Enrollment challenges.

Protocol Summary

• Title: A Phase I study of ExoFlo, an ex vivo culture-expanded adult allogeneic bone marrow mesenchymal stem cell derived extracellular vesicle isolate product, for the treatment of medically refractory ulcerative colitis.
• Short Title: ExoFlo for ulcerative colitis
• Phase: 1
• Methodology: Open label
• Study Duration: 24 months
• Subject Participation: 58 weeks
• Single or Multi-Site: Multi-Site

Primary Objectives:

• To evaluate the feasibility of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
• To evaluate the safety of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.

Secondary Objectives:

• To evaluate the efficacy of intravenous ExoFlo in inducing clinical remission in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
• To evaluate the efficacy of intravenous ExoFlo in inducing clinical response in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
• To evaluate the efficacy of intravenous ExoFlo in improving disease-specific health-related quality of life.
• To evaluate the pharmacokinetics and pharmacodynamics of ExoFlo therapy, including changes in C-reactive protein (CRP) and fecal calprotectin.

Number of Subjects: 10

Diagnosis and Main Inclusion Criteria: Subjects must have medically refractory ulcerative colitis and have no prior intestinal surgery for ulcerative colitis.

Study Product, Dose, Route, Regimen:

IV administration of 15 mL of study agent at Day 0, Day 2, Day 4, and 30 mL at Week 2, Week 6 and every 4 weeks thereafter to week 46 (n=10), (total # doses = 15).

Statistical Methodology: This is a safety study with exploratory assessment of efficacy. The study has insufficient power to confirm efficacy. All assessments of efficacy will be exploratory for the purpose of hypothesis generation in larger sample sizes.

Inclusion Criteria:

1. Males and Females 18-75 years of age

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

   1. Failed to have improvement of disease while receiving at least one monoclonal antibody (infliximab, adalimumab, certolizumab, golimumab, vedolizumab, ustekinumab) or tofacitinib for 8 weeks duration prior to enrollment.
   2. Or is intolerant or has a contra-indication to monoclonal antibodies

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 8 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 be on a stable dose for at least 4 weeks prior to receiving the first dose of the study drug.
   2. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks prior to receiving the first dose of the study drug.
   3. If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks prior to receiving the first dose of the study drug.
   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 prior to receiving the first dose of the study drug.
   5. If receiving budesonide, the dose must have been stable for at least 2 weeks prior to receiving the first dose of the study drug.
   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 prior to receiving the first dose of the study drug.

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

   1. TNF-antagonist therapy (e.g. infliximab, etanercept, certolizumab, adalimumab, golimumab, vedolizumab, ustekinumab) for at least 8 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 rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks.
   5. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks.
   6. Parenteral corticosteroids for at least 2 weeks.
   7. Total parenteral nutrition (TPN) for at least 2 weeks.
   8. 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. Stated willingness to comply with all study procedures and availability for the duration of the study

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

Exclusion Criteria:

1. Inability to give informed consent.

2. Clinically significant medical conditions within the six months before administration of ExoFlo: 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. Patients with confirmed HIV, Hepatitis B, or Hepatitis C infections

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. eGFR < 60
   6. HbA1C > 8%

6. Subjects with abnormal coagulation studies:

   1. Prothrombin time (PT) > 1.5 times the upper limits of normal
   2. Partial thromboplastin time (aPTT) > 1.5 times the upper limits of normal
   3. International normalized ratio (INR) > 1.5 times the upper limits of normal

7. Subjects with hyperbilirubinemia and evidence of liver disease as defined by AST > 100 or ALT > 100 or PT > 1.5 times the upper limits or normal or PT/INR > 1.5 time the upper limits of normal.

8. Subjects with abnormal vital signs prior to first ExoFlo delivery as defined by any of the following:

   1. Systolic blood pressure >160 or <90 mmHg
   2. Diastolic blood pressure >90 or <60 mmHg
   3. Pulse <60 or >105 bpm
   4. Respiratory Rate <9 and >25 breaths per minute
   5. Temperature: >100.4 degrees Fahrenheit
   6. SpO2: <92%

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

10. Investigational drug within one year of study enrollment

11. Pregnant or breast feeding.

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

13. Fulminant colitis requiring emergency surgery

14. Concurrent active clostridium difficile infection of the colon

15. Concurrent CMV infection of the colon via colonic biopsy with CMV stain taken within 90 days

16. Evidence of colonic perforation

17. Massive hemorrhage from the colon requiring emergent surgery in the 6 months prior to screening.

18. Crohn's colitis or indeterminate colitis

19. Microscopic, ischemic or infectious colitis

20. Neoplasia of the colon and preoperative biopsy

21. Presence of an ostomy

22. Prior small bowel resection

23. Previous colonic resection

24. Colonic stricture that unable to pass an adult colonoscope

25. Active or latent tuberculosis

26. Unable to wean off corticosteroids

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

28. 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

29. Patients with known allergy to local anesthetics

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

31. Individuals with previously diagnosed, known inherited or acquired hypercoagulable states

32. Electrocardiogram demonstrating cardiac arrhythmia, except for sinus tachycardia within the predefined limit of no greater than 105 bpm.