1: Clinical Study overview A phase 2 trial could be conducted to determine whether mirikizumab is safe and effective in subjects with moderate to severe CD. Such a study could assess safety and determine clinical activity as defined by improvements in CD activity measures and key patient-reported outcome (PRO) measures.

[0153] the purpose The primary objective of such a Phase II trial is to demonstrate that treatment with mirikizumab is superior to placebo in inducing an endoscopic response at week 12. Secondary objectives may include: -Evaluation of the safety and tolerability of treatment with mirikizumab, - Assessment of the effect of mirikizumab on the proportion of subjects achieving an endoscopic response at week 52 - To evaluate the efficacy of mirikizumab over placebo in endoscopic remission at week 12, - Assessment of the effect of mirikizumab on the proportion of subjects achieving endoscopic remission at week 52 -Evaluation of the efficacy of mirikizumab over placebo in achieving PRO remission at week 12, - Assessment of the effect of mirikizumab on the proportion of subjects achieving PRO remission at Week 52 Assessment of the effect of mirikizumab on health outcomes / quality of life measures at weeks 12 and 52, and - Characterization of the PK profile of mirikizumab.

[0154] Endpoints can be defined using the SES CD score. Endoscopy can be centrally read. Endoscopic cure rates can be determined at 12 and 52 weeks. Endpoint definitions are as follows: [Table 1]

[0155] method The study may be a multicenter, randomized, parallel-group, placebo-controlled trial with approximately 191 randomized subjects. Subjects may be stratified into the following categories, with the exact number enrolled in any one group depending on the enrollment rate of each subject population: i) at least approximately 30% of subjects are naive to biologic CD therapy (including experimental biologic CD therapy); and ii) At least 50% of subjects have received prior biologic CD therapy (including experience with experimental biological CD therapy). The study will consist of the following periods:

[0156] Screening (approximately 4 weeks): Subjects were enrolled before the baseline visit. < Subjects may be assessed for study eligibility on Day 28. Subjects must be enrolled in the study at least 28 days prior to initiation of study treatment unless otherwise defined. < You may be considered for the study only if you meet all of the following criteria within the 28-day screening period: Type of subject and disease characteristics i) Baseline > Diagnosed with CD 3 months ago ii) Absolute SF > 4 (loose and watery stools defined as Bristol Stool Form Scale category 6 or 7) and / or AP at baseline within 14 days prior to the first dose of study treatment > In subjects with an SES-CD score of 2, ileocolonic disease > 7 (central reading) or in subjects with isolated ileal disease > have active CD defined as 4

[0157] Previous IBD treatment A) Subjects must have received prior treatment for CD (either "a") or "b") below, or a combination of both): a) History of inadequate response to or inability to tolerate oral or IV corticosteroids, aminosalicylsate, 6-mercaptopurine (6-MP), or azathioprine (AZA), or history of corticosteroid dependence (inability to successfully taper corticosteroids without recurrence of CD) or b) >have been treated with 1 biologic agent (e.g., TNF antagonists, vedolizumab, experimental biologic CD treatments) with or without a documented history of failure to respond to or tolerate such treatment; Treatment must have been discontinued according to the following timeline: Anti-TNF therapy at least 8 weeks prior to baseline Vedolizumab treatment at least 12 weeks prior to baseline - Experimental biologic CD therapy at least 8 weeks prior to baseline.

[0158] B) May be receiving therapeutic administration of the following drugs: a) Oral 5-aminosalicylic acid (ASA) compounds: If the prescribed dose was stable for at least 3 weeks prior to the screening colonoscopy, or if treatment was discontinued for at least 3 weeks prior to the screening colonoscopy, b) Oral corticosteroids are used in doses equivalent to prednisone. < 20 mg / day or < The oral corticosteroid treatment should be 9 mg / day budesonide and should be on a stable dose for at least 3 weeks prior to the screening colonoscopy. If oral corticosteroid treatment is discontinued before baseline, it should be discontinued at least 3 weeks prior to the screening colonoscopy. c) AZA, 6-MP, or methotrexate (MTX): Stable prescribed dose for at least approximately 4 weeks prior to the screening endoscopy. Subjects who discontinue treatment with AZA, 6-MP, or MTX must have stopped taking the medication for at least approximately 4 weeks prior to the screening endoscopy to be considered eligible for enrollment. c) CD-specific antibiotics: if the prescribed dose was stable approximately 4 weeks prior to baseline or treatment was discontinued at least 3 weeks prior to screening endoscopy.

[0159] Treatment group assignment Assignment to treatment groups can be determined by a computer-generated random sequence using an interactive web response system (IWRS). To achieve comparability between groups, subjects are stratified into these treatment groups based on previous treatment (see below), and this stratification is controlled by the IWRS. - At least approximately 30% of subjects must have never received a biologic CD therapy (including experimental biologic CD therapy). - At least 50% of subjects can be prior biologic CD therapy recipients (including prior experimental biologic CD therapy). In Period 2, subjects assigned to mirikizumab at baseline may be randomized to either the baseline treatment assignment or 300 mg SC mirikizumab Q4W, except for all subjects in the placebo group and subjects in the mirikizumab treatment group who received 1000 mg intravenous (IV) mirikizumab Q4W and did not experience improvement in SES-CD score (as determined by central reading) from baseline at Week 12. Preferably, all subjects receive both IV and SC administration of either mirikizumab or placebo during Period 2 in a double-dummy design.

