This invention generally relates to method of treating Crohn’s Disease (CD) with antibodies that bind to the pl9 subunit of human IL-23.

CD is a chronic disease of unknown etiology with environmental, genetic, and immunologic influences. Transmural inflammation affecting any part of the

gastrointestinal tract from the mouth to the anus, usually appearing as discontinuous lesions, are normal characteristics for CD (Baumgart D C and Sandbom WJ, Lancet, Vol. 369, pages 1641-57, 2007). Symptoms include chronic diarrhoea (often bloody and containing pus or mucus), abdominal pain, weight loss, fever, fatigue, anaemia, rectal bleeding, and a feeling of fullness in the abdomen. Symptoms depend on the severity of the disease and location of the disease, with the majority of patients experiencing an abscess, fistula, stricture or an obstruction requiring surgical intervention. Relapsing-remitting symptoms, meaning that many patients have intermittent disease flares that are interspersed with periods of remission, is very common in CD (Lichtenstein G R et al ., American Journal of Gastroenterology, Vol. 113, pages 481-517, 2018). Treatment goals in clinical practice are control of symptoms and healing of the intestinal mucosa.

Treatment of autoimmune/inflammatory diseases with IL-23 targeted therapy is being pursued. The first such biologic to demonstrate clinical benefit in autoimmune disease was ustekinumab, which is a Food and Drug Administration (FDA)-approved monoclonal antibody for the treatment of psoriasis, psoriatic arthritis and CD.

Ustekinumab binds the common p40 subunit of IL-12 and IL-23; therefore, it targets both cytokines, rather than IL-23 specifically. Blockade of the IL-12 pathway may prevent Thl cell-induced interferon blockade of Thl7 cell development, thus potentially limiting the clinical activity of p40 targeting antibodies. Experimental studies suggest that blocking the åL-23/Thl7/IL-17 immune axis alone is sufficient to treat autoimmune inflammation (Monteleone G et al ., Mediators of Inflammation, E-publication, 27 May 2009). Agents specifically targeting the IL-23 pl9 subunit have demonstrated 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 J G et al, J Allergy Clin Immunol., Vol. 136, No. 1, pages 116-124 e7, 2015). IL-23 pl9-specific antibodies have also demonstrated clinical activity in CD (Sands B E et al,

Gastroenterology, Vol. 148, No. 4, Supplement 1, S163-S164, Abstract 830, 2015;

Feagan B G et al., Gastroenterology, Vol. 150, No. 4, Supplement 1, S1266, Abstract 812a, 2016).

Treatment regimens for CD with anti-IL-23pl9 antibodies are disclosed in WO 2014/143540 A1 and WO 2017/048901 Al.

There remains a need for treatment options for CD that lead to favourable 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 dosage regimen of mirikizumab that provides optimal efficacy in the treatment of CD.

Accordingly, in a first aspect of the present invention, there is a provided a method for treating CD comprising administering mirikizumab to a patient, said method comprising:

a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises about 200 mg to about 1200 mg of mirikizumab; and

b) administering at least one maintenance dose of mirikizumab to the patient after the last induction dose is administered, wherein the maintenance dose comprises about 100 mg to about 600 mg of mirikizumab.

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

In a still further embodiment of the method of the present invention, the patient is conventional-failed.

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

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

In a still further embodiment of the method 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.

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

In a still further embodiment of the method of the present invention, one, two, three or four induction doses are administered to the patient.

In a preferred embodiment of the method of the present invention, three induction doses are administered to the patient at about 4-week intervals.

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

In a still further embodiment of the method of the present invention, if the patient has not achieved endoscopic response about 4 to about 12 weeks after the last induction dose is administered, at least one extended induction dose(s) of mirikizumab is administered to the patient, wherein the at least one maintenance dose(s) of mirikizumab is administered to the patient if the patient has achieved endoscopic response about 4 to about 12 weeks after the last extended induction dose is administered, and wherein endoscopic response is defined as a 50% reduction from baseline in SES-CD Score.

In a still further embodiment of the method of the present invention, the at least one extended induction dose(s) are administered to the patient if the patient has not achieved endoscopic response about 4 weeks after the last induction dose is administered.

In a still further embodiment of the method of the present invention, wherein multiple extended induction doses are administered at about 4 week intervals.

In a further preferred embodiment of the method of the present invention, three extended induction doses are administered at about 4 week intervals.

In a still further embodiment of the method of the present invention, the extended induction dose(s) comprise 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.

Preferably, the extended induction dose(s) comprise about 200 mg, about 600 mg, about 900 mg or about 1000 mg of mirikizumab.

Further preferably, the extended induction dose(s) comprise(s) about 900 mg of mirikizumab.

In a still further embodiment of the method of the present invention, the one, two or three extended induction dose(s) are administered by intravenous infusion.

In a still further embodiment of the method of the present invention, the 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.

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

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

In a still further embodiment of the method of the present invention, the at least one maintenance dose is administered 2-16 weeks after the last induction dose is administered.

In a still further embodiment of the method of the present invention, the 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.

In a still further preferred embodiment of the method of the present invention, the at least one maintenance dose is administered about 4 weeks after the last induction dose is administered.

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

In a still further embodiment of the method of the present invention, multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

In a still further embodiment of the method 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.

In a still further preferred embodiment of the method of the present invention, the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

In an alternative further 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.

In a still further embodiment of the method of the present invention, one or more further maintenance dose(s) are administered at about 4, about 8 or about 12 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the method of the present invention, one or more further maintenance dose(s) are administered at about 4 week interval(s) after administration of the first maintenance dose.

In an a still further preferred embodiment of the method of the present invention, one or more further maintenance dose(s) are administered at about 8 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the method of the present invention, the maintenance dose(s) are administered by subcutaneous injection.

In a still further preferred embodiment of the method of the present invention, the method comprising:

a) administering three induction doses of mirikizumab to the patient by

intravenous injection, wherein each induction dose comprises about 900 mg of mirikizumab; and

b) administering maintenance dose(s) of mirikizumab to the patient by

subcutaneous injection at about 4 week or about 8 week intervals, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered and wherein each maintenance dose comprises 200 mg or 300 mg of mirikizumab,

wherein the CD is moderate to severe CD.

