The Osaka Study Evaluated a Typical European Transplant Population and Showed Similar Efficacy for ADVAGRAF™ and PROGRAF™ in Renal Transplantation at the Same 0.2MG/KG Starting Dose

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Astellas Pharma Europe Limited

05 Sep, 2011, 12:29 GMT

STAINES, England, September 5, 2011 /PRNewswire/ --

- Optimizing ImmunoSuppression After Kidney Transplantation with ADVAGRAF (OSAKA) study results presented at the European Society for Organ Transplantation 2011 congress

- Results show non-inferiority of ADVAGRAF vs PROGRAF at the same daily dose in renal transplantation

- Higher starting dose of ADVAGRAF gave no additional efficacy benefits

- The overriding factor influencing kidney function after transplantation was donor age

The results of one of the largest clinical studies ever conducted in de novo kidney transplant recipients, the 6-month OSAKA study, demonstrate that tacrolimus prolonged release (QD; ADVAGRAF™, Graceptor® in Japan)-based therapy is non-inferior to the same initial daily dose of tacrolimus immediate release (BID; PROGRAF™)-based therapy (0.2mg/kg/day) for efficacy in renal transplantation. These data were presented this week at the European Society for Organ Transplantation (ESOT) 2011 congress in Glasgow.

In an era when there are few promising new immunosuppressants in the pipeline for kidney transplantation, the OSAKA study investigated how to optimise exposure to tacrolimus QD in comparison with the current clinical standard, tacrolimus BID.

The study was conducted in 110 centres across 22 countries, and included more than 1,200 patients. The study evaluated patients and donors in a largely European transplant population, with recognised declining organ quality and an ageing patient population. Approximately two-thirds of patients in the study were male and mean age was around 50 years. The mean age of organ donors in the study was 51.5 years and approximately 50% were defined as extended criteria donors.

At 6 months, efficacy comparison revealed no significant difference between treatment arms in the primary composite endpoint of efficacy failure. Graft dysfunction (measured at the study end) was the primary cause of efficacy failure in all treatment arms. The level of estimated glomerular filtration rate (eGFR) set for graft dysfunction (<40mL/min/1.73m2) and the high number of extended criteria donors are likely to account for the high incidence of graft dysfunction as a reason for efficacy failure.

Efficacy failure increased markedly with donor age. The impact of donor age, HLA matching and living donation outweighed any effect of starting dose, regimen or tacrolimus formulation on outcomes.

Rates of biopsy-confirmed acute rejection (BCAR) were low, and there was no significant difference between treatment arms in the incidence of and time to first incidence of BCAR. The severity grade of BCAR was comparable across treatment arms.

Renal function was similar on tacrolimus prolonged release- and immediate release-based therapies. The study also showed that a higher starting dose of tacrolimus QD (0.3mg/kg/day) was not associated with any additional clinical benefit. Steroid-free therapy was associated with less reported diabetes mellitus and improved lipid profiles compared with the other treatment arms, but poorer renal function, which may have been due to donor-related factors. There were no significant differences in adverse events between arms.

Prof Dr Bernhard Banas from the University Medical Center Regensburg, Germany, who presented the study results at the ESOT congress, commented: 'The OSAKA study findings add to the evidence on the use of tacrolimus QD after kidney transplantation, and help to provide a complete picture of the relative efficacy of the QD and BID formulations in an open-label setting. The results support the use of tacrolimus QD as the basis of immunosuppressive therapy across a wide range of donor and recipient characteristics.'

BACKGROUND

About the OSAKA study

The OSAKA study was an international, multicentre, randomised, 24-week, open-label, four-armed, parallel-group, comparative phase IIIb study designed to investigate immunosuppressive regimens with tacrolimus QD or tacrolimus BID in adult kidney transplant recipients.

Subjects (1,251) were randomised 1:1:1:1 to four treatment arms:

  • Arm 1: tacrolimus BID 0.2mg/kg initial dose + mycophenolate mofetil (MMF) + corticosteroids (24 weeks)
  • Arm 2: tacrolimus QD 0.2mg/kg initial dose + MMF + corticosteroids (24 weeks)
  • Arm 3: tacrolimus QD 0.3mg/kg initial dose + MMF + corticosteroids (24 weeks)
  • Arm 4: tacrolimus QD 0.2mg/kg initial dose + MMF + basiliximab + perioperative corticosteroids (bolus)

The primary composite endpoint was efficacy failure rate, defined as the incidence of and time to first incidence of graft loss, BCAR or graft dysfunction (defined as eGFR <40mL/min/1.73m2 at Week 24). This endpoint was used in accordance with the European Medicines Agency guideline on clinical investigation of immunosuppressants for solid organ transplantation.[1] The OSAKA study was one of the first, and largest, studies to use such a composite endpoint in transplantation. Secondary endpoints included renal function, assessment of acute rejections (incidence, time, severity and overall frequency), and graft and patient survival.

OSAKA study results at the ESOT 2011 congress

Three presentations on the OSAKA study results were made on 5 September at the ESOT 2011 congress:

  • Influence of donor-related factors on outcomes with tacrolimus-based immunosuppression after kidney transplantation − the OSAKA study (rapid oral presentation by Dr Frank Lehner, Hannover Medical School, Germany)
  • Efficacy and safety of tacrolimus prolonged release and immediate release in de novo renal transplantation - the OSAKA study (oral presentation by Professor Nassim Kamar, Toulouse University Hospital, France)
  • Acute rejection in renal transplantation recipients treated with tacrolimus prolonged release- and immediate release-based therapy - the OSAKA study (oral presentation by Professor Dr Bernhard Banas, University Medical Center Regensburg, Germany)

For further information about ESOT, please visit http://www.esot.org

About tacrolimus

Tacrolimus has become an established immunosuppressive agent for the prophylaxis and treatment of renal allograft rejection. It is available worldwide as a twice-a-day formulation (PROGRAF) and as a prolonged-release formulation (ADVAGRAF), which has been developed to provide once-daily dosing. The prolonged-release formulation allows tacrolimus to be available for absorption over a greater proportion of the gastrointestinal tract.

About Astellas Pharma Europe Ltd

Astellas Pharma Europe Ltd, 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 pharmaceuticals. The organisation is committed to becoming a global company by combining outstanding research and development (R&D) and marketing capabilities and continuing to grow in the world pharmaceutical market. Astellas Pharma Europe Ltd is responsible for 21 affiliate offices located across Europe, the Middle East and Africa, an R&D site and three manufacturing plants. The company employs approximately 4,000 staff across these regions. For more information about Astellas Pharma Europe, please visit http://www.astellas.eu

Reference

[1]. European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on clinical investigation of immunosuppressants for solid organ transplantation. London, 24 July 2008.