New Data Provides Insights into the Prophylaxis of Organ Rejection and Prophylaxis of Fungal Infections in Liver Transplant Patients

CHERTSEY, England, September 9, 2013 /PRNewswire/ --

In liver transplant patients, late renal failure is a significant cause of morbidity and is associated with premature mortality^[1],[2],[3]

Invasive fungal infections affect between 8.4%-17.7% of liver transplant patients and are associated with a high mortality rate^{[4],[5],[6],[7]}

New data presented at the 16^th Congress of the European Society for Organ Transplantation (ESOT) demonstrate that in liver transplant patients, initiating ADVAGRAF™ prolonged-release capsules (tacrolimus) therapy immediately post transplant, at a dose 25% lower than the upper recommended limit,^[8] in combination with basiliximab, results in significantly better renal function and a lower incidence of acute organ rejection when compared with standard dose ADVAGRAF therapy.^[9] Furthermore, delaying the introduction of ADVAGRAF post transplant gives no additional advantage in terms of renal function.^[9]

In a separate study and the largest of its kind, MYCAMINE^[TM] (micafungin) was found to be non-inferior to standard of care in preventing fungal infections in liver transplant patients and showed similar safety outcomes.^[10]

Results from the DIAMOND (ADVAGRAF studied In combinAtion with MycOphenolate mofetil aND basiliximab in liver transplantation) study show that an initial dose of prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus MMF and induction therapy (without maintenance steroids) resulted in better renal function and a significantly lower incidence of acute rejection over 24 weeks compared to the other regimens; tacrolimus (initial dose: 0.2mg/kg/day) vs tacrolimus (0.2mg/kg/day delayed to day 5) plus basiliximab.^[9]

"These data provide new insights and considerations for immunosuppressive treatment in the immediate post-operative period," comments Dr. Ayad Abdulahad, Senior Vice President Medical Affairs and Health Economics, Astellas Pharma Europe Ltd. "Renal function is a vital predictor of long-term transplant success; the DIAMOND study suggests potential for balancing the risk of rejection, whilst minimising the risk of renal damage and potentially reducing the risk of long-term complications. This study shows that lower dose tacrolimus, given immediately post-transplantation, offers the potential advantages of an immunosuppressive regimen which minimises risk of graft rejection whilst preserving renal function without the need for maintenance steroids."

Infections are one of the major complications after transplantation and the incidence of infections in liver transplant patients is higher compared with recipients of other organs.^[4] Between 8.4% and 17.7% of liver transplant patients can be affected by fungal infections and these are associated with organ rejection, increased mortality and prolonged stay in the Intensive Care Unit.^{[4],[5],[6],[7]}

In the TENPIN (Liver Transplant EuropeaN Study Into the Prevention of Fungal INfection) study, the first randomised controlled trial of an echinocandin in this setting and the largest study of its kind, micafungin proved to be at least as effective as centre-specific standard of care (fluconazole, liposomal amphotericin B or caspofungin) in the prevention of invasive fungal infections in liver transplant patients. Current guidelines recommend either fluconazole or liposomal amphotericin B for prevention of invasive candidiasis in liver transplantation,^[11] and either lipid formulations of amphotericin B or an echinocandin for prevention of invasive aspergillosis.^[12] In addition, liver and renal safety of micafungin was also similar to study standard of care.^[10]

The TENPIN study included more than 340 liver transplant patients at high-risk of fungal infection, who were randomised to micafungin 100mg (2mg/kg in patients ≤40kg) once daily (n=173) or centre-specific standard of care (fluconazole 200-400mg; liposomal amphotericin B 1-3mg/kg/day; or caspofungin 70mg loading, 50mg maintenance) once daily (n=172). At the end of treatment, 98.6% of patients on micafungin in the Per Protocol population (n=140) were free of invasive fungal infections and had no need for further antifungals compared to 99.3% for standard of care (n=137).^[10]

"The low incidence of invasive fungal infections seen in this study clearly demonstrates the value of prophylactic antifungal treatment in high risk liver transplant patients," comments Professor Saliba, Associate Professor in Hepatology and Gastroenterology,Hôpital Paul Brousse Villejuif, France. "With current guideline-recommended treatments having their limitations, with risk of both resistance and drug interactions, micafungin looks to be a welcome and much needed additional treatment option."

