WO2024077113A1

WO2024077113A1 - Methods of treating fatigue in ulcerative colitis

Info

Publication number: WO2024077113A1
Application number: PCT/US2023/076034
Authority: WO
Inventors: Theresa Hunter GIBBLE; Xingyuan Li; Nathan John MORRIS
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2022-10-06
Filing date: 2023-10-05
Publication date: 2024-04-11
Anticipated expiration: 2025-04-06

Abstract

The present invention generally relates to methods of reducing fatigue in a patient having ulcerative colitis with an anti-IL-23p19 antibody, in particular dosage regimens for the treatment of the disease.

Description

METHODS OF TREATING FATIGUE IN ULCERATIVE COLITIS

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “30444 US PR1 Sequence Listing” created 06-0ctober-2022 and is 18 kilobytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.

FIELD

The present invention relates to methods of treating fatigue in patients having ulcerative colitis (UC), with an anti-IL23pl9 antibody. More particularly, the present invention relates to methods of treating fatigue in patients having moderate to severe ulcerative colitis (UC), with an anti-IL23pl9 antibody.

BACKGROUND

Ulcerative colitis (UC) is a chronic relapsing immune-mediated inflammatory bowel disease (IBD) of the colon and rectum. UC is characterized by mucosal inflammation of the colon leading to symptoms of diarrhea, rectal bleeding, and bowel urgency. While patients often experience all of these concurrently, a distinct and highly debilitating symptom that is frequently overlooked is fatigue.

Fatigue in IBD is described as an extreme persistent sense of tiredness, weakness or exhaustion, which can be physical, mental or both and is not easily resolved by sleep or rest. More than 50% of patients with active UC and about 30% to 48% of patients with UC in remission suffer from fatigue. (Jonefjall B, et al., United European Gastroenterol J.

2018;6(l): 148-58). Fatigue significantly impairs quality of life (QoL), impacting for example, physical function, sleep, psychosocial functioning, role functioning, mental health, and general health perceptions. Prevalence of sleep disorders has been reported to be as high as 64% in patients with fatigue in UC. (Chavarria M, et al., Journal of Crohn's and Colitis, 2019, 996- 1002). Although, various factors such as anxiety, depression, presence of extraintestinal manifestations (EIMs), sleep disturbances, treatment with systemic corticosteroids, psychological factors such as emotional stress and anxiety, have been associated with the severity of fatigue in IBD such as UC, the mechanism(s) underlying fatigue have not been fully elucidated. Despite the prevalence of fatigue in UC and its importance to patients with UC, and evident patient impact, due to the underlying complexity of factors contributing to fatigue, treatments are often empirical, and resolution of symptoms is difficult to achieve, and thus fatigue has not been an outcome typically included in clinical trials for UC.

Interleukin-23 (IL-23), a member of the interleukin- 12 (IL-12) family of cytokines, is a heterodimeric protein composed of two subunits: the p40 subunit, which is shared by IL-12, and the pl9 subunit, which is specific to IL-23. IL-23 receptor engagement leads to activation of JAKs (mainly TYK2 and JAK2) and signal transducer and activator of transcription 3 and 4 (STAT3 and STAT4), triggering transcription of downstream target genes. IL-23 promotes the differentiation, maintenance and stabilization of pathogenic T-cell lineages, including populations that simultaneously produce multiple pro-inflammatory cytokines, such as interferon-y, IL- 17 A, IL-17F and IL-22, as well as activation and induction of effector function of colitogenic innate lymphoid cells. Therapeutic blockade of p40 is effective in both UC and Crohn’s Disease (CD), and drugs targeting pl9 are being studied for both UC and CD. The first such biologic was ustekinumab, a monoclonal antibody approved 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. Agents specifically targeting the IL-23 pl9 subunit have demonstrated clinical activity in psoriasis and CD (Kopp T et al.. Nature, Volume 521, No. 7551, pages 222-226, 2015; Sands BE et al., Journal of Crohn's and Colitis, Volume 9, Issue Supplement 1, ppS15-S16, 2015).

There remains a need for anti-IL23pl9 antibodies for the treatment of UC that lead to favourable outcomes for patients, in terms of efficacy, safety, and symptom relief, such as fatigue. Particularly, there remains a need for anti-IL2319 antibodies for the treatment of fatigue in patients having UC.

DETAILED DESCRIPTION

As such, the present invention provides methods of treating fatigue in a patient having UC. The present invention further provides methods of treating fatigue in a patient having UC with an anti-IL23pl9 antibody, wherein the patient has a reduction in fatigue. The present invention further provides methods of treating fatigue in a patient having UC with an anti- IL23pl9 antibody, wherein the patient has an early response to treatment. The present invention further provides methods of treating fatigue in a patient having UC with an anti-IL23pl9 antibody, wherein the patient has an early response to treatment of within 2 weeks of the first treatment dose. The present invention further provides methods, wherein the patient maintains the early response to treatment through week 12, and/ or week 40 of treatment. The present invention further provides methods of treating fatigue in a patient having UC with an anti- IL23pl9 antibody, wherein the patient having reduced fatigue experiences for example one or more of improvement in, anxiety, depression, sleep disturbance, emotional stress, physical function, sleep, quality of life, work productivity, psychosocial functioning, and/ or role functioning.

Accordingly, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of an anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody.

In one embodiment of the method of the present disclosure, the anti-IL-23pl9 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab, or brazikumab.

In one embodiment, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of an anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose is administered. In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose. In other embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS). In such embodiments the response to treatment (reduction in fatigue) is reported as the least square mean (LSM) change from baseline. In embodiments of the present disclosure, baseline refers to the last non-missing assessment recorded on or prior to the date of Visit 1 (Week 0 of therapy) for each patient.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 2 weeks, by about 4, by about 6, by about 8, by about 10, or by about 12 weeks after administration of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, patient has a response to treatment from baseline by about 0.7 by about week 2 after the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 1.15 by about week 4 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.48 by about week 6 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.65 by about week 8 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.79 by about week 10 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.88 by week 12 of the induction dosing.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient response to treatment from baseline is sustained in the maintenance dosing from about week 12 from start of maintenance dosing to about week 40. In some embodiments, the response to treatment from baseline is about 2.5 to about 2.69 during the maintenance dosing. In some embodiments, the response to treatment from baseline is about 2.69 by about week 40 of the maintenance dosing.

In one embodiment of the present disclosure, the UC is moderate to severe ulcerative colitis.

In one embodiment of the present disclosure, the patient has a response to treatment comprising an improvement in quality of life. In further embodiments, the patient has an improvement in the patients social, work, mental, physical, emotional and psychological health, such as for example, anxiety, depression, sleep disturbance, emotional stress, physical function, sleep, work productivity, psychosocial functioning, and/ or role functioning.

In another embodiment, the patient achieves one or more therapeutic effects of clinical response, clinical remission, corticosteroid free remission, endoscopic response, endoscopic remission, histologic response, histologic remission, symptomatic remission, and/ or symptomatic response.

In another embodiment, the patient has a reduction in bowel urgency. In another embodiment, the patient has a reduction in abdominal pain. In a further embodiment, the patient has a reduction in bowel urgency and abdominal pain.

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

In one embodiment, the anti-IL23pl9 antibody is mirikizumab.

In one embodiment, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, one, two, or three extended induction doses of the anti-IL23p!9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered. In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein subsequent maintenance dose(s) of anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is acute fatigue or chronic fatigue. In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS).

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose.

In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose.

In some embodiments, the patient has a response to treatment from baseline after administering of one, two, or three extended induction doses. In some embodiments, the patient has a response to treatment from baseline during the extended induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In one embodiment, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein if the patient develops a loss of response during maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance doses of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti-IL23pl9 antibody, and wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first further maintenance dose.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose and subsequent further maintenance doses of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first further maintenance dose

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS).

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing.

In some embodiments, the patient has a response to treatment from baseline after one, two, or three rescue doses. In some embodiments, the patient response to treatment from baseline after one, two, or three rescue doses is sustained in the maintenance dosing. In some embodiments, the patient response to treatment from baseline after one, two, or three rescue doses is sustained in the maintenance dosing and the further maintenance dosing.

In one embodiment of the present disclosure, the patient has an improvement in quality of life.

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

In one embodiment, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of the anti-IL23pl9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance dose(s) of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti- IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In a further preferred embodiment of the method of the present invention, subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first further maintenance dose.