In a still further embodiment of the present invention, the patient is conventional -failed.

In an alternative embodiment of the present invention, the patient is biologic-experienced.

In a further alternative embodiment of the present invention, the patient is biologic-failed.

In a still further preferred embodiment of the method of the present invention, three induction doses of mirikizumab are administered at about 4 week intervals and the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

In a further aspect of the present invention there is provided mirikizumab for use in the treatment of CD, said treatment comprising:

a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises about 200 mg to about 1200 mg of mirikizumab; and

b) administering at least one maintenance dose of mirikizumab to the patient after the last induction dose is administered, wherein the maintenance dose comprises about 100 mg to about 600 mg of mirikizumab.

In an embodiment of the present invention, the CD is moderate to severe CD.

In a further embodiment of the present invention, the patient is conventional-failed.

In an alternative embodiment of the present invention, the patient is biologic-experienced.

In a further alternative embodiment of the present invention, the patient is biologic-failed.

In a still further embodiment 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.

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

In a still further embodiment of the present invention, one, two, three or four induction doses are administered to the patient.

In a further preferred embodiment of the present invention, three induction doses are administered to the patient at about 4-week intervals.

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

In a still embodiment of the present invention, if the patient has not achieved endoscopic response about 4 to about 12 weeks after the last induction dose is administered, at least one extended induction dose(s) of mirikizumab is administered to the patient, wherein the at least one maintenance dose(s) of mirikizumab is administered to the patient if the patient has achieved endoscopic response about 4 to about 12 weeks after the last extended induction dose is administered, and wherein endoscopic response is defined as a 50% reduction from baseline in SES-CD Score.

In a still further preferred embodiment of the present invention, the at least one extended induction dose(s) are administered to the patient if the patient has not achieved endoscopic response about 4 weeks after the last induction dose is administered.

In a still further embodiment of the present invention, multiple extended induction doses are administered at about 4 week intervals.

In a still further preferred embodiment of the present invention, three extended induction doses are administered at about 4 week intervals.

In a still further embodiment of the present invention, the extended induction dose(s) comprise 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.

Preferably, the extended induction dose(s) comprise about 200 mg, about 600 mg, about 900 mg or about 1000 mg of mirikizumab.

Further preferably, the extended induction dose(s) comprise(s) about 900 mg of mirikizumab.

In a still further preferred embodiment of the present invention, the one, two or three extended induction dose(s) are administered by intravenous infusion.

In a still further embodiment of the present invention, the 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.

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

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

In a still further embodiment of the present invention, the at least one maintenance dose is administered 2-16 weeks after the last induction dose is administered.

In a still further embodiment of the present invention, the 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.

In a still further preferred embodiment of the present invention, the at least one maintenance dose is administered about 4 weeks after the last induction dose is administered.

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

In a still further embodiment of the present invention, multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

In a still further embodiment 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.

In a still further preferred embodiment of the present invention, the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

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

In a still further embodiment of the present invention, one or more further maintenance dose(s) are administered at about 4, about 8 or about 12 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the present invention, one or more further maintenance dose(s) are administered at about 4 week interval(s) after

administration of the first maintenance dose.

In an alternative further preferred embodiment of the present invention, one or more further maintenance dose(s) are administered at about 8 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the present invention, the maintenance dose(s) are administered by subcutaneous injection.

In a still further preferred embodiment of the present invention, the treatment comprises:

a) administering three induction doses of mirikizumab to the patient by intravenous injection, wherein each induction dose comprises about 900 mg of mirikizumab; and

b) administering maintenance dose(s) of mirikizumab to the patient by

subcutaneous injection at about 4 week or about 8 week intervals, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered and wherein each maintenance dose comprises 200 mg or 300 mg of mirikizumab,

wherein the CD is moderate to severe CD.

In a still further embodiment of the present invention, the patient is conventional-failed.

In an alternative embodiment of the present invention, the patient is biologic-experienced.

In a further alternative embodiment of the present invention, the patient is biologic-failed.

In a still further preferred embodiment of the present invention, three induction doses of mirikizumab are administered at about 4 week intervals and the first

maintenance dose is administered about 4 weeks after the last induction dose is administered.

In a still further aspect of the present invention there is provided use of mirikizumab in the manufacture of a medicament for use in the treatment of CD, said treatment comprising:

a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises about 200 mg to about 1200 mg of mirikizumab; and

b) administering at least one maintenance dose of mirikizumab to the patient after the last induction dose is administered, wherein the maintenance dose comprises about 100 mg to about 600 mg of mirikizumab.

In an embodiment of the present invention, the CD is moderate to severe CD.

In a further embodiment of the present invention, the patient is conventional-failed.

In an alternative embodiment of the present invention, the patient is biologic-experienced.

In an alternative further embodiment of the present invention, the patient is biologic-failed.

In a still further embodiment 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.

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

In a still further embodiment of the present invention, one, two, three or four induction doses are administered to the patient.

In a further preferred embodiment of the present invention, three induction doses are administered to the patient at about 4-week intervals.

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

In a still embodiment of the present invention, if the patient has not achieved endoscopic response about 4 to about 12 weeks after the last induction dose is

administered, at least one extended induction dose(s) of mirikizumab is administered to the patient, wherein the at least one maintenance dose(s) of mirikizumab is administered to the patient if the patient has achieved endoscopic response about 4 to about 12 weeks after the last extended induction dose is administered, and wherein endoscopic response is defined as a 50% reduction from baseline in SES-CD Score.

In a still further preferred embodiment of the present invention, the at least one extended induction dose(s) are administered to the patient if the patient has not achieved endoscopic response about 4 weeks after the last induction dose is administered.

In a still further embodiment of the present invention, multiple extended induction doses are administered at about 4 week intervals.

In a still further preferred embodiment of the present invention, three extended induction doses are administered at about 4 week intervals.

In a still further embodiment of the present invention, the extended induction dose(s) comprise 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.

Preferably, the extended induction dose(s) comprise about 200 mg, about 600 mg, about 900 mg or about 1000 mg of mirikizumab.

Further preferably, the extended induction dose(s) comprise(s) about 900 mg of mirikizumab.

