Treg Immunotherapy in Crohn's Disease

Inclusion Criteria:

1. Able and willing to provide written informed consent and able to comply with the protocol requirements

2. Male or female aged between 18 and 80 (inclusive) years of age

3. A diagnosis of Crohn's disease (CD) established ≥3 months prior to consent by standard clinical, radiological, endoscopic and histological criteria

4. Documented moderate-to-severe CD with a Crohn's Disease Activity Index (CDAI) >= 220 within 3 months of screening

5. Active CD (mucosal inflammation) including ulceration, as assessed by colonoscopy at screening

6. Failure to tolerate or to respond to at least 2 prior lines of standard CD medication intended to induce or maintain remission, as determined by the referring gastroenterologist. Examples of such medications include, but are not limited to, azathioprine, mercaptopurine, methotrexate or anti-tumour necrosis factor antibody therapy. This does not include steroids and 5-ASA medications

7. Stable doses of concomitant medications

8. Normal or non-clinically significant electrocardiogram (ECG), as assessed by the Investigator at screening

9. Negative stool test for Clostridium difficile and faecal culture for standard pathogens at screening. For non-pathogenic organism, inclusion will be at the discretion of the Principal Investigator (PI)

10. Negative serology for HIV, Hepatitis B (cAb and sAg), Hepatitis C, HTLV and Syphilis at screening

11. Subject is judged by the principal investigator to be in otherwise good health based upon the results of all screening investigations in combination with medical history and physical examination

12. Clinical Blood Tests prior to dosing, assessed on Day-1 at Week 0 and Week 8:

1. Hb > 100g/L and WBC > 3.5 x 109/L and Plt > 100 x 109/L

2. Creatinine < 1.5x ULN

3. Total bilirubin ≤ 34 µmol/L and ALT ≤ 2x ULN and GGT ≤ 2xULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed

13. Negative urine pregnancy test for female of childbearing potential prior to dosing, assessed on Day-1 at Week 0 and Week 8

Exclusion Criteria:

1. A diagnosis of ulcerative colitis or IBD-unclassified

2. CD treatment-naïve patients, defined as patients who have never received or have refused standard CD treatment

3. History of clinically significant drug or alcohol abuse in the last 12 months

4. Any history of major immune deficiency disorder, except Crohn's disease

5. Patients with a history of pulmonary embolism or deep vein thrombosis. Current or recent history (within 1 year prior to screening) of major organ or system failure or condition, acute or chronic that in the opinion of the investigator should preclude enrollment, except Crohn's disease

6. History of intestinal resection or intra-abdominal surgery within 6 months prior to visit 1 (screening)

7. Requirement for immediate or imminent surgical, endoscopic or radiological intervention for indications including (but not limited to) toxic megacolon, obstruction, massive haemorrhage, perforation, sepsis, or intra-abdominal or perianal abscess

8. Patients with ileostomy or colostomy

9. Patients with short bowel syndrome (less than 1.5m of small bowel)

10. Complication of Crohn's disease such as strictures/stenosis, penetrating disease, or any other manifestation that might require surgery. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to screening and/or during the screening period

11. Patients who are currently using anticoagulants including but not limited to warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban (note that anti-platelet agents such as aspirin up to 325mg daily or clopidogrel are permitted)

12. Current medically significant infection i.e. infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to screening or oral anti-infectives for non-Crohn's disease related infections within 14 days prior to screening visit

13. Subject with an active systemic viral infection or any active viral infection that based on the investigator's clinical assessment makes the subject unsuitable for the study

14. History of tuberculosis (TB), unless there is documented evidence of completion of a full course of anti-TB treatment prior to screening. For patients with latent TB, as defined by a physician specialised in TB, they must have received prophylactic treatment for 4 weeks minimum prior to dosing

15. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident (within 6 months of screening) and any other condition which, in the opinion of the investigator, would put the subject at risk by participation in the study

16. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in any biopsy performed during the screening endoscopy or endoscopy performed within 45 days of baseline unless this is deemed to be a sporadic adenoma and has been completely removed

17. Significant laboratory abnormalities:

Hb < 100g/L or WBC < 3.5 x 109/L or Plt < 100 x 109/L Creatinine > 1.5x ULN Total bilirubin ≥ 34 µmol/L or ALT ≥ 2x ULN or GGT ≥ 2xULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed

18. Anti-TNF,vedolizumab or ustekinumab therapy within 8 weeks of study treatment initiation. Exposure to cyclosporine or tacrolimus within 2 weeks of anticipated study date of consent

19. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during the course of the study

20. Received another investigational drug within 60 days of anticipated study date of consent or 5 half lives whichever is greater

21. Subject who previously received stem cell transplantation

22. Current evidence of dysplasia or history of malignancy within the last 5 years (except successfully treated squamous cell or basal cell carcinoma, without metastases or localised carcinoma in situ of the cervix)

23. Pregnant and lactating patients (females of childbearing potential must have a negative dipstick pregnancy test at study entry)

24. Female patients of childbearing potential (i.e. not post-menopausal or surgically sterilised) who are not willing to use effective methods of contraception (included but not limited to hormonal contraception, Intrauterine devices, sexual abstinence, vasectomised partner) to prevent pregnancy or abstain from heterosexual activity for the duration of the trial up to W21 visit

25. Male patients who are not willing to use an effective method of contraception (included but not limited to use of condom, vasectomy, sexual abstinence) for the duration of the study up to W21 visit, when engaging in sexual activity with a female of childbearing potential

26. Allergy to any component / excipients used for the manufacture of TR004

27. Subject is considered by the investigator, for any reason, to be an unsuitable candidate for the study

28. Inability to comply with the study protocol