In an alternative preferred embodiment of the method of the present invention, subsequent maintenance doses of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose and subsequent further maintenance doses of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first further maintenance dose.

In further embodiments the anti-IL23pl9 antibody is mirikizumab.

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.

In some embodiments, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered. In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose. In other embodiments, subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose.

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS).

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 2 weeks, by about 4, by about 6, by about 8, by about 10, or by about 12 weeks after administration of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, patient has a response to treatment from baseline by about 0.7 by about week 2 after the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 1.15 by about week 4 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.48 by about week 6 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.65 by about week 8 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.79 by about week 10 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.88 by week 12 of the induction dosing.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient response to treatment from baseline is sustained in the maintenance dosing from about week 12 to about week 40. In some embodiments, the response to treatment from baseline is about 2.5 to about 2.69 during the maintenance dosing. In some embodiments, the response to treatment from baseline is about 2.69 by about week 40 of the maintenance dosing.

In one embodiment of the present disclosure, the patient has a response to treatment and wherein, the patient has an improvement in quality of life. In further embodiments, the patient has an improvement in the patients social, work, mental, physical, emotional and psychological health, such as for example, anxiety, depression, sleep disturbance, emotional stress, physical function, sleep, work productivity, psychosocial functioning, and/ or role functioning.

In a further embodiment, the patient is biologic-naive. In an alternative embodiment, the patient is biologic-experienced. In a further alternative embodiment, the patient is biologic-failed or conventional-failed. In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered,

In a further preferred embodiment of the method of the present invention, subsequent maintenance doses of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose.

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

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance doses of mirikizumab are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2- 8 weeks after the last rescue dose is administered, wherein each maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment of the method of the present invention, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In a further preferred embodiment of the method of the present invention, subsequent maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first further maintenance dose.

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

In some embodiments, the present disclosure provides a method of treating fatigue in a patient having ulcerative colitis in need thereof, the method comprising, comprising administering mirikizumab to the patient in need thereof, comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance dose(s) of mirikizumab are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, and wherein each maintenance dose and each further maintenance dose is 200 mg of mirikizumab.

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

This embodiment of the method of the present invention comprises administration of one, two or three further induction doses - termed “extended induction dose” to distinguish it from the initial induction dose - if the patient does not achieve therapeutic effect at the end of the initial induction period. The dose and dosing intervals during the extended induction period are typically the same as dose and dosing intervals during the initial induction period but may be changed if the attending health care professional has reason to believe that the patient may benefit from changes such as an increased dose of the anti-IL-23pl9 antibody or more frequent dosing. If the patient achieves therapeutic effect at the end of the extended induction period, at least one maintenance dose of the anti-IL-23pl9 antibody is administered to maintain the therapeutic effect such as clinical remission, endoscopic remission, endoscopic healing, symptomatic remission, and/or symptomatic relief.

The first maintenance dose is administered 4-12 weeks after the last extended induction dose is administered to the patient. The 4-12 week period accommodates variation in the period between the administration of last extended induction dose and the end of extended-induction assessment. The variation may arise from variation in the dosing frequency in the extended induction period. For instance, the dosing frequency in the extended induction period is every 4 weeks and the end-of-extended induction assessment occurs 4 weeks after the last extended induction dose is administered. If the patient has achieved therapeutic effect, the first maintenance dose may be administered at the end-of-induction assessment visit (that is, 4 weeks after administration of the last extended induction dose) or may be administered at a subsequent visit scheduled to occur shortly thereafter. Alternatively, the dosing frequency in the extended induction period is every 8 weeks and the end-of-extended induction assessment occurs 8 weeks after the last extended induction dose is administered. If the patient has achieved therapeutic effect, the first maintenance dose may be administered at the end-of-induction assessment visit (that is, 8 weeks after administration of the last extended induction dose) or may be administered at a subsequent visit scheduled to occur shortly thereafter.

In a still further embodiment of the method of the present invention, the one, two or three extended induction dose(s) are administered to the patient if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered.

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

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: c) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti- IL23pl9 antibody; and d) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody,

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In a further embodiment, the patient is biologic-naive. In an alternative embodiment, the patient is biologic-experienced. In a further alternative embodiment, the patient is biologic-failed or conventional-failed.

In one embodiment, the anti-IL23pl9 antibody is mirikizumab.

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect4 weeks after the last induction dose is administered, one, two, or three extended induction doses of the anti-IL23pl9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered. In some embodiments, subsequent maintenance dose(s) of anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose.

In some embodiments, the fatigue is acute fatigue or chronic fatigue. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS).

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose.

In some embodiments, the patient has a response to treatment from baseline after administering of one, two, or three extended induction doses. In some embodiments, the patient has a response to treatment from baseline during the extended induction dosing and wherein the response to treatment is sustained in the maintenance dosing.

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein optionally during the maintenance dosing, three rescue doses of the anti-

IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance doses of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti-IL23pl9 antibody, and wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first further maintenance dose.

In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose and subsequent further maintenance doses of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first further maintenance dose

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In some embodiments, the patient has a response to treatment from baseline after one, two, or three rescue doses. In some embodiments, the patient response to treatment from baseline after one, two, or three rescue doses is sustained in the maintenance dosing. In some embodiments, the patient response to treatment from baseline after one, two, or three rescue doses is sustained in the maintenance dosing and the further maintenance dosing.

In a further embodiment, the patient is biologic-naive. In an alternative embodiment the present invention, the patient is biologic-experienced. In a further alternative embodiment, the patient is biologic-failed or conventional-failed.

In a preferred embodiment, three extended induction doses are administered at 4 week intervals.

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance dose(s) of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti- IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In a further preferred embodiment, subsequent maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first further maintenance dose.

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

In further embodiments the anti-IL23pl9 antibody is mirikizumab.

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab. In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered.

In some embodiments, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered.

In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 0.67 at Week 2 to about 1.88, by week 12 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.88 by week 12 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.79 by about week 10 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.65 by about week 8 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.48 by about week 6 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.15 by about week 4 of the induction dosing. In some embodiments, patient has a response to treatment from baseline by about 0.7 by about week 2 after the first induction dose. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient response to treatment from baseline is sustained in the maintenance dosing from about week 12 to about week 40. In some embodiments, the response to treatment from baseline is about 2.5 to about 2.69 during the maintenance dosing. In some embodiments, the response to treatment from baseline is about 2.69 by about week 40 of the maintenance dosing. In one embodiment of the present disclosure, the UC is moderate to severe ulcerative colitis.

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.

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

In a further preferred embodiment, subsequent maintenance doses of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose.

In an alternative preferred embodiment, subsequent maintenance doses of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose. In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance doses of mirikizumab are administered to the patient if the patient achieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, and wherein each maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

In a further preferred embodiment subsequent maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first further maintenance dose.

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

In one embodiment provided herein, is an anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance dose(s) of mirikizumab are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, and wherein each maintenance dose and each further maintenance dose is 200 mg of mirikizumab.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In another embodiment, the patient achieves one or more therapeutics effects of clinical response, clinical remission, corticosteroid free remission, endoscopic response, endoscopic remission, histologic response, histologic remission, symptomatic remission, and/ or symptomatic response.

In one embodiment, the anti-IL23p!9 antibody is mirikizumab. In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, one, two, or three extended induction doses of the anti-IL23pl9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the patient has a response to treatment from baseline after administering of one, two, or three extended induction doses. In some embodiments, the patient has a response to treatment from baseline during the extended induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein optionally during the maintenance dosing, three rescue doses of the anti- IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance doses of the anti-IL23pl9 antibody are administered to the patient if the patient achieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti-IL23pl9 antibody, and wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In some embodiments, the subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first maintenance dose and subsequent further maintenance doses of the anti-IL23pl9 antibody are administered at 12 week intervals after administration of the first further maintenance dose In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of anti-IL23pl9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance dose(s) of the anti-IL23pl9 antibody are administered to the patient if the patient achieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti- IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

In further embodiments the anti-IL23pl9 antibody is mirikizumab. In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered.

In some embodiments, the fatigue is acute fatigue or chronic fatigue.

