A Phase Ib/IIa Study of INT-210 Capsules in Participants With Active Ulcerative Colitis

A Multicenter, Randomized, Open-label Clinical Study to Evaluate the Safety and Efficacy of INT-210 Capsules in Participants With Active Ulcerative Colitis

A Multicenter, Randomized, Open-label Clinical Study to Evaluate the Safety and Efficacy of INT-210 Capsules in Participants with Active Ulcerative Colitis.

The study aims to evaluate the safety, efficacy, pharmacokinetic (PK) characteristics, pharmacodynamic (PD) characteristics of INT-210 in participants with active ulcerative colitis (UC).

Inclusion Criteria:

1. Voluntarily participate in the study and sign the informed consent form (ICF);

2. Males or females aged ≥18 and ≤75 years at the time of signing the ICF;

3. Diagnosed with UC for ≥3 months at the time of signing the ICF, with the diagnosis of UC supported by clinical manifestations and colonoscopy evidence, and confirmed by a histopathology report (pre-randomization colonoscopy and histopathology examination are acceptable as supporting evidence);

4. Active UC, defined as: a modified Mayo score (including hematochezia, stool frequency, and endoscopy findings) of 4-9, with an endoscopy subscore of ≥2 (confirmed by central reading) and a hematochezia subscore of ≥1 in the Mayo score;

5. At pre-randomization colonoscopy, the extent of UC lesions extends beyond the rectum (active disease ≥15 cm from the anal verge on colonoscopy, confirmed by central reading);

6. Participants must have had an inadequate response or intolerance to at least one of the following UC treatments (inadequate response is defined as that the participant has previously discontinued the corresponding drug due to lack of efficacy as judged by the investigator; intolerance is defined as that the participant has previously discontinued the drug due to adverse reactions as judged by the investigator): oral sulfasalazine (SASP) and/or 5- aminosalicylate (5-ASA); oral corticosteroids; azathioprine or 6- mercaptopurine; marketed anti-tumor necrosis factor-α (TNF-α) agents: infliximab or adalimumab, etc.; vedolizumab; marketed JAK inhibitors: tofacitinib, upadacitinib, etc.; marketed interleukin 12/23 (IL-12/23) inhibitors: ustekinumab, etc.; selective sphingosine-1-phosphate (S1P) receptor modulators: etrasimod, etc.; sulfasalazine (SASP) and/or 5- aminosalicylate (5-ASA); oral corticosteroids; azathioprine or 6- mercaptopurine; marketed anti-tumor necrosis factor-α (TNF-α) agents: infliximab or adalimumab, etc.; vedolizumab; marketed JAK inhibitors: tofacitinib, upadacitinib, etc.; marketed interleukin 12/23 (IL-12/23) inhibitors: ustekinumab, etc.; selective sphingosine-1-phosphate (S1P) receptor modulators: etrasimod, etc.;

7. If participants are currently using the following drugs to treat UC, they must also meet the following requirements:

   • Glucocorticoid therapy: oral prednisone ≤20 mg/d (or equivalent drug dose) or budesonide ≤9 mg/d or beclomethasone ≤5 mg/d, with a stable dose for at least 2 weeks before the screening colonoscopy;
   • Aminosalicylate preparations: oral sulfasalazine and/or 5- aminosalicylate must be stable for at least ≥2 weeks before the screening colonoscopy and must remain stable during the study;

8. Throughout the entire study period from the signing of the ICF and for 3 months after the last dose, female participants of childbearing potential and male participants who have not undergone vasectomy must comply with the specified contraception requirements.

Exclusion Criteria:

1. Pregnant or lactating women, or those planning to become pregnant during the study;

2. Known allergy to any component of INT-210;

3. Based on medical history and endoscopy and/or histological results, participants with suspected or confirmed Crohn's disease, unclassified colitis, acute fulminant colitis, toxic megacolon, intestinal perforation, microscopic colitis, ischemic colitis, or radiation colitis;

4. Participants who have undergone surgery for UC or are planning surgery (including stoma creation, or total or partial proctectomy/colectomy, etc.);

5. Evidence of unresected adenoma or dysplasia in the colon, including lowgrade or high-grade atypical hyperplasia, and unclassified atypical hyperplasia; presence of high-risk progressive adenoma, defined as:

   ① Adenoma diameter ≥10 mm; or ② Villous adenoma or mixed adenoma with villous structure exceeding 25%; or ③ Accompanied by high-grade intraepithelial neoplasia.

