An Investigation of Oral BT051 in Subjects With Moderately to Severely Active Ulcerative Colitis (UC)

A Multicenter, Randomized, Placebo-Controlled, Multiple-Ascending-Dose Investigation of the Oral Anti-Inflammatory Agent BT051 in Subjects With Moderately to Severely Active Ulcerative Colitis (UC)

This is a randomised, double-blind, placebo-controlled study to assess the safety and tolerability of multiple ascending doses of BT051 in subjects with moderately to severely active ulcerative colitis. Subjects will be randomised using a 3 active:1 placebo ratio to 3 ascending dose cohorts of 8 subjects and will be dosed daily for 28 days. The 3 initial dose levels will be 200 mg, 800 mg and 3200 mg per day. Progression to the next cohort will be based on the safety and tolerability of the previous cohort.

This is a randomized, placebo-controlled, multiple-ascending-dose (MAD) study enrolling subjects with moderately to severely active UC. Subjects with prior exposure to biologic or JAK inhibitors will be limited to 30% of the total subject population; those who have failed 2 or more biologic therapies (i.e., biologic and JAK inhibitor, 2 biologics in the same class, or 2 biologics from different classes) will be limited to 20% of the total subject population. Subjects will be randomized to one of 3 doses of oral BT051 (200 mg, 800 mg, or 3200 mg) or placebo, in ascending dose groups based on the safety and tolerability of the previous cohort. Safety and tolerability will be assessed by a Safety Review Committee (SRC) after all subjects in each cohort have completed at least 14 days of treatment, before proceeding to the next higher dose cohort. The SRC may recommend that the next cohort proceed with a higher dose as planned, or the SRC may recommend additional subjects be dosed at the current, previous, or lower dose of study drug.

Each planned dose escalation cohort (Cohorts 1-3) will include 8 subjects randomized 3:1 to receive active drug or placebo. Starting with the lowest dose, each cohort of subjects will receive once daily oral BT051 or placebo for a period of 28 days. Follow-up visits will be performed at 7 and 30 days after the last dose.

Inclusion Criteria

1. Provide written documentation of informed consent to participate in the study.
2. Male or female aged 18 to 75 years.
3. Subjects with a confirmed diagnosis of UC of at least 3 months' disease duration prior to Screening (diagnosis established by endoscopy and histology).
4. Moderately to severely active UC, defined as a Mayo Score ≥6 points with a rectal bleeding subscore ≥1 point, a stool frequency subscore ≥1 point, and moderate to severe disease on endoscopy (Mayo endoscopic subscore [MES] ≥2 points).
5. Subjects treated with stable doses (>4 weeks) of the following UC treatments prior to randomization: 6-mercaptopurine, azathioprine, sulfasalazine or 5-aminosalicylic acid. Subjects will need to maintain stable doses of these drugs for at least 4 weeks during study treatment and an additional 7 days of follow-up.
6. Subjects treated with oral corticosteroids will be eligible if the dose is ≤20 mg/day prednisone (≤9 mg/day budesonide) or equivalent. The corticosteroid therapy will have to be stable for at least 2 weeks prior to the Screening sigmoidoscopy, throughout study treatment and an additional 7 days of follow-up.
7. Colonoscopy within the past 1 year to exclude adenomas, dysplasia, and colon cancer for subjects with 1/3 of colon involved and 8 years of disease; those without a colonoscopy in the past year may use the Screening colonoscopy to confirm eligibility.
8. Female subjects must be surgically sterile, postmenopausal (i.e., no menses for at least 2 years or documented by follicle stimulating hormone), or if of child-bearing potential must have a negative pregnancy test and must be willing to use a highly effective form of contraceptive through 30 days after the last dose of study drug. The following are considered highly effective contraceptives: combined and progestogen-only hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable, implantable), intrauterine device/hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or abstinence. Abstinence should only be used as a contraceptive method if it is in line with the subject's usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, post ovulation methods) is not an acceptable method of contraception.
9. Male subjects must be surgically sterile, abstinent, agree to use an appropriate contraception method (i.e., condom), or have a female sexual partner who is surgically sterile, postmenopausal, or using a highly effective form of contraceptive as noted above through 30 days after the last dose of study drug. Abstinence should only be used as a contraceptive method if it is in line with the subject's usual and preferred lifestyle.