In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline after administering of the first induction dose. In such embodiments the response to treatment is reported as the least square mean (LSM) change from baseline. In some embodiments, the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. In some embodiments, the patient has a response to treatment from baseline by about 0.67 at Week 2 to about 1.88, by week 12 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.88 by week 12 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.79 by about week 10 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.65 by about week 8 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about 1.48 by about week 6 of the induction dosing. In some embodiments, the patient has a response to treatment from baseline by about

1.15 by about week 4 of the induction dosing. In some embodiments, patient has a response to treatment from baseline by about 0.7 by about week 2 after the first induction dose. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing. In some embodiments, the fatigue is assessed according to a Numeric Rating Scale (NRS), wherein the patient response to treatment from baseline is sustained in the maintenance dosing from about week 12 to about week 40. In some embodiments, the response to treatment from baseline is about 2.5 to about 2.69 during the maintenance dosing. In some embodiments, the response to treatment from baseline is about 2.69 by about week 40 of the maintenance dosing.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of mirikizumab.

In an alternative preferred embodiment, subsequent maintenance doses of mirikizumab are administered at 12 week intervals after administration of the first maintenance dose.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance period, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance doses of mirikizumab are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2- 8 weeks after the last rescue dose is administered, and wherein each maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered. In a further preferred embodiment subsequent maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first further maintenance dose.

In one embodiment provided herein, is use of an anti-IL-23pl9 antibody in the manufacture of a medicament for use in the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, and, wherein each induction dose and each extended induction dose comprise 300 mg of mirikizumab; and b) administering maintenance doses of mirikizumab to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein optionally during the maintenance dosing, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of mirikizumab, wherein further maintenance dose(s) of mirikizumab are administered to the patient if the patient achieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose(s) is administered 2-8 weeks after the last rescue dose is administered, and wherein each maintenance dose and each further maintenance dose is 200 mg of mirikizumab.

In a preferred embodiment, the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered. In a further preferred embodiment, subsequent maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first maintenance dose and subsequent further maintenance dose(s) of mirikizumab are administered at 4 week intervals after administration of the first further maintenance dose.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A: illustrates the change from baseline in Fatigue NRS during the Induction Period. Figure 2A: illustrates the change from baseline in Fatigue NRS during the Maintenance Period.

UC is a form of colitis, an inflammatory disease of the intestine, usually the colon, which includes characteristic ulcers. Symptoms of active disease usually include diarrhea mixed with blood, usually accompanied with varying degrees of abdominal pain, from mild discomfort to severely painful cramps.

There are a number of methods for assessing the severity of disease, including the Mayo Score, the Modified Mayo Score (MMS) and Ulcerative Colitis Disease Activity Index (UCDAI).

The Mayo score is a composite instrument comprised of the following 4 subscores:

(i) Stool Frequency (SF): The SF subscore is a patient-reported measure. This item reports the number of stools in a 24-hour period, relative to the normal number of stools for that patient in the same period, on a 4-point scale. A stool is defined as a trip to the toilet when the patient has either a bowel movement, or passes blood alone, blood and mucus, or mucus only. The total number of stools passed in a 24- hour period is recorded by the patient. The reference “normal” SF for that patient is typically recorded at the outset of a study or period of observation. Normal SF for that patient is on the reported SF when the patient was in remission or, if the patient has never achieved remission, the reported SF before initial onset of signs and symptoms of UC.

Stool Frequency Sub score Score

Normal number of stools for subject 0

1 to 2 stools more than normal 1

3 to 4 stools more than normal 2 5 or more stools than normal 3

(ii) Rectal Bleeding (RB): The RB subscore is a patient-reported measure. This item reports the most severe amount of blood passed per rectum for a given day, on a 4-point scale.

Rectal Bleeding Subscore Score

No blood seen 0

Streaks of blood with stool less than half of the time 1

Obvious blood (more than just streaks) or streaks of blood with stool most of the time 2

Blood alone passed 3

(iii) Endoscopic Subscore (ES): The ES is a physician-reported measure that reports the worst appearance of the mucosa on flexible sigmoidoscopy or colonoscopy, on a 4-point scale. Consistent with current clinical practice, friability is excluded from the definition of an ES of 1.

Endoscopic Subscore Score

Normal or inactive disease 0

Mild disease (erythema, decreased vascular pattern) 1

Moderate disease (marked erythema, absent vascular pattern, friability, erosions) 2

Severe disease (spontaneous bleeding, ulceration) 3

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

Physician’s Global Assessment Score

Normal 0 Mild disease 1

Moderate disease 2

Severe disease 3 Each subscore is scored on a 4-point scale, ranging from 0 to 3, to give a maximum Mayo score of 12.

The MMS is a modification made to the original Mayo Index reference (Schroeder et al., New Eng J Med, 317(26): 1625-1629, 1987) and includes 3 of the 4 subscores of the Mayo Score. It does not include the Physician’s Global Assessment. The MMS evaluates three subscores, each on a scale of 0 to 3 with a maximum total score of 9. The following table summarizes the respective MMS subscales for scoring.

Table 1: Modified Mayo Score

Patients who have a Mayo Score of 6-12 or a MMS of 4-9, each with an ES of > 2, are defined as having moderate to severely active ulcerative colitis. As used herein, the term “fatigue” is used in relation to a patient having an IBD disease (such as UC or CD) refers to an extreme and persistent sense of tiredness, weakness or exhaustion, which can be physical, mental or both and is not easily resolved by sleep or rest. Fatigue can be attributed to both physical and mental exertion or as the outcome of pathological processes. The International Classification of Diseases code presents fatigue as an assortment of physical, cognitive and emotional symptoms affecting undertaking of daily tasks. In some embodiments the fatigue may be “acute fatigue”. In some embodiments, the fatigue may be “chronic fatigue”.

As used herein the “Numeric Rating Score” or “NRS score” or “NRS fatigue rating score” or “fatigue NRS” used interchangeably herein, refers to a system of measuring fatigue in a patient having ulcerative colitis. The Fatigue NRS is a single item that measures the “worst fatigue (weariness, tiredness) in the past 24 hours” using an 11 -point NRS ranging from 0 (no fatigue) to 10 (fatigue as bad as you can imagine). Patients are provided with an electronic diary tool during screening to record information daily pertaining to their worst fatigue experience. As used herein “baseline” refers to the last non-missing assessment recorded on or prior to the date of Visit 1 (Week 0 of therapy) for each patient. As used herein, “response to treatment” or “reduction in fatigue” used interchangeably herein refers to a measure of the reduction in fatigue NRS from baseline in response to treatment with an anti-IL23pl9 antibody. The response to treatment is reported / presented as the least squares mean (LSM) change from baseline (Week 0 of therapy) using the analysis of covariance (ANCOVA).

As used herein, “quality of life” or “QoL” measures include but are not limited to factors impacting an individual’s social, work, mental, physical, emotional, psychological health, such as for example, anxiety, depression, sleep disturbance, sleep, sleep loss, emotional stress, physical function, activity impairment, work productivity, psychosocial functioning, and/ or role functioning. As used herein, the term, “Work Productivity and Activity Impairment” refers to absenteeism, presenteeism, work productivity loss, and activity impairment (Reilly Associates [WWW]). Scores are calculated as impairment percentages (Reilly et al. 1993), with higher numbers indicating greater impairment and less productivity (Reilly Associates [WWW]), i.e, worse outcomes.

As used herein, “corticosteroid-free remission” at week 40 is defined as clinical remission at Week 40, and symptomatic remission at Week 28, and no corticosteroid use for >12 weeks prior to Week 40. Corticosteroid-free remission without surgery at Week 40 among induction clinical remitters, is defined as, clinical remission at Week 40, and no corticosteroid use for >12 weeks prior to Week 40. Corticosteroid-free remission without surgery at Week 40, is defined as, clinical remission at Week 40, and symptomatic remission at Week 28, and no corticosteroid use for >24 weeks prior to Week 40.

Using the MMS, as used herein, “clinical remission” is defined as a RB subscore of 0, SF subscore of 0 or 1 (with >l-point decrease from baseline), and ES of 0 or 1 (excluding friability).

Using the MMS, as used herein, “clinical response” is defined as achieving a decrease in 9-point MMS subscore of >2 points and > 30-35% from baseline, with either a decrease of RB sub score of >1 or a RB sub score of 0 or 1.

Using the MMS, as used herein, “endoscopic remission” is defined as achieving a Mayo ES of O.

