Efficacy/Safety of ALTB-268 in Subjects w/Moderately to Severely Active UC Refractory to Biologics

Phase 2a, Multicenter, Open-Label Study Evaluating the Efficacy and Safety of ALTB-268 in Subjects With Moderately to Severely Active Ulcerative Colitis Refractory to Biologic Therapy

ALTB-268-201 is a Phase 2a, multicenter, single arm, multiple-dose, open-label study evaluating the efficacy and safety of ALTB-268 in subjects with moderately to severely active UC. The study consists of a Screening Phase, an Induction Phase and a LTE (Long Term Extension)

ALTB-268-201 is a Phase 2a, multicenter, single arm, multiple-dose, open-label study evaluating the efficacy and safety of ALTB-268 in subjects with moderately to severely active UC.

The study consists of a Screening Phase, an Induction Phase and a LTE. Upon successful completion of the Screening Phase, subjects will return to the clinic for their first visit, which must occur within 28 days of the initial Screening Visit. Eligible subjects will be enrolled to receive a SC loading dose of ALTB-268, followed by a weekly maintenance dose of ALTB-268 in the 12-week Induction Study Phase. Participants entering the LTE will continue to receive the SC dose of ALTB-268 weekly or biweeky, up to 2 years. Upon completion of the LTE, study participants will be asked to return for an end of study visit in approximately 4 weeks.

Inclusion Criteria:

1. Adult participants 18 to 75 years old, inclusive, at Screening.

2. Willing to provide informed consent and to be compliant with the schedule of study visits and protocol assessments.

3. Diagnosis of UC established at least 12 weeks prior to Screening by standard clinical and endoscopic evidence and corroborated by a histopathology report.

4. Moderately to severely active UC, at the time of Screening, defined as a modified Mayo Score (mMS) of 5-9, inclusive, with an endoscopic subscore of ≥ 2 (from central reading), and a rectal bleeding (RB) subscore of ≥ 1.

5. Evidence of active UC, extending proximal to the rectum with ≥ 15 cm of involved colon.

6. Stable doses of concomitant medications:

   1. Subjects receiving oral corticosteroids for the treatment of UC must be on a stable dose of ≤ 20 mg/day (prednisone or equivalent), or ≤ 9 mg/day budesonide. This dose must be stable from the initial Screening visit until the end of the Induction Phase.
   2. Subjects receiving oral 5-aminosalicylic acid (5-ASA) must be on a stable dose from the initial Screening visit until the end of study.
   3. Subjects receiving immunosuppressants (azathioprine, 6-mercaptopurine [6-MP] or methotrexate) must be on a stable dose for 4 weeks prior to Screening until the end of study treatment. Subjects taking methotrexate are also advised to take folic acid 5 mg/week (or equivalent) if there is no contraindication.
   4. Subjects receiving probiotics must be on a stable dose from the initial Screening visit until the end of study.
   5. Subjects receiving an anti-diarrhetic must be on a stable dose for ≥ 2 weeks prior to Screening until the end of study.

7. Previous treatment with one or two advanced therapy that demonstrated an inadequate response and/or loss of response.

8. Negative pregnancy test during Screening and Day 1 (V0) in females of childbearing potential.

9. Females with reproductive potential must be sexually abstinent or be willing to use a highly effective method of contraception from study start to ≥ 3 months after the final dose of the study drug. Highly effective methods of contraception include:

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

10. Male subjects must be either surgically sterile (must have documented proof), agree to be sexually abstinent, 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 to ≥ 3 months after the final dose administration.

11. Male subjects must agree to refrain from donating sperm from first study drug administration to ≥ 3 months after final dose administration.

Exclusion Criteria:

1. Diagnosis of Crohn's colitis, colitis yet to be classified, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID)-induced colitis, idiopathic colitis (i.e., colitis not consistent with UC), or radiation-induced colitis.

2. Ulcerative colitis limited to the rectum (ulcerative proctitis).

3. Presence of short bowel syndrome.

4. History of colectomy, or presence of an ileostomy or colostomy.

5. History of, or active colonic mucosal dysplasia.

6. Treatment with any intravenous (IV) corticosteroid or rectal therapy during the Screening period.

7. Treatment with any calcineurin inhibitor (e.g., cyclosporine, tacrolimus) from the initial Screening visit.

8. Treatment with NSAIDs within 4 weeks prior to Screening. Short-term use (<7 days) of NSAIDs for non-UC related symptoms is allowed.

