A Study of LY3471851 in Adult Participants With Moderately to Severely Active Ulcerative Colitis (UC)

The reason for this study is to determine if the study drug LY3471851 is safe and effective in adult participants with active ulcerative colitis (UC). The study treatment will last about 52 weeks.

In stage 1, two doses (high and low) of LY3471851 will be compared to placebo. In stage 2, up to two additional doses (to be confirmed) of LY3471851 will be compared to placebo.

LY3471851 (NKTR-358) is a potential first-in-class therapeutic that may address an underlying immune system imbalance in people with many autoimmune conditions. It targets the interleukin (IL-2) receptor complex in the body in order to stimulate proliferation of inhibitory immune cells known as regulatory T cells. By activating these cells, LY3471851 may act to bring the immune system back into balance.

Eligibility Criteria:
Inclusion Criteria:

* Have moderately to severely active ulcerative colitis (UC) as defined by a modified Mayo score (MMS) of 4 to 9 with an endoscopic subscore (ES) ≥2, with endoscopy performed within 14 days before baseline.
* Have evidence of UC extending proximal to the rectum (with ≥15 centimeters (cm) of involved colon).
* Have up-to-date colorectal cancer surveillance performed according to local standard.
* Participants are either one of the following:
* Have failed conventional treatments including inability to tolerate oral or intravenous corticosteroids or immunomodulators (6-mercaptopurine or azathioprine or methotrexate), or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of UC) and neither failed or demonstrated intolerance to advanced therapy (eg, tumor necrosis factor (TNF) antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase (JAK) inhibitor) OR,
* Have failed advanced therapies such as treatment with 1 or more advance therapies (eg, tumor necrosis factor \[TNF\] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase \[JAK\] inhibitor) at doses approved for the treatment of UC with documented history of failure to respond to or tolerate such treatment.
* Have had an established diagnosis of UC of ≥3 months in duration before baseline which includes endoscopic evidence of UC and a histopathology report that supports a diagnosis of UC. Supportive endoscopy and histopathology reports must be available in the source documents.
* Women of child-bearing potential (WOCBP) must test negative for pregnancy as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to first exposure to study drug.

Exclusion Criteria:

* Have been diagnosed with indeterminant colitis, proctitis (colitis limited to the rectum only; less than 15 centimeter (cm) from the anal verge or Crohn's disease.
* Have received any of the following for treatment of UC: cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 2 weeks of screening, rectally administered corticosteroids or 5-aminosalicylic acid treatments within 2 weeks of screening.
* Have had or will need abdominal surgery for UC (for example, subtotal colectomy).
* Have failed 3 or more classes of advanced therapies approved for treatment of UC (eg, tumor necrosis factor \[TNF\] antagonists, anti-integrin therapies, anti-IL12/23p40 therapies, Janus kinase \[JAK\] inhibitor).
* Have evidence of toxic megacolon, intra-abdominal abscess, or stricture/stenosis within the small bowel or colon.
* Have any history or evidence of cancer of the gastrointestinal tract
* Have myocardial infarction, unstable ischemic heart disease, stroke or heart failure within 12 months prior to screening.