Using the MMS, as used herein, “endoscopic healing” is defined as having achieved a Mayo ES of 0 or 1.

Using the MMS, as used herein “symptomatic remission” is defined as having achieved a SF = 0 or SF = 1 with a >1 -point decrease from baseline, and a RB = 0.

As used herein “symptomatic response” is defined as having achieved at least a 30% decrease from baseline in composite SF and RB. Symptomatic response may further include achieving a reduction in bowel urgency.

Using the MMS, as used herein, “loss of response” is defined as: (a) >2 -point increase from baseline in the combined stool frequency (SF) and rectal bleeding (RB) scores (b) combined SF and RB score of >4, on 2 consecutive visits > 7 days apart with confirmation of negative Clostridium difficile testing and (c) endoscopic subscore (ES) of 2 or 3.

As used herein, “dose” or “dosing” refers to to the administration of a substance (for example, an anti-IL-23pl9 antibody) to achieve a therapeutic objective (for example, the treatment of ulcerative colitis).

As used herein, “induction period” refers to a period of treatment of a patient comprising administration of an anti-IL-23pl9 antibody to the patient in order to induce clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic remission, symptomatic response, histologic remission, reduction in fatigue, and/ or reduction in bowel urgency, each of these terms as defined above. There is no minimum or maximum duration of the “induction period but it is typically 4, 8 or 12 weeks in duration. The end of induction period is typically an end-of- induction assessment occurring 4 or 8 weeks after the last induction dose has been administered.

As used herein, “induction dose” refers to a first dose of an anti-IL-23pl9 antibody administered to a patient in order to induce a desired therapeutic effect, such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response, and/or symptomatic remission, 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 an anti-IL-23pl9 antibody to the patient that is required in order to induce a desired therapeutic effect, such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response, and/or symptomatic remission, each of these terms as defined above, the extended induction dosing is administered because the desired therapeutic effect, such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response and/or symptomatic remission was not achieved during an initial induction period. There is no minimum or maximum duration of the “extended induction period” but it is typically 4, 8 or 12 weeks in duration. The end of extended induction period is typically an end-of-extended induction assessment occurring 4 or 8 weeks after the last extended induction dose has been administered. The “extended induction period” may be 4, 8 or 12 weeks in duration.

As used herein, “extended induction dose” refers to an induction dose of an anti-IL-23pl9 antibody administered to a patient during the extended induction period, in order to induce a desired therapeutic effect, such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response, and/or symptomatic remission, each of these terms as defined above. The extended induction dose is administered because a desired therapeutic effect such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response, and/or symptomatic remission was not achieved during an initial induction period. The “extended induction dose” can be a single dose or, alternatively, a set of doses.

As used herein, “maintenance period” refers to a period of treatment comprising administration of an anti-IL-23pl9 antibody to a patient in order to maintain a desired therapeutic effect, such as clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic remission, and/ or symptomatic response, corticosteroid-free remission, histologic remission, reduction in fatigue, and/ or reduction in bowel urgency, 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 is achieved.

As used herein, “maintenance dose” refers to a dose of an anti-IL-23pl9 antibody administered to a patient after the induction dose or after the extended induction dose to maintain or continue a desired therapeutic effect, namely, clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic response, and/or symptomatic remission, each of these terms as defined above. A “maintenance dose” can be a single dose or, alternatively, a set of doses.

In the context wherein a patient develops a loss of response during the maintenance period, re-achieves a desired therapeutic effect after administration of one or more rescue doses and is restarted on maintenance therapy, the maintenance dose is referred to as “further maintenance dose”. The “maintenance dose” or “further maintenance dose” is administered during the maintenance period of therapy. The further maintenance dose and dosing intervals during the restarted maintenance period are typically the same as dose and dosing intervals during the initial maintenance period but may be changed if the attending health care professional has reason to believe that the patient may benefit from changes such as an increased dose of the anti-IL-23pl9 antibody or more frequent dosing.

As used herein, the term “rescue dose” refers to a dose of an anti-IL-23pl9 antibody administered to a patient that has developed a loss of therapeutic effect or response in order to re- induce/re-achieve the therapeutic effect achieved at the end of an induction period, the therapeutic effect being clinical remission, clinical response, endoscopic remission, endoscopic healing and/or symptomatic remission, each of these terms defined above.

As used herein, the term “rescue period” refers to a period of treatment of a patient comprising administration of an anti-IL-23pl9 antibody to the patient in order to re-induce clinical remission the therapeutic effect achieved at the end of an induction period, the therapeutic effect being clinical response, endoscopic remission, endoscopic healing and/or symptomatic remission, each of these terms as defined above. The “rescue period” may be 4, 8 or 12 weeks in duration.

The rescue dose and dosing intervals during the rescue period are typically the same as dose and dosing intervals during the initial induction period but may be changed if the attending health care professional has reason to believe that the patient may benefit from changes such as an increased dose of the anti-IL-23pl9 antibody or more frequent dosing.

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.

The term “antibody,” as used herein, refers to an immunoglobulin molecule that binds an antigen. Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, bispecific or multispecific antibody, or conjugated antibody. The antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4). An exemplary antibody of the present disclosure is an immunoglobulin G (IgG) type antibody comprised of four polypeptide chains: two heavy chains (HC) and two light chains (LC) that are cross-linked via inter-chain disulfide bonds. The aminoterminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region. The IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specific interactions with the antigen. Assignment of amino acid residues to the CDRs may be done according to the well-known schemes, including those described in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212). Assignment of amino acid residues to the CDRs may be done according to a combination of the schemes described above.

Embodiments of the present disclosure also include antibody fragments or antigenbinding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, scFab, disulfide-linked Fvs (sdFv), a Fd fragment.

As used herein “anti-IL-23pl9 antibody” refers to an antibody 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.

Examples of anti-IL-23pl9 antibodies that may be used in the methods of the present invention include guselkumab, tildrakizumab, risankizumab, mirikizumab and brazikumab.

Guselkumab, CAS Registry No. 1350289-85-8, is a fully human IgGi lambda monoclonal antibody that binds to the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 7,935,344.

Tildrakizumab, CAS Registry No. 1326244-10-3, is a humanized, IgGl kappa monoclonal antibody targeting the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 8,293,883.

Risankizumab, CAS Registry No. 1612838-76-2, is a humanized, IgGl kappa monoclonal antibody targeting the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 8,778,346.

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.

Brazikumab, CAS Registry No. 1610353-18-8, is a humanized, IgG2-lambda monoclonal antibody targeting the pl9 subunit of human IL-23. The antibody and methods of making same are described in US Patent No. 8,722,033.

The anti-IL-23pl9 antibody, 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 an anti-IL-23pl9 antibody 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, 19^th edition (1995), (A. Gennaro el al., Mack Publishing Co.) and comprise an antibody as disclosed herein, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A pharmaceutical composition of the present invention contains an “effective” or “therapeutically effective” amount, as used interchangeably herein, of an antibody of the present invention. An effective amount refers to an amount necessary (at dosages and for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of the antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the antibody of the present invention are outweighed by the therapeutically beneficial effects.

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 UC, in particular, for the treatment of moderate to severe UC. Such patients may or may not have been administered a conventional medicine for the treatment of UC. Conventional medicines for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressive drugs such as azathioprine (AZA) and 6-mercaptopurine (6-MP).

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 UC, in particular, for the treatment of moderate to severe UC. Such patients may or may not have been administered a conventional medicine for the treatment of UC. Conventional medicines for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressive drugs such as azathioprine (AZA) and 6-mercaptopurine (6-MP). Such patients have an inadequate response to, loss of response to, or are intolerant to biologic therapy for UC (such as anti-TNF antibodies or anti-integrin antibodies) or to j anus kinase (JAK) inhibitors (such as tofacitinib). 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 UC biologic therapy). In the context of the term “biologic-failed”, intolerance means a history of intolerance to infliximab, adalimumab, golimumab, vedolizumab, tofacitinib or other approved biologies or JAK inhibitors (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 UC, in particular, for the treatment of moderate to severe UC. Such patients may or may not have been administered a conventional medicine for the treatment of UC. Conventional medicines for the treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressive drugs such as azathioprine (AZA) and 6-mercaptopurine (6-MP).

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:

(i) corticosteroids

Corticosteroid-refractory colitis is defined as signs and/or symptoms of active UC despite oral prednisone (or equivalent) at doses of at least 30 mg/day for a minimum of 2 weeks.

