Study of Mesenchymal Stem Cells for the Treatment of Medically Refractory Ulcerative Colitis (UC)

A Phase IB/IIA Study of Remestemcel-L, an ex Vivo Culture-expanded Adult Allogeneic Bone Marrow Derived Mesenchymal Stem Cell Product, for the Treatment of Medically Refractory Ulcerative Colitis

The purpose of this study is to determine the safety and efficacy of using remestemcel-L, an ex vivo culture-expanded adult allogeneic bone marrow derived mesenchymal stem cell product (MSCs) delivered by targeted endoscopic delivery to treat people for medically refractory ulcerative colitis.

This study will enroll adult patients with medically refractory ulcerative colitis who are planning to switch biologic therapy or undergo colectomy as the next stage in their treatment plan.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon and rectum, which continues to increase in incidence for unknown reasons, resulting in a significant burden to the healthcare system. UC is characterized by persistent mucosal inflammation of the colon and rectum with a chronic remitting and relapsing behavior which leaves patients on chronic immunosuppression and hospitalizations to treat the disease symptoms, but unable to cure the disease. Despite the ever-growing armamentarium of immunosuppressive medication, up to 30% of patients still require a colectomy for medically refractory disease.

Participants with medically refractory ulcerative colitis will be treated by targeted endoscopic delivery of remestemcel-L, an ex vivo culture expanded allogeneic bone marrow derived mesenchymal stem cell product at a dose of 150 or 300 million. This will be injected into the submucosal layer of the colon and rectal wall.

Patients will receive a second dose of remestemcel-L at a dose of 150 or 300 million MSCs (same dose as initial). If at 3 months post injection of remestemcel-L there is clinical remission, escalation of medical management and/or surgery will be delayed and patients observed. If there is worsening or no improvement in treated patients, then patients will proceed with escalation of medical management or colectomy as per standard of care. Control patients without improvement will cross over to receive remestemcel-L at 3 months and may be retreated at 6 months. All patients will be followed for two years post initial treatment.

There will be a total of 4 cohorts of 3 patients (2 treatment:1 control) receiving the 150 million MSC dose of study drug and a total of 4 cohorts of 3 patients (2 treatment:1 control) receiving 300 million MSCs dose of study drug. This study plans to enroll a total of 24 participants.

The primary endpoint of this study is to determine the safety and feasibility of endoscopic injection of remestemcel-L, an ex vivo culture expanded allogeneic bone marrow derived mesenchymal stem cell product for treatment of medically refractory ulcerative colitis.

Inclusion Criteria

1. Males and Females 18-75 years of age.

2. Ulcerative colitis of at least 6 months duration with medically refractory symptoms

3. Exposure to corticosteroids, 5-ASA drugs, thiopurines, methotrexate, anti-TNF therapy, anti-integrin and anti-interleukin in the past are permitted but a washout period of 4 weeks for any monoclonal antibody is necessary.

   1. If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks.
   2. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks.
   3. If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks.
   4. If receiving oral corticosteroids, the dose must be ≤20 mg/day prednisone or its equivalent and must have been stable for at least 4 weeks.
   5. If receiving budesonide, the dose must have been stable for at least 2 weeks.
   6. If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks.

4. The following medications/therapies must have been discontinued before first administration of study agent:

   1. TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, golimumab), vedolizumab, ustekinumab for at least 4 weeks.
   2. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks.
   3. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks.
   4. Rectal corticosteroids (ie, corticosteroids [including budesonide] administered to the
   5. rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks.
   6. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks.
   7. Parenteral corticosteroids for at least 2 weeks.
   8. Total parenteral nutrition (TPN) for at least 2 weeks.
   9. Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for at least 2 weeks.

5. No colonic dysplasia and malignancy as ruled out by colonoscopy within 30 days of MSC delivery

6. Ability to comply with protocol

7. Competent and able to provide written informed consent

8. Must have lost response to at least one monoclonal antibody (anti-TNF, anti-interleukin, or anti-integrin therapy), tofacitinib, or have a contra-indication to biologic therapy

9. If patient is of reproductive capacity, willing to use adequate birth control measures while they are in the study

Exclusion Criteria for all patients to join the protocol

1. Inability to give informed consent.

2. Clinically significant medical conditions within the six months before administration of MSCs: e.g. myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient.

3. Specific exclusions;

   1. HIV
   2. Hepatitis B or C

4. Abnormal AST or ALT at screening defined as AST >100 or ALT > 100

5. Abnormal basic laboratory values with the following cut-offs:

   1. Alkaline phosphate >200
   2. WBC >13
   3. Hemoglobin <7
   4. Platelets <50 or > 1 million
   5. Creatinine >1.5

6. History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment

7. Investigational drug within one year of study enrollment

8. Pregnant or breast feeding.

9. Fulminant colitis requiring emergency surgery

10. Concurrent active clostridium difficile infection of the colon

11. Concurrent CMV infection of the colon

12. Evidence of colonic perforation

13. Massive hemorrhage from the colon requiring emergent surgery

14. Crohn's colitis or indeterminate colitis

15. Microscopic, ischemic or infectious colitis

16. Neoplasia of the colon and preoperative biopsy

17. Presence of an ostomy

18. Prior small bowel resection

19. Previous colonic resection

20. Colonic stricture that unable to pass an adult colonoscope

21. Active or latent tuberculosis

22. Unable to wean off corticosteroids

23. Patients with extra colonic ulcerative colitis including primary sclerosing cholangitis

24. Patients with history of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 90 days of study entry

25. Patients with known allergy to local anesthetics

26. Patients with a known allergy to DMSO, porcine and/or bovine proteins

27. Patients taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix) to reduce the risk of bleeding/ hemarthrosis

28. If patient is of reproductive capacity, unwilling to use adequate birth control measures while they are in the study

Control patients will have additional criteria that need to be met prior to the patients crossing over to receive treatment.

Inclusion Criteria for control patients prior to entering the treatment phase:

1. Received placebo at the point of first injection
2. Completed all study visits to date
3. Clinical status has remained the same or improved, not worsened

Exclusion Criteria for control patients who will be entering the treatment phase:

1. Required repeat hospitalization for a colitis flare
2. Given oral and intravenous steroids for a colitis flare
3. Had worsening abdominal pain frequency of bowel movements, blood in stool
4. Desires exclusion from the study to pursue escalation in medical management or surgery Allogeneic Bone
5. Has a colonic perforation that requires surgery
6. Has colonic bleeding that requires surgery