Efficacy&Safety of ALTB-168 in Patients With Moderate to Severe Active,Anti-TNF Alpha and/or Anti-integrin Refractory UC

To evaluate the efficacy and safety of Neihulizumab (ALTB-168) administered intravenously in patients with moderate to severe active ulcerative colitis who are refractory or intolerant to anti-Tumor Necrosis Factor α and/or anti-integrin treatments.

This is a Phase II, open label, single arm, multiple dose proof of principle study to test the efficacy and safety of Neihulizumab in patients with moderate to severe active ulcerative colitis and who has failed or are intolerant to anti-TNFα and/or anti-integrin therapy. A minimum of 30 patients and a maximum of 40 will be recruited in 1 dosing group. For efficacy evaluation, the primary endpoint is the proportion of patients with clinical response, defined as ≥ 3- point reduction in MCS, a 30% or greater decrease from the baseline score, and with a 1-point or greater decrease of the rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1 at Week 12. Safety assessments will consist of evaluating physical examination, vital signs (blood pressure, heart rate, respiratory rate, body temperature and oxygen saturation), safety laboratory tests, adverse events and tolerability.

Eligibility Criteria:
Inclusion Criteria:

1. Patients must provide written informed consent;
2. Age 18-75 years;
3. Diagnosis of UC ≥ 12 weeks prior to screening by full colonoscopy (i.e., ≥ 12 weeks after first diagnosis by a physician according to American College of Gastroenterology guidelines);
4. Moderate-to-severe active UC, at time of screening, defined as:

   1. Mayo Clinic Score (MCS) of 6 points or higher, AND
   2. a centrally read MCS endoscopic subscore of grade 2 or higher, AND
   3. MCS rectal bleeding subscore of 1 point or higher, AND
   4. disease extending 15 cm or more from the anal verge;
5. Stable doses of concomitant medications, including :

   1. Stable oral corticosteroids (i.e., ≤ 20 mg/day of prednisone, ≤ 9 mg/day of budesonide) ≥ 2 weeks before D1 dosing; Taper of oral corticosteroids per Investigator's discretion during the study is allowed;
   2. Stable oral 5-amyinosalicylic acid dose ≥ 2 weeks before D1 dosing;
   3. Stable immunosuppressant including azathioprine, mercaptopurine, or methotrexate ≥ 8 weeks before D1 dosing. Patients taking methotrexate also are advised to take folic acid 1 mg/day or equivalent if there is no contraindication;
   4. Stable doses of probiotics ≥ 2 weeks before D1 dosing;
   5. Stable anti-diarrheas ≥ 2 weeks before D1 dosing;
6. Patients must have previously received anti-tumor necrosis factor alpha (anti- TNF alpha and/or anti-integrin therapy for UC and demonstrated an inadequate response, loss of response, or intolerance, and must have discontinued therapy ≥ 8 weeks before D1 dosing;
7. Patients previously treated with cyclosporine or tacrolimus must have discontinued therapy ≥ 4 weeks before D1 dosing;
8. Topical corticosteroids and topical 5-amyinosalicylic acid preparations must have been withdrawn ≥ 2 weeks before D1 dosing;
9. Nonsteroidal anti-inflammatory drugs (NSAIDs) must have been discontinued ≥ 4 weeks before D1 dosing;
10. Tofacitinib or other Janus kinase (JAK) inhibitors must have been discontinued ≥ 2 weeks before D1 dosing;
11. Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 weeks before D1 dosing;
12. Females with reproductive potential must have a negative pregnancy test result before enrollment. Men and women with reproductive potential have to be willing to use a highly effective method of contraception from study start to ≥ 3 months after the final dose of the study drug. A highly effective method of birth control is defined as one which results in a low failure rate (less than 1% per year).

Exclusion Criteria:

GI related exclusion criteria:

1. Indeterminate colitis (Inflammatory bowel disease unclassified, IBD-U) or suspected Crohn's disease
2. Any history of colectomy
3. Presence of an ileostomy or colostomy
4. A history or evidence of colonic mucosal dysplasia
5. Short gut syndrome

   General health related exclusion criteria:
6. Pregnant or lactating
7. Inability to comply with study protocol in the opinion of the investigator
8. History of dysplasia or malignancy in recent 5 years, except completely excised basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
9. Cirrhosis or active alcohol abuse per the judgement of investigator
10. Poorly controlled diabetes (HbA1c \> 8.0%)
11. Significant screening ECG abnormalities, including evidence of acute myocardial infarction, complete left bundle branch block, second-degree heart block, or complete heart block
12. Impaired renal function (calculated creatinine clearance \< 60 mL/min)
13. Impaired hepatic function in the absence of diagnosis of primary sclerosing cholangitis, serum transaminase \> 2.5x Upper Limit Normal (ULN), alkaline phosphatase \> 2.5x ULN, or increased total bilirubin judged by the investigator to be clinically significant, or a diagnosis of primary sclerosing cholangitis, serum transaminases \> 3x ULN, alkaline phosphatase \> 3x ULN, or total bilirubin \> 2.5x ULN judged by the investigator to be clinically significant
14. Moderate to severe anemia (Hb \< 8g/dL)
15. Thrombocytopenia (platelet count \< 75,000/uL)
16. Evidence of current or previous clinically significant disease, medical condition or finding in the medical examination that in the opinion of the investigator, would compromise the safety of the patient or quality of the data
17. Requiring parenteral corticosteroid treatment.
18. Received any investigational product within 1 year.
19. History of drug abuse according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) criteria within 12 months prior to screening or positive drug screening tests.

    Infection related exclusion criteria:
20. Human immune deficiency virus (HIV) infection or known HIV-related malignancy.
21. Acute or chronic hepatitis B or C, or carrier status. Patients with anti-HBc Ab but with undetectable anti-HBs Ab should also be excluded.
22. Positive IgM antibody titers in the presence of negative IgG titers to Epstein-Barr virus
23. Positive stool test for ova or parasites, positive stool culture for pathogens, or positive stool toxin assay for Clostridium difficile at screening. Patients with the positive stool toxin assay for C. difficile at screening could be rescreened if they are being treated for C. difficile and a repeat stool toxin assay at least 4 weeks after the completion of treatment is negative with no evidence of recurrence.
24. Intestinal mucosa biopsy positive for cytomegalovirus (CMV) at screening.
25. Positive screening test for latent Mycobacterium tuberculosis (TB) infection. Patients with a history of latent TB infection who received an appropriate and documented course of therapy can be included if the screening examination and a chest x-ray performed ≤ 3 months before screening revealed no evidence of current active infection. If a Quantiferon TB test is indeterminate, the test should be repeated, and if the result is again indeterminate, such patient should be excluded.
26. History of any opportunistic infection ≤ 12 weeks before D1 dosing.
27. Any current or recent (≤ 4 weeks before D1 dosing) symptoms/signs of infection.
28. Received oral antibiotics ≤ 4 weeks before D1 dosing or intravenous antibiotics ≤ 8 weeks before D1 dosing.
29. Received a live attenuated vaccine ≤ 4 weeks before D1 dosing.
30. Neutropenia (absolute neutrophil count \< 1,500/uL).
31. Lymphocytopenia (absolute lymphocyte count \< 500 /uL).