In a still further preferred embodiment of the present invention, the one, two or three extended induction dose(s) are administered by intravenous infusion.

In a still further embodiment of the present invention, the 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.

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

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

In a still further embodiment of the present invention, the at least one maintenance dose is administered 2-16 weeks after the last induction dose is administered.

In a still further embodiment of the present invention, the 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.

In a still further preferred embodiment of the present invention, the at least one maintenance dose is administered about 4 weeks after the last induction dose is administered.

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

In a still further embodiment of the present invention, multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

In a still further embodiment 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.

In a still further preferred embodiment of the present invention, the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

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

In a still further embodiment of the present invention, one or more further maintenance dose(s) are administered at about 4, about 8 or about 12 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the present invention, one or more further maintenance dose(s) are administered at about 4 week interval(s) after administration of the first maintenance dose.

In an alternative further preferred embodiment of the present invention, one or more further maintenance dose(s) are administered at about 8 week interval(s) after administration of the first maintenance dose.

In a still further preferred embodiment of the present invention, the maintenance dose(s) are administered by subcutaneous injection.

In a still further preferred embodiment of the present invention, the treatment comprises:

a) administering three induction doses of mirikizumab to the patient by

intravenous injection, wherein each induction dose comprises about 900 mg of mirikizumab; and

b) administering maintenance dose(s) of mirikizumab to the patient by

subcutaneous injection at about 4 week or about 8 week intervals, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered and wherein each maintenance dose comprises 200 mg or 300 mg of mirikizumab,

wherein the CD is moderate to severe CD.

In a still further embodiment of the present invention, the patient is conventional-failed.

In an alternative embodiment of the present invention, the patient is biologic-experienced.

In a further alternative embodiment of the present invention, the patient is biologic-failed.

In a still further preferred embodiment of the present invention, three induction doses of mirikizumab are administered at about 4 week intervals and the first

maintenance dose is administered about 4 weeks after the last induction dose is administered.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates the average serum concentrations of mirikizumab during the induction period in the study described in Example 1. Average concentration estimated based on population PK analyses using the individual subject clearance values and the total dose received during the induction period. Subjects with low outlier concentrations are mainly the result of subjects that discontinued from the study and did not receive all the planned mirikizumab administrations.

Figure 2 illustrates the average serum concentrations of mirikizumab during the maintenance period in the study described in Example 1. Average concentration estimated based on population PK analyses using the individual subject clearance values and the dose received during the maintenance period.

Figure 3 depicts population pharmacokinetic model-estimated clearance versus body weight in the study of Example 1.

Figure 4 depicts population pharmacokinetic model-estimated central volume of distribution versus body weight in the study of Example 1.

Figure 5 depicts a visual predictive check of model fit of Week 12 endoscopic response in the study of Example 1.

Figure 6 depicts a visual predictive check of model fit of Week 12 endoscopic remission in the study of Example 1.

Figure 7 illustrates a simulation of endoscopic response and endoscopic remission rates at Week 12 for mirikizumab doses and exposures of interest for the study of Example 2.

DETAILED DESCRIPTION

There are various measurements of CD disease activity level 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).

The SES-CD is an endoscopic scoring system for CD based on 4 endoscopic variables (presence and size of ulcers, proportion of surface covered by ulcers, proportion of surface affected by disease, and presence and severity of stenosis), which are assessed in 5 ileocolonic bowel segments (ileum; right, transverse, and left colon; and rectum). Each of the 4 endoscopic variables is scored from 0 to 3: presence and size of ulcers (none = score 0; diameter 0.1 cm to 0.5 cm = 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 narrowing (none = 0; single, can be passed = 1; multiple, can be passed = 2; cannot be passed = 3). The grand total is obtained as the sum of all endoscopic scores across all bowel segments. Scores range from 0 to 56, with higher scores indicating more severe disease.

The Crohn’s Disease Activity Index (CDAI is an 8-item disease activity measure comprised of a composite of 3 patient-reported and 5 physician-reported/laboratory items (physical signs and a laboratory parameter [hematocrit]). Patient responses are summed over a 7-day period and all items are subsequently weighted, yielding a total score range of 0 to 600 points. See Appendix 10.8 for additional descriptions of Patient Reported Outcomes (PROs)(e.g. CDAI-SF, CDAI-AP, and CDAI-wellbeing).

PROs include the following:

• Bowel Movement Count (BMC)

• Crohn’s Disease Activity Index - Stool Frequency (CDAI-SF)

Note: Bristol Stool Scale is used as a reference to complete CDAI-SF.

• Crohn’s Disease Activity Index - Abdominal Pain (CDAI-AP)

• Crohn’s Disease Activity Index - Well-Being (CDAI-well-being)

• Abdominal Pain NRS

• Urgency NRS

• Patient Global Rating of Severity (PGRS)

• Functional Assessment of Chronic Illness Therapy -Fatigue (FACET - Fatigue)

• Inflammatory Bowel Disease Questionnaire (IBDQ)

As used herein, the term“biologic experienced” refers to patients that have been administered a biologic for example, an anti-TNF-a antibody, for the treatment of CD, in particular, for the treatment of moderate to severe CD. Such patients may or may not have been administered a conventional medicine for the treatment of CD. Conventional medicines for the treatment of CD include aminosali sates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA) and steroids.

As used herein, the term“biologic-failed” refers to patients that have been administered a biologic, for example, an anti-TNF-a antibody, for the treatment of CD, in particular, for the treatment of moderate to severe CD. Such patients may or may not have been administered a conventional medicine for the treatment of CD. Conventional medicines for the treatment of CD include aminosali sates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA) and steroids. Such patients have an inadequate response to, loss of response to, or are intolerant to biologic therapy for CD (such as anti-TNF antibodies). In the context of the terms“biologic-failed”, inadequate response means signs and symptoms of persistently active disease despite induction treatment at the approved induction dosing that was indicated in the product label at the time of use. In the context of the term“biologic-failed”, loss of response is defined as recurrence of signs and symptoms of active disease during approved maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify as having failed or being intolerant to CD biologic therapy). In the context of the term“biologic-failed”, intolerance means a history of infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, or other approved biologies (including but not limited to infusion-related event, demyelination, congestive heart failure, or any other drug-related AE that led to a reduction in dose or discontinuation of the medication).

