The present invention relates to methods of treating ulcerative colitis. Ulcerative colitis (UC) is a chronic disease of unknown cause that is characterized by inflammation in the colon. Patients have intermittent disease flares interspersed with periods of remission; the primary symptoms are blood in the stool, diarrhea, and abdominal pain, which reduce overall quality of life. Many patients with UC experience a severe clinical course: approximately 30% require colectomy within 10 years of diagnosis (Ordás et al., Lancet, Vol. 380, No. 9853, pp1606-1619, 2012). The treatment goal in UC is the induction and maintenance of remission (including steroid-free remission). Conventional medications used for treatment of UC include 5-aminosalicylic acid (5-ASA), steroids, and immunosuppressive drugs such as azathioprine (AZA) and 6-mercaptopurine (6-MP). However, as many as 40% of patients with UC do not respond or maintain a response to conventional medications and require secondary drug treatment or colectomy (Burger D et al., Gastroenterology, Vol. 140, No. 6, pp1827-1837, 2011). As a result, various biologics that target specific immunological pathways have been studied as potential therapeutics for UC. Anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies and more recently vedolizumab, an integrin receptor antagonist, have been approved by the Food and Drug Administration and by the European Medicines Agency.

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 p19 subunit, which is specific to IL-23. IL-23 is produced by antigen-presenting cells, such as dendritic cells and macrophages and is critically involved in the maintenance and amplification of T helper 17 (Th17) cells. Stimulation of these cells with IL-23 induces a unique inflammatory signature that includes interleukin-17A, interleukin-17F, interleukin-6, granulocyte-macrophage-colony stimulating factor, tumor necrosis factor α, chemokine ligand 20, chemokine ligand 22, and IL-23 receptor. In addition to Th17 cells, many innate immune cells respond to IL-23 and are important both in resistance to infection and in mediating pathology in many autoimmune/inflammatory diseases including UC and Crohn's Disease (CD). Treatment of a number of conditions with IL-23 targeted therapy is being pursued by several companies. The first such biologic to demonstrate clinical benefit in autoimmune disease was ustekinumab, which is a Food and Drug Administration—approved monoclonal antibody for the treatment of psoriasis, psoriatic arthritis and CD. Ustekinumab binds the common p40 subunit of IL-12 and IL-23; therefore, it targets both cytokines, rather than IL-23 specifically. Blockade of the IL-12 pathway may prevent Th1 cell—induced interferon blockade of Th17 cell development, thus potentially limiting the clinical activity of p40 targeting antibodies. Agents specifically targeting the IL-23 p19 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).

The IL-23/Th17 pathway is believed to have a role in UC (El-Bassat H et al, Journal of Molecular Biomarkers & Diagnosis, Vol. 5, No. 5, 100191, 2014). Nevertheless, clinical evaluation of an IL-23 targeted therapy in UC has yet to occur and there remains a need for treatment options for ulcerative colitis that lead to favourable outcomes for patients, for example, in terms of efficacy, safety and/or tolerability of the treatment. In particular, there remains a need for treatment options in the form of dosage regimen that provide optimal efficacy.

Accordingly, in a first aspect of the present invention, there is a provided a method of treating ulcerative colitis (UC) comprising administering to a patient in need thereof an effective amount of an anti-IL-23p19 antibody, said method comprising:

a) administering at least one induction dose of the anti-IL-23p19 antibody to the patient, wherein the induction dose comprises 50 mg to 1200 mg of the antibody; and

b) administering at least one maintenance dose(s) of the anti-IL-23p19 antibody to the patient after the last induction dose is administered, wherein the maintenance dose comprises 150 to 400 mg of the anti-IL-23p19 antibody.

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

There is no minimum or maximum duration of the induction period but it is typically 4, 8 or 12 weeks in duration, with the end of induction period being an end-of-induction assessment typically occurring 4 or 8 weeks after the last induction dose has been administered. For instance, an induction period of 4 weeks may comprise administration of an induction dose at Week 0 and an end-of-induction assessment at Week 4. An induction period of 8 weeks may comprise administration of induction doses at Week 0 and Week 4 and an end-of-induction assessment at Week 8. An induction period of 12 weeks may comprise administration of induction doses at Week 0, Week 4 and Week 8 and an end-of-induction assessment at Week 12.

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

In a further embodiment of the method of the present invention, the patient is biologic-naïve. 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 a still further embodiment of the method of the present invention, the at least one induction dose comprises 200 mg to 1000 mg of the anti-IL-23p19 antibody.