[0160] Period 1 (Week 0-12): A 12-week induction dosing period can be designed to evaluate the efficacy and safety of mirikizumab administered intravenously (IV) at weeks 0, 4, and 8. At baseline, subjects can be randomized in a 2:1:1:2 allocation to four treatment arms and stratified based on prior exposure to biologic therapy for the treatment of CD. [Table 2]

[0161] Period 1 will be designed to establish the efficacy (endoscopic changes and primary PROs) and safety of mirikizumab versus placebo in subjects with moderate to severe Crohn's disease. Subjects will be able to continue their background medications for CD as permitted by the protocol. Therefore, the choice of placebo as a comparator in this subject population is justified to effectively evaluate the safety and efficacy of mirikizumab.

[0162] Period 2 (Weeks 12-52): Period 2 (weeks 12–52) will allow for continued evaluation of efficacy and safety through investigation of baseline treatment regimens and SC dosing, except for all subjects in the placebo group and subjects in the mirikizumab-treated group who did not experience improvement in CD-SES scores from baseline at week 12.

[0163] Subjects in Period 2 may receive both IV and subcutaneous (SC) dosing to maintain blinding from Week 12 through Week 48. Dosing will be administered Q4W. Randomization was stratified based on endoscopic response (i.e., a 50% reduction from baseline in SES CD score).

[0164] All subjects who received placebo in Period 1 must receive IV mirikizumab 1000 mg plus SC placebo in Period 2. Patients receiving mirikizumab who achieve an improvement in SES CD score from baseline (defined as a numerical reduction) at Week 12 may be randomized to either continue their Period 1 IV treatment assignment with SC placebo or continue IV placebo with SC mirikizumab 300 mg. Subjects receiving mirikizumab who do not achieve an improvement in SES CD score above baseline must receive IV mirikizumab 1000 mg plus SC placebo.

[0165] Period 3 (Weeks 52-104): Period 3 aims to provide extended treatment to subjects deemed to be receiving clinical benefit and provides a long-term assessment of safety and durability of clinical benefit.

[0166] All subjects with clinical benefit, defined as having an endoscopic response (50% reduction from baseline in SES CD score) or a combination of a 25% reduction from baseline in SES CD score and a 40% reduction from baseline in SF or AP score, will continue study treatment and advance to Period 3, where they will receive 300 mg SC mirikizumab Q4W, open-label, from Week 52 to Week 104. Subjects not experiencing clinical benefit at Week 52 will be required to discontinue treatment and enter a 16-week follow-up period.

[0167] Alternatively, patients may proceed to Period 3 if there is clinical benefit as determined by the investigator.

[0168] Follow-up At week 104, subjects will discontinue treatment and be followed for an additional 16 weeks for safety.

[0169] statistical analysis The primary endpoint was the endoscopic response rate (defined as a 50% reduction in SES-CD) at week 12. The expected endoscopic response rates for mirikizumab and placebo were 35% and 15%, respectively.

[0170] Treatment comparisons for the primary endpoint and other categorical efficacy variables can be performed using logistic regression analysis with treatment, geographic region, and use of prior biologic CD therapy (yes / no) in the model. Unless otherwise specified, efficacy and health status analyses can be performed on the intent-to-treat (ITT) population.

[0171] A Phase II trial was conducted essentially as described above in this Example 1.

[0172] Results: Patient population Period 1 The intention-to-treat (ITT) population consisted of 191 subjects: 64 subjects in the placebo group, 31 subjects in the mirikizumab 200 mg IV group, 32 subjects in the mirikizumab 600 mg IV group, and 64 subjects in the mirikizumab 1000 mg IV group.

[0173] Of the 191 subjects who received at least one dose, 176 subjects (92.1%) completed Period 1, and 15 subjects (7.9%) did not complete Period 1. Early discontinuations were balanced across treatment groups, except for the mirikizumab 600 mg IV group (placebo 7.8%, 200 mg IV 6.5%, 600 mg IV 12.5%, 1000 mg IV 6.3%). The higher discontinuation rate observed in the 600 mg IV group was reflected in the discontinuation rate due to AEs. Of the 15 subjects who discontinued early, 8 (4.2%) did so due to AEs: 4 subjects (6.3%) in the placebo group, 1 subject (3.2%) in the mirikizumab 200 mg IV group, and 3 subjects (9.4%) in the mirikizumab 600 mg IV group. Early study discontinuation due to AEs is further discussed in Section 1.9 of this supplement. Two subjects in the mirikizumab 1000 mg IV group discontinued early due to subject decision (“subject-initiated withdrawal”).

