Envarsus XR (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies were conducted in male and female rats and mice. In the 80-week mouse oral study and in the 104-week rat oral study, no relationship of tumor incidence to tacrolimus dosage was found. The highest dose used in the mouse was 3mg/kg/day (0.84 times the AUC at the recommended clinical dose of 0.14 mg/kg/day ) and in the rat was 5 mg/kg/day (0.24 times the AUC at the recommended clinical dose of 0.14 mg/kg/day) [see Boxed Warning and Warnings and Precautions (5.1)].

A 104-week dermal carcinogenicity study was performed in mice with tacrolimus ointment (0.03%-3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or 3.3-354 mg/m2 /day. In the study, the incidence of skin tumors was minimal and the topical application of tacrolimus was not associated with skin tumor formation under ambient room lighting. However, a statistically significant elevation in the incidence of pleomorphic lymphoma in high-dose male (25/50) and female animals (27/50) and in the incidence of undifferentiated lymphoma in high-dose female animals (13/50) was noted in the mouse dermal carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment; 2.5-fold the human exposure in stable adult renal transplant patients converted from tacrolimus immediate-release product to ENVARSUS XR). No drug-related tumors were noted in the mouse dermal carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment). The relevance of topical administration of tacrolimus in the setting of systemic tacrolimus use is unknown.

The implications of these carcinogenicity studies are limited; doses of tacrolimus were administered that likely induced immunosuppression in these animals, impairing their immune system’s ability to inhibit unrelated carcinogenesis.

Mutagenesis

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Impairment of Fertility

Tacrolimus subcutaneously administered to male rats at paternally toxic doses of 2 mg/kg/day (2.3 times the recommended clinical dose based on body surface area) or 3 mg/kg/day (3.4 times the recommended clinical dose based on body surface area) resulted in a dose-related decrease in sperm count. Tacrolimus administered orally at 1mg/kg (1.2 times the recommended clinical dose based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre- and post-implantation loss and increased numbers of undelivered and nonviable pups. When administered at 3.2 mg/kg (3.7 times the recommended clinical dose based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

14 CLINICAL STUDIES

14.1 Clinical Studies in De Novo Kidney Transplant Recipients

Study 1

Study 1 (NCT 01187953) was a Phase 3, 12-month, randomized, double-blind, multinational study comparing once daily ENVARSUS XR (N=268) to twice daily tacrolimus [immediate-release] capsules (N=275) in patients who received a de novo kidney transplant. Patients received the first dose of the study drug anytime within 48 hours of graft reperfusion. All patients received only IL-2 receptor antagonist induction therapy and concomitant treatment with mycophenolate mofetil (MMF) and corticosteroids. Approximately 97% of all patients received antibody induction therapy with basiliximab and 91% of all patients received corticosteroids and MMF.

The mean age of the study population was 46 years; 65% were male; 77% were Caucasian, 5% were African-American, 4% were Asian and 14% were categorized as other races. Living donors provided 49% of the organs and 51% of patients received a kidney transplant from a deceased donor. Patients with clinically relevant ECG abnormalities (including QTc prolongation and reversible ischemia) and clinically symptomatic congestive heart failure or patients with documented left ventricular ejection fraction of less than 45% were excluded. Patients with a panel reactive antibody (PRA) >30%, who received a kidney from a non-heart-beating donor or with cold ischemia time >30 hours were also excluded. Premature discontinuation from treatment at the end of one year occurred in 22% of ENVARSUS XR patients and 19% of tacrolimus [immediate-release] capsules patients.

Tacrolimus Therapy

In Study 1, de novo kidney transplant patients were dosed initially at a starting dosage of 0.17 mg/kg given once daily for ENVARSUS XR (approximately 1.2-fold higher than the recommended starting dosage) and 0.1 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsule, with doses then modified to maintain tacrolimus trough concentrations between 6-11 ng/mL for the first 30 days and then between 4-11 ng/L for the remainder of the study. In the first week of dosing, the tacrolimus doses administered were, on average, ~40% higher in the ENVARSUS XR group compared to the tacrolimus capsule group and were similar in both treatment groups from Day 10 to Week 3. Thereafter, tacrolimus doses were, on average, 10% to 20% lower for ENVARSUS XR than in the tacrolimus capsule group.

Tacrolimus whole blood trough concentrations were monitored on Days 2, 3, 4, 7, 10, 14, 21, 30, 45, 60, 90, 120, 180, 270, and 360. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above and below the target tacrolimus trough concentration range of 6 to 11 ng/mL was 33%, 39%, and 28%, respectively, compared to 27%, 12%, and 61%, in the tacrolimus [immediate release] capsule group. The average tacrolimus trough concentrations (per local laboratory reading) for the ENVARSUS XR group were above the target range during the first week post-transplant, and higher than in the tacrolimus capsule group during the first 2 weeks post-transplant (see Figure 1). Thereafter, the mean tacrolimus trough concentrations were similar between the treatment groups.

