📋 Eligibility rules (as published)
Inclusion Criteria:
* Nonpregnant, nonlactating adults with a diagnosis of UC extending ≥ 15 cm from the anal verge, established at least 3 months prior to Screening by clinical and endoscopic evidence of UC (colonoscopy or flexible sigmoidoscopy) and confirmed by histology.
* Moderately to severely active UC, defined as an mMS of 5 to 9, inclusive, with MES of at least 2 and RB subscore of at least 1.
* At Screening, a colonoscopy will be required if the participant has had extensive colitis or pancolitis of \> 8 years duration or left-sided colitis of \> 12 years duration but has not had a colonoscopy within 1 year of the initial Screening visit. If the participant has had a colonoscopy within 1 year of the initial Screening date, a flexible sigmoidoscopy may be used instead.
* Demonstrated, in the opinion of the investigator, an inadequate response, loss of response, or intolerance/medical contraindication to at least 1 of the following treatments at doses approved for the treatment of UC:
* Oral 5-ASA compounds or sulfasalazine
* Oral corticosteroids (eg, prednisone, budesonide)
* Immunosuppressants (eg, AZA, 6-MP, MTX)
* An approved anti-integrin antibody (eg, vedolizumab)
* An approved anti-IL-12/23 antibody (eg, ustekinumab)
* An approved anti-IL-23 p19 antibody (eg, risankizumab, guselkumab, or mirikizumab)
* An approved S1PR modulator (eg, ozanimod or etrasimod) Note: Participants who have had an inadequate response to more than 1 advanced therapy (eg, anti-integrin, anti-IL 12/23, IL-23 p19 antibody, or S1PR modulator) are not eligible (see Exclusion Criterion #15).
* Participant may be receiving a therapeutic dosage of the following drugs:
* Oral 5-ASA compounds or sulfasalazine, prescribed dose must be stable for at least 2 weeks before Screening endoscopy or stopped at least 2 weeks prior to Screening endoscopy
* Oral corticosteroids - prednisone (max. 20 mg/day) (or equivalent) or budesonide (max. 9 mg/day) and have been at a stable dose for at least 2 weeks prior to Screening endoscopy or stopped at least 2 weeks prior to Screening endoscopy
* Immunosuppressants (AZA, 6-MP, MTX) if the prescribed dose has been stable for at least 8 weeks before Screening endoscopy or stopped at least 8 weeks prior to Screening endoscopy
* POCBP:
1. Is eligible to participate if not pregnant or breastfeeding, and the following conditions apply:
* Of childbearing potential and using an acceptable contraceptive method during treatment with the IMP and for a minimum until 28 days after the last dose of IMP. The investigator should evaluate the potential or contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of IMP. AND
* Must have a negative highly sensitive pregnancy test as required by local regulations within 24 hours before the first dose of IMP,
2. Must agree not to donate eggs (ova, oocytes) for the purpose of assisted reproduction during the study and for a period of 28 days after receiving the last dose of IMP.
* Able to participate fully in all aspects of this clinical trial. Full comprehension of consent language and informed consent must be obtained from the participant, or the participant's legally acceptable representative.
Exclusion Criteria:
* The following complications:
* Acute severe ulcerative colitis, defined by at least 6 bloody diarrhea/day AND any 1 of the following criteria: pulse \> 90 beats/min, temperature \> 37.8°C, hemoglobin \< 105 g/l, erythrocyte sedimentation rate \> 30 mm/h, or C-reactive protein \> 30 mg/l, or in the investigator's opinion, hospitalization for the treatment of UC may be imminent
* Previous extensive colonic resection (subtotal or total colectomy)
* Short bowel syndrome
* Ileostomy, colostomy, ileoanal pouch, fistulae, or known fixed symptomatic stenosis of the intestine
* Toxic megacolon or recent history (within less than 6 months) of toxic megacolon or bowel perforation
* Diagnosis of CD or the presence or history of a fistula consistent with CD, indeterminate colitis, ischemic colitis, NSAID-induced colitis, idiopathic colitis (ie, colitis not consistent with UC), radiation colitis, microscopic colitis, infectious colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption.
* Primary sclerosing cholangitis with uncontrolled liver function
* Malignancies or history of malignancy within 5 years of Screening (including solid tumors and hematological malignancies), except for adequately treated or completely excised nonmetastatic basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.
* History of adenomatous polyps, unless removed.
* History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
* Class III or IV cardiovascular morbidity.
* Clinically significant abnormal vital signs, physical examination, or 12-lead ECG at Screening or Day 1 (prolonged QTc using Fredericia's formula \[\> 460 ms for males and \> 470 ms for females\]), or conditions leading to additional risk for QT prolongation (eg, congenital long-QT syndrome). Participants with electrolyte abnormalities such as hypokalemia and hypomagnesemia that would increase the risk of QT prolongation should be corrected prior to randomization (an ECG may be repeated after electrolyte correction for determining eligibility, if needed).
* History of bleeding disorders (eg, complement disorders, hemophilia, history of uncontrolled bleeding).
* History of any major neurological disorders including stroke, epilepsy, or demyelinating or neurodegenerative disease.
* Increased risk of infectious complications (eg, recent pyogenic infection, any congenital or acquired immunodeficiency \[eg, HIV infection\], or past organ or stem cell transplantation).
* Systemic or opportunistic infections:
* A positive diagnostic TB test at Scree
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