As used herein, the term“biologic-naive” refers to patients that have not been administered a biologic, for example, an anti-TNF-a antibody, for the treatment of CD, in particular, for the treatment of moderate to severe CD. Such patients may or may not have been administered a conventional medicine for the treatment of CD. Conventional

medicines for the treatment of CD include aminosali sates, 6-mercaptopurine (6-MP) or azathioprine (AZA), corticosteroids, 5-aminosalicylic acid (5-ASA) and steroids.

As used herein, the term“conventional-failed” refers to patients who have an inadequate response to, loss of response to, or are intolerant to at least one of the following medications: 5-aminosalicylic (ASA) compounds; corticosteroids; AZA, 6-MP, or methotrexate (MTX) or CD-specific antibiotics. Conventional-failed patients have neither failed nor demonstrated an intolerance to a biologic medication (anti-TNF antibody or anti-integrin antibody) that is indicated for the treatment of CD.

As used herein,“moderate to severe CD” is defined as a diagnosis of CD for >3 months, have active CD and have a SES-CD score >7 (centrally read) for subjects with ileal colonic or >4 for subjects with isolated ileal disease within 14 days before the first dose of study treatment.

As used herein,“clinical benefit” is defined as having an endoscopic response (50% reduction from baseline in SES-CD score), or 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

As used herein,“endoscopic response” is defined as a 50% reduction from baseline in SES-CD Score.

As used herein,“endoscopic remission SES-CD < 4” is defined as total SES-CD score of < 4 and at least a 2- point reduction versus baseline and no subscore >1

As used herein,“endoscopic remission SES-CD 0-2” is defined as a total SES-CD score of < 2.

As used herein“ clinical remission by PRO” is defined as an unweighted daily average SF < 2.5 or < 3 (number of liquid or very soft stools [as taken from the Crohn’s Disease Activity Index, CDAI], defined using the Bristol Stool Scale Category 6 or 7 [Lewis and Heaton 1997], i.e., liquid or watery stools) and the unweighted daily average AP <1 (AP [4-point scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe]) and both SF and AP no worse than baseline

As used herein,“clinical response by PRO” is defined as at least a 30% decrease in SF and/or AP and no worse than baseline.

As used herein,“clinical remission by CDAI” is defined as a CDAI score <150.

As used herein“clinical response by CDAI” is defined as a reduction in CDAI score by >100 points compared to baseline and/or being in clinical remission by CDAI.

As used herein,“dose” or“dosing” refers to to the administration of a substance (for example, mirikizumab) to achieve a therapeutic objective (for example, the treatment of CD).

As used herein,“induction period” refers to a period of treatment of a patient comprising administration of mirikizumab to the patient in order to induce 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, each of these terms as defined above. There is no minimum or maximum duration of the“induction period” but it is typically about 4, about 8 or about 12 weeks in duration. The end of induction period is typically an end-of-induction assessment occurring about 4 weeks or about 8 weeks after the last induction dose has been administered.

As used herein,“induction dose” refers to a first dose of mirikizumab

administered to a patient in order to induce 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, each of these terms as defined above. The“induction dose” can be a single dose or, alternatively, a set of doses. The“induction dose” is administered during the induction period.

As used herein,“extended induction period” refers to a period of treatment of a patient comprising administration of mirikizumab to the patient that is required in order to induce 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, each of these terms as defined above, because 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, clinical response by CDAI was not achieved during an initial induction period. The “extended induction period” may be about 4, about 8 or about 12 weeks in duration.

As used herein,“extended induction dose” refers to a further induction dose of an mirikizumab administered to a patient in order to induce 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, clinical response by CDAI, each of these terms as defined above, because 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 was not achieved during an initial induction period. The“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 about 4, about 8 or about 12 weeks in duration. The end of extended induction period is typically an end-of-extended induction assessment occurring about 4 or about 8 weeks after the last extended induction dose has been administered. The“extended induction dose” is administered during the extended induction period.

As used herein,“maintenance period” refers to refers to a period of treatment comprising administration of mirikizumab to a patient in order to maintain a desired therapeutic effect, the desired therapeutic effect 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, each of these terms as defined above. The“maintenance period” follows the induction period or extended induction period, and, therefore, is initiated once a desired therapeutic effect -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 - is achieved.

As used herein,“maintenance dose” refers to a subsequent dose of mirikizumab administered to a patient to maintain or continue a desired therapeutic effect, namely, 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, each of these terms as defined above. A“maintenance dose” is administered subsequent to the induction dose. A“maintenance dose” can be a single dose or, alternatively, a set of doses.

As used herein, the terms“treating,”“treat,” or“treatment,” refer to restraining, slowing, lessening, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease, or ameliorating clinical symptoms and/or signs of a condition. Beneficial or desired clinical results include, but are not limited to,

alleviation of symptoms, diminishment of the extent of a disease or disorder, stabilization of a disease or disorder (i.e., where the disease or disorder does not worsen), delay or slowing of the progression of a disease or disorder, amelioration or palliation of the disease or disorder, and remission (whether partial or total) of the disease or disorder, whether detectable or undetectable. Those in need of treatment include those already with the disease.

As used herein“anti-IL-23pl9 antibody” refers to an antibody, or fragment thereof, that binds to the pl9 subunit of human IL-23 but does not bind to the p40 subunit of human IL-23. An anti-IL-23pl9 antibody thus binds to human IL-23 but does not bind to human IL-12.

Mirikizumab, CAS Registry No. 1884201-71-1, is a humanized, IgG4-kappa monoclonal antibody targeting the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 9,023.358.

Mirikizumab, or pharmaceutical compositions comprising the same, may be administered by parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal).

The term "intravenous infusion" refers to introduction of an agent into the vein of an animal or human patient over a period of time greater than approximately 15 minutes, generally between approximately 30 to 90 minutes.

The term "subcutaneous injection" refers to introduction of an agent under the skin of an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching or drawing the skin up and away from underlying tissue may create the pocket.

Pharmaceutical compositions comprising 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.