[0174] period 2 Of the 176 subjects who continued treatment in Period 2, 28 subjects discontinued as of the interim analysis database lock date. Of the 28 subjects who discontinued by the end of Period 2 (Week 52), 11 discontinued due to AEs: 1 subject in the mirikizumab 1000 mg IV group, 1 subject in the mirikizumab 300 mg SC group, 3 subjects in the mirikizumab 1000 mg IV NI group, and 6 subjects in the placebo / 1000 mg mirikizumab IV group. Eight subjects discontinued early due to subject decision ("subject withdrawal").

[0175] Of the 176 subjects who continued treatment in Period 2, 39 subjects discontinued as of the final analysis database lock date. Of the 39 subjects who discontinued by the end of Period 2 (Week 52), 12 discontinued due to AEs: 1 subject in the mirikizumab 1000 mg IV group, 1 subject in the mirikizumab 300 mg SC group, 3 subjects in the mirikizumab 1000 mg IV NI group, and 7 subjects in the placebo / 1000 mg mirikizumab IV group.

[0176] Results: Demographic and disease characteristics Demographic characteristics Demographic characteristics were balanced between the mirikizumab and placebo groups. Of the 191 randomized subjects, 98 subjects (51.3%) were women. The mean age (± standard deviation) was 38.65 years (± 12.86 years). A total of 159 subjects (83.2%) were white.

[0177] The mean baseline weight was 72.71 kg (±15.71 kg). The mean baseline body mass index (BMI) was 25.18 kg / m² (±4.88 kg / m²).

[0178] Disease characteristics Disease characteristics were balanced across the mirikizumab treatment group, the individual dosing groups, and placebo. Overall, 62.8% of subjects had been previously exposed to biologic therapy, and this proportion was balanced across treatment groups. Important baseline disease characteristics, including disease duration, previous biologic use, and disease activity (CDAI, endoscopic score, and PROs), were generally balanced across the four treatment groups. The proportion of patients with prior resections in the mirikizumab 200 mg group was lower than in the other treatment groups.

[0179] Concomitant and previous drug treatments for CD at baseline Concomitant and prior CD medications at baseline in Period 1 are shown in Table 1a. [Table 3]

[0180] There were no significant differences between the mirikizumab group overall or any individual medication group and placebo regarding the proportion of subjects receiving corticosteroids or immunosuppressants at baseline.

[0181] Concomitant and prior CD medications in period 2 are shown in Table 1b. [Table 4]

[0182] Results: Effectiveness Period 1 The primary endpoint was endoscopic response (defined as a 50% reduction in SES-CD) at week 12. Data show increasing efficacy (or improvement) with increasing mirikizumab dose: 10.9% (95% CI: 3.3%, 18.6%) of subjects in the placebo group, 25.8% (95% CI: 10.4%, 41.2%) of subjects receiving mirikizumab 200 mg IV, 37.5% (95% CI: 20.7%, 54.3%) of subjects receiving mirikizumab 600 mg IV, and 43.8% (95% CI: 31.6%, 55.9%) of subjects receiving mirikizumab 1000 mg IV reached the endoscopic response endpoint. In a subgroup analysis of bio-experienced subjects, the proportion of subjects with an endoscopic response at week 12 was numerically greater with the 1000 mg dose compared with the 600 mg dose: 46.2% vs. 31.6% responses.

[0183] Clinical remission was assessed at week 12 using a PRO-based definition. Clinical remission according to PRO(2.5,1) was defined as SF in this study. < 2.5 and AP <The proportion of subjects with clinical remission by PRO (2.5, 1) was significantly higher for the 600 mg and 1000 mg doses compared with placebo, with the remission rate for 600 mg (28.1%, 95% CI [12.5%, 43.7%]) numerically higher than for 1000 mg (21.9%, 95% CI [11.7%, 32.0%]). < 3.0 and AP < Using clinical remission defined as a PRO(3,1) not worse than baseline, with the cutoff definition in Example 2, the proportion of subjects in clinical remission was significantly higher for the 600 mg and 1000 mg doses compared to placebo, with the remission rate for the 600 mg dose (28.1%, 95% CI [12.5%, 43.7%]) being similar to that of the 1000 mg dose (28.1%, 95% CI [17.1%, 39.1%]).

[0184] A summary of efficacy measures at 12 weeks is presented in Table 2. [Table 5-1] [Table 5-2]

[0185] period 2 a) Re-randomized groups Subjects receiving mirikizumab who achieve an improvement in SES CD score from baseline at Week 12 will be randomized to continue their treatment assignment in Period 1 (mirikizumab 1000 mg IV, 600 mg IV, or 200 mg IV Q4W plus placebo administered SC or placebo IV Q4W plus mirikizumab 300 mg SC Q4W). This re-randomization is designed to address the question of whether there is an advantage to continuing IV dosing compared with SC dosing and to evaluate possible differences in efficacy between various dosing groups representing a wide range of exposures.

[0186] At the time of database lock for the interim analysis, 46 of the 191 subjects enrolled in the re-randomization groups had either completed Week 52 or discontinued early (200 / 200 mg IV—5 patients, 600 / 600 mg IV—6 patients, 1000 / 1000 mg IV—12 patients, and 300 mg SC—23 patients). Efficacy measures at Week 52 are summarized in Table 3.