Corticosteroid-dependent colitis, defined as (a) an inability to reduce corticosteroids below the equivalent of prednisone 10 mg/day within 3 months of starting corticosteroids without a return of signs and/or symptoms of active UC and (b) a relapse within 3 months of completing a course of corticosteroids.

A history of intolerance of corticosteroids includes, but is not limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, or neuropsychiatric side-effects, including insomnia, associated with corticosteroid treatment).

(ii) immunomodulators: signs and/or symptoms of persistently active disease despite at least 3 months’ treatment with one of the following:

(a) oral AZA (>1.5 mg/kg/day) or 6-MP (>0.75 mg/kg/day), or

(b) oral AZA or 6-MP within a therapeutic range as judged by thioguanine metabolite testing, or (c) a combination of a thiopurine and allopurinol within a therapeutic range as judged by thioguanine metabolite testing

A history of intolerance to at least one immunomodulator includes but is not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, and lymphopenia)

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 UC.

EXAMPLES

EXAMPLE 1: CLINICAL STUDY

PART A

Overview

This study is a multicenter, randomized, double-blind, parallel-arm, placebo-controlled study designed to evaluate the safety and efficacy of mirikizumab, compared with placebo, over a 12-week induction period. The study population included patients with moderately to severely active UC who had an inadequate response to, loss of response to, or were intolerant to corticosteroid or immunomodulator therapy for UC (termed “conventional-failed” in this study), and those who had an inadequate response to, loss of response to, or were intolerant to biologic therapy for UC (termed “biologic-failed” in this study). Patients who completed Part A through Week 12 were either complete post-treatment follow-up within Part A or were eligible to participate in Part B.

Patients who discontinued treatment prior to the Week 12 assessment, or those who were unable or are not willing to participate in Part B completed post-treatment follow-up 16 weeks after their last visit. The study comprised of a screening period of up to a maximum of 28 days, and a 12-week blinded intravenous therapy period.

Objectives and Endpoints

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

Table 2: Objectives and Endpoints for Part A

a All primary and major secondary endpoints will be evaluated for mirikizumab versus placebo. All primary and major secondary endpoint analyses will utilize the multiplicity control approach based on ‘graphical multiple testing procedure’ to control the overall family -wise type I error rate at a 2- sided alpha level of 0.00125. The graphical multiple testing procedure described in Bretz et al. (2009) will be used. b The order of testing of the major secondary endpoints will be determined from the results of the statistical simulations. Therefore the order of the secondary endpoints does not reflect the order of the statistical testing.

Endpoints were defined using the MMS. Endoscopies were read centrally. Additional analysis were conducted for the objectives in Table 1 at other time periods from Week 0 to Week 12.

Rates of endoscopic healing were also evaluated at Week 2, 4, 6, 8, and Week 12.

Methods

This study comprised a screening period and a 12-week blinded intravenous induction period. a) Screening Period

Patients were evaluated for study eligibility <28 days before the baseline visit. At the baseline visit, patients who fulfilled the eligibility criteria were randomized equally to 1 of 4 induction treatment arms.

Eligible patients were male or female patients aged 18-80 years at the time of initial screening. Patients must have had: i) an established diagnosis of UC of >3 months in duration before baseline (Week 0), which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC; ii) moderately to severely active UC as defined by a modified Mayo score (MMS) of 4 to

9 with an endoscopic subscore (ES) >2, with endoscopy performed within 10 days before baseline; iii) evidence of UC extending proximal to the rectum (distal to the rectosigmoid junction, which lies approximately 10-15 cm from anal margin). iv) documentation of a) a surveillance colonoscopy (performed according to local standard) within 12 months before baseline for: patients with pancolitis of >8 years’ duration, or patients with left-sided colitis of >12 years’ duration, or patients with primary sclerosing cholangitis.

OR b) in patients for whom a) does not apply, up-to-date colorectal cancer surveillance (performed according to local standard). At the discretion of the investigator, a colonoscopy (instead of a flexible sigmoidoscopy) can be performed as the screening endoscopy for this study. Patients who do not have a colonoscopy report available in source documentation will have a colonoscopy at screening.

Patients may have been receiving a therapeutic dosage of the following drugs:

(a) oral 5-ASA compounds: if the prescribed dose has been stable for at least two weeks before baseline;

(b) oral corticosteroid therapy prednisone <20 mg/day or equivalent, or budesonide extended release tablets 9 mg/day [budesonide MMX]); if the prescribed dose has been stable for at least 2 weeks before the screening endoscopy; or

(c) AZA, 6-MP and methotrexate: if these immunomodulators have been prescribed at a stable dose for at least 8 weeks before the screening endoscopy. b) Induction Period

This study involved a comparison of IV administration of mirikizumab versus placebo during a 12-week induction period:

Treatment Group Description

Mirikizumab Dose Arm 1 300 mg given as an intravenous infusion (Weeks 0, 4, 8)

Control Placebo given as an intravenous infusion (Weeks, 0, 4, 8)

IV infusion of mirikizumab or placebo occurred over at least 30 minutes.

The primary endpoint was clinical remission at Week 12 (mirikizumab versus placebo). Clinical remission was based on the MMS.

The MMS and the composite SF and RB score, derived from assessment of the Mayo score were used to determine the major secondary endpoints. Results

Measure of Fatigue NRS. Fatigue was measured using the Fatigue Numeric Rating Scale (NRS), a single-question patient-reported instrument that measures the “worst fatigue in the past 24 hours” with an 11 -point NRS (0=no fatigue, 10=fatigue as bad as you can imagine), on an electronic daily diary. Weekly measures were calculated by averaging data from all available daily eDiary entries of Fatigue NRS scores for a 7-day period in the Induction period. The treatment difference in least squares mean (LSM) change from baseline (WO of therapy) in Fatigue NRS scores was determined using the analysis of covariance model. Treatment difference in Fatigue NRS was assessed using the analysis of covariance (ANCOVA) model adjusting for the stratification factors. Least squares mean (LSM) change from baseline (Week 0 of therapy) was reported. Modified baseline observation carried forward was used to impute missing data.

Reduction in Fatigue NRS in the induction period: The results of the Fatigue NRS Data are presented as LSM change from baseline using ANCOVA with mBOCF (mITT). ANCOVA, analysis of covariance; CI, confidence interval; IV, intravenous; LSM, least squares mean; mBOCF, modified baseline observation carried forward; miri, mirikizumab; mITT, modified intent-to-treat population; N, number of patients in each group; NRS, Numeric Rating Scale; PBO, placebo; SC, subcutaneous.

The results from the Fatigue NRS evaluation are shown in Figure 1 A. The results in Figure 1 A, show that treatment with Mirikizumab had a statistically significant reduction in Fatigue NRS score versus placebo as early as Week 2 (LSM difference [95% CI]: -0.25 [-0.45, -0.05], p=0.013) of induction study. The significant reduction in Fatigue NRS was maintained through Week 12. The LSM difference from baseline at Week 12 was -0.69 (-0.98, -0.40; p<0.001).

PART B

Overview

Part B was a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study evaluating the safety and efficacy of 200 mg mirikizumab Q4W SC in maintaining treatment response at Week 40 (that is, in combination with Part A, 52 weeks of continuous therapy). The study population included patients with moderately to severely active UC who completed Part A. Part A included patients who had an inadequate response to, loss of response to, or were intolerant to conventional (non-biologic) therapy for UC (“conventional-failed”), and those who had an inadequate response to, loss of response to, or were intolerant to biologic therapy for UC (“biologic-failed”).

Patients who achieved clinical response with blinded mirikizumab treatment during Part A are randomized 2: 1 to blinded 200 mg mirikizumab Q4W SC or blinded placebo. Patients who responded to blinded placebo in their induction study remained on blinded placebo in Part B. Open-label rescue therapy with 300 mg mirikizumab Q4W intravenous (IV) were administered for 3 doses if patients lose response.

Patients who did not achieve clinical response with either blinded mirikizumab or blinded placebo during Part A received open-label extended induction therapy with 300 mg mirikizumab Q4W IV administered for 3 doses. Patients who achieved delayed clinical response (defined using induction study baseline) received open-label 200 mg mirikizumab Q4W SC. Extended induction study non-responders who do not achieve clinical response at Week 12 of Part A were discontinued.

