Study of Mesenchymal Stem Cells for the Treatment of Medically Refractory Crohn's Colitis

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 Crohn's Colitis

Crohn's disease has several phenotypes (inflammatory, stricturing, fistulizing) and location (small bowel, ileocecal, colon, and perianal). Approximately one third of patients have inflammation limited to the colon. Up to two thirds will become medically refractory and require a total abdominal colectomy for symptom control. The purpose of this study is to determine the safety and efficacy of using allogeneic bone marrow derived mesenchymal stem cells (MSCs) delivered by targeted endoscopic delivery to treat people for medically refractory Crohn's colitis.

Participants with medically refractory Crohn's 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 Crohn's colitis.

Inclusion Criteria for all patients to join the protocol

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

2. Crohn's colitis of at least 6 months duration with medically refractory symptoms who has failed one anti-TNF therapy, with a next step of subtotal colectomy or escalation in medical management.

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.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.
   4. If receiving budesonide, the dose must have been stable for at least 2 weeks.
   5. 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 atleast 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), or tofacitinib, or have a contra-indication to biologic therapy

Exclusion Criteria

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
   3. Abnormal AST or ALT at screening defined as > 3x upper limit of normal?

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

5. Investigational drug within one year of study enrollment

6. Pregnant or breast feeding.

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

8. Fulminant colitis requiring emergency surgery

9. Concurrent active clostridium difficile infection of the colon

10. Concurrent CMV infection of the colon

11. Evidence of colonic perforation

12. Massive hemorrhage from the colon requiring emergent surgery

13. Ulcerative colitis or indeterminate colitis

14. Neoplasia of the colon on preoperative biopsy

15. Presence of an ostomy

16. Three or more prior small bowel resections

17. Colonic stricture that unable to pass an adult colonoscope

18. Active or latent tuberculosis

19. Unable to wean off corticosteroids

20. Patients with primary sclerosing cholangitis

21. Patients with a known allergy to DMSO, porcine and/or bovine proteins. 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
5. Has a colonic perforation that requires surgery
6. Has colonic bleeding that requires surgery