[0187] Endoscopic responses were observed in 50% to 66.7% of patients across this re-randomized group. The endoscopic response rate for patients receiving 300 mg SC was 65.2%, which is comparable to rates observed in other IV dosing groups. The endoscopic remission rate was 16.7% to 33.3% (200 mg IV - 20.0%, 600 mg IV - 16.7%, 1000 mg IV - 33.3%) compared with 34.8% for patients receiving 300 mg SC. Exposure increased predictably between the 300 mg SC regimen and the IV regimen, as expected.

[0188] Clinical remission by PRO shows the same results whether assessed at an SF cutoff of 2.5 or 3.0. The proportion of patients in clinical remission by PRO was similar in the 600 mg IV, 1000 mg IV, and 300 mg SC dosing groups (25.0%-33.3%) and greater in the 200 mg IV group (80%).

[0189] At database lock for the final analysis, a total of 87 patients had been re-randomized and had either completed week 52 or discontinued early. [Table 6]

[0190] Efficacy measures at week 52 are summarized in Table 4. Among those with endoscopic improvers at week 12, the endoscopic response rates at week 52 were 58.5% (24 / 41) and 58.7% (27 / 46) in the IV and SC groups, respectively. Among patients with an endoscopic response at week 12, 69.6% (16 / 23) and 66.7% (16 / 24) in the IV-C and SC groups, respectively, had an endoscopic response at week 52. Other secondary and exploratory endpoints are reported for the combined randomized group (IV+SC) (Table 4).

[0191] The results of this re-randomized group support the comparable efficacy of SC and IV dosing and the lack of clear changes in efficacy with increasing exposure seen with IV dosing.

[0192] b) Non-randomized group Subjects who received mirikizumab and did not achieve improvement in SES CD score received IV mirikizumab 1000 mg plus SC placebo in Period 2. Additionally, all subjects who received placebo in Period 1 received IV mirikizumab 1000 mg plus SC placebo in Period 2. These patients were assigned to the highest IV dose to evaluate the optional impact of maximum exposure on patients initially lacking endoscopic improvement and to evaluate the impact of a shorter exposure period (9 months) on patients previously randomized to placebo. For these reasons, these two groups of patients represent separate patient populations and have different fundamental baseline characteristics compared with patients re-randomized to 1000 mg IV due to lack of endoscopic improvement or 12 weeks of untreated disease. Therefore, these groups will be analyzed separately when evaluating long-term exposure to 1000 mg IV.

[0193] At the time of database lock for the interim analysis, 46 of the 191 enrolled subjects had either completed week 52 or discontinued early (1000 mg IV / NI—14 patients; placebo / 1000 mg IV—32 patients).

[0194] Endoscopic response was observed in 14.3% of subjects who did not improve (NI) in Period 1 and in 46.9% of patients who received placebo in Period 1. The latter outcome was comparable to the endoscopic response rate observed in the re-randomized dosing group, but a lower rate was observed in the group without endoscopic improvement. Endoscopic remission outcomes were comparable: the endoscopic remission rate for patients who received 1000 mg IV without endoscopic improvement was 7.1%, compared with 15.6% for patients who received placebo followed by 1000 mg IV.

[0195] At week 52, clinical remission by PRO (2.5, 1) was 21.4% in the 1000 mg IV / NI group and 34.4% in the placebo / 1000 mg group. Clinical remission by PRO (3.0, 1) was also similar.

[0196] At the time of database lock for the final analysis, a total of 89 patients who were non-improvers or received placebo through week 12 received treatment through week 52 or discontinued as follows: [Table 7]

[0197] Endoscopic response was observed in 20% of subjects who did not improve (NI) in Period 1 and in 42.4% of patients who received placebo in Period 1. Endoscopic remission was comparable to the endoscopic response outcome: patients who did not improve endoscopically and then received 1000 mg IV had an endoscopic remission rate of 13.3%, while patients who received placebo followed by 1000 mg IV had an endoscopic remission rate of 18.6%.

[0198] At week 52, clinical remission by PRO (2.5, 1) was 36.7% in the 1000 mg IV / NI group and 40.7% in the placebo / 1000 mg group. Clinical remission by PRO (3.0, 1) was also similar.

[0199] The results of the NI and PBO groups were comparable to those of the IV and SC groups combined, except that PRO remission, CDAI remission, and endoscopic endpoints were numerically lower in the NI group. CDAI scores decreased throughout the maintenance period. [Table 8] [Table 9]

[0200] Result: Safety A summary of adverse events (AEs) by study period is presented in Table 5a for Period 1 and Table 5b for Period 2. [Table 10] [Table 11]

[0201] Mirikizumab was well tolerated, but 4 patients (3.1%) discontinued due to adverse events (AEs) in Period 1 and 12 patients (5.7%) discontinued due to adverse events (AEs) in Period 2. The incidence of serious adverse events (SAEs) was higher in the placebo group than in the mirikizumab-treated group in Period 1, with no dose-related relationship observed. The incidence of TEAEs was similar between the placebo and mirikizumab-treated groups in Period 1, with no dose-related relationship observed.