Objectives

The primary objective was to test the hypothesis that mirikizumab is superior to placebo in maintaining clinical remission at Week 40 (Week 52 of continuous therapy) among patients induced into clinical response with mirikizumab.

Secondary objectives include the following:

• To evaluate the effect of mirikizumab compared to placebo on change in fatigue during the maintenance phase, week 12 through Week 40.

• To evaluate the efficacy of mirikizumab compared to placebo on bowel movement urgency improvement at Week 40, among patients who: (1) had bowel urgency symptoms at induction baseline and (2) were induced into clinical response with mirikizumab.

• To evaluate the efficacy of mirikizumab compared to placebo on endoscopic remission at Week 40 among patients induced into clinical response with mirikizumab.

• To evaluate the efficacy of mirikizumab compared to placebo in achieving corticosteroid- free remission without surgery among patients induced into clinical response with mirikizumab and receiving corticosteroids at induction baseline.

• To evaluate, in the subgroup of patients in whom biologic agents have failed or caused intolerance, clinical remission at Week 40 among patients induced into clinical response with mirikizumab. • To evaluate, in the subgroup of patients in whom biologic agents have failed or caused intolerance, endoscopic remission at Week 40 among patients induced into clinical response with mirikizumab.

• To evaluate, in the subgroup of patients in whom biologic agents have failed or caused intolerance, clinical remission at Week 40 among patients induced into clinical remission with mirikizumab.

• To evaluate the efficacy of mirikizumab compared to placebo in achieving corticosteroid-free remission without surgery among patients induced into clinical remission with mirikizumab and receiving corticosteroids at induction baseline.

Endpoints are defined using the MMS. Endoscopies were read centrally.

Rates of endoscopic healing were also determined at periods from Week 12 to Week 52.

Additional analysis during the extended the induction period, maintenance period, further maintenance period, and loss or response period may be conducted to determine reduction in fatigue, clinical remission, clinical response, endoscopic remission, endoscopic healing, symptomatic remission, symptomatic response, corticosteroid-free remission, histologic remission, and/ or reduction in bowel urgency.

The endpoint definitions are as follows:

• Change from induction baseline from week 0 to Week 40 in the Fatigue NRS score.

The Fatigue NRS score refers to a system of measuring fatigue in a patient having ulcerative colitis. The Fatigue NRS is a single item that measures the “worst fatigue (weariness, tiredness) in the past 24 hours” using an 11 -point NRS ranging from 0 (no fatigue) to 10 (fatigue as bad as you can imagine). Patients are provided with an electronic diary tool during screening to record information daily pertaining to their worst fatigue experience.

• The proportion of patients with bowel movement urgency improvement at Week 40 as defined in the study SAP.

• Clinical remission: Having achieved the following MMS subscores: a rectal bleeding (RB) subscore of 0, stool frequency (SF) subscore of 0 or 1 (with 1 point decrease from baseline), and endoscopic subscore (ES) of 0 or 1 (excluding friability). • Clinical response: Having achieved a decrease in 9 point Mayo subscore of >2 points and >30% from baseline, with either a decrease of RB subscore of >1 or a RB subscore of 0 or 1.

• Endoscopic remission: Having achieved a Mayo ES of 0.

• Endoscopic healing: Having achieved a Mayo ES of 0 or 1.

• Symptomatic remission: SF= 0, or SF = 1 with a >l-point decrease from baseline, and RB = 0.

• Symptomatic response: at least a 30% decrease from baseline in composite SF and RB.

• Corticosteroid-free remission without surgery is defined as:

Clinical remission; and

- No corticosteroid use for >12 weeks prior to assessment

Methods

Patient Population

Patients with moderately to severely active UC who completed Part A and who meet eligibility requirements were enrolled in this study. The study enrolled patients who achieved clinical response or clinical remission with blinded mirikizumab or placebo dosing in Part A, as well as patients who do not achieve clinical response with blinded mirikizumab or placebo during Part A.

Treatment Assignments

Maintenance study treatment assignment was dependent on whether patients responded to study drug dosing in Part A and whether they experienced a loss of response (LOR) during this study as follows: i) Mirikizumab Responders from Part A

Patients who achieved clinical response with blinded mirikizumab in Part A were randomized to receive blinded 200 mg mirikizumab Q4W SC or blinded placebo SC Q4W (randomized withdrawal) in a 2: 1 ratio. Randomization was stratified to achieve between-group comparability, based on biologic-failed status (yes or no), induction remission status (yes or no), corticosteroid use (yes or no), and region (North America/Europe/Other). Patients continued on the randomized treatment assignment for the remainder of Part B unless they develop secondary LOR.

Loss of Response (LOR) is defined as:

>2-point increase from Part B baseline in the combined SF + RB scores; combined SF + RB score of >4, on 2 consecutive visits (>7 days apart, and with confirmation of negative C. difficile testing); and

Confirmed by centrally read endoscopic subscore (ES) of 2 or 3

SC dosing was continued according to dosing schedule until endoscopy determined whether LOR was confirmed. If LOR was confirmed based on endoscopy at or after Week 12 (and C. difficile stool toxin testing was negative), patients were rescued with open-label 300 mg mirikizumab Q4W IV for 3 doses. The first IV rescue dose may have been administered as soon as LOR was confirmed by centrally read endoscopy, if >7 days from the most recent SC dose. Subsequent doses were given every 4 weeks for total of 3 doses.

If endoscopy did not confirm secondary LOR, patients continued SC study drug dosing, maintaining the scheduled dosing interval. If study drug dosing was continued, an additional endoscopy was performed at Week 40, early termination visit (ETV) or unscheduled visit (UV).

Patients who, in the opinion of the investigator, received clinical benefit after completion of the LOR rescue therapy (12 weeks after first IV rescue dose) were considered for enrollment into the long term extension study Part C to receive further

SC dosing. Once the LOR IV rescue therapy was initiated, no further SC dosing is available in Part B. ii) Placebo Responders from Part A

Patients who achieved clinical response with blinded placebo in Part A continued to receive blinded placebo for the remainder of the maintenance study. Placebo

SC injections were administered Q4W to maintain study blind. If LOR was confirmed based on endoscopy at or after Week 12 (and C. difficile stool toxin testing was negative), patients were rescued with open-label mirikizumab 300 mg Q4W IV for 3 doses. The same LOR assessments and procedures were performed as described for the mirikizumab responders from Part A. iii) Mirikizumab and Placebo Non-responders from Part A

Patients who do not achieve clinical response to blinded mirikizumab or blinded placebo in Part A received open-label extended induction therapy with 300 mg mirikizumab IV at Weeks 0, 4, and 8, and underwent endoscopy at Week 12.

Patients who achieved delayed clinical response (compared to induction study baseline) with extended mirikizumab induction therapy at Week 12 subsequently received open-label 200 mg mirikizumab Q4W SC starting at Week 12. Patients continued on this dose regimen and underwent endoscopy at Week 40.

Patients who, in the opinion of the investigator, received clinical benefit were considered for enrollment into the long term extension study Part C to receive further SC dosing.

Patients who did not achieve clinical response to mirikizumab IV extended induction therapy at Week 12, compared to induction baseline, discontinue study drug and underwent procedures for early termination of the study drug, including post-treatment follow-up. iv) Post-Treatment Follow-up Period

Patients underwent a maximum 16-week post-treatment follow-up period:

- Patients who discontinued study drug with last dose administered IV return for posttreatment follow-up visits at 4 and 16 weeks after the end-of-treatment visit.

- Patients who discontinued study drug with last dose administered SC return for posttreatment follow-up visits at 4 and 12 weeks after the end-of-treatment visit.

- Patients who subsequently entered the long term extension study Part C do not need to complete the post-treatment follow-up period.

