Advagraf® Now Approved Across Europe As A Once-daily Immunosuppressant In Organ Transplantation

Main Category: Transplants / Organ Donations
Also Included In: Immune System / Vaccines
Article Date: 30 Apr 2007 - 7:00 PDT

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Astellas announced today that the European Commission has approved the immunosuppressant Advagraf® (generic name: tacrolimus, prolonged release) for prophylaxis of transplant rejection in adult kidney or liver allograft recipients and for the treatment of allograft rejection resistant to treatment with other immunosuppressive drugs in adult patients throughout the European Union (EU).

Advagraf® combines the proven safety and high efficacy of Prograf®, the leading immunosuppressive agent of care for the prevention of rejection in organ transplantation, in a prolonged release formulation that offers patients a convenient, once-daily dosing option.

"A number of studies indicate that non-adherence to medication has become a key concern in transplant patients and the availability of a once-daily dosing regimen represents a highly desirable step forward in patient management," said Professor Johannes van Hooff, Professor of Medicine, Department of Nephrology at University Hospital Maastricht, The Netherlands. "Advagraf® has the potential to improve adherence and hence the long-term efficacy of immunosuppression."

Transplant patients are prescribed a variety of medications that require multiple dosing at various times throughout the day. Because of the variety of medications and the complicated dosing schedule, non-compliance rates for transplant recipients can be over 45 per cent1, resulting in acute and chronic rejection and graft loss2. A recent study in kidney transplant recipients was able to show a statistically significant improvement in adherence associated with once-daily dosing compared with twice-daily dosing regimens3.

Clinical data overview

The EU approval of Advagraf® is based on the results of Phase II trials in liver, kidney and heart transplant patients (n=613) and a phase III trial4 (n=638). These studies have confirmed the safety and efficacy of once-daily Advagraf® to be similar to that of twice-daily Prograf®.

The 638 adult kidney transplant recipients in the Phase III trial were randomised 1:1:1 and received Advagraf®, Prograf® or ciclosporin. All patients received standard basiliximab induction, mycophenolate mofetil (MMF) and corticosteroids. The primary efficacy endpoint was the efficacy failure rate - a composite endpoint that included all patients who died, had graft loss (returned to dialysis or re-transplanted), biopsy proven acute rejection (BPAR) or lost to follow-up. A pre-specified non-inferiority margin of 10% was used to compare efficacy failure rate.

The demographics and baseline characteristics among all groups were similar. The one-year results showed that for efficacy failure rate, both Advagraf® and Prograf® groups were non-inferior to ciclosporin and had significantly less treatment failure and crossover due to treatment failure. Overall, the side-effect profiles of Advagraf® and Prograf® were comparable. One-year patient and graft survival were comparable between Advagraf (98.6% and 96.7%) and Prograf (95.7% and 92.9%).

The Advagraf® and Prograf® groups had significantly higher creatinine clearance (Cockcroft & Gault estimates: 58.7 mL/min, 57.7 mL/min) compared to the ciclosporin group (54.6 mL/min), less use of antibody therapy for rejection (3.7%, 2.8% compared with 8.5%) and better lipid profiles (LDL cholesterol: 102.4 mg/dL, 97.1 mg/dL compared with 113.4 mg/dL) than ciclosporin.

About Advagraf®

Advagraf® will be available as early as June 2007 in the UK and Germany, followed by launches in additional European countries throughout the year and in 2008.

About Astellas

Astellas Pharma Europe Limited, located in the UK, is a European subsidiary of Tokyo-based Astellas Pharma Inc. Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. The organisation is committed to becoming a global pharmaceutical company by combining outstanding R&D and marketing capabilities and continuing to grow in the world pharmaceutical market. Astellas Pharma Europe is responsible for 19 affiliate offices located across Europe, the Middle East and Africa, 2 R&D establishments and 3 manufacturing plants with approximately 3,000 staff.

www.astellas-europe.co.uk

References
1. Greenstein, S., Siegal B. Compliance and Noncompliance in Patients with a Functioning Renal Transplant: A Multicenter Study. Transplantation 1998; 66(12): 1718-1726.
2. Denhaerynck, K., Dobbels, F., Cleemput, I., et al. Prevalence, consequences and determinants of nonadherence in adult renal transplant patients: a literature review. Transplant Int 2005; 18(10): 1121-1133.
3. Weng, FL., Israni, AK., Joffe, MM., et al. Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol 2005; 16(6): 1839-1848.
4. Silva, HT. Jr., Yang, HC., Aboulijoud, M., et al. for the Tacrolimus Extended-Release De Novo Kidney Study Group. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007; 7(3):595-608.