[0202] The number of SAEs observed in Period 1 was higher in (a) the cohort that received placebo in Period 1 and 1000 mg IV mirikizumab in Period 2 and (b) the cohort that was a non-improver in Period 1 and received 1000 mg IV mirikizumab in Period 2. However, the sample size does not support the conclusion that administration of 1000 mg IV mirikizumab increases the incidence of SAEs, especially when examined with SAE data from the improver cohort that received 1000 mg IV mirikizumab in Period 1 and 1000 mg IV mirikizumab in Period 2.

[0203] Results: PK and exposure-response analysis a) PK analysis - summary of mirikizumab serum exposure during induction and maintenance periods Figure 1 shows the mean mirikizumab concentrations during Period 1 (the induction period), calculated using individual subject clearance estimated by population PK analysis and the total dose each subject received during the induction period. As shown in these graphs, serum exposure of mirikizumab increased with dose, with some overlap in individual subject exposure across the doses evaluated. Note that some individual subjects had very low mean concentrations compared to other subjects in the same treatment group. This is primarily the result of these subjects dropping out of the study and not receiving all planned doses, resulting in low mean concentrations throughout the 12-week induction period.

[0204] Figure 2 shows the mean mirikizumab concentrations during the maintenance period for subjects who demonstrated improved endoscopic efficacy during induction and were randomized to either continue the IV dosing received during induction or switch to the 300 mg SC Q4W dosing. The 300 mg SC Q4W regimen produced the lowest mean concentrations of the four regimens evaluated; however, the 200 mg IV Q4W regimen produced similar exposures. The trough concentrations produced by the 300 mg SC Q4W regimen were also similar to those produced by the 200 mg IV Q4W regimen.

[0205] b) Overview of population PK analysis At the time of the interim analysis of this study, a total of 1,814 serum mirikizumab concentration samples from 186 patients from the induction, extension, and maintenance periods were included in the PK analysis. These 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 total body clearance was 0.028 L / h (4.3% standard error of estimate), and the interpatient variability in apparent clearance was 24% (coefficient of variation %). The estimated SC bioavailability was 42%. The estimated typical population values ​​for central and peripheral volumes of distribution and intercompartmental clearance were 3.2 L, 4.2 L, and 0.067 L / h, respectively. A total of 24 samples (1.2%) were below the lower limit of quantitation (100 ng / mL) of the mirikizumab assay. When these samples were excluded from PK modeling compared with standard imputation or conditional estimation methods, no impact on estimated PK parameters was observed.

[0206] A population PK model was used to evaluate the effects of the following covariates: age, sex, BMI, weight, ethnic origin, dose level, injection site, previous biological conditions, baseline albumin, time-varying albumin, baseline C-reactive protein (CRP), baseline fecal calprotectin, baseline bilirubin, baseline SES-CD score, baseline CDAI score, baseline PRO2 score (PRO2 is a two-item measure consisting of the SF and AP items of the CDAI [weighted], derived as follows: PRO2 = (7-day mean of SF) * 2 + (7-day mean of AP score) * 5), and immunogenicity (ADA + / -, TE-ADA + / -, ADA titer, neutralized ADA + / -). Baseline SES-CD score, weight, and time-varying albumin were found to have a statistically significant effect on clearance, and weight was found to have a statistically significant effect on central volume of distribution.

[0207] Patients with lower body weight tended to have lower clearance (Figure 3) and lower central volume of distribution (Figure 4). Compared to the median body weight of 71 kg observed in this study, using the model-estimated relationships, a subject weighing 40 kg would typically be expected to have a 22% lower clearance and a 28% lower volume of distribution. The magnitude of these effects is small compared to the overall random variation in clearance and volume of distribution. Including body weight in the model reduced the random variation in clearance by 14% and the random variation in volume of distribution by 34%. These results indicate that body weight did not have a clinically relevant effect on the PK of mirikizumab.

[0208] Patients with lower baseline SES-CD scores tended to have lower clearance, while patients with higher albumin concentrations tended to have lower clearance. Baseline SES-CD scores also tended to increase with decreasing baseline albumin concentrations. The median baseline SES-CD score in the study was 11. Patients in the study with a baseline SES-CD score of less than 11 had a model-estimated median clearance 23% lower than those with a baseline SES-CD score of 11 or higher (0.023 vs. 0.030 L / h). These model-estimated clearance values ​​account for the effects of both baseline SES-CD score and baseline albumin concentration observed in these patients. Including baseline SES-CD score and albumin in the model reduced the random variability in clearance by 25% and 17%, respectively. Based on the magnitude of the effects of baseline SES-CD score and albumin on clearance and the magnitude of the reduction in random variability in the model, these covariates did not have a clinically relevant effect on mirikizumab clearance.

[0209] c) Relationship between mirikizumab exposure and efficacy score observed at week 52 Absolute changes in SESCD, PRO2, and CDAI from Week 12 to Week 52 and estimated C values ​​from the PK model during the maintenance period avgThe relationship between the variance and the maintenance treatment group was assessed (data not shown). As with the induction period, the observed relationships show a large overlap in score changes between individual subjects in the treatment groups. No discernible exposure-response trends were observed across the maintenance treatment groups.