Figure 1. Study 1 Tacrolimus Trough Concentrations by Treatment Group and Visits

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(click image for full-size original)

Concomitant Immunosuppressive Drugs

In Study 1, the concomitant use of mycophenolate products was comparable between the ENVARSUS XR and tacrolimus [immediate-release] capsule treatment groups. Patients in both groups started MMF at an average dose of 1 gram twice daily. The MMF daily dose was reduced to less than 2 grams over the course of the study; the mean MMF equivalent total daily dose was approximately 1.5 grams at Month 12 in both treatment groups. Likewise, the average doses of corticosteroids were comparable between the two treatment groups throughout the 12-month study period. Majority (96% ENVARSUS XR and 99% tacrolimus [immediate-release] capsules) of the patients received two 20 mg doses of basiliximab for antibody induction.

Efficacy Results

The efficacy failure rates including patients who developed biopsy-proven acute rejection (BPAR), graft failure, death, and/or lost to follow-up at 12 months, as well as the rates of the individual events, are shown by treatment group in Table 10 for the intent-to-treat population.

Table 10. Incidence of BPAR, Graft Loss, Death or Lost to Follow-up at 12 Months in De Novo Kidney Transplant Patients in Study 1

a 95% CI was calculated using normal approximation.
ENVARSUS XR, MMF, steroids, and IL-2 receptor antagonist induction therapy N=268 Tacrolimus [Immediate-Release] capsules, MMF, steroids, and IL-2 receptor antagonist induction therapyN=275
Overall Treatment Difference of efficacy failure compared to tacrolimus immediate-release (95% CI)a -1.0% (-7.6%, 5.6%)
Treatment Failure50 (18.7%)54 (19.6%)
Biopsy Proven Acute Rejection 36 (13.4%)37 (13.5%)
Graft Failure9 (3.4%)11 (4.0%)
Death 8 (3.0%)8 (2.9%)
Lost to Follow-up4 (1.5%)5 (1.8%)

Glomerular Filtration Rates

Renal function was assessed as change from Day 30 (baseline) by eGFR calculated using the MDRD7 equation. Baseline eGFR values were 53.8 ml/min/1.73 m2 and 54.4 ml/min/1.73 m2 , and 12 month eGFR values were 58.6 ml/min/1.73 m2 and 59.8 ml/min/1.73 m2 in the ENVARSUS XR and the tacrolimus [immediate-release] capsule groups, respectively, maintaining the small difference of approximately 1ml/min/1.73 m2 between the treatment groups.

Study 2

Study 2 (NCT 00765661) was an open-label Phase 2 study conducted in de novo kidney transplant patients randomized to once daily ENVARSUS XR (N=32) or twice daily tacrolimus [immediate-release] capsule(N=31). The study was conducted in the US and patients received an organ from a deceased or living donor. Pharmacokinetics were evaluated during the first 2 weeks with an additional 50-week treatment and follow-up to evaluate safety and efficacy.

Study 2 did not have any exclusion criteria based on cardiac disease or ECG findings but patients who received a kidney from a non-heart-beating donor or with cold ischemia time ≥ 36 hours were excluded. Patients were randomized within 12 hours after transplantation and received the first dose of the study drug within 48 hours of graft reperfusion. Induction treatment and concomitant immunosuppressive therapy were allowed per center-specific practices.

The mean age of study population was 47 years (range 23-69); 68% were male; 75% were Caucasian, 21% were African- American, 5% were Asian. Two patients in each group withdrew early from the study due to adverse events.

Tacrolimus Therapy

In Study 2, de novo kidney transplant patients received a starting dosage of 0.14 mg/kg/day (given once daily) for ENVARSUS XR and 0.20 mg/kg/day (given twice daily) for tacrolimus [immediate-release] capsule. On Day 2 predose, the proportion of patients in the ENVARSUS XR group with tacrolimus trough concentration that were within, above, and below 6 to 11 ng/mL was 53%, 11%, and 37%, respectively. In Study 1, the proportion of de novo kidney transplant patients receiving a starting dose of 0.1 mg/kg/day of tacrolimus capsules that were within, above, and below 6 to 11 ng/mL on Day 2 predose was 27%, 12%, and 61%, respectively.

Concomitant Immunosuppressive Drugs

In Study 2, concomitant therapy with mycophenolate products or azathioprine, corticosteroids, and antibody induction was permitted but not required. The mean daily MMF, prednisone, and antibody induction doses were similar between the ENVARSUS XR and tacrolimus capsules treatment groups.

Efficacy

There were no deaths or graft failures in Study 2. Acute rejection rates at 12 months were 3.1% (1/32) in the ENVARSUS XR group and 6.5% (2/31) in the tacrolimus capsules group and 2 patients (one in each group) were lost to follow-up.

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