A Study Evaluating the Efficacy and Safety of ST-0529 in Subjects With Moderately to Severely Active Ulcerative Colitis

Study CYC-202 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of ST-0529 in subjects with moderately to severely active UC, defined as a score of 5 to 9 on the 3-Component Adapted Mayo Score (comprised of rectal bleeding, stool frequency and endoscopy sub-scores; score range 0-9).

The study consists of a Screening period, Treatment period and Follow-up. The Screening period is comprised of two separate in-clinic visits, SV1 and SV2. At the initial Screening visit (SV1), subjects will be required to provide written informed consent to participate in the study and will then be assessed for eligibility. Electronic diaries will be provided to subjects at this visit to use for the duration of the study in order to record information relating to their UC disease. Subjects will return to the clinic for their Screening endoscopic assessment (SV2). Ulcerative colitis disease activity for eligibility will be assessed using the 3-Component Adapted Mayo Score. Upon successful completion of the Screening period, subjects will return to the clinic for their Baseline visit.

During the Treatment period, subjects will be evaluated in the clinic at Baseline (Day 1), Week 2, Week 4, Week 8, and Week 12 (End of Treatment Period). At Week 6 and Week 10, subjects will be contacted by telephone to assess Adverse Events (AEs), concomitant medication usage and study drug regimen adherence.

Subjects who complete the 12-week Treatment period will attend the Week 16 End of Study (EOS) visit. Subjects who discontinue study drug and withdraw or are withdrawn from the study before the Week 12 visit will be requested to return to the clinic as soon as possible to complete an Early Termination (ET) visit.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female adult subjects 18 to 75 years old, inclusive.
2. Willing to provide written informed consent and to be compliant with the schedule of study visits and protocol assessments.
3. Diagnosis of UC established at least 3 months prior to the Baseline visit, by clinical and endoscopic evidence (colonoscopy or flexible sigmoidoscopy)
4. Moderately to severely active UC defined as the 3-Component Adapted Mayo Score of 5-9, inclusive, with an endoscopic sub-score of ≥ 2 (from central reading), and a rectal bleeding sub-score of ≥ 1, as determined 10 days (± 3 days) prior to Baseline.
5. Evidence of active UC, confirmed histologically (from local read), extending proximal to the rectum with ≥ 15 cm of involved colon.
6. At Screening, a colonoscopy will be required if the subject 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 date. If the subject has had a colonoscopy within 1 year of the initial screening date, a flexible sigmoidoscopy may be used.
7. Subjects presenting at Screening with moderately to severely active UC demonstrating an inadequate response or loss of response or intolerance/medical contraindication to at least one of the following conventional therapies for UC:

   a. Corticosteroids:

   i. Signs and symptoms of active disease despite treatment with an adequate dose (e.g., prednisolone \> 40 mg/day or equivalent) over a period of 4 weeks for oral therapy or intravenously (IV) for up to 1 week or ≥ 9 mg/day oral budesonide;

   OR

   ii. Unable to reduce corticosteroids below the equivalent of prednisolone 10 mg daily orally within 3 months of starting steroids or having experienced a relapse within 3 months of stopping steroids;

   OR

   iii. History of, or current intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection).

   b. Immunomodulators:

   i. Signs and symptoms of active disease despite at least 3 months of treatment with a sufficient dose (oral azathioprine ≥ 1.5 mg/kg or 6-mercaptopurine \[6-MP\] ≥ 0.75 mg/kg);

   OR

   ii. History of, or current dose-limiting toxicity associated with use of the agent (e.g., but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test \[LFT\] abnormalities, lymphopenia, TPMT genetic mutation, infection).

   c. Anti-tumor necrosis factor (anti-TNF) agents:

   i. Signs and symptoms of active disease despite treatment with a single anti-TNF agent. Treatment failure is defined as a relapse after an initial response to therapy as follows:
   * Infliximab: At least 4 infusions of at least 5 mg/kg within a 14-week timeframe for induction and maintenance;
   * Adalimumab: Induction regimen incorporating 160 mg at Week 0 (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days) and 80 mg at Week 2, followed by maintenance treatment of 40 mg every other week up to at least Week 8;
   * Golimumab: Induction regimen incorporating 200 mg subcutaneous (sc) injection at Week 0, followed by 100 mg at Week 2 and then maintenance treatment of 50 mg or 100 mg (weight dependent) every 4 weeks after completion of the induction regimen up to at least Week 12;

   OR

   ii. History of, or current intolerance (with an initial response), defined as the presence of clinically significant side-effects, including infusion-related hypersensitivity.

   d. Vedolizumab:

   i. Signs and symptoms of active disease despite a history of at least one induction regimen, defined as at least a 14-week (10 weeks in the EU) induction consisting of 300 mg IV at Weeks 0, 2 and 6.

