Inclusion Criteria:

• Participants are assigned male at birth or nonpregnant, nonlactating participants assigned female at birth, 18 to 75 years of age at randomization.
• Participants have UC of at least 90-days duration before randomization confirmed by endoscopy and histology at any time in the past. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents.
• Participants have UC with minimum disease extent of 15 cm from the anal verge.
• Participants have moderately to severely active UC as determined by endoscopy occurring during screening with a total mMCS of 5 to 9 points, including a centrally read endoscopic subscore of at least 2.
• Participants have an inadequate response or loss of response or is intolerant to at least 1 of the following conventional UC treatments:
  • Corticosteroids
    •  Active disease despite a history of at least an induction regimen of a dose equivalence to oral prednisone 30 mg daily for 2 weeks; OR
    • 2 failed attempts to taper corticosteroids below a dose equivalent of 10 mg daily prednisone; OR
    • History of corticosteroids intolerance including, but not limited to, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, serious infections, depressions, allergic reactions, mood disturbances, or any other conditions that contributed to discontinuation of the agent.
  •  Immunomodulators:
    •  Active disease despite a history of at least a 12-week regimen of oral azathioprine (≥ 2 mg/kg/day) or 6-MP (≥ 1 mg/kg/day); OR
    • History of intolerance to azathioprine or 6-MP including, but not limited to, serious infections, hepatotoxicity, cytopenia, pancreatitis, thiopurine methyltransferase (TPMT) genetic mutation (any genotype other than *1/*1), allergic reactions, or another condition to discontinuation of the agent.
  • OR (Participants must meet criteria #5 or #6).
• Participants have an inadequate response or loss of response or are intolerant to 1 to ≤ 2 AT mechanisms of action UC:
  • TNF-α inhibitor (eg, infliximab, adalimumab, golimumab, or biosimilars);
  • IL-12/23 inhibitor (eg, ustekinumab) (Part 1 only: No prior exposure in Part 2);
  • Sphingosine 1-phosphate receptor modulator (eg, ozanimod);
  • Janus kinase inhibitor (eg, tofacitinib, filgotinib, upadacitinib).
• Participants who have a history of UC for 8 or more years must have documentation of a surveillance colonoscopy for screening for dysplasia in the 24 months immediately prior to screening.
• All participants who have a history of UC for < 8 years must be up to date on colon cancer screening prior to randomization per local or national guidelines, as based on age, family history, or increased personal risk of colon cancer.
• Participants may be receiving concomitant therapy for UC at the time of enrollment as specified below, provided the dose prescribed has been stable as indicated prior to screening endoscopy:
  • Participants may be receiving oral 5-aminosalicylate (5-ASA) compounds provided the dose prescribed has been stable for at least 6 weeks immediately prior to screening endoscopy;
  • Participants may be on oral corticosteroids at a dose equivalent of prednisone ≤ 20 mg provided the dose has been stable for 2 weeks immediately prior to screening endoscopy.
• Participants must meet the following TB screening criteria:
  • No evidence of active TB, latent TB, or inadequately treated TB as evidenced by symptom evaluation by the investigator and 1 of the following:
    • A negative QuantiFERON TB-Gold test or equivalent assay reported by the central laboratory at screening or within 90 days prior to randomization for participants rescreening; OR
    • A history of fully treated active or latent TB according to local standard of care. Investigator must verify adequate previous anti-TB treatment and provide documentation; these participants do not require QuantiFERON testing and eligibility must be approved by the sponsor prior to enrollment in the study; AND
    • A chest radiograph (views as per local guidelines with the report or films available for investigator review) taken at screening or within the 4 months prior to randomization without evidence of active or latent TB infection.
• Participants must have laboratory assessments at screening within the following parameters:
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 x upper limit of normal (ULN);
  • Direct bilirubin < 1.5 ´ ULN;
  • Estimated glomerular filtration rate (eGFR) > 60 mL/min (using the applicable Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation as outlined in Section 6.3.10.1);
  • Hemoglobin ≥7.5 g/dL (≥ 75g/L);
  • Absolute neutrophil count ≥ 1.5 ´ 103 /µL (≥ 1.5 GI/L);
  • Platelets ≥ 100 ´ 103 /µL (≥ 100 GI/L);
  • White blood cells ≥ 3 ´ 103/µL (≥ 3 GI/L);
  • Absolute lymphocyte count ≥ 0.75 ´ 103/µL (≥ 0.75 GI/L).
• Participants must have the ability to understand and sign a written informed consent form (ICF). Each participant must sign a separate ICF if he or she agrees to participate in the optional genomic testing. Refusal to give consent for the optional genomic testing does not exclude a participant from participation in the study.
• Participants have a negative urine drug screen result. A positive drug screen will exclude participants unless it can be explained by the use of a medication (prescription or nonprescription) that is being used under the direction of a physician. Cocaine use is exclusionary.
• If assigned female at birth and of childbearing potential, participants must have a negative pregnancy test at screening and agree to use protocol-specified method(s) of pregnancy testing and contraception as described in Appendix 11.5.
• Participants assigned male at birth who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.5. 4.3.

