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

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

  PR Newswire

  CHERTSEY, England, September 9, 2013

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 (A D VAGRAF studied I n combin A tion with M yc O
phenolate mofetil a ND 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 T ransplant E uropea N Study Into the P revention of
Fungal IN fection) 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/1.73m ^2 ). 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 ^[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 ^[ ^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

1. Cohen AJ, et al . Chronic Renal Dysfunction Late After Liver
Transplantation. Liver Transpl . 2002 Vol 8, No 10 (October): pp 916-921.

2. Fisher NC, et al . Chronic Renal Failure Following Liver Transplantation.
Transplantation . 1998; 66:59-66.

3. Ojo AO, et al . Chronic Renal Failure after Transplantation of a Nonrenal
Organ. N Engl J Med . 2003; 349:931-40.

4. Vera A, et al . Incidence and risk factors for infections after liver
transplant: single-center experience at the University Hospital Fundación
Santa Fe de Bogotá, Colombia. Transpl Infect Dis . 2011 Dec;13(6):608-15. doi:
10.1111/j.1399-3062.2011.00640.x.

5. Zhou T, et al . Invasive fungal infection after liver transplantation: risk
factors and significance of immune cell function monitoring. J Dig Dis . 2011
Dec;12(6):467-75. doi: 10.1111/j.1751-2980.2011.00542.x.

6. Pacholczyk M, et al . Invasive fungal infections following liver
transplantation - risk factors, incidence and outcome. Ann Transplant . 2011
Jul-Sep;16(3):14-6.

7. Raghuram A, et al . Invasive fungal infections following liver
transplantation: incidence, risk factors, survival, and impact of
fluconazole-resistant Candida parapsilosis (2003-2007). Liver Transpl . 2012
Sep;18(9):1100-9. doi: 10.1002/lt.23467.

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.

Contact: For further information please contact: Donna Wright, Ruder Finn,
dwright@ruderfinn.co.uk, Tel: +44(0)207-438-3085; Mindy Dooa, Astellas Pharma
Europe Ltd, Mindy.dooa@astellas.com, Tel: +44(0)7826-912-339