PALI-2108A Trial to Investigate PALI-2108 Versus Placebo in Participants With Moderately to Severely Active Ulcerative Colitis

Key Inclusion Criteria:

• Documented clinical diagnosis of UC for ≥ 3 months prior to Screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence.

• If a histopathology report is not available in the source records, a biopsy for a local histopathology evaluation (to obtain a report) can be obtained during the screening endoscopy procedure.
• Moderately to severely active UC, defined as:

• mMS of 5 to 9 (inclusive), AND
• ES ≥ 2, AND
• RB ≥ 1.
• Participants must satisfy at least one of the criteria listed under item a OR at least one of the criteria listed under item b:

a. History of inadequate response or loss of response, or intolerance to at least one prior UC therapy, defined as: i. Oral prednisone ≥ 40 mg/day (or equivalent) or budesonide ≥ 9 mg/day for ≥ 2 weeks.

ii. Corticosteroid dependence: unable to taper < 10 mg/day prednisone equivalent within 3 months, or relapse within 3 months of discontinuation.

iii. Immunosuppressants: azathioprine ≥ 2 mg/kg/day, 6-mercaptopurine (6-MP) ≥ 1.0 mg/kg/day (or therapeutic 6-thioguanine nucleotide \[6-TGN\] level) for ≥ 12 weeks, or methotrexate ≥ 15 mg/week subcutaneous or intramuscular.

iv. Approved advanced therapies at the approved labelled dose:

1. Anti-tumor necrosis factor (TNF), anti-integrin (vedolizumab), or anti-IL-12/23 for at least 8 weeks; anti-IL 23 for at least 12 weeks.
2. Janus kinase (JAK) inhibitor for at least 8 weeks; sphingosine-1-phosphate receptor (S1PR) modulator for at least 12 weeks.

Note: Demonstration of intolerance requires no minimum dose nor duration of use.

b. Currently receiving one or more of the following treatments: i. Stable oral prednisone at ≤ 20 mg/day (or equivalent) or budesonide ≤ 9 mg for ≥ 2 weeks prior to randomization.

ii. Stable dose of thiopurine (azathioprine or 6-MP) for ≥ 4 weeks prior to randomization, and have started the treatment ≥ 12 weeks prior to randomization.

iii. Stable dose of oral aminosalicylates for ≥ 2 weeks prior to randomization.

Key Exclusion Criteria:• Diagnosis of Crohn's disease or IBD-Unclassified (IBD-U; indeterminate colitis) or a history of ischemic colitis or radiation colitis.

• UC limited to rectum (< 15 cm from anal verge).
• Any prior history of suicidal behavior (actual, interrupted, aborted attempt, or preparatory acts).
• Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation type 4 or 5, or any active suicidal ideation with some intent to act.
• Severe depression at Screening based on a validated scale threshold (e.g., Patient Health Questionnaire-9 \[PHQ-9\] ≥ 20, or PHQ-9 item 9 > 0) at Screening.
• Failure or intolerance of > 3 classes of approved advanced therapies or > 4 approved individual advanced therapies.