6. With primary sclerosing cholangitis;

7. History of alcohol or drug abuse or addiction within one year prior to screening;

8. Have undergone other major surgery within 6 months prior to screening, or are planning surgery during the study; have a history of myocardial infarction, acute stroke or transient ischemic attack, thrombotic events such as deep vein thrombosis or pulmonary embolism, clinically significant arrhythmia or unstable angina pectoris, coronary artery bypass grafting, or severe or pulmonale or pulmonary arterial hypertension that would affect the evaluation of study results, within 6 months prior to screening;

9. Presence of clinically severe diseases, such as a history of cardiovascular, hepatic, endocrine, gastrointestinal, metabolic, neurological, pulmonary, or psychiatric diseases, or clinically significant diseases, conditions, or other evidence that the investigator considers would pose a risk to participant safety or interfere with the conduct, progress, or completion of the study;

10. Have received two or more classes of biological products/small molecule targeted drugs (e.g., anti-TNF-α monoclonal antibodies, anti-integrin antibodies, anti-IL12/23 monoclonal antibodies, JAK inhibitors, S1P receptor modulators) and have been assessed by the investigator as treatment failure (UC disease progression requiring salvage therapy, inability to taper glucocorticoid during the maintenance phase, or need for other effective therapies);

11. Participants receiving the following drug therapies:

    • Use of non-steroidal anti-inflammatory drugs (excluding stable use of

      ≤100 mg/day aspirin for prevention of cardiovascular and cerebrovascular diseases and temporary use of ≤2000 mg/day acetaminophen for no more than three days for infectious pyrexia or mild to moderate pain), intestinal probiotics (including fecal transplant), fish oil, JAK inhibitors, immunoadsorption therapy, Chinese herbal medicines, or compound preparations containing Chinese herbal medicines within 2 weeks prior to randomization;

    • Use of azathioprine or 6-mercaptopurine, cyclosporine, thalidomide, methotrexate, mycophenolate, tacrolimus/sirolimus within 4 weeks prior to randomization;

    • Use of intravenous corticosteroids within 4 weeks prior to randomization, or rectal corticosteroids or rectal 5-ASA within 2 weeks prior to randomization;

    • Use of interferon or TNF-α inhibitors within 8 weeks prior to randomization;

    • Intravenous immunoglobulin injection or therapeutic plasma exchange within 8 weeks prior to randomization;

    • Use of S1P receptor modulators within 10 weeks prior to randomization;

    • Use of vedolizumab, IL-12/23 antibodies, cyclophosphamide, or chlorambucil within 12 weeks prior to randomization;

    • Use of leflunomide within 12 weeks prior to randomization, unless discontinued for 4 weeks before randomization and accelerated elimination (e.g., oral cholestyramine or activated charcoal) was completed at least 2 weeks prior to randomization, with corresponding medical history records required;

    • Use of rituximab within 1 year prior to randomization;

    • Use of any other investigational or marketed products with immunosuppressive effects within 8 weeks or 5 drug half-lives (whichever is longer) prior to randomization;

12. Positive for Mycobacterium tuberculosis or judged by the investigator to have a potential M. tuberculosis infection, such as: positive T-SPOT.TB test or purified protein derivative (PPD) induration ≥5 mm (within 3 months prior to screening); chest imaging within 3 months prior to screening suggesting active tuberculosis infection lesions;

13. History of recurrent invasive fungal infections or other chronic infections; herpes zoster or cytomegalovirus infection within 8 weeks prior to signing the ICF; clinically diagnosed clostridioides difficile infection or other intestinal infections within 30 days before the screening colonoscopy; positive clostridium test result during the screening period; infection requiring systemic anti-pathogen drugs (including antibacterial, antiviral, antifungal, anti-parasitic, etc.) for control within 7 days prior to randomization;

14. Presence of any disease that may require treatment with systemic glucocorticoid during the study (e.g., moderate to severe asthma, dermatitis atopic, rheumatoid arthritis, etc.);

15. Malignant tumors within 5 years prior to screening (except for adequately treated or resected basal cell or squamous cell skin cancer); or previous neoplasm screening that did not rule out tumor lesions;

16. Participants with conditions that may affect the absorption of oral drugs, such as gastrectomy or clinically significant diabetes mellitus-related gastrointestinal diseases, or specific types of obesity surgery such as gastric bypass; participants who have only undergone simple gastric banding-like procedures that divide the stomach into separate pouches are not excluded;

17. Participants who have undergone small intestine or colon operation and have evidence of colonic dysplasia or intestinal stenosis;

18. Any of the following abnormalities in screening laboratory tests:

    • Hemoglobin <9 g/dL or white blood cells <3.0×109/L or neutrophils <1.5×109/L, platelets <100×109/L
    • Total bilirubin (TBIL), aspartate transaminase (AST), or alanine transaminase (ALT) ≥1.5 times the upper limit of normal (ULN)
    • Blood creatinine >1.5 times ULN
    • Any other abnormal laboratory test results that the investigator considers may expose the participant to unacceptable risks by participating in this study
    • Positive for hepatitis B surface antigen (HBsAg), or test results are HBsAg negative, hepatitis B core antibody (HBcAb) positive, and positive for hepatitis B virus deoxyribonucleic acid (HBV-DNA); positive for hepatitis C virus antibody (HCV-Ab) and positive for hepatitis C virus ribonucleic acid (HCV-RNA); positive for human immunodeficiency virus (HIV) antibody
    • Positive for intestinal pathogens (excluding colonizing microorganisms interpreted by the investigator to be non-pathogenic);

19. Clinically significant electrocardiogram abnormal during the screening period, which the investigator judges may increase the participant's safety risk;

20. Have received any live vaccine within 3 months prior to randomization or plan to receive any live vaccine during the clinical study;

21. Participants whom the investigator considers have other factors that make them unsuitable for participation in this study.