EXAMPLES

EXAMPLE 1: CLINICAL STUDY

Overview

A Phase 2 study may be conducted to determine whether mirikizumab, is safe and efficacious in subjects with moderate to severe CD. Such a study may evaluate safety and determine the clinical activity defined by improvement in CD activity measures and key patient-reported outcomes (PRO) measures.

Objectives

The primary objective of such a Phase II study would be to demonstrate that treatment with mirikizumab is superior to placebo in inducing endoscopic response at Week 12. Secondary objectives may include the following:

• evaluation of the safety and tolerability of treatment with mirikizumab;

• evaluation of the effect of mirikizumab on the proportion of subjects with

endoscopic response at Week 52;

• evaluation of the efficacy of mirikizumab as superior to placebo in endoscopic remission at Week 12;

• evaluation of the effect of mirikizumab on the proportion of subjects with

endoscopic remission at Week 52,

• evaluation of the effect of mirikizumab as superior to placebo in PRO remission at Week 12;

• evaluation of the effect of mirikizumab on the proportion of subjects with PRO remission at Week 52;

• evaluation 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.

Endpoints may be defined using the SES CD score. Endoscopies may be centrally read. Rates of endoscopic healing may be determined at Weeks 12 and 52. Endpoint definitions are as follows:

• Endoscopic response: >50% reduction from baseline in SES-CD

Total score

• Endoscopic remission SES-CD <4: SES-CD Total Score <4 and at least a 2- point reduction versus baseline and no sub score >1

• Endoscopic remission SES-CD 0-2: SES-CD Total Score <2

• Clinical remission by PRO Unweighted daily average SF <3 (number of liquid or very soft stools [as taken from the Crohn’s Disease Activity Index, CDAI], defined using the Bristol Stool Scale Category 6 or 7 [Lewis and Heaton 1997], i.e., liquid or watery stools) and the unweighted daily average AP <1 (AP [4- point scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe]) and both SF and AP no worse than baseline

• Clinical response by PRO At least a 30% decrease in SF and/or AP and no worse than baseline

• Clinical remission by CDAI CDAI score <150

• Clinical response by CDAI A reduction in CDAI score by >100 points compared to baseline and/or being in clinical remission by CDAI

Methods

This study may be a multi-centre, randomized, parallel-arm, placebo-controlled trial in which about 191 are randomized. Subjects may be stratified to the following categories, and the exact number enrolled in either group will be dependent upon the enrolment rate of each subject population:

i) A minimum of approximately 30% of subjects were naive to biologic CD therapy (including experimental biologic CD therapy); and ii) At least 50% of the subjects were prior biologic CD therapy-experienced (including experience with experimental biologic CD therapy).

The study comprises the following periods:

Screening (Approximately 4 Weeks):

Subjects may be evaluated for study eligibility < 28 days before the baseline visit. Subjects may be eligible for the study only if they meet all of the following criteria within the screening period, which is < 28 days prior to the start of study treatment, unless specifically defined:

Type of Subject and Disease Characteristics

i) Have had a diagnosis of CD for >3 months before baseline

ii) Have active CD as defined as absolute SF >4 (loose and watery stools defined as Bristol Stool Scale Category 6 or 7) and/or AP > 2 at baseline have a SES-CD score >7 (centrally read) for subjects with ileal-colonic or >4 for subjects with isolated ileal disease within 14 days before the first dose of study treatment

Prior IBD Treatment

A) Subjects must have received prior treatment for CD (according to either “a)” or“b)” below or combination of both):

a) history of inadequate response to, or failure to tolerate treatment with aminosalicylsates, 6-mercaptopurine (6-MP) or azathioprine (AZA), oral or IV corticosteroids or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of CD)

OR

b) Have received treatment with >1 biologic agents (such as TNF antagonists, vedolizumab, experimental biologic CD therapeutics) with or without documented history of failure to respond to or tolerate such treatment:

The treatment must have been discontinued according to the following timeline:

• anti-TNF therapy at least 8 weeks before baseline

• vedolizumab treatment at least 12 weeks before baseline

• experimental biologic CD therapy at least 8 weeks before baseline.

B) May be receiving a therapeutic dosage of the following drugs:

a) Oral 5 -aminosalicylic (ASA) compounds: if the prescribed dose has been stable for at least 3 weeks before screening colonoscopy or stopped treatment at least 3 weeks prior to screening

colonoscopy;

b) Oral corticosteroids must be at a prednisone-equivalent dose of <20 mg/day, or < 9 mg/day of budesonide, and have been at a stable dose for at least 3 weeks prior to the screening colonoscopy. If stopping oral corticosteroid treatment prior to baseline, they must be stopped at least 3 weeks prior to screening colonoscopy;

c) AZA, 6-MP, or methotrexate (MTX): if the prescribed dose has been stable for at least about 4 weeks before screening endoscopy. Subjects who have discontinued therapy with AZA, 6-MP, or MTX must have stopped the medication at least about 4 weeks prior to screening endoscopy to be considered eligible for enrolment.

c) CD-specific antibiotics: if the prescribed dose has been stable

about 4 weeks prior to baseline or stopped treatment at least 3 weeks prior to screening endoscopy.

Assignment of treatment groups

Assignment to treatment groups may be determined by a computer-generated random sequence using an interactive web-response system (IWRS). To achieve between-group comparability, subjects are stratified to these arms based upon their prior therapy (below); this stratification is controlled by IWRS.

• A minimum of approximately 30% of subjects may be naive to biologic CD

therapy (including experimental biologic CD therapy).

• At least 50% of the subjects may be prior biologic CD therapy-experienced

(including experience with experimental biologic CD therapy).

• For Period 2, subjects assigned to mirikizumab at baseline may be randomized to either baseline treatment assignment or 300 mg SC mirikizumab Q4W - except for all subjects in the placebo group, and subjects in the mirikizumab treatment groups who have not had any improvement in SES-CD score from baseline at Week 12 (determined by the central reader), who receive 1000 mg intravenous (IV) mirikizumab Q4W. Preferably, all subjects receive IV and SC administration of either mirikizumab or placebo during Period 2 in a double-dummy design.