In a still further embodiment of the method of the present invention, the at least one induction dose comprises 200 mg to 600 mg of the anti-IL-23p19 antibody.

In a still further embodiment of the method of the present invention, the at least one induction dose comprises 50 mg, 100 mg, 200 mg, 250 mg, 300 mg or 600 mg of the anti-IL-23p19 antibody.

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

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

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

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

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

In a still further embodiment of the method of the present invention, if the patient has not achieved clinical response 4-12 weeks after the last induction dose is administered, one, two or three extended induction dose(s) of the anti-IL-23p19 antibody are administered to the patient, wherein the at least one maintenance dose(s) of the anti-IL-23p19 antibody is administered to the patient if the patient has achieved clinical response 4-12 weeks after the last extended induction dose is administered, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of >2 points and >30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of >1 or a RB subscore of 0 or 1.

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 clinical response 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-23p19 antibody or more frequent dosing. If the patient achieves clinical response at the end of the extended induction period, at least one maintenance dose of the anti-IL-23p19 antibody is administered to maintain clinical response or other desired therapeutic effect(s) such as clinical remission, endoscopic remission, endoscopic healing and/or symptomatic remission.

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 clinical response, 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 clinical response, 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 clinical response 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 a preferred embodiment of the method of the present invention, three extended induction doses are administered at 4 week intervals. In a still further embodiment of the method of the present invention, one, two or three extended induction dose(s) comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg or 600 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the method of the present invention, the one, two or three extended induction dose(s) comprise 300 mg of the anti-IL-23p19 antibody. In a still further embodiment of the method of the present invention, the one, two or three extended induction dose(s) are administered by intravenous infusion.

In a still further embodiment of the method of the present invention, the at least one maintenance dose comprises 150 mg, 200 mg, 250 mg or 300 mg of the anti-IL-23p19 antibody.

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

In a still further embodiment of the method of the present invention, multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 8 weeks after the last induction dose or last extended induction dose is administered.

Preferably, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or last extended induction dose is administered.

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

Still further preferably, the first maintenance dose is administered 4 weeks after the last induction dose or last extended induction dose is administered.

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

Preferably, subsequent maintenance dose(s) are administered at 4 week interval(s).

Alternatively, preferably subsequent maintenance dose(s) are administered at 8 week interval(s).

Alternatively preferably, subsequent further maintenance dose(s) are administered at 12 week interval(s).

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

In a still further embodiment of the method of the present invention, if the patient develops a loss of response during the maintenance period, one, two or three rescue dose(s) of the anti-IL-23p19 antibody are administered to the patient, wherein one or more further maintenance dose(s) of the anti-IL-23p19 antibody are administered to the patient if the patient achieves clinical response 4-12 weeks after the last rescue dose is administered, wherein 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, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1.

This embodiment of the present invention comprises administration of one, two or three rescue doses of the anti-IL-23p19 antibody if the patient develops a loss of response during the maintenance period. The rescue dose is a dose of an anti-IL-23p19 antibody administered to a patient in order to re-induce/re-achieve the therapeutic effect achieved at the end of the induction period, the therapeutic effect being clinical remission, clinical response, endoscopic remission, endoscopic healing and/or symptomatic remission. The rescue dose and dosing intervals during the rescue dosing 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-23p19 antibody or more frequent dosing.

If the patient achieves clinical response at the end of the rescue dosing period, maintenance therapy is restarted and one or more further maintenance dose(s) of the anti-IL-23p19 antibody is administered to the patient. These maintenance doses are termed “further maintenance dose(s)” to identify them as doses the maintenance doses that are administered when maintenance therapy is restarted. The further maintenance dose is a dose of an anti-IL-23p19 antibody administered to a patient to maintain or continue a clinical response or other desired therapeutic effect(s) such as clinical remission, endoscopic remission, endoscopic healing and/or symptomatic remission that is achieved after administration of rescue dose(s) during the rescue period. The further maintenance dose(s) and dosing intervals during the restarted maintenance therapy are typically the same as maintenance 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-23p19 antibody or more frequent dosing.

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

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

In a still further embodiment of the method of the present invention the one, two or three rescue dose(s) comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg or 600 mg of the anti-IL-23p19 antibody.

Preferably, the one, two or three rescue dose(s) comprise 300 mg of the anti-IL-23p19 antibody.