General Exclusion Criteria

1. Any clinically significant disease: renal, hepatic, neurological, cardiovascular, pulmonary, endocrinology, psychiatric, hematologic, urologic, or other acute or chronic disease that in the opinion of the Investigator would not make the subject a suitable candidate for this study.

2. Subjects with planned hospitalization or surgery during the course of the study.

3. Female subjects who have a positive pregnancy test, are breast feeding, or intend to become pregnant during the course of the study. Male subjects who intend female partner pregnancy during the course of the study.

4. Known hypersensitivity to any of the components of BT051 drug product including cyclosporine A and polyethylene glycol.

5. Relative to upper limit of normal (ULN):

   1. Serum bilirubin >1.5×
   2. Serum creatinine >1.5×
   3. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >2.0×

6. International normalized ratio (INR) >1.5

7. Hemoglobin <8 g/dL

8. Cell counts (/μL):

   1. Platelets <100,000 or >800,000
   2. White blood cells <3500
   3. Absolute neutrophil count <1500

9. Systemic antibiotic, antiviral, or anti-fungal therapy within the 2 weeks prior to Screening.

10. Live or live-attenuated virus vaccination within the 2 weeks prior to randomization or planned vaccination during the study. Vaccination against SARS-CoV-2 using licensed vaccines will be permitted.

11. History of cancer within the past 5 years (permitted exceptions: subjects with excised basal cell carcinoma, squamous cell carcinoma of the skin, and cervical carcinoma in situ who have been treated and cured).

12. Drug, chemical, or alcohol dependency within the past 2 years as determined by the investigator.

13. A positive diagnostic tuberculosis (TB) test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the subject may have the test repeated once and if their second test is negative, they will be eligible. In the event a second test is also indeterminate, or QuantiFERON is unavailable, the investigator has the option to perform a purified protein derivative (PPD) skin test (PPD skin test may not be used if subject was previously vaccinated with bacille Calmette-Guerin [BCG]). If the PPD reaction is <5 mm, then the subject is eligible. If the reaction is ≥5 mm, or PPD testing is not done, the subject is not eligible.

14. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at Screening. If the initial test is positive but reflex testing (performed on the same sample) is negative, then the subject is eligible.

15. Inability to comply with study requirements.

16. Other unspecified reasons that, in the opinion of the Investigator, make the subject unsuitable for enrollment.

17. Subjects enrolled in another clinical trial assessing an investigational drug (or medical device) within 30 days or 5 half-lives (whichever is longer) prior to Screening (or within 60 days prior to Screening if investigational drug was a biologic).

    Gastrointestinal Exclusion Criteria

18. Fulminant colitis, toxic megacolon, or severe ulcerative colitis as defined: currently hospitalized for UC, fever, persistent tachycardia, or hemoglobin <8 g/dL.

19. Subject has any of the following conditions: primary sclerosing cholangitis, Crohn's disease, diverticulitis, bowel fistulas, history of colitis-associated colonic dysplasia, or active peptic ulcer disease.

20. Ulcerative colitis diagnosis limited to isolated proctitis.

21. Current ileostomy or colostomy.

22. Proctocolectomy or total colectomy.

23. Known symptomatic colonic stricture.

24. Current stool cultures or tests positive for an enteric infection, including parasitic infection and Clostridioides difficile toxin.

25. Short bowel syndrome requiring enteral or parenteral nutrition supplementation or total parenteral nutrition.

26. Diagnosis of microscopic or indeterminate colitis.

27. Bowel surgery within 3 months prior to randomization, or likely to need bowel surgery in next 4 months.

28. Any known history of listeria infection.

29. A current bacterial, parasitic, fungal, or viral infection (except blastocystis hominis).

    Prior Medication Exclusion Criteria

30. Prior biologic therapy:

    1. Adalimumab, infliximab, golimumab, etanercept, ustekinumab or certolizumab within the 60 days prior to Day 1.
    2. Vedolizumab within 120 days prior to Day 1.

31. Topical mesalamine or corticosteroid (i.e., enemas or suppositories) within the 14 days prior to Day 1.

32. Tofacitinib within the 30 days prior to Day 1.

33. Subjects treated with parenteral corticosteroids or calcineurin inhibitors cyclosporine, or tacrolimus within 4 weeks prior to randomization.

34. Regular use of other medications not mentioned above, including over-the-counter medications or supplements, that may impact the subject's UC or intestinal motility as determined by the investigator.