Period 1 (Weeks 0 to 12):

A 12-week induction dosing period may be designed to evaluate the efficacy and safety of mirikizumab administered intravenously (IV) at Weeks 0, 4, 8. At baseline, subjects may be randomized with a 2: 1 : 1 :2 allocation across the 4 treatment arms and stratified on the basis of previous exposure to biologic therapy for treatment of CD:

Mirikizumab Dose Arm 1 1000 mg IV Mirikizumab Q4W Mirikizumab Dose Arm 2 600 mg IV Mirikizumab Q4W Mirikizumab Dose Arm 3 200 mg IV Mirikizumab Q4W Placebo Placebo administered IV Q4W

Period 1 may be designed to establish the efficacy (endoscopic changes and key PRO) and safety of mirikizumab versus placebo in subjects with moderate to severe Crohn’s disease. Subjects may continue background pharmacotherapies for CD as permitted per protocol; therefore, the selection of placebo as a comparator in this subject population is justified to effectively evaluate the safety and efficacy of mirikizumab.

Period 2 (Weeks 12 to 52):

Period 2 (Weeks 12 to 52) allows for continued evaluation of efficacy and safety with baseline treatment regimens and exploration of SC dosing - except for all subjects in the placebo group and subjects in the mirikizumab treatment groups who have not had any improvement in SES-CD score from baseline at Week 12.

Period 2 subjects may receive both IV and subcutaneously (SC) dosing to maintain blinding from Weeks 12 through 48. Dosing occurred Q4W. Randomization

was stratified based on endoscopic response (i.e., achieving a 50% reduction in SES CD score from baseline).

All subjects who receive placebo in Period 1 should receive IV mirikizumab 1000 mg and SC placebo in Period 2. Patients who receive mirikizumab and who achieved an improvement, defined as any numeric decrease, in their SES CD score from baseline at Week 12 may be randomized to either continue Period 1 IV treatment assignment with SC placebo or IV placebo with SC mirikizumab 300 mg. Subjects who receive mirikizumab and who do not achieve an improvement that is, a score equal to baseline or higher, in their SES CD score should receive IV mirikizumab 1000 mg and SC placebo.

Period 3 (Weeks 52 to 104):

Period 3 is intended to provide extension therapy for subjects considered to be receiving clinical benefit and provides longer term evaluation of safety and durability of clinical benefit.

All subjects having clinical benefit defined as having an endoscopic response (50% reduction from baseline in SES CD score), or a 25% reduction from baseline in SES CD score, combined with a 40% reduction from baseline in SF or AP score could continue on study treatment and proceed to Period 3 and receive 300 mg SC mirikizumab Q4W open label starting at Week 52 through Week 104. Subjects not receiving clinical benefit at Week 52 should discontinue treatment and enter the 16 week Follow Up period.

Alternatively, patients could proceed to Period 3 if judged to have clinical benefit per the judgment of the investigator.

Follow-Up:

At Week 104, subjects stop treatment and ARE followed for safety for an additional 16 weeks.

Statistical Analysis

The primary endpoint is Week 12 endoscopic response rate (defined as a 50% reduction in SES-CD). For endoscopic response, the assumed mirikizumab and placebo rates are 35% and 15%, respectively.

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

A Phase II study essentially as described above in this Example 1 was performed.

Results: Patient Population

Period 1

There were 191 subjects in the intent to treat (ITT) population: 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.

Of the 191 subjects who received at least 1 dose, 176 subjects (92.1%) completed Period 1 while 15 subjects (7.9%) did not complete Period 1. Early discontinuations were balanced across the treatment groups with the exception of 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 rate of discontinuation noted in the 600 mg IV group was reflected in the rates of discontinuation for AE. Of the 15 subjects who discontinued early, 8 (4.2%) discontinued early due to an AE: 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 discontinuations from the study due to an AE are further discussed in Section 1.9 of this appendix. Two subjects in the mirikizumab 1000 mg IV group discontinued early because of subject decision (“withdrawal by subject”).

Period 2

Of the 176 subjects who continued treatment in Period 2, 28 subjects had 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 an AE: 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 for NI group, and 6 subjects in the placebo/1000 mg mirikizumab IV group. Eight subjects discontinued early because of subject decision (“withdrawal by subject”).

Of the 176 subjects who continued treatment in Period 2, 39 subjects had 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 an AE: 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 for NI group, and 7 subjects in the placebo/1000 mg mirikizumab IV group.

Results: Demographics and Disease Characteristics

Demographic Characteristics

Demographic characteristics were balanced between the total mirikizumab group and placebo. Of the 191 randomized subjects, 98 subjects (51.3%) were female. The mean age (±standard deviation) was 38.65 years (± 12.86 years). A total of 159 subjects (83.2%) were white.

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).

Disease Characteristics

Disease characteristics were balanced between the total mirikizumab treatment group and individual dosing groups and placebo. Overall, 62.8% of subjects had been previously exposed to biologic therapies, and this percentage was balanced across the treatment groups. Important baseline disease characteristics, such as disease duration, prior biologic use and disease activity (CDAI, endoscopic score and PROs) were generally balanced across the 4 treatment groups. The percentage of patients with a history of resection in the mirikizumab 200 mg group was lower than the other treatment groups.

Concomitant and Prior Medications for CD at Baseline

The concomitant and prior CD medications at Period 1 baseline are shown in

Table la.

aAlthough prior induction dosing of ustekinumab (UST) use was allowed, no patients had prior UST treatment.

bInadequate response, loss of response, or intolerance to medication.

Table la: Concomitant and prior medications for CD at Period 1 baseline

There were no meaningful differences between the total mirikizumab group or individual dosing groups and placebo with regard to the proportion of subjects receiving corticosteroids or immunosuppressants at baseline.

The concomitant and prior CD medications at Period 2 are shown in Table lb.

aAlthough prior induction dosing of ustekinumab (UST) use was allowed, no patients had prior UST treatment.

blnadequate response, loss of response, or intolerance to medication.