NOTES FOR EDITORS

About ADVAGRAF™ and tacrolimus

Tacrolimus is a leading immunosuppressive drug used for the prevention of transplant allograft rejection after organ transplantation. It is available worldwide as a twice-a-day formulation (PROGRAF™) and as a prolonged-release formulation (ADVAGRAF™) which provides the convenience of once-daily dosing with more consistent tacrolimus exposure. Tacrolimus levels require careful management to maintain a minimum exposure of tacrolimus for the prevention of transplant allograft rejection, whilst avoiding excessive levels which may increase the risk of serious side effects. The prolonged-release formulation of ADVAGRAF allows tacrolimus to be available for absorption over a greater proportion of the gastrointestinal tract. This alteration in release profile provides the potential for reduced variability in tacrolimus exposure, achieving and maintaining consistent target trough levels with a reduced requirement for dose adjustments, and improved medication adherence as a single, morning dose.^[8],[13] Emerging data indicate that these properties of ADVAGRAF may favourably influence clinical outcomes.^[14]

About DIAMOND

DIAMOND is a multicentre, randomised study involving 901 patients designed to investigate renal function with ADVAGRAF prolonged-release capsules (tacrolimus). Patients received either prolonged-release tacrolimus (0.15-0.175mg/kg/day) and Basiliximab induction therapy; tacrolimus (initial dose: 0.2mg/kg/day) or tacrolimus (0.2mg/kg/day delayed to day 5) plus basiliximab.^[9] All patients received MMF and maintenance steroids were not used.

In the study, patients on a lower dose of tacrolimus (0.15-0.175mg/kg/day) plus MMF and induction therapy (without maintenance steroids) had a higher eGFR than those treated with tacrolimus (0.2mg/kg/day) vs tacrolimus (0.2mg/kg/day delayed to day 5) plus basiliximab (76.4 vs 67.4 vs 73.3mL/min/1.73m²). Patients on the lower dose tacrolimus regimen also had a significantly better rejection free survival when compared with other regimens (85.7% vs 79.9% vs 79.6%). Adverse events were comparable between all treatment regimens.^[9]

About MYCAMINE

Mycamine is an antifungal of the echinocandin class.^[15] In Europe, the indications for adults, adolescents 16 years of age and older, and the elderly are: treatment of invasive candidiasis, treatment of oesophageal candidiasis in patients for whom intravenous therapy is appropriate, and prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count <500 cells/mcL) for 10 or more days.^[15]

For children (including neonates) and adolescents younger than 16 years of age, micafungin is indicated for treatment of invasive candidiasis and prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count <500 cells/mcL) for 10 or more days.^[15]

About TENPIN

TENPIN is an open-label, randomised, multicentre trial involving 345 liver transplant patients. The study was designed to investigate the efficacy and safety of micafungin compared with site-approved standard of care prophylaxis in liver transplant patients at high risk of invasive fungal disease. After transplant, patients were randomised to iv micafungin 100mg once daily (n=173) or iv standard of care according to centre-specific standard protocols (fluconazole 200-400mg once daily or liposomal amphotericin B 1-3mg/kg/day or caspofungin 70mg loading, 50mg maintenance once daily; n=172).^[10]

At end of prophylaxis (mean drug duration 17 days), clinical success was 98.6% for micafungin (n=140) and 99.3% for standard of care (n=137) in the Per Protocol population (primary efficacy endpoint). In the Full Analysis population clinical success was 96.5% for micafungin (n=172) and 93.6% for standard of care (n=172). Incidences of drug-related adverse events for micafungin and standard of care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. Liver and renal function were similar between groups.^[10]

About Astellas Pharma Europe Ltd.

Astellas Pharma Europe Ltd., located in the UK, is the European headquarters 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 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 4,300 staff across these regions. For more information about Astellas Pharma Europe Ltd., please visit http://www.astellas.eu.

References

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8. European Public Assessment Report (EPAR). Advagraf. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000712/WC500022235.pdf. Last accessed August 2013.

9. Trunecka P et al. Preserving Renal Function with Prolonged-Release Tacrolimus-Baesd Immunosuppression in De Novo Liver Tranplantation: Initial Results from the DIAMOND Study. 16th Congress of the European Society for Organ Transplantation; Vienna, Austria, 8-11 September 2013. [Abstract No: LB02].

10. Saliba F, et al. Micafungin as Antifungal Prophylaxis in High-Risk Liver Transplantation: Randomised Multicentre Trial. 16th Congress of the European Society for Organ Transplantation; Vienna, Austria, 8-11 September 2013. [Abstract No: P217].

11. Pappas PG et al. Guidelines for Treatment of Candidiasis. Clin Infect Dis. 2004;38:161-89.

12. Singh N et al. Invasive Aspergillosis in Solid Organ Transplant Recipients. Am J Transpl. 2009;9(4):S180-S191.

13. Abrams et al. Role of tacrolimus prolonged release in the prevention of allograft rejection. Transpl Research and Risk Management, 2010:2 65-70.

14. Valente G, et al. Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplant Patients: Effectiveness in a Real-World Setting. Transplantation Proceedings, 45, 1273-1275 (2013).

15. Mycamine Summary of Product Characteristics. Available at http://www.medicines.org.uk/emc/medicine/20997/SPC/Mycamine+50mg+and+100mg+powder+for+solution+for+infusion/#INDICATIONS. Last accessed August 2013.