The main purpose of the study is to evaluate the effectiveness and safety of LY4268989 when given with mirikizumab compared to mirikizumab alone in adult participants with moderately to severely active ulcerative colitis (UC).

Study participation will last approximately 118 weeks, including 104 weeks of treatment and may include up to 21 visits.

Inclusion Criteria:

• Have had an established diagnosis of UC of ≥3 months in before baseline, which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC
• Have moderately to severely active UC as defined by a mMS of 5 to 9 with an ES ≥2 confirmed by central reader at screening endoscopy and RB ≥1.
• Participants with greater than 8 years of UC symptoms have documented evidence of having had a surveillance colonoscopy within 1 year, or according to local country or regional medical guidelines, to evaluate for polyps, dysplasia, or malignancy, prior to randomization
• Are up-to-date on colorectal cancer surveillance per local society guidelines
• Have an inadequate response to, loss of response to, or intolerance to at least 1 of the medications:
• Conventional-failed participants: Participants who have had an inadequate response to or a loss of response to or are intolerant to at least 1 of the following medications: corticosteroids or immunomodulators (Does not apply to US)

NOTE: After the interim analysis, participants with inadequate response, loss of response, or intolerance to conventional UC therapy without prior exposure to biologics may be enrolled if deemed appropriate (Applies to the US)

• Advanced therapy-failed participants: Participants who have an inadequate response to or a loss of response to, or are intolerant to advanced therapy for UC, defined as:

  • a biologic or biosimilar medication such as anti-tumor necrosis factor (anti-TNF) antibodies or anti-interleukin antibodies (IL-12/23, or IL-23p19), except for

    • mirikizumab.

  • Janus kinase inhibitors (JAK) such as filgotinib, tofacitinib, or upadacitinib

  • sphingosine 1-phosphate receptor 1 inhibitors (S1PR) such as etrasimod or ozanimod

Exclusion Criteria:

• Have a current diagnosis of

  • Crohn's disease
  • Inflammatory Bowel Disease (IBD) unclassified (formerly known as indeterminate colitis), or
  • primary sclerosing cholangitis

• Have had or will need bowel resection or intestinal or intra-abdominal surgery

• Have evidence of toxic megacolon, intra-abdominal abscess, or stricture or stenosis within small bowel or colon that cannot be traversed by a colonoscope or that are symptomatic

• Have any adenomatous polyp occurring in areas of the colon not involved by colitis, that has not been removed

Note: If such an adenomatous polyp has been completely removed and shows only low-grade dysplasia, this criterion would no longer apply

• Have a current or recent acute, active infection

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.