Results

Measure of Reduction in Fatigue NRS in the induction period and the maintenance period: Fatigue was measured using the Fatigue Numeric Rating Scale (NRS), a single-question patient- reported instrument that measures the “worst fatigue in the past 24 hours” with an 11 -point NRS (0=no fatigue, 10=fatigue as bad as you can imagine), on an electronic daily diary. For the induction period, weekly measures were calculated by averaging data from all available daily eDiary entries of Fatigue NRS scores for a 7-day period. For the maintenance period, Fatigue NRS score was collected as a single measurement at each visit from Week 4 to Week 36, and then from Week 36 to 40, weekly measures were calculated by averaging data from all available daily eDiary entries of Fatigue NRS scores for a 7-day period. The treatment difference in least squares mean (LSM) change from baseline (WO of therapy) in Fatigue NRS scores was determined using the analysis of covariance model. Treatment difference in Fatigue NRS was assessed using the analysis of covariance (ANCOVA) model adjusting for the stratification factors. Least squares mean (LSM) change from baseline (Week 0 of therapy) was reported. Modified baseline observation carried forward was used to impute missing data. The results from the Fatigue NRS evaluation are shown in Figure 1A and Figure IB. The results in Figure 1 A, show that treatment with Mirikizumab had a statistically significant reduction in Fatigue NRS score versus placebo as early as Week 2 (LSM difference [95% CI]: -0.25 [-0.45, -0.05], p=0.013) of induction study. The significant reduction in Fatigue NRS was maintained through Week 12. The LSM difference from baseline at Week 12 was -0.69 (-0.98, -0.40; p<0.001. The results in Figure IB, show that among patients who responded to mirikizumab induction therapy at Week 12, treatment with mirikizumab demonstrated a statistically significant reduction in Fatigue NRS score compared to placebo from Week 16 (-0.48 [-0.89, -0.07]; p=0.021) and sustained through Week 40 (-1.10 [-1.53, -0.67]; p<0.001).

PART C

Overview

Part C is a single-arm, outpatient, open-label, multicenter, long-term extension study evaluating the efficacy and safety of mirikizumab in patients with moderately to severely active UC who have participated in an originator mirikizumab UC study, including, but not limited to, the study described in Example 1.

Objectives

The primary objective is to evaluate the long-term efficacy of mirikizumab. A secondary objective is to evaluate the effect of long term mirikizumab therapy on histologic remission (mucosal healing).

Methods

Patients from the Example 1 study are eligible for enrollment into Part C.

Patient Population

The Example 1 study is a randomized, double-blind, placebo-controlled study investigating the efficacy and safety of mirikizumab in patients with moderate-to-severe UC. The study consists of a 12-week double-blind induction period followed by either a maintenance period (up to 144 weeks) or an extension period (12 weeks extension induction, up to 132 weeks extension maintenance) for up to 156 weeks total. Study patients eligible for consideration for enrollment into Part C include the following:

• Patients who complete the maintenance period Week 52 endoscopy visit and the assessments at the end of study/early termination visit, or

• Patients who complete the extension period Week 40 endoscopy visit and the assessments at the end of study/early termination visit. At the time of their last Example 1 study visit, a patient may be receiving blinded mirikizumab 200 mg SC Q4W, blinded mirikizumab 200 mg SC Q12W, blinded placebo SC Q4W, or unblinded (open label) mirikizumab 200 mg SC Q4W. Patients receiving blinded placebo SC at the time of their last visit in the Example 1 study will receive mirikizumab for the first time in Part C.

Part B is a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of 200 mg mirikizumab administered SC Q4W in maintaining treatment response at Week 40 (Week 52 of continuous therapy) in patients with moderately to severely active UC who completed 12 weeks of induction treatment.

Part B patients eligible for consideration for enrollment into Part C include the following:

• Patients who complete Week 40 visit on blinded SC mirikizumab or placebo therapy without experiencing loss of response (LOR) during Part B

• Patients who complete Week 40 visit on open-label SC mirikizumab after responding to re-induction with IV mirikizumab

• Patients who complete Part B early termination visit after receiving IV rescue for LOR and who had clinical benefit at the time of their last Part B visit,

A patient may be receiving blinded mirikizumab 200 mg SC Q4W, blinded placebo SC Q4W, open -label (unblinded) mirikizumab 300 mg IV, or open-label mirikizumab 200 mg SC Q4W. Patients receiving blinded placebo SC at the time of their last visit in Part B will be receiving mirikizumab for the first time in Part C.

Study Treatment

Mirikizumab 200 mg are administered subcutaneously every 4 weeks. Patients receive open-label mirikizumab in Part C, regardless of whether they were receiving blinded or unblinded (open-label) mirikizumab or blinded placebo when their participation ended in the originating study. No rescue with mirikizumab is available during Part C.

Endoscopy is performed at Week 52 (Year 1), Week 100 (Year 2), and Week 160 (Year 3) of Part C. The last endoscopy performed in the originator study may be used as baseline for Part C. Patients from Part C who have not had endoscopy performed within 8 months of Week 0 of Part C have an endoscopy performed at Week 0. Patients with pancolitis of >8 years’ duration, left-sided colitis of >12 years’ duration, or primary sclerosing cholangitis require colorectal cancer surveillance colonoscopy for

UC-associated dysplasia and malignancy. Patients with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or with other known risk factors also require colonoscopy for colorectal cancer surveillance.

SEQ ID NO: 1 Mirikizumab HCDR1

GYKFTRYVMH

SEQ ID NO: 2 Mirikizumab HCDR2

YINPYNDGTNYNEKFKG

SEQ ID NO: 3 Mirikizumab HCDR3

ARNWDTGL

SEQ ID NO: 4 Mirikizumab LCDR1

KASDHILKFLT

SEQ ID NO: 5 Mirikizumab LCDR 2

GATSLET

SEQ ID NO: 6 Mirikizumab LCDR3

QMYWSTPFT

SEQ ID NO: 7 Mirikizumab HCVR

QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYND GTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVS S

SEQ ID NO: 8 Mirikizumab LCVR

DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIK

SEQ ID NO: 9 Mirikizumab Heavy Chain

QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPYND GTNYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPS

VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS

TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLG

SEQ ID NO: 10 Mirikizumab Light Chain

DIQMTQSPSSLSASVGDRVTITCKASDHILKFLTWYQQKPGKAPKLLIYGATSLETGVPSR

FSGSGSGTDFTLTISSLQPEDFATYYCQMYWSTPFTFGGGTKVEIKRTVAAPSVFIFPPSDE

QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 11 - Mirikizumab HCVR DNA

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAA

GGTCTCCTGCAAGGCTTCTGGATATAAATTCACTCGTTATGTTATGCACTGGGTGCGA

CAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATATATTAATCCTTACAATGATGGT

ACTAACTACAATGAGAAGTTCAAAGGCAGAGTCACGATTACCGCGGACAAATCCAC

GAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT

ACTGTGCGAGAAACTGGGACACAGGCCTCTGGGGCCAAGGCACCACTGTCACAGTC TCCTCA

SEQ ID NO: 12 - Mirikizumab LCVR DNA

GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC

ACCATCACTTGCAAGGCAAGTGACCACATTCTCAAATTTTTAACTTGGTATCAGCAG

AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCAACCAGTTTGGAAACTGG

GGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAG

CAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAAATGTATTGGAGTACTCC

GTTCACGTTCGGAGGGGGGACCAAGGTGGAAATAAAA

SEQ ID NO: 13 - Mirikizumab HC DNA

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAA

GGTCTCCTGCAAGGCTTCTGGATATAAATTCACTCGTTATGTTATGCACTGGGTGCGA

CAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATATATTAATCCTTACAATGATGGT ACTAACTACAATGAGAAGTTCAAAGGCAGAGTCACGATTACCGCGGACAAATCCAC

GAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT

ACTGTGCGAGAAACTGGGACACAGGCCTCTGGGGCCAAGGCACCACTGTCACAGTC

TCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGC

ACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG

GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT

GTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGC

AGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAA

GGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACC

TGAGGCCGCCGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCT

CATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAG

ACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAG

ACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCAC

CGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACA

AAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA

GAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT

CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGA

AAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG

ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAG

GGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAG

AAGAGCCTCTCCCTGTCTCTGGGT

SEQ ID NO: 14 - Mirikizumab LC DNA

GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTC

ACCATCACTTGCAAGGCAAGTGACCACATTCTCAAATTTTTAACTTGGTATCAGCAG

AAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCAACCAGTTTGGAAACTGG

GGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAG

CAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAAATGTATTGGAGTACTCC

GTTCACGTTCGGAGGGGGGACCAAGGTGGAAATAAAACGAACTGTGGCTGCACCAT

CTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGT

GTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATA

ACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC

AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACA CAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA

GCTTCAACAGGGGAGAGTGC

SEQ ID NO: 15 - hIL23 protein sequence

RAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEGDEETTNDVPHIQCGDGC

DPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSPVGQLHASLLGLSQLLQPE

GHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVFAHGAATLSP

Claims

1. A method of treating fatigue in a patient having ulcerative colitis (UC) in need thereof, the method comprising: a) administering three induction doses of an anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

2. The method of claim 1, wherein the induction doses are administered to the patient at Week 0, Week 4, and Week 8.

3. The method of claim 1 or claim 2, wherein the induction dose is administered over an induction dosing period of 12 weeks.

