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The goal of this study is to learn if tilpisertib fosmecarbil (formerly known as GS-5290) is effective and safe in treating participants with moderate to severe ulcerative colitis. The study will compare participants in different treatment groups treated with tilpisertib fosmecarbil with participants treated with placebo.

The primary objective of this study is to demonstrate the efficacy of tilpisertib fosmecarbil, compared to placebo control, in achieving Clinical Response at Week 12.

Key Inclusion Criteria:

• Individuals assigned male at birth, or nonpregnant, nonlactating individuals assigned female at birth, 18 to 75 years of age based on the date of the screening visit.

• Ulcerative colitis (UC) of at least 90-day duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 cm from the anal verge. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents prior to the initiation of screening.

• Moderately to severely active UC as determined during screening with a modified Mayo Clinic Score based on the sum of Stool Frequency, Rectal Bleeding, and Endoscopic Finding of 5 to 9 points and an endoscopic subscore of 2 to 3 (determined by central reader).

• Previous treatment history of approved UC therapy with at least one advanced therapy mechanisms of action but failure (ie, loss of response or lack of response) of no more than 3 different advanced therapy mechanisms of action.

• A surveillance colonoscopy for dysplasia is required prior to randomization if indicated by regional guidelines for individuals with UC.

Key Exclusion Criteria:

• Current diagnosis of Crohn's Disease (CD) or diagnosis of indeterminate colitis due to an enteric pathogen, lymphocytic or collagenous colitis.

• Individuals with disease limited to the rectum (ulcerative proctitis) during screening endoscopy.

• Requirement for ongoing therapy with or prior use of any prohibited medications.

• Active clinically significant infection, or any infection requiring hospitalization or treatment with intravenous anti-infectives within 8 weeks.

of randomization; or any infection requiring oral anti-infective therapy within 6 weeks

of randomization.

• History of opportunistic infection.

• Current diagnosis of acute severe colitis, fulminant colitis, or toxic megacolon.

Note: Other protocol-defined Inclusion/Exclusion criteria may apply.