Vedolizumab Monotherapy Vs Combination Therapy With Tacrolimus in UC

Phase III studies have shown that patients with UC who received vedolizumab had a higher rate
of clinical response, clinical remission and mucosal healing when compared to placebo3.
Nevertheless, while clinical response rate was almost 50%, the rate of clinical remission at
6 weeks was only 16.9. In comparison, in the ACT trials almost 40% of patients achieved
remission at week 84. The delayed onset of action of vedolizumab monotherapy in patients with
UC may lead to a higher colectomy rate and limit the use of vedolizumab in patients with
active disease who require rapid induction of remission. Corticosteroids are used as a
bridging agent to rapidly induce remission. However, steroid refractory or dependent disease
and steroid intolerance are common. Furthermore, steroids have devastating side effects.

Tacrolimus inhibits the complexion of calcineurin with its respective cytoplasmic receptors
cyclophilin and FK-binding protein 12 (FKBP-12), both of which regulate a calmodulin
dependent-phosphatase. Tacrolimus has been found to be efficacious in the treatment of
patients with moderate to severe UC. Unfortunately, because of the safety profile with long
term use, the drug is mostly used as an induction agent.

While switching to vedolizumab from another drug that has not been efficacious or has lost
effectiveness (or starting vedolizumab as a first agent) can be beneficious in the long term,
patients need an induction agent in order to achieve remission in a short period of time.
Tacrolimus is a widely used drug to prevent implant rejection after a transplant. Randomized
controlled trials have shown that is highly effective with good response rates even after 2
weeks of therapy. In order to avoid side effects, tacrolimus is usually used for a limited
amount of time (12-14 weeks), which is sufficient time to induce remission of disease.
Unfortunately, as other inflammatory bowel diseases, UC recurs and patients also require a
maintenance therapy. While tacrolimus has been used with good results as a long term agent,
the ideal scenario is to avoid its long term use as there is still a potential for side
effects and a need for a very strict close monitoring. This is why a long term maintenance
agent is needed to keep the patient in remission. Until recently, no ideal agent was
available for this purpose, as while anti-tumor necrosis factor agents (infliximab and
adalimumab) have been approved for ulcerative colitis, its combination with another agent
that induces systemic immunosuppression (in this case, tacrolimus) could potentially increase
the risk of infections and/or malignancies. Because vedolizumab is gut selective, does not
affect the entire immune system and post-marketing studies have confirmed its safety profile.
This makes it a perfect combination agent to tacrolimus, theoretically decreasing the
potential side effect while increasing its efficacy.

The hypothesis is that the addition of tacrolimus as an induction agent to a standard regimen
of vedolizumab increases the efficacy of the drug, decreasing the rate of need for colectomy
and other complications while quickly improving the patients' quality of life without
significantly increasing the risk of adverse events.

Inclusion Criteria:

1. Patients aged 18 to 65 years with a confirmed diagnosis of UC.

2. Diagnosis of UC established at least 6 months before enrollment or evidence of
chronicity in colonic biopsies.

3. Patients with UC disease extent beyond 15 cm (must involve at least the sigmoid colon)

4. In female patients:

- Post-menopausal for ≥1 year before screening, or

- Surgically sterile, or

- Agree to be on a contraceptive method from the screening visit through 4 weeks
after discontinuing tacrolimus (or placebo), or

- Completely abstain from heterosexual intercourse.

5. In male patients:

o Agreement not to father a child through 4 weeks after discontinuing tacrolimus
(through contraception or abstinence).

6. Moderate to severe UC

- Mayo Clinic partial UC score of 6 to 12, with a baseline sigmoidoscopy sub-score
of at least 2, and disease that extended 15 cm or more from the anal verge.

- Steroid dependent patients (Appendix 1)

- Steroid naïve or steroid responsive

7. Patients are planned to start vedolizumab as part of their clinical care.

8. 5-aminosalicilates (oral or topical) are permitted as long as the dose is stable for
at least 2 weeks before screening.

9. Patients with or without previous exposure to anti-TNF agents can be included.
Patients with previous exposure to anti-TNF must be off infliximab for 8 weeks and off
adalimumab for 4 weeks.

10. Anti-diarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic
diarrhea are not permitted.The patient must be off anti-diarrheal at the time of
screening.

11. Immunosupressants (thiopurines or methotrexate) must be stopped 4 weeks prior to
starting the study medications.

12. Patients with previous Clostridium Difficile infection can be included as long as they
received a full course of therapy and have a negative Clostridium Difficile PCR test
and are infection free for 60 days prior to screening.

Exclusion Criteria:

1. Positive stool test for parasites or stool culture for pathologic bacteria within 30
days prior to enrollment.

2. Evidence or history of Clostridium Difficile infection within 60 days prior to
enrollment.

3. Active Cytomegalovirus (CMV) infection evidenced by a positive CMV PCR in serum and/or
positive immunohistochemistry stain in colonic tissue.

4. Uncontrolled hypertension.

5. Chronic kidney disease (defined as a glomerular filtration rate < 60 mL/min,
calculated using the Modification of Diet in Renal Disease (MDRD) formula)

6. Chronic liver disease.

7. A refractory electrolyte disorder (e.g. hypomagnesemia).

8. Persistent hypomagnesemia that does not respond to oral magnesium supplementation
defined as a value <1.3 mEq/L in two separate readings, despite the administration of
oral magnesium [10 meq of slow-release magnesium chloride three times per day for 48
hours].

9. Persistent hypophosphatemia defined as levels <2.2 mg/dL in two separate readings, 48
hours apart despite phosphate supplementation (sodium phosphate/potassium phosphate
500 mg up to three times daily for 48 hours).

10. Creatinine values of 1.5 mg/dL in 2 separate readings.

11. Established diagnosis of diabetes mellitus.

12. Clinical or radiological evidence of megacolon.

13. Intestinal perforation, or abdominal abscess within 3 months prior to enrollment.

14. Active clinically significant bacterial infection (within 30 days of enrollment).

15. Personal history of total or sub-total colectomy.

16. Current Pregnancy or lactation.

17. Unstable or uncontrolled medical disorder.

18. Personal history of malignant neoplasm.

19. Inability to give informed consent.

20. History of alcohol or illicit drug abuse in the previous 6 months to enrollment.

21. Patient that have received any experimental drug within 6 months prior to enrollment.

22. Patients with previous exposure to vedolizumab, cyclosporine or tacrolimus.

23. Personal history of congenital or acquired immunodeficiency (eg, common variable
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation)
excluding pharmacologic immunosuppressant.

24. Any of the following laboratory abnormalities during the screening period:

1. Hemoglobin level <9 g/dL

2. WBC count <3 × 109/L

3. Lymphocyte count <0.5 × 109/L

4. Platelet count <100 × 109/L or >1200 × 109/L

5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × the upper
limit of normal (ULN)

25. To avoid interactions, patients on medications that induce or inhibit the Cytochrome
p450 family 3, subfamily A (CYP3A) will be excluded. CYP3A inducers and inhibitors are
shown in Appendix 3