4. The method of Claims 1-2, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose is administered.

5. The method of Claim 4, wherein the first maintenance dose is administered 4 weeks after the last induction dose is administered.

6. The method of Claims 5, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

7. The method of any one of Claims 1-6, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS).

8. The method of any one of Claims 1-7, wherein the patient has a response to treatment from baseline after administering of the first induction dose.

9. The method of any one of Claims 1-7, wherein the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose.

10. The method of any one of Claims 1-7, wherein patient has a response to treatment from baseline by about week 2, 4, 6, 8, 10, or 12 of administration of the first induction dose.

11. The method of any one of Claims 1-7, wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing.

12. The method of Claims 11, wherein the response to treatment is sustained in the maintenance dosing from about week 12 to about week 40.

13. The method of any one of Claims 1-12, wherein the patient has a response to treatment, and wherein the patient has an improvement in quality of life, anxiety, depression, sleep disturbance, emotional stress, physical function, sleep, quality of life, work productivity, psychosocial functioning, and/ or role functioning.

14. The method of any one of Claims 1-13, wherein the patient achieves one or more therapeutic effects of clinical response, clinical remission, corticosteroid free remission, endoscopic response, endoscopic remission, histologic response, histologic remission, symptomatic remission, and/ or symptomatic response.

15. The method of any one of Claims 1-13, wherein the patient has a reduction in bowel urgency.

16. The method of one of Claims 1-13, wherein the patient has a reduction in bowel urgency and abdominal pain.

17. The method of Claim 1, wherein the method of treating fatigue in a patient having ulcerative colitis in need thereof, comprises: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved a therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of the anti-IL23pl9 antibody are administered by intravenous infusion to the patient to induce the therapeutic effect, and, wherein each induction dose and each extended induction dose is 300 mg of the anti- IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody.

18. The method of Claim 17, wherein the extended induction dose(s) are administered to the patient if the patient has not achieved the therapeutic effect 4-6 weeks after the last induction dose is administered.

19. The method of Claims 17-18, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered.

20. The method of any Claim 19, wherein subsequent maintenance dose(s) of the anti- IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

21. The method of Claim 17, wherein the patient has a response to treatment from baseline after administering of the one, two, or three extended induction doses.

22. The method of Claim 18, wherein the response to treatment from baseline after administering of the one, two, or three extended induction doses is maintained in the maintenance dosing.

23. The method of claim 1, wherein the method of treating fatigue in a patient in need thereof having ulcerative colitis comprises: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered and wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein optionally during maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient by intravenous infusion at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance doses of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti-IL23pl9 antibody, and wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.

24. The method of Claim 23, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose is administered and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

25. The method of any one of Claims 23-24, wherein subsequent maintenance doses and subsequent further maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose or first further maintenance dose.

26. The method of Claim 23, wherein the patient has a response to treatment from baseline after administering of the first induction dose.

27. The method of Claim 23, wherein the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose. The method of Claim 23, wherein the patient has a response to treatment from baseline after one, two, or three rescue doses. The method of Claim 28, wherein the response to treatment from baseline after the one, two, or three rescue doses, is sustained in the further maintenance dosing. The method of claim 1, wherein the method of treating fatigue in a patient in need thereof having ulcerative colitis comprises: a) administering three induction doses of the anti-IL23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved therapeutic effect 4 weeks after the last induction dose is administered, three extended induction doses of the anti-IL23pl9 antibody are administered to the patient, and, wherein each induction dose and each extended induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL23pl9 antibody to the patient by subcutaneous injection at 4 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose or last extended induction dose is administered, wherein optionally during maintenance dosing, three rescue doses of the anti-IL23pl9 antibody are administered to the patient at 4 week intervals, wherein each rescue dose is 300 mg of the anti-IL23pl9 antibody, wherein further maintenance doses of the anti-IL23pl9 antibody are administered to the patient if the patient reachieves therapeutic effect 4 weeks after the last rescue dose is administered, wherein the first further maintenance dose is administered 2-8 weeks after the last rescue dose is administered, wherein each maintenance dose and each further maintenance dose is 200 mg of the anti-IL23pl9 antibody. The method of Claim 30, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose or last extended induction dose is administered and the first further maintenance is administered 4-6 weeks after the last rescue dose is administered. The method of any one of claims 1-31, wherein the fatigue is acute fatigue or chronic fatigue. The method any one of claims 1-31, wherein the patient is biologic-naive. The method of any one of claims 1-31, wherein the patient is biologic-experienced. The method of any one of claims 1-31, wherein the patient is biologic-failed or is conventional-failed. The method of any one of claims 1-32, wherein the anti-IL23pl9 antibody is mirikizumab. An anti-IL-23pl9 antibody for use in the treatment of fatigue in a patient having ulcerative colitis in need thereof, the treatment comprising: a) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8. The antibody for use according to Claim 37, wherein the first maintenance dose is administered 4-6 weeks after the last induction dose is administered. The antibody for use according to any one of Claims 37-38, wherein subsequent maintenance dose(s) of the anti-IL23pl9 antibody are administered at 4 week intervals after administration of the first maintenance dose.

40. The antibody for use according to any one of Claim 37-39, wherein the fatigue is assessed according to a Numeric Rating Scale (NRS).

41. The antibody for use according to any one of Claims 37-40, wherein the patient has a response to treatment from baseline after administering of the first induction dose.

42. The antibody for use according to any one of Claims 37-40, wherein the patient has a response to treatment from baseline for up to about week 12 after administering of the first induction dose.

43. The antibody for use according to any one of Claims 37-40, wherein patient has a response to treatment from baseline by about week 2, 4, 6, 8, 10, or 12 of administration of the first induction dose.

44. The antibody for use according to any one of Claims 37-40, wherein the patient has a response to treatment from baseline during the induction dosing and wherein the response to treatment is sustained in the maintenance dosing.

45. The antibody for use according to any one of Claims 37-40, wherein the patient has a response to treatment from baseline, wherein the response to treatment is sustained in the maintenance dosing from about week 12 to about week 40.

46. The antibody for use according to any one of Claims 1-45, wherein the patient has a response to treatment, and wherein the patient has an improvement in quality of life, anxiety, depression, sleep disturbance, emotional stress, physical function, sleep, quality of life, work productivity, psychosocial functioning, and/ or role functioning.

47. The antibody for use according to any one of Claims 1-46, wherein the patient achieves one or more of clinical response, clinical remission, corticosteroid free remission, endoscopic response, endoscopic remission, histologic response, histologic remission, symptomatic remission, and/ or symptomatic response.

48. The antibody for use according to Claim 47, wherein the patient has a reduction in bowel urgency.

49. The antibody for use according to anyone of Claims 37-48, wherein the fatigue is acute fatigue or chronic fatigue.

50. The antibody for use according to anyone of Claims 37-49, wherein the patient is biologic-naive.

51. The antibody for use according to anyone of Claims 37-49, wherein the patient is biologic-experienced.

52. The antibody for use according to anyone of Claims 37-49, wherein the patient is biologic-failed or is conventional-failed.

53. The antibody for use according to anyone of Claims 37-49, wherein the anti-IL23pl9 antibody is mirikizumab.

54. Use of an anti-IL-23pl9 antibody in the manufacture of a medicament for the treatment of fatigue in a patient having ulcerative colitis, the treatment comprising: a) administering three induction doses of the anti-IL-23pl9 antibody to the patient by intravenous infusion at 4 week intervals, wherein each induction dose is 300 mg of the anti-IL23pl9 antibody; and b) administering maintenance doses of the anti-IL-23pl9 antibody to the patient by subcutaneous injection at 4 week or 12 week intervals, wherein the first maintenance dose is administered 2-8 weeks after the last induction dose is administered, wherein each maintenance dose is 200 mg of the anti-IL23pl9 antibody, wherein the anti-IL23pl9 antibody is an antibody comprising a variable heavy chain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain having the amino acid sequence of SEQ ID NO: 8.