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.

Targeted endoscopic delivery of remestemcel-L, at a dose of 150 million cells into the submucosal layer of the colon wall at baseline If at 3 months post injection of remestemcel-L there is clinical, endoscopic or radiographic improvement, patients will receive a second dose of remestemcel-L at a dose of 150 million MSCs (same dose at initial)

Targeted endoscopic delivery of remestemcel-L, at a dose of 300 million cells into the submucosal layer of the colon wall at baseline. If at 3 months post injection of remestemcel-L there is clinical, endoscopic or radiographic improvement, patients will receive a second dose of remestemcel-L at a dose of 300 million MSCs (same dose at initial).

Direct injection of normal saline into the submucosal layer of the colon wall. If not completely healed after 3 months, participants will then cross over to the treatment group to receive a direct injection of remestemcel-L, at a dose of 150 or 300 million cells into the submucosal layer of the colon wall. If at 6 months post injection of remestemcel-L there is clinical, endoscopic or radiographic improvement, patients will receive a second dose of remestemcel-L at a dose of 150 or 300 million MSCs (same dose at initial).

adult allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory Crohn's colitis

adult allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory Crohn's colitis

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

Number of participants with complete clinical healing post-injection of 150 or 300 million bone marrow allogeneic derived mesenchymal stem cells for the treatment of medically refractory Crohn's colitis. Complete healing is defined as: Clinical and endoscopic remission Clinical Healing: Normalization of CRP to <2.87 mg per liter, CDAI drops to <150 Radiographic Healing: MR enterography with improvement of inflammation Endoscopic healing: Absence of mucosal ulceration and SES-CD score of 0-5

Number of participants with clinical response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory Crohn's colitis. Clinical response is defined as: Clinical Healing: Normalization of CRP to <2.87 mg per liter, CDAI drops to <150 Radiographic Healing: MR enterography with improvement of inflammation Endoscopic healing: Absence of mucosal ulceration and SES-CD score of 0-5

Number of participants with partial clinical response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory Crohn's colitis. Partial clinical response is defined as: Clinical Healing: >25% reduction of CRP, decrease in CDAI by <100 points Radiographic Healing: MR enterography with improvement in inflammation Endoscopic healing: Decreased SES-CD by >25% but < 50% or to score of 10-15

Number of participants with lack of response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory Crohn's colitis. Lack of response is defined as: Clinical Healing: No improvement Radiographic Healing: MR enterography without resolution of inflammation Endoscopic healing: No improvement in SES-CD

Crohn's disease activity index will be used to measure quality of life in participants. *Remission of Crohn's disease is defined as CDAI below 150. Severe disease is defined as a value of greater than 450.

Inflammatory bowel disease questionnaire will be used to measure quality of life in participants. *Score ranges from 32 (best health) to 224 (worst health)

EuroQol 5 Dimensions survey will be used to measure quality of life in participants. *Score ranges from 5 (full health) to 25 (worst health).

IBD-patient reported treatment impact survey will be used to measure quality of life in participants. *Score ranges from 3 (most satisfied) to 15 (least satisfied)

Short Form 36 health survey will be used to measure quality of life in participants. *Score ranges from 0 (least favorable health state) to 3600 (most favorable health state)

Inclusion Criteria for all patients to join the protocol Males and Females 18-75 years of age. 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. 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. 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. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks. 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. If receiving budesonide, the dose must have been stable for at least 2 weeks. If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks. The following medications/therapies must have been discontinued before first administration of study agent: TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, golimumab), vedolizumab, ustekinumab for at least 4 weeks. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks. Rectal corticosteroids (ie, corticosteroids [including budesonide] administered to the rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks. Parenteral corticosteroids for at least 2 weeks. Total parenteral nutrition (TPN) for at least 2 weeks. Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for atleast 2 weeks. No colonic dysplasia and malignancy as ruled out by colonoscopy within 30 days of MSC delivery Ability to comply with protocol Competent and able to provide written informed consent 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 Inability to give informed consent. 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. Specific exclusions; HIV Hepatitis B or C Abnormal AST or ALT at screening defined as > 3x upper limit of normal? History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment Investigational drug within one year of study enrollment Pregnant or breast feeding. If patient is of reproductive capacity, unwilling to use adequate birth control measures while they are in the study Fulminant colitis requiring emergency surgery Concurrent active clostridium difficile infection of the colon Concurrent CMV infection of the colon Evidence of colonic perforation Massive hemorrhage from the colon requiring emergent surgery Ulcerative colitis or indeterminate colitis Neoplasia of the colon on preoperative biopsy Presence of an ostomy Three or more prior small bowel resections Colonic stricture that unable to pass an adult colonoscope Active or latent tuberculosis Unable to wean off corticosteroids Patients with primary sclerosing cholangitis 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: Received placebo at the point of first injection Completed all study visits to date Clinical status has remained the same or improved, not worsened Exclusion Criteria for control patients who will be entering the treatment phase: Required repeat hospitalization for a colitis flare Given oral and intravenous steroids for a colitis flare Had worsening abdominal pain frequency of bowel movements, blood in stool Desires exclusion from the study to pursue escalation in medical management or surgery Has a colonic perforation that requires surgery Has colonic bleeding that requires surgery