[0210] Given that no exposure-response trends were observed at week 52, model-based exposure-response assessment was not performed on the week 52 data.

[0211] d) Summary of model-based exposure-response analysis of clinical efficacy endpoints at 12 weeks Logistic regression models were used to assess the relationship between mirikizumab exposure in individual patients and the probability of achieving endoscopic response, endoscopic remission, or PRO remission at week 12. Models were also used to assess the relationship between change in SES-CD score at week 12 and mirikizumab exposure. The maximum effect size (E) between mirikizumab exposure and these endpoints was calculated. max ) relationship was assumed, but linear models were also tested. Exposure measures evaluated in the model were the observed concentration at 12 weeks, the PK model-estimated concentration at 12 weeks, and the PK model-estimated C avg The following covariates were also evaluated in these models: baseline albumin, baseline CRP, baseline fecal calprotectin, previous biologic treatment status, disease duration, baseline SES-CD, baseline CDAI, baseline SF subscore, baseline AP subscore, and weight.

[0212] For the endoscopic response model, all exposure measures evaluated were similar in their ability to fit the observed data, and the PK model estimated 12-week concentrations with minimal uncertainty were 50% effective concentration (EC 50The endoscopic response model was able to detect a significant treatment effect (p<0.001) and a significant exposure-response (p=0.003) compared to placebo. None of the evaluated covariates were found to have a significant effect on the endoscopic response model. A visual predictive check was used to validate the model (Figure 5), and good agreement was found between the observed and model-predicted endoscopic response rates across treatment groups.

[0213] In the endoscopic remission model, the EC concentration estimated by the PK model at week 12 was the lowest uncertainty. 50 The endoscopic remission model was able to detect a significant treatment effect (p<0.001) and a strong exposure-response trend (p=0.03) compared to placebo. None of the evaluated covariates were found to have a significant effect on the endoscopic remission model. A visual predictive check was used to validate the model (Figure 6), and good agreement was found between the observed endoscopic remission rates across treatment groups and those predicted by the model.

[0214] Model fits for change in SES-CD score at week 12 did not detect a significant relationship between mirikizumab exposure and change in SES-CD score.Model fits for PRO remission at week 12 also did not detect a significant relationship between mirikizumab exposure and PRO remission.Because no significant exposure-response relationships were detected for these endpoints, model fits and simulated profiles are not shown.

[0215] Figure 7 shows the simulated endoscopic response and endoscopic remission rates for mirikizumab doses and exposures of interest in Phase III.

[0216] e) Summary of PK and exposure-response analysis The PK of mirikizumab in this study was dose-proportional, consistent with previous studies and typical for a monoclonal antibody. Although serum albumin, baseline SES-CD score, and body weight were statistically significant factors affecting mirikizumab PK, the magnitude of these factors' effects on random PK variability and the observation that efficacy in individual patients was not strongly dependent on exposures within the range of interest in the Example 2 study suggest that these patient factors did not have a clinically relevant impact on PK or efficacy in the Example 2 study.

[0217] Examination of the relationship between mirikizumab exposure and SES-CD, PRO, and CDAI scores at week 12 for individual patients observed in this study, as well as a model-based analysis of endoscopic response at week 12, suggests that near-maximal efficacy was achieved between the 600 and 1000 mg doses. A model-based analysis of the relationship between mirikizumab exposure and PRO remission suggests that the probability of a subject achieving PRO remission was not strongly dependent on mirikizumab exposure within the range of exposure evaluated in this study. During the maintenance period, the dosing regimens evaluated provided a wide range of mirikizumab exposure. Across maintenance groups, there was no discernible relationship between mirikizumab exposure and efficacy at 52 weeks.

[0218] Example 2: Clinical Study overview A phase III, multicenter, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, treat-through design study of mirikizumab could be conducted in patients with moderate to severe CD. More specifically, three intervention groups in Phase 1 and four intervention groups in Phase 2 could be studied in participants with moderate to severe CD: Mirikizumab 900 mg intravenously every 4 weeks for three doses, followed by 300 mg subcutaneously every 4 weeks. Ustekinumab approximately 6 mg / kg intravenously once, followed by 90 mg subcutaneously every 8 weeks. -placebo Upon completion of Period 1 (Week 12), responders will continue to receive placebo, and Non-responders (NR) at week -12 will receive mirikizumab as above.

[0219] The total duration of the combined treatment period will be a maximum of 52 weeks. The maximum total duration of each participant's study participation, including screening and post-treatment follow-up periods, will be 72 weeks.

[0220] Participants in either active group will receive a placebo matched to the other active group using a double-dummy design, and participants in the placebo group will receive both double-dummy placebos.