Table lb: Concomitant and prior medications for CD at Period 2

Results: Efficacy

Period 1

The primary endpoint was endoscopic response (defined as a 50% reduction in

SES-CD) at Week 12. The data show increased (or improved) efficacy with increasing mirikizumab dose: 10.9%, 95% Cl (3.3%, 18.6%) of subjects in the placebo group, 25.8%, 95% Cl (10.4%, 41.2%) of subjects in the mirikizumab 200 mg IV, 37.5%, 95% Cl (20.7%, 54.3%) of subjects in the mirikizumab 600 mg IV, and 43.8%, 95% Cl (31.6%, 55.9%) of subjects in the mirikizumab 1000 mg IV) attaining the endpoint of endoscopic response. In a subgroup analysis of bio-experienced subjects, the proportion of subjects with endoscopic response at Week 12, with the 1000 mg dose compared to the 600 mg dose was numerically greater, with 46.2% versus 31.6% responding.

Clinical remission was assessed at Week 12 using a definition based on PRO. Clinical remission by PRO (2.5,1) was defined in this study as SF < 2.5 and AP < 1 and no worse than baseline. 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% Cl [12.5%, 43.7%]) numerically higher than 1000 mg (21.9%, 95% Cl [11.7%, 32.0%]). Using clinical remission by PRO (3,1) defined as SF < 3.0 and AP < 1 and no worse than baseline, the cut-off definition in Example 2, the proportion of subjects with clinical remission was significantly higher for the 600 mg and 1000 mg doses compared with placebo with the remission rate for the 600 mg dose (28.1%, 95% Cl [12.5%, 43.7%]) was the same as the 1000 mg dose (28.1%, 95% Cl [17.1%, 39.1%]).

CLAIMS:

1. A method for treating Crohn’ s Disease (CD) comprising administering

mirikizumab to a patient, said method comprising:

a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises about 200 mg to about 1200 mg of mirikizumab; and

b) administering at least one maintenance dose of mirikizumab to the patient after the last induction dose is administered, wherein the maintenance dose comprises about 100 mg to about 600 mg of mirikizumab.

2. A method according to claim 1, wherein the CD is moderate to severe CD.

3. A method of treating CD according to claim 1 or claim 2, wherein the patient is conventional-failed.

4. A method of treating CD according to claim 1 or claim 2, wherein the patient is biologic-experienced.

5. A method of treating CD according to claim 1 or claim 2, wherein the patient is biologic-failed.

6. A method of treating CD according to any one of claims 1-4, wherein 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.

7. A method of treating CD according to any one of claims 1-6, wherein the at least one induction dose comprises about 900 mg of mirikizumab.

8. A method of treating CD according to any one of claims 1-7, wherein one, two, three or four induction doses are administered to the patient.

9. A method of treating CD according to any one of claims 1-8, wherein three induction doses are administered to the patient at about 4-week intervals.

10. A method of treating CD according to any one of claims 1-9, wherein the at least one induction dose is administered by intravenous infusion.

11. A method of treating CD according to any one of claims 1-10, wherein, if the patient has not achieved endoscopic response about 4 to about 12 weeks after the last induction dose is administered, at least one extended induction dose(s) of mirikizumab is administered to the patient, wherein the at least one maintenance dose(s) of mirikizumab is administered to the patient if the patient has achieved endoscopic response about 4 to about 12 weeks after the last extended induction dose is administered, and wherein endoscopic response is defined as a 50% reduction from baseline in SES-CD Score.

12. A method of treating CD according to claim 11, wherein the at least one extended induction dose(s) are administered to the patient if the patient has not achieved endoscopic response about 4 weeks after the last induction dose is administered.

13. A method of treating CD according to claim 11 or claim 12, wherein multiple extended induction doses are administered at about 4 week intervals.

14. A method of treating CD according to any one of claims 11 to 13, wherein three extended induction doses are administered at about 4 week intervals.

15. A method of treating CD according to any one of claims 11 to 14, wherein the extended induction dose(s) comprise about 200 mg, about 600 mg, about 900 mg or about 1000 mg of mirikizumab.

16. A method of treating CD according to any one of claims 11-15, wherein the

extended induction dose(s) comprise(s) about 900 mg of mirikizumab.

17. A method of treating CD according to any one of claims 11-16, wherein the one, two or three extended induction dose(s) are administered by intravenous infusion.

18. A method of treating CD according to any one of claims 1-17, wherein the 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.

19. A method of treating CD according to any one of claims 1-18, wherein the at least one maintenance dose comprises about 200 mg or about 300 mg of mirikizumab.

20. A method of treating CD according to any one of claims 1-19, wherein the at least one maintenance dose is administered 2-16 weeks after the last induction dose is administered.

21. A method of treating CD according to any one of claims 1-20, wherein the 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.

22. A method of treating CD according to any one of claims 1-21, wherein the at least one maintenance dose is administered about 4 weeks after the last induction dose is administered.

23. A method of treating CD according to any one of claims 1-21, wherein the at least one maintenance dose is administered about 8 weeks after the last induction dose is administered.

24. A method of treating CD according to any one of claims 1-20, wherein multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

25. A method of treating CD according to claim 24, wherein 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.

26. A method of treating CD according to claim 24 or claim 25, wherein the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

27. A method of treating CD according to claim 24 or claim 25, wherein the first maintenance dose is administered about 8 weeks after the last induction dose is administered.

28. A method of treating CD according to any one of claims 24-27, wherein one or more further maintenance dose(s) are administered at about 4, about 8 or about 12 week interval(s) after administration of the first maintenance dose.

29. A method of treating CD according to any one of claims 24-28, wherein one or more further maintenance dose(s) are administered at about 4 week interval(s) after administration of the first maintenance dose.

30. A method of treating CD according to any one of claims 24-28, wherein one or more further maintenance dose(s) are administered at about 8 week interval(s) after administration of the first maintenance dose.

31. A method of treating CD according to any one of claims 1-28, wherein the

maintenance dose(s) are administered by subcutaneous injection.

32. A method of treating CD according to any one of claims 1-5, said method

comprising:

a) administering three induction doses of mirikizumab to the patient by

intravenous injection, wherein each induction dose comprises about 900 mg of mirikizumab; and

b) administering maintenance dose(s) of mirikizumab to the patient by

subcutaneous injection at about 4 week or about 8 week intervals, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered and wherein each maintenance dose comprises about 200 mg or about 300 mg of mirikizumab,

wherein the CD is moderate to severe CD.

