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Once-a-Day or Twice-Daily Tacrolimus as Effective as Cyclosporine in Kidney Transplant Recipients

Additional Milligram-to-Milligram Conversion Studies Demonstrates Safety and Efficacy of Prograf(R) and Prograf MR(TM)

BOSTON, MA -- August 3, 2006 -- Study results presented today at the World Transplant Congress (WTC) demonstrated that investigational drug, once-daily Prograf MR(TM) (Modified Release) (tacrolimus or TAC) and twice-daily standard Prograf(R) (tacrolimus or TAC) are as effective as Neoral(R) (cyclosporine or CsA) in de novo kidney transplant recipients.

Prograf MR is a modified release version of the FDA-approved twice-daily formulation of Prograf, which is a leading immunosuppressive agent used to treat patients who have received kidney, liver or heart transplants. Both formulations of Prograf also showed significantly less treatment failure and better renal function than patients treated with Neoral.

Additionally, studies in adult kidney, adult liver, adult heart and pediatric liver transplant recipients have demonstrated continued maintenance of the efficacy and safety of milligram-to-milligram conversion of twice-daily Prograf to once-daily Prograf MR.

One of the studies presented at the WTC was the one-year follow-up results in pediatric liver transplant recipients converted from Prograf to Prograf MR. Recipients enrolled in the study were between the ages of five and 12 and were evaluated based on dosing and trough levels, laboratory values, concomitant medications, graft survival and adverse events. In the 18 pediatric transplant recipients taking Prograf MR for one year, there were no patient deaths, no graft losses, no acute rejection and laboratory values remained stable.

Most transplant patients are prescribed a multitude of medications that require multiple dosing at various times throughout the day. According to an article in the journal Transplantation(1), depending on the post-transplant time-frame and measurement method, non-adherence rates for transplant recipients can be more than 45%, due to the number of medications and the regimented schedule of taking those medications.

"A number of recent studies indicate that non-adherence has become a vital issue afflicting transplant patients," said Paul C. Kuo, MD, Chief of the Division of General Surgery at Duke University and study investigator. "The availability of a once-daily formulation could increase the number of patients adhering to their medication regimen."

Phase 3 Study to Compare Twice-Daily Prograf and Once-Daily Prograf MR to Neoral in De Novo Kidney Recipients

A prospective, randomized, open label study to confirm the safety and efficacy failure rate of once-daily modified release tacrolimus (MR) or twice- daily tacrolimus (TAC) versus cyclosporine ME (CsA). In this multi-center, non-inferiority study, 638 de novo adult kidney transplant recipients were randomized 1:1:1 and received MR, TAC or CsA. All patients received standard basiliximab induction, MMF and corticosteroids. The primary efficacy endpoint, efficacy failure was a composite primary end point of death, graft loss, biopsy confirmed acute rejection (BCAR) and lost to follow-up. A pre- specified non-inferiority margin of 10% was used to compare efficacy failure rate.

There was no difference in demographics and baseline characteristics among all groups. For efficacy failure rate, both MR and TAC groups were non- inferior to CsA/MMF and had significantly less treatment failure and crossover due to treatment failure. The one-year results found both MR and TAC groups had significantly better renal function, less use of antibody therapy for rejection (3.7%, 2.8% compared to 8.5%) and better lipid profiles (LDL cholesterol; 102.4mg/dL, 97.09mg/dL compared to 113.4mg/dL) than CsA/MMF. There was a significantly higher incidence of glucose intolerance in TAC/MMF (74.7%) compared to CsA/MMF (61.2%).

One Year Follow-Up Study of Pediatric Liver Recipients Converted from Twice-Daily Prograf to Once-daily Prograf MR(TM)

Study assessed the safety and efficacy one year following conversion from tacrolimus (TAC) twice daily (BID) to Modified Release (MR) tacrolimus once daily (QD) in stable pediatric liver transplant recipients. After completing a pharmacokinetic study (days 0-14), which indicated that mg-for-mg conversion from TAC to MR resulted in equivalent TAC exposure, 18 pediatric liver transplant recipients (5 males, 13 females) were subsequently maintained on MR QD.

Patients were evaluated for MR dosing and trough levels, laboratory values, concomitant medications, graft survival and adverse events. The mean dose of MR was 5.3 mg/day at conversion and was 5.4 mg/day at one year, and the corresponding mean TAC trough concentrations were 5.5 ng/mL and 4.9 ng/mL, respectively. No significant changes in laboratory parameters were observed during the PK portion of the study and one year follow-up period.

About Prograf(R) (tacrolimus)
Prograf(R) is indicated for the prophylaxis of organ rejection in patients receiving a liver, kidney, or heart transplant in the US. Prograf has been marketed in North America, Europe and Japan, and is commercially available in more than 70 countries.

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Prograf. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Insulin-dependent post-transplant diabetes mellitus was reported in 11% to 22% of Prograf-treated liver, kidney, and heart transplant patients with no prior history of diabetes mellitus, but was reversible in some patients. Black and Hispanic kidney transplant patients were at increased risk. Prograf has been associated with nephrotoxicity, particularly when used in high doses.

Common adverse reactions include tremor, headache, hypertension, gastrointestinal disturbance, abnormal renal function, hyperglycemia, leukopenia, CMV infection, infection, and hyperlipemia. Prograf is contraindicated in patients with a hypersensitivity to tacrolimus. Prograf injection is contraindicated in patients with a hypersensitivity to castor oil.

REFERENCE:
1. Greenstein, Stuart and Bonita Siegal. "Compliance and Noncompliance in Patients with a Functioning Renal Transplant: A Multicenter Study 1, 2." Transplantation: Volume 66(12), 27 December 1998, pp 1718-1726.

Neoral(R) is a registered trademark of Novartis Pharmaceuticals.


SOURCE: Astellas US LLC

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