Extended Release Tacrolimus vs. Twice-Daily Tacrolimus

Kidney transplantation is the treatment of choice for most patients with end-stage renal
disease. Lifelong immunosuppressive therapies are required to prevent organ rejection.
However, long term exposure to immunosuppressive therapy after kidney transplantation can
place patients at risk for multiple adverse events. The optimal immunosuppressive therapy is
not well established. Tacrolimus, a calcineurin inhibitor (CNI) is highly effective in
preventing acute rejection after organ transplantation (2). It is used as part of the
immunosuppression regimen for the majority of kidney and liver transplant recipients (3).
However, treatment with current formulation of Tacrolimus generates high peaks and low
troughs in drug concentrations in the blood. It is known that high exposure to CNI is
associated with renal toxicities and adverse events (4). New once-daily dosage formulations
are now developed with the hope of minimizing side effects while maintaining excellent
outcomes (5-8).

LCP-Tacro (Envarsus® XR, Veloxis Pharmaceuticals), a new once-daily formulation of
tacrolimus, was approved by the FDA in 2015 for conversion from twice-daily tacrolimus in
kidney transplant recipients. It is a prolonged-release tacrolimus formulation, utilizing a
MeltDose drug delivery technology designed to improve the bioavailability of drugs with low
water solubility (1). Recent clinical data demonstrated that once-daily LCP-Tacro has
improved pharmacokinetic bioavailability, rapid achievement of therapeutic trough levels,
less fluctuation and swing in whole blood concentration, non-inferior efficacy and similar
safety, with lower tacrolimus dose than other tacrolimus formulations.

The target population is adult recipients of immediately functioning living and deceased
donor renal allografts. Immediate function will be defined as the absence of the need for
hemodialysis in the first week following renal transplantation.

Prospective randomized single center open label study of 2 groups of kidney transplant
patients

- Group 1 : standard of care (SOC) control group will receive tacrolimus twice-daily
(n=25)

- Group 2 : LCP-Tacro (Envarsus® XR) group will receive LCPT tablets once daily (n=25)

Inclusion Criteria:

1. Patients who are males or females aged 18-65 years. 2. Use of the following induction
medications: basiliximab and rituximab. 2. Donors aged 18-65 years. 3. No prior organ
transplant 4. Patients who are single-organ recipients (kidney only). 5. Women who are of
childbearing potential must have a negative serum pregnancy test before transplantation and
agree to use a medically acceptable method of contraception throughout the treatment
period.

6. Subject (recipient) is able to understand the consent form and give written informed
consent

Exclusion Criteria:

1. Delayed graft function (please see above).

2. Known sensitivity or contraindication to alemtuzumab, Envarsus® XR, tacrolimus or MMF.

3. Use of the following induction medications: basiliximab and rituximab

4. Patient with significant or active infection.

5. Patients with a positive flow cytometric crossmatch using donor lymphocytes and
recipient serum.

6. Patients with PRA > 40%

7. Patients with current or historic donor specific antibodies

8. Body Mass Index (BMI) of < 18 or > 35

9. Patients who are pregnant or nursing mothers.

10. Patients whose life expectancy is severely limited by diseases other than renal
disease.

11. Ongoing active substance abuse, drug or alcohol.

12. Major ongoing psychiatric illness or recent history of noncompliance.

13. Significant cardiovascular disease (e.g.):

- Significant non-correctable coronary artery disease;

- Ejection fraction below 30%;

- History of recent myocardial infarction.

14. Malignancy within 3 years, excluding non-melanoma skin cancers.

15. Serologic evidence of infection with HIV or HBVs-Ag positive.

16. Patients with a screening/baseline total white blood cell count < 4,000/mm3; platelet
count < 100,000/mm3; triglyceride > 400 mg/dl; total cholesterol > 300 mg/dl.

17. Investigational drug within 30 days prior to transplant surgery.

18. Anti-T cell therapy within 30 days prior to transplant surgery.

19. Diagnosis of atypical-Hemolytic Uremic Syndrome (aHUS).

20. Subjects transplanted with a Hepatitis C NAT-positive kidney.