[0221] the purpose The primary objective is to evaluate whether treatment with mirikizumab is superior to placebo in the treatment of moderate to severe CD as assessed by endoscopic response at week 52 and clinical remission by PROs at week 52. Secondary objectives include: To evaluate the efficacy of mirikizumab treatment compared with placebo on endoscopic response at week 12; To evaluate the efficacy of mirikizumab treatment compared with placebo in achieving clinical remission as measured by PROs at week 12. To evaluate the efficacy of treatment with mirikizumab compared with placebo in endoscopic remission at week 52. To evaluate the efficacy of treatment with mirikizumab compared with placebo in achieving corticosteroid-free clinical or endoscopic remission by PROs at week 52. -To evaluate the efficacy of mirikizumab treatment compared to placebo in the stability of clinical remission as measured by PROs through week 52; To evaluate the efficacy of mirikizumab treatment compared with placebo in the durability of endoscopic response at 52 weeks; To evaluate the efficacy of treatment with mirikizumab compared with placebo in achieving endoscopic remission at week 12. To evaluate whether mirikizumab is superior to ustekinumab in achieving endoscopic response at week 52. To evaluate whether mirikizumab is superior to ustekinumab in achieving endoscopic remission at week 52. and To evaluate whether mirikizumab is non-inferior to ustekinumab in clinical remission by CDAI at week 52.

[0222] Endpoints can be defined using the SES-CD score. Endoscopy can be centrally read. Endoscopic cure rates can be determined at 12 and 52 weeks. Endpoint definitions are as follows: -Endoscopic response: 50% reduction from baseline in SES CD score. Endoscopic remission: SES-CD score <4 for ileocolonic disease or <2 for isolated ileal disease, with no subscore >1. - Clinical remission by PRO: Average daily AP score < 1 (and not worse than baseline) and average daily SF < 3.0 (liquid or very soft stools defined using Bristol Stool Form Scale category 6 or 7, i.e., absolute number of liquid or watery stools) (and not worse than baseline).

[0223] method A phase III, multicenter, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled treat-through study to evaluate the safety and efficacy of mirikizumab compared with placebo and ustekinumab can be conducted. The study population should include participants with moderate to severe active CD who have had an inadequate response, loss of response, or intolerance to conventional or biologic therapy for CD.

[0224] The study could be a parallel double-blind treatment study with three groups in period 1 and four groups in period 2.

[0225] Participants will be randomized to receive treatment in a 6:3:2 ratio. Mirikizumab 900 mg intravenously every 4 weeks for three doses, followed by 300 mg subcutaneously every 4 weeks. Ustekinumab approximately 6 mg / kg administered intravenously once, followed by 90 mg administered subcutaneously every 8 weeks -placebo Upon completion of Period 1 (Week 12), responders will continue to receive placebo, and Non-responders (NR) to placebo at week -12 will receive mirikizumab as above.

[0226] To maintain blinding, participants will receive a placebo in a double-dummy fashion. The maximum total duration of study participation for each participant is 72 weeks over the following study periods: i) Screening: up to 4 weeks; ii) Intervention period 1: 12 weeks; iii) Intervention period 2: 40 weeks, and iv) Post-treatment follow-up: 12-16 weeks

[0227] i) Screening (approximately 4 weeks) CD participants may be considered for enrollment only if they meet all of the following criteria during screening, unless otherwise specified below: a) Patient characteristics -At first screening > 18 years old and < An 80-year-old male or female patient b) Disease characteristics - Has been diagnosed with established CD or CD with fistulas at least 3 months prior to enrollment confirmed by clinical, endoscopic, and histological criteria. NOTE: To meet this inclusion criterion, a histopathology report supporting the diagnosis of CD must be available in the source document prior to randomization. If a histopathology report supporting the diagnosis of CD is not available in the source document prior to randomization, the investigator may obtain an additional biopsy for this purpose at the screening endoscopy (to be sent to the local histopathology laboratory). - Unweighted daily average SF > 4 (loose, watery stools defined as Bristol Stool Form Scale category 6 or 7) and / or unweighted mean daily AP at baseline > and have moderate to severe active CD as defined by 2 (Visit 2). - In patients with ileocolonic disease within 14 days prior to the first dose of study treatment > 7, or in patients with isolated ileal disease > An SES-CD score of 4 will be centrally read. Participants with a family history of colorectal cancer, a personal history of increased risk for colorectal cancer, age >50 years, or other known risk factors must be up-to-date on colorectal cancer surveillance according to local guidelines. If not, documentation of this negative colorectal cancer surveillance may be obtained during screening according to local guidelines. c) Previous medication failure criteria Participants must have had an inadequate response, loss of response, or intolerance to at least one of the medications listed in inclusion criteria [A] or [B]. For relevant medications specified in these criteria, documentation of the dose, frequency, route of administration, and duration of qualifying failure is required. [A] Patients with conventional drug failure: Patients who have an inadequate response, loss of response, or are intolerant to at least one of the following medications: -Corticosteroids - Corticosteroid-refractory disease is defined as the presence of signs and / or symptoms of active CD despite oral prednisone (or equivalent) at a dose of at least 30 mg / day for a minimum of 4 weeks. - Corticosteroid-dependent disease, defined as: a. Inability to reduce corticosteroids to less than the equivalent of 10 mg / day of prednisone or 3 mg / day of budesonide within 3 months of initiating corticosteroids without recurrence of signs and / or symptoms of active CD, or b. Relapse occurs within 3 months of completing a course of corticosteroids. - History of corticosteroid intolerance (including evidence of side effects severe enough to prevent continued treatment with corticosteroids, including but not limited to Cushing's syndrome, osteopenia / osteoporosis, hyperglycemia, or neuropsychiatric side effects, including insomnia, associated with corticosteroid treatment). -Immunomodulators: - Have signs and / or symptoms of persistent active disease despite at least 3 months of treatment with one of the following: -Oral AZA( > 1.5mg / kg / day) or 6-MP( > 0.75 mg / kg / day) or methotrexate 25 mg (intramuscular [IM] or SC weekly), or Oral AZA or 6-MP within the therapeutic range as determined by thioguanine metabolite testing, or - Thiopurine and allopurinol combination within 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, liver function tests), and no failure or demonstrated intolerance to a biologic agent (anti-TNF antibody or anti-integrin antibody) approved for the treatment of CD. Discontinuation despite clinical benefit is not considered failure of or intolerance to conventional therapy for CD. [B] Biologic Failure Patients: Participants with inadequate response, loss of response, or intolerance to approved biologic therapies for CD (e.g., anti-TNF or anti-integrin antibodies). Treating physicians must be able to document adequate medical history of use of induction and / or maintenance doses. Participants must meet one of the following criteria: - Inadequate response: signs and symptoms of persistent active disease despite induction treatment at the approved induction dose indicated in the product label at the time of use, or - Loss of response: recurrence of signs and symptoms of active disease following previous clinical benefit while on approved maintenance medication; or - Intolerance: History of intolerance (including but not limited to infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, or other approved biologic agents) to infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, or other approved biologic agents. Discontinuation despite clinical benefit is not considered failure of or intolerance to biologic therapy for CD.