33. A method of treating CD according to claim 32, wherein three induction doses of mirikizumab are administered at about 4 week intervals and the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

34. Mirikizumab for use in the treatment of CD, said treatment comprising:

a) administering at least one induction dose of mirikizumab to the patient, wherein the induction dose comprises about 200 mg to about 1200 mg of mirikizumab; and

b) administering at least one maintenance dose of mirikizumab to the patient after the last induction dose is administered, wherein the maintenance dose comprises about 100 mg to about 600 mg of mirikizumab.

35. Mirikizumab for use in the treatment of CD according to claim 34, wherein the CD is moderate to severe CD.

36. Mirikizumab for use in the treatment of CD according to claim 34 or claim 35, wherein the patient is conventional-failed.

37. Mirikizumab for use in the treatment of CD according to claim 34 or claim 35, wherein the patient is biologic-experienced.

38. Mirikizumab for use in the treatment of CD according to claim 34 or claim 35, wherein the patient is biologic-failed.

39. Mirikizumab for use in the treatment of CD according to any one of claims 34-38, wherein 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.

40. Mirikizumab for use in the treatment of CD according to any one of claims 34-39, wherein the at least one induction dose comprises about 900 mg of mirikizumab.

41. Mirikizumab for use in the treatment of CD according to any one of claims 34-40, wherein one, two, three or four induction doses are administered to the patient.

42. Mirikizumab for use in the treatment of CD according to any one of claims 34-41, wherein three induction doses are administered to the patient at about 4-week intervals.

43. Mirikizumab for use in the treatment of CD according to any one of claims 34-42, wherein the at least one induction dose is administered by intravenous infusion.

44. Mirikizumab for use in the treatment of CD according to any one of claims 34-43, wherein, if the patient has not achieved endoscopic response about 4 to about 12 weeks after the last induction dose is administered, at least one extended induction dose(s) of mirikizumab is administered to the patient, wherein the at least one maintenance dose(s) of mirikizumab is administered to the patient if the patient has achieved endoscopic response about 4 to about 12 weeks after the last extended induction dose is administered, and wherein endoscopic response is defined as a 50% reduction from baseline in SES-CD Score.

45. Mirikizumab for use in the treatment of CD according to claim 44, wherein the at least one extended induction dose(s) are administered to the patient if the patient has not achieved endoscopic response about 4 weeks after the last induction dose is administered.

46. Mirikizumab for use in the treatment of CD according to claim 44 or claim 45, wherein multiple extended induction doses are administered at about 4 week intervals.

47. Mirikizumab for use in the treatment of CD according to any one of claims 44 to 46, wherein three extended induction doses are administered at about 4 week intervals.

48. Mirikizumab for use in the treatment of CD according to any one of claims 44 to 47, wherein the extended induction dose(s) comprise about 200 mg, about 600 mg, about 900 mg or about 1000 mg of mirikizumab.

49. Mirikizumab for use in the treatment of CD according to any one of claims 44-48, wherein the extended induction dose(s) comprise(s) about 900 mg of

mirikizumab.

50. Mirikizumab for use in the treatment of CD according to claims 44-49, wherein the one, two or three extended induction dose(s) are administered by intravenous infusion.

51. Mirikizumab for use in the treatment of CD according to any one of claims 34-50, wherein the 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.

52. Mirikizumab for use in the treatment of CD according to any one of claims 34-51, wherein the at least one maintenance dose comprises about 200 mg or about 300 mg of mirikizumab.

53. Mirikizumab for use in the treatment of CD according to any one of claims 34-52, wherein the at least one maintenance dose is administered 2-16 weeks after the last induction dose is administered.

54. Mirikizumab for use in the treatment of CD according to any one of claims 34-53, wherein the 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.

55. Mirikizumab for use in the treatment of CD according to any one of claims 34-54, wherein the at least one maintenance dose is administered about 4 weeks after the last induction dose is administered.

56. Mirikizumab for use in the treatment of CD according to any one of claims 34-54, wherein the at least one maintenance dose is administered about 8 weeks after the last induction dose is administered.

57. Mirikizumab for use in the treatment of CD according to any one of claims 34-52, wherein multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 16 weeks after the last induction dose is administered.

58. Mirikizumab for use in the treatment of CD according to claim 57, wherein 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.

59. Mirikizumab for use in the treatment of CD according to claim 57 or claim 58, wherein the first maintenance dose is administered about 4 weeks after the last induction dose is administered.

60. Mirikizumab for use in the treatment of CD according to claim 57 or claim 58, wherein the first maintenance dose is administered about 8 weeks after the last induction dose is administered.

61. Mirikizumab for use in the treatment of CD according to any one of claims 57-60, wherein one or more further maintenance dose(s) are administered at about 4, about 8 or about 12 week interval(s) after administration of the first maintenance dose.

62. Mirikizumab for use in the treatment of CD according to any one of claims 57-61, wherein one or more further maintenance dose(s) are administered at about 4 week interval(s) after administration of the first maintenance dose.

63. Mirikizumab for use in the treatment of CD according to any one of claims 57-61, wherein one or more further maintenance dose(s) are administered at about 8 week interval(s) after administration of the first maintenance dose.

64. Mirikizumab for use in the treatment of CD according to any one of claims 34-63, wherein the maintenance dose(s) are administered by subcutaneous injection.

65. Mirikizumab for use in the treatment of CD according to any one of claims 34-38, said treatment comprising:

a) administering three induction doses of mirikizumab to the patient by

intravenous injection, wherein each induction dose comprises about 900 mg of mirikizumab; and

b) administering maintenance dose(s) of mirikizumab to the patient by

subcutaneous injection at about 4 week or about 8 week intervals, wherein the first maintenance dose is administered about 4 weeks or about 8 weeks after the last induction dose is administered and wherein each maintenance dose comprises 200 mg or 300 mg of mirikizumab,

wherein the CD is moderate to severe CD.

66. Mirikizumab for use in the treatment of CD according to claim 65, wherein three induction doses of mirikizumab are administered at about 4 week intervals and the first maintenance dose is administered about 4 weeks after the last induction dose is administered.