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

In a still further embodiment of the method of the present invention, the one or more further maintenance dose(s) comprise 150 mg, 200 mg, 250 mg or 300 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the method of the present invention, the one or more further maintenance dose(s) comprise 200 mg of the anti-IL-23p19 antibody. In a still further embodiment of the method of the present invention, multiple further maintenance doses are administered to a patient and wherein the first further maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last rescue dose is administered.

Preferably, the first further maintenance dose is administered 4 weeks after the last rescue dose is administered.

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

Preferably, subsequent further maintenance dose(s) are administered at 4 week interval(s).

Alternatively preferably, subsequent further maintenance dose(s) are administered at 8 week interval(s).

Further alternatively preferably, subsequent further maintenance dose(s) are administered at 12 week interval(s).

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

In a still further embodiment of the method of the present invention, the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab or brazikumab.

In a preferred embodiment of the method of the present invention, the anti-IL-23p19 antibody is mirikizumab. In a still further embodiment of the method of the present invention, the method comprises:

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose comprises 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 comprises 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.

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

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved clinical response 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 comprises 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 a still further embodiment of the method of the present invention, the method comprises:

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose comprises 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 if the patient develops a loss of response during the maintenance period, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose comprises 300 mg of mirikizumab,
  - wherein further maintenance doses of mirikizumab are administered to the patient if the patient achieves clinical response 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 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,
  - wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1; and
  - wherein each maintenance dose comprises 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 a still further embodiment of the method of the present invention, the method comprises:

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved clinical response 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 if the patient develops a loss of response during the maintenance period, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose comprises 300 mg of mirikizumab,
  - wherein further maintenance dose(s) of mirikizumab are administered to the patient if the patient achieves clinical response 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 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,
  - wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1,
  - and wherein each maintenance dose and each further maintenance dose comprises 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 and the first further maintenance dose is administered 4-6 weeks after the last rescue dose is administered.

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.

In a further aspect of the present invention, there is provided an anti-IL-23p19 antibody for use in the treatment of UC, wherein the treatment comprises:

- a) administering at least one induction dose of the anti-IL-23p19 antibody to the patient, wherein the induction dose comprises 50 mg to 1200 mg of the antibody; and
  - b) administering at least one maintenance dose(s) of the anti-IL-23p19 antibody to the patient after the last induction dose is administered, wherein the maintenance dose comprises 150 to 400 mg of the anti-IL-p19 antibody.

In an embodiment of the present invention, the UC is moderate to severe ulcerative colitis.

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

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

In a still further embodiment of the present invention, the at least one induction dose comprises 200 mg to 1000 mg of the anti-IL-23p19 antibody.

In a still further embodiment of the present invention, the at least one induction dose comprises 200 mg to 600 mg of the anti-IL-23p19 antibody.

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

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

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

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

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

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

In a still further embodiment of the present invention, if the patient has not achieved clinical response 4-12 weeks after the last induction dose is administered, one, two or three extended induction dose(s) of the anti-IL-23p19 antibody are administered to the patient, wherein the at least one maintenance dose(s) of the anti-IL-23p19 antibody is administered to the patient if the patient has achieved clinical response 4-12 weeks after the last extended induction dose is administered, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1.

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

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

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

In a still further embodiment of the present invention, one, two or three extended induction dose(s) comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg or 600 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the present invention, the one, two or three extended induction dose(s) comprise 300 mg of the anti-IL-23p19 antibody.

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

In a still further embodiment of the present invention, the at least one maintenance dose comprises 150 mg, 200 mg, 250 mg or 300 mg of the anti-IL-23p19 antibody.

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

In a still further embodiment of the present invention, multiple maintenance doses are administered to a patient and wherein the first maintenance dose is administered 2 to 8 weeks after the last induction dose or last extended induction dose is administered.

Preferably, the first maintenance dose is administered 4 to 6 weeks after the last induction dose or last extended induction dose is administered.

Further preferably, the first maintenance dose is administered 4 weeks after the last induction dose or last extended induction dose is administered.

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

Preferably, subsequent maintenance dose(s) are administered at 4 week interval(s).

Alternatively preferably, subsequent further maintenance dose(s) are administered at 8 week interval(s).

Further alternatively preferably, subsequent maintenance dose(s) are administered at 12 week interval(s).

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

In a still further embodiment of the present invention, if the patient develops a loss of response during the maintenance period, one, two or three rescue dose(s) of the anti-IL-23p19 antibody are administered to the patient, wherein one or more further maintenance dose(s) of the anti-IL-23p19 antibody are administered to the patient if the patient achieves clinical response 4-12 weeks after the last rescue dose is administered, wherein 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, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of >1 or a RB subscore of 0 or 1.