9. Treatment with tofacitinib or other Janus Kinase (JAK) inhibitors from the initial Screening visit.

10. Treatment with sphingosine-1-phosphate receptor (S1PR) modulators from the initial Screening visit.

11. Biologic therapy within 56 days or 5 half-lives (whichever is longer) prior to Screening. Confirmation of undetectable or non-therapeutic serum levels, as assessed by the Investigator, will allow for eligibility.

12. Tube feeding, defined formula diets, or parenteral alimentation/nutrition within 3 weeks of first dosing.

13. Treatment with oral antibiotics within 4 weeks prior to Screening or IV antibiotics within 8 weeks prior to Screening.

14. Vaccination with a live or live-attenuated vaccine within 4 weeks prior to Screening.

15. History of dysplasia or malignancy in the past 5 years, except completely excised basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.

16. 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, or any other severe comorbidity that, in the opinion of the Investigator, could confound the study results or put the subject at unreasonable risk.

17. Significant screening electrocardiogram (ECG) abnormalities, including evidence of acute myocardial infarction, complete left bundle branch block, second-degree heart block, or complete heart block.

18. For males, a QTc interval (Fridericia's correction) of >450 ms, and for females, a QTc interval (Fridericia's correction) of >470 ms.

19. Any of following laboratory abnormalities during the Screening period. If values are initially outside prescribed limits, the evaluation may be repeated once within the Screening period to determine eligibility:

    1. Calculated creatinine clearance < 60 mL/min
    2. Serum transaminases > 2.0x Upper Limit Normal (ULN)
    3. Alkaline phosphatase (ALP) > 2.0x ULN
    4. Bilirubin > 1.5x ULN; does not apply to subjects with Gilbert's Syndrome (Meulengracht Syndrome)
    5. Hemoglobin < 8g/dL
    6. Platelets < 75,000/μL
    7. Absolute neutrophil count < 1,500/ μL
    8. Absolute lymphocyte count < 800/ μL

20. Human immune deficiency virus (HIV) infection or known HIV-related malignancy.

21. Acute or chronic hepatitis B (HBV) or hepatitis C (HCV), or carrier status. Subjects with anti-HBc (hepatitis B core) antibodies (Ab) but with undetectable anti-HBs (hepatitis B surface) Ab should be excluded.

22. Positive immunoglobulin M (IgM) Ab titers in the presence of negative immunoglobulin G (IgG) Ab titers to Epstein-Barr virus (EBV).

23. Positive stool test for ova or parasites, positive stool culture for pathogens, or positive stool toxin assay for Clostridium difficile at Screening.

24. Active cytomegalovirus (CMV) infection at Screening, as assessed by the Investigator.

25. Positive QuantiFERON® TB test at Screening for latent Mycobacterium tuberculosis (TB) infection. If a QuantiFERON® TB test is indeterminate, the test should be repeated. If the result is again indeterminate, the subject should be excluded.

    Subjects with a history of latent TB infection who received or are receiving an appropriate and documented course of therapy can be included if the screening examination and a chest x-ray performed within 3 months prior to Screening revealed no evidence of current active infection.

26. History of any opportunistic infection within 12 weeks of first dosing.

27. Any current or recent symptoms/signs of infection, except nasopharyngitis, within 4 weeks of first dosing.

28. Cirrhosis or active alcohol abuse, pr the judgment of the Investigator.

29. History of drug abuse according teo the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria within 12 months prior to Screening or a positive drug screening test.

30. Currently breast feeding, or pregnant.

31. Known hypersensitivity or intolerance to ALTB-268 or any of its excipients.

32. Participation in another clinical trial AND having received investigational medication within 30 days or 5 half-lives (whichever is longer) prior to Screening or having used an investigational device treatment within 30 days prior to Screening. Concurrent participation in an observational or long-term follow-up study and not actively receiving an investigational drug or device treatment may be eligible for participation in this study.

33. Inability to comply with the study protocol, in the opinion of the Investigator.