[0228] Participants who have been exposed to previously approved biologic therapy and do not meet inclusion criterion [B] must continue to meet inclusion criterion [A] to be eligible to participate in the study.

[0229] Participants previously exposed to an investigational drug for the treatment of CD must still meet inclusion criteria [A] or [B].

[0230] Participants who meet both inclusion criteria [A] and [B] will be considered "biologic failures" for the purposes of this study.

[0231] ii) Period 1 (weeks 0-12) Participants who meet all criteria for enrollment may be randomized to double-blind treatment. To achieve comparability between groups, participants may be stratified into treatment groups based on these factors: a) biologic failure status (yes / no), b) baseline corticosteroid use (yes / no), c) baseline SES-CD total score (<12, > 12), d) region (North America / Europe / Other), and e) baseline SF. > 7 and / or baseline AP > 2.5 (yes / no). This stratification will be controlled by an interactive web-response system (IWRS). There will be three intervention groups in period 1. [Table 12]

[0232] ii) Period 2 (Weeks 12-52) There could be four intervention groups in period 2. [Table 13]

[0233] iii) Follow-up Participants who complete this study may be given the option to enroll in an extension study, if eligible. Participants who do not meet the extension study enrollment criteria or who choose not to participate in the extension study will return for two post-treatment follow-up visits. The first such follow-up visit may be 4 weeks after the last dose. The second such follow-up visit may be 12-16 weeks after the last dose.

Claims

1. 1. A method for treating Crohn's disease (CD) in a patient, comprising administering mirikizumab to a subject comprising: The patient has never received a biological agent (biologic-naive), a) three induction doses of mirikizumab are administered to the patient by intravenous infusion at weeks 0, 4, and 8, each of the induction doses containing 900 mg of mirikizumab; b) Multiple maintenance doses of mirikizumab are administered to the patient by subcutaneous injection at intervals of 4 to 8 weeks, the first maintenance dose being administered 2 to 8 weeks after the last induction dose, each maintenance dose containing 300 mg of mirikizumab.

2. The therapeutic agent of claim 1, wherein the CD is moderate to severe CD.

3. The therapeutic agent according to claim 1 or 2, wherein the patient is a conventional-failed patient.

4. The therapeutic agent according to claim 1 or 2, wherein the patient is not a conventional-failed patient.

5. The therapeutic agent according to any one of claims 1 to 4, wherein one, two or three extended induction doses of mirikizumab are administered to the patient by intravenous infusion to induce a therapeutic effect if the patient has not achieved a therapeutic effect 4 to 12 weeks after the administration of the final induction dose, each of the extended induction doses containing 900 mg of mirikizumab, and a first maintenance dose is administered 2 to 8 weeks after the administration of the final induction dose or the final extended induction dose.

6. The therapeutic agent according to any one of claims 1 to 5, wherein the maintenance dose is administered about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, or about 12 weeks after the administration of the final induction dose or the final extended induction dose.

7. The therapeutic agent according to any one of claims 1 to 6, wherein the maintenance dose is administered about 4 weeks after the final induction dose or the final extended induction dose is administered.

8. The therapeutic agent according to any one of claims 1 to 7, wherein the multiple maintenance doses are administered at intervals of 4 weeks.

Images