Exclusion Criteria:

• Have a current diagnosis of CD or clinical findings suggestive of CD, diagnosis of indeterminate colitis due to etiologies such as an enteric pathogen, or lymphocytic or collagenous colitis.  
• Have a current diagnosis of toxic megacolon, symptomatic colonic stricture, acute severe colitis, fulminant colitis, or abdominal abscess at screening or randomization.
• Have a history of microscopic colitis, ischemic colitis, radiation colitis, or ileoanal pouch anastomosis.
• Have a history of ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
• Have a history of extensive colonic resection, subtotal or total colectomy or anticipated surgical intervention for UC or another colon disease during the study.
• Part 1 and Part 2: have any history of exposure to vedolizumab.
• Part 2 only: have any history of exposure to interleukin 12/23 or 23 inhibitor (eg ustekinumab.
• Are on antidiarrheal drugs and are not willing to discontinue the medication at least 2 weeks immediately prior to screening endoscopy.
• Have a history or evidence of incompletely resected colonic mucosal dysplasia or presence of adenomatous colon polyps which were not removed completely prior to randomization.
• Have a history of fecal microbiota transplant for UC within 24 weeks prior to screening endoscopy.
• Used IV corticosteroids within 2 weeks prior to screening.
• Used rectal corticosteroids, rectal mesalamine/rectal 5-ASA (enemas or suppositories) within 2 weeks prior to screening endoscopy.
• Planned concurrent treatment with immunomodulatory agents (eg, azathioprine, 6MP) after randomization. Participants receiving azathioprine or 6 MP at screening must discontinue treatment with these agents prior to 2 weeks before screening endoscopy.
• Chronic NSAID use (note: occasional use of NSAIDs for (eg, headache, arthritis, or menstrual cramps) permitted.
• Have a known history of significant gastric malabsorption which would prevent absorption of the study treatment.
• Have any history of stroke, seizure disorder, multiple sclerosis, neurodegenerative diseases of brain (such as Parkinson’s disease, dementias), or brain tumor.
• Have a positive PML symptomatic checklist at screening and at randomization prior to the administration of the first dose of study drug.
• Have evidence of or treatment for Clostridium difficile (C difficile) infection within 60 days prior to randomization, or other intestinal pathogens such as Salmonella, Shigella, Campylobacter jejuni, enterohemorrhagic E. coli or parasitic intestinal infections (such as amebiasis or giardiasis) at screening laboratory examination.  
• Have an active clinically significant extraintestinal infection or any infection requiring hospitalization or treatment with intravenous anti-infective therapy within 8 weeks prior to randomization.
• Have a chronic infection (infections lasting > 3 months) requiring extended therapy: use of any chronic systemic (oral or intravenous) anti-infective therapy including preventive therapy for chronic infections (such as Pneumocystis carinii, cytomegalovirus or herpes zoster) within 6 months prior to screening. (See guidance for anti-infective therapy in Section 5.4.)
• Have a positive HIV antibody test.
• Have a positive HBV surface antigen test. Participants with negative hepatitis B surface antigen (HBsAg) test and positive hepatitis B core antibody (HBcAb) test must have an HBV DNA less than the LLOQ.
• Have a positive HCV antibody test and HCV RNA greater than the LLOQ as described in Section 6.3.10.5.
• Has or has ever had a nontuberculous mycobacterial infection or serious opportunistic infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis).
• Are unable to take oral medication or are dependent on total parenteral nutrition.
• Have current malignancy or a history of malignancy within the past 5 years prior to screening except for adequately treated nonmelanoma skin cancer or cervical carcinoma in situ that has not recurred for at least 1 year prior to randomization.
• Have a history of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.
• Have any progressive chronic medical condition, including, but not limited to, cardiac, pulmonary, renal, hepatic (eg, cirrhosis, primary sclerosing cholangitis), or psychiatric problem (including alcohol or drug abuse) that, in the opinion of the investigator or sponsor, would make the participant unsuitable for the study or would prevent compliance with the study protocol.
• Have a transplanted organ except for a corneal transplant.
• Have had any major surgery or trauma (as determined by the principal investigator) within weeks prior to randomization.
• Are likely to require any type of major surgery during the study.
• Have a history of symptomatic herpes zoster within 16 weeks of randomization or any history of disseminated herpes simplex, disseminated herpes zoster, ophthalmic zoster, or varicella zoster virus central nervous system infections.
• Received a live-attenuated vaccine within 4 weeks of randomization (Section 5.5).
• Are participants assigned female at birth who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the study and up to 14 days (or by the institutional guideline as indicated, whichever is longer) after the last dose of study drug administered during Part 1 of this clinical study, or until 15 weeks after the last administered injection of ustekinumab/ustekinumab PTM or 14 days after the last dose of GS-1427/GS-1427 PTM, whichever date comes later during Part 2 of this clinical study.
• Are participants assigned male at birth who have a female partner of childbearing age and unwilling to refrain from sperm donation for at least 14 days (or by the institutional guideline as indicated, whichever is longer) after last dose of study drug administered during Part 1 of this clinical study or until 15 weeks after the last administered injection of ustekinumab/ustekinumab PTM or 14 days after the last dose of GS-1427/GS-1427 PTM, whichever date comes later during Part 2 of this clinical study.
• Have any known condition or contraindication as addressed in the local labeling for ustekinumab that would preclude the participant from participating in Part 2 of this study.
• Requirement for ongoing therapy with or use of any prohibited medication as specified in the protocol (See Table 4 and Table 5).

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

Eligibility last updated 1/12/24. Questions regarding updates should be directed to the study team contact.