The main purpose of this study is to evaluate the safety and effectiveness of LY4268989 when compared to placebo in adult participants with moderately to severely active ulcerative colitis (UC). The study drug will be administered orally.

The study will last up to approximately 108 weeks, excluding screening.

Inclusion Criteria:

• Have had an established diagnosis of ulcerative colitis (UC) for ≥3 months prior to randomization, which includes endoscopic evidence of UC
• Have moderately to severely active UC defined by a Modified Mayo Score (mMS) of 5 to 9 with an Endoscopic Score (ES)≥2 confirmed by central reader and rectal bleeding (RB)≥1
• Have evidence of UC extending proximal to the rectum
• Have documented evidence of having had a surveillance colonoscopy within 1 year, or according to local guidelines, to evaluate for polyps, dysplasia, or malignancy, prior to randomization, if the participant has a history of UC symptoms for more than 8 years
• Have an inadequate response to, loss of response to, or intolerance to at least one conventional medication (including corticosteroids) or one advanced therapy (including biologics, Janus Kinase (JAK) inhibitors, or sphingosine-1-phosphate (S1P) immunomodulators). Participants with inadequate response to vedolizumab are excluded
• Must meet contraception requirements

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 an inherited immunodeficiency syndrome or known monogenic cause of UC-like colonic inflammation

• 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 prior or current evidence of cancer gastrointestinal (GI) tract, or specified lesions with increased risk of GI malignancies

• Have a diagnosis or history of malignant disease within 5 years prior to randomization

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 or approval of the indication studied in the US and European Union (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.

Non-responders at week 10 will receive Open Label LY4268989 in maintenance study