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

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

In a still further embodiment of the present invention, the one, two or three rescue dose(s) comprise 50 mg, 100 mg, 200 mg, 250 mg, 300 mg or 600 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the present invention, the one, two or three rescue dose(s) comprise 300 mg of the anti-IL-23p19 antibody.

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

In a still further embodiment of the present invention, the one or more further maintenance dose(s) comprise 150 mg, 200 mg, 250 mg or 300 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the present invention, the one or more further maintenance dose(s) comprise 200 mg of the anti-IL-23p19 antibody.

In a preferred embodiment of the present invention, multiple further maintenance doses are administered to a patient and wherein the first further maintenance dose is administered 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the last rescue dose is administered.

Preferably, the first further maintenance dose is administered 4 weeks after the last rescue dose is administered.

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

Preferably, the subsequent further maintenance dose(s) are administered at 4 week interval(s).

Alternatively preferably, subsequent further maintenance dose(s) are administered at 8 week interval(s).

Further alternatively preferably, subsequent further maintenance dose(s) are administered at 12 week interval(s).

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

In a still further embodiment of the present invention, the anti-IL-23p19 antibody is mirikizumab, guselkumab, tildrakizumab, risankizumab or brazikumab.

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

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

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose comprises 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 comprises 200 mg of mirikizumab.

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

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

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

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

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved clinical response 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, wherein each induction dose and each extended induction dose comprises 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 comprises 200 mg of mirikizumab.

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

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

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein each induction dose comprises 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 if the patient develops a loss of response during the maintenance period, three rescue doses of mirikizumab are administered to the patient at 4 week intervals,
  - wherein each rescue dose comprises 300 mg of mirikizumab,
  - wherein further maintenance doses of mirikizumab are administered to the patient if the patient achieves clinical response 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 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,
  - wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1,
  - and wherein each maintenance dose and each further maintenance dose comprises 200 mg of mirikizumab.

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

- a) administering three induction doses of mirikizumab to the patient by intravenous infusion at 4 week intervals, wherein, if the patient has not achieved clinical response 4 weeks after the last induction dose is administered, three extended induction doses of mirikizumab are administered to the patient, wherein each induction dose and each extended induction dose comprises 300 mg of mirikizumab,
- wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1, 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 if the patient develops a loss of response during the maintenance period, three rescue doses of mirikizumab are administered to the patient at 4 week intervals, wherein each rescue dose comprises 300 mg of mirikizumab,
  - wherein further maintenance doses of mirikizumab are administered to the patient if the patient achieves clinical response 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 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,
  - wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of ≥2 points and ≥30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of ≥1 or a RB subscore of 0 or 1,
  - and wherein each maintenance dose and each further maintenance dose comprises 200 mg of mirikizumab.

In a preferred embodiment 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 is administered 4-6 weeks after the last rescue dose is administered.

In a further aspect of the present invention, there is provided use of anti-IL-23p19 antibody in the manufacture of a medicament for use in the treatment of UC, wherein the treatment comprises:

- a) administering at least one induction dose of the anti-IL-23p19 antibody to the patient, wherein the induction dose comprises 50 mg to 1200 mg of the antibody; and
- b) administering at least one maintenance dose(s) of the anti-IL-23p19 antibody to the patient after the last induction dose is administered, wherein the maintenance dose comprises 150 to 400 mg of the anti-IL-23p19 antibody.

In an embodiment of the present invention, the UC is moderate to severe ulcerative colitis.

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

In a still further embodiment of the present invention, the at least one induction dose comprises 200 mg to 1000 mg of the anti-IL-23p19 antibody. In a still further embodiment of the present invention, the at least one induction dose comprises 200 mg to 600 mg of the anti-IL-23p19 antibody.

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

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

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

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

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

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

In a still further embodiment of the present invention, if the patient has not achieved clinical response 4-12 weeks after the last induction dose is administered, one, two or three extended induction dose(s) of the anti-IL-23p19 antibody are administered to the patient, wherein the at least one maintenance dose(s) of the anti-IL-23p19 antibody is administered to the patient if the patient has achieved clinical response 4-12 weeks after the last extended induction dose is administered, and wherein clinical response is defined as achieving a decrease in the 9 point Modified Mayo Score (MMS) subscore of >2 points and >30-35% from baseline, with either a decrease of rectal bleeding (RB) subscore of >1 or a RB subscore of 0 or 1.