   OR

   ii. History of intolerance to vedolizumab including, but not limited to, serious infections, hepatotoxicity, heart failure, allergic reactions, or any other condition that contributed to discontinuation of the agent.
8. Subjects receiving oral corticosteroids for the treatment of UC must be on a stable dose of ≤ 40 mg/day (prednisolone or equivalent), or ≤ 9 mg/day budesonide. This dose must be stable from the initial Screening visit until 1 week after the initiation of study treatment.
9. Subjects receiving oral 5-ASA must be on a stable dose from the initial Screening visit until the end of the study.
10. Subjects willing to cease the use of any therapeutic enema or suppository or foams, other than that required in preparation for study-mandated colonoscopy/flexible sigmoidoscopies, from the initial Screening visit until the end of the study.
11. Subjects willing to cease use of azathioprine or 6-MP from the initial Screening visit until the end of the study.
12. Negative serum pregnancy test in females of childbearing potential at Screening.
13. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control from the initial Screening visit until 30 days after the last dose of study drug is administered:

    1. Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants);
    2. Intrauterine contraceptive system;
    3. Surgical sterilization or partner sterile (must have documented proof);

    AND

    One of the following effective methods of birth control:
    1. Male/female condom;
    2. Cervical cap with spermicide;
    3. Diaphragm with spermicide;
    4. Contraceptive sponge.
14. Male subjects must be either surgically sterile (must have documented proof), agree to be sexually inactive or use a double-barrier method of birth control (e.g., condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.

Exclusion Criteria:

If a subject has any of the following criteria, they will be excluded from the study:

1. Subjects without previous treatment for UC.
2. Ulcerative colitis limited to rectum (ulcerative proctitis).
3. Evidence of acute severe colitis with toxic megacolon, abdominal abscess, bowel stricture or bowel perforation.
4. A diagnosis of Crohn's colitis, colitis yet to be classified, ischemic colitis, NSAID-induced colitis, idiopathic colitis (i.e., colitis not consistent with UC) or radiation colitis.
5. Subjects with evidence of pathogenic bowel infection (Clostridium difficile, Escherichia coli, Salmonella, Shigella or Campylobacter).
6. Previous surgery for UC or, in the opinion of the Investigator, will likely require surgery for UC during the study.
7. Any histological evidence of mucosal dysplasia.
8. Subjects with a current or recent history of severe, progressive or uncontrolled cardiac (including uncontrolled hypertension), renal, hepatic, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurological (e.g., history of seizures) disease, abnormal magnesium or potassium levels, hypocholesterolemia, or any other severe co-morbidity that, in the opinion of the Investigator, could confound the study results or put the study subject at unreasonable risk.
9. Malignancies or history of malignancy within 5 years of the initial Screening visit, with the exception of adequately treated or excised non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin.
10. Any of the following laboratory abnormalities during the screening period - if values are initially outside the prescribed limits, the evaluation may be repeated once within the screening period to determine eligibility:

    1. Hemoglobin level \< 8.0 g/dL
    2. Absolute WBC count \< 3.0 × 10\^9/L
    3. Absolute Lymphocyte count \< 0.5 × 10\^9/L
    4. Absolute neutrophil count \< 1.2 × 10\^9/L
    5. Platelet count \< 100 × 10\^9/L or \>1200 × 10\^9/L
    6. ALT or AST \> 2.0 × ULN
    7. Alkaline phosphatase \> 2.0 × ULN
    8. Serum creatinine \> 1.5 × ULN
    9. Bilirubin \> 1.5 × ULN
11. Subjects with active TB infection or known history of prior treated or untreated TB infection.
12. Subject with a positive serology test result for HIV (HIV type 1 or type 2).
13. Subject with a positive serology test result for active HBV or HCV infection.
14. Treatment with biologic agents for UC within 56 days or 5 half-lives (whichever is greater) prior to the Baseline visit.
15. Treatment with any calcineurin inhibitor (e.g. cyclosporine or tacrolimus) within 28 days prior to the Baseline visit.
16. Treatment with methotrexate or JAK inhibitors (e.g. tofacitinib) from the initial Screening visit until the end of the study.
17. Initiation of treatment with an oral or IV corticosteroid from the initial Screening visit until the end of the study.
18. Use of any strong inhibitors of CYP enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, grapefruit juice and HIV antivirals) within 14 days prior to the Baseline visit.
19. Use of strong or moderate P-gp inhibitors (e.g., amiodarone, azithromycin, clarithromycin, itraconazole, ketoconazole, dronedarone, lapatinib, quinidine, ranolazine, verapamil) within 14 days prior to the Baseline visit.
20. Use of any herbal medication for the treatment of UC or which might interfere with CYP enzymes within 14 days prior to the Baseline visit.
21. Subjects vaccinated with a live or live-attenuated vaccine within 14 days of the Baseline visit, or planned vaccination during conduct of the study.
22. Subjects with a QTcF of \> 450 ms for males and \> 470 ms for females at Screening.
23. A history of risk factors for Torsades de pointes (e.g., history of heart failure, hypokalemia, family history of Long QT Syndrome).
24. Known hypersensitivity to cyclosporine or any excipients contained in ST-0529.
25. History of alcohol or drug abuse in the year prior to the initial Screening visit.
26. Subjects currently breast feeding, pregnant, or unwilling to delay initiation of breast feeding for at least 90 days after the last dose of study drug is administered.
27. Participation in another clinical trial and having received investigational medication within 30 days or within 5 half-lives (whichever is longer) prior to the Baseline visit, or concurrent participation in another clinical trial.
28. Subjects who, in the opinion of the Investigator, are unsuitable for inclusion in the study.