DB-3Q bmMSC-EVs in Patients With Perianal Fistulizing Crohn's Disease

A Phase 2a Study of Allogeneic Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicle Isolate Product (DB-3Q) in Patients With Perianal Fistulizing Crohn's Disease

This is a double-blind, randomized, placebo-controlled, sequential cohort, ascending dose clinical trial to evaluate the safety and determine the efficacy of ascending doses of DB-3Q for the treatment of Perianal Fistulizing Crohn's Disease.

Inclusion Criteria:

1. Written informed consent from participant
2. Men and women 18-75 years of age with a diagnosis of Crohn's Disease for at least six months duration prior to Day 1
3. One or two perianal fistula(s) with 1 or two external openings, that are actively draining
4. Failed at least one medical therapy within the last year including, but not limited to, antibiotics, immunomodulators (6-MP, methotrexate, azathioprine), monoclonal antibodies (adalimumab, certolizumab, golimumab, guselkumab, infliximab, risankizumab, ustekinumab, vedolizumab), or small molecule inhibitors (tofacitinib, upadacitinib)
5. Previous failed surgical intervention, including seton placement at least two weeks prior to screening, or are not candidates for surgical intervention or are not willing to undergo surgical intervention for the management of their fistula
6. Medical therapy for CD stable for at least 2 months prior to Day 1 (Changes in dosing or dosing intervals related to serum drug levels are not permitted)
7. Antibiotics for the treatment of CD (e.g., ciprofloxacin, metronidazole, or rifaximin) must have been stable for at least 2 weeks prior to Day 1
8. Oral corticosteroids ≤ 20 mg/day prednisone or its equivalent and must have been stable for at least 4 weeks prior to Day 1
9. Approval of a screening pelvic MRI by review of a central radiologist. The definition of an acceptable screening pelvic MRI is provided in the study imaging manual.
10. Fulfillment of radiologic inclusion by a central radiologist. Radiologic inclusion on MRI is presence of 1 or 2 qualifying perianal fistula(s). Radiologic inclusion assesses anatomic criteria of a perianal fistula and study-defined imaging endpoint criteria. a. Anatomically, a qualifying perianal fistula on MRI fulfills the following from central radiologist assessment: i. has a communication with the internal sphincter of the anal canal ii. is classified as a Parks intersphincteric, transsphincteric, or suprasphincteric perianal fistula. b. For study imaging endpoints, a central radiologist confirms that a fistula has a minimum score of 7 (range 0 to 25) on MAGNIFI-CD and a fistula fibrosis -to-fluid ratio of less than 80%.25, 37 Within components of MAGNIFI-CD, the fistula has a length of 2.5 cm or greater and has a composition of either 'predominantly fluid/pus' or 'predominantly granulation tissue'. c. Within components of fistula fibrosis-to-fluid ratio, the ratio of hypointense scarring or fibrosis on MRI T2 weighted sequences to hyperintense fluid on MRI T2 weighted sequences is below 80%.25 The fistula is categorized into one of following ranges of fibrosis-to- fluid ratio: i) 0%, ii) 1-19%, iii) 20-39%, iv) 40-59%, or v) 60-79%

Exclusion Criteria

1. Lack of informed consent

2. Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test, or woman who is breast feeding

3. A participant who is unwilling to use medically acceptable contraception methods during participation in study

4. Active perianal abscess or infection at screening or Day 1

5. Clinically significant medical conditions within six months before Day 1 that would, in the opinion of the Investigator, compromise the safety of the participant

6. Confirmed HIV, Hepatitis B, or Hepatitis C infections

7. History of cancer including melanoma (with the exception of localized non-melanoma skin cancers) within one year of screening

8. History of colorectal cancer within 2 years of screening

9. History of coagulation disorders and/or are currently on anti- coagulant therapy

10. Presence of a recto/ano-vaginal fistula

11. Presence of an ileal anal pouch and/or history of proctectomy

12. Presence of severe proctitis (SES CD >6)

13. Any condition which, in the opinion of the Investigator, would make it unsafe or unsuitable for participant to undergo MRI evaluations (i.e., presence of implantable or external MRI unsafe device that cannot be removed, body weight exceeding limitations, claustrophobia, etc.)

14. The following out of range laboratory results at screening

    • WBC > 13 x 109 /L
    • Hemoglobin < 8 g/dL
    • Platelet count < 100,000/mL
    • AST/ALT > 3 times the upper limit of normal
    • Creatinine > 2 μmol/L
    • PT/INR: 2 times the upper limit of normal
    • Hemoglobin A1c > 6.5 mg/dL

15. Use of investigational therapy or treatment within 30 days prior to Day 1

16. Does not meet the radiologic anatomic inclusion criteria: i) has a primary communication with the rectum and not the anal canal; ii) is classified as a Parks extrasphincteric fistula

17. Does not meet the minimum thresholds for the radiologic imaging endpoint inclusion criteria: i) has a MAGNIFI-CD score of <7 (range 0-6) on screening pelvic MRI; ii) has a fibrosis-to-fluid ratio of 80% or more (range 80-100%) on screening pelvic MRI