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Study demonstrates significant survival benefit in patients treated with once-daily Advagraf over standard of care in liver transplantation

Results of a large observational study published in the American Journal of Transplantation (AJT) has demonstrated that early and sustained use of Advagraf, a once-daily immunosuppressant, offers a significant graft survival benefit in patients over twice-daily tacrolimus (tacrolimus BID or immediate release).i Tacrolimus is currently the standard of care for the prevention of organ rejection in .

The results of the study showed a significant graft survival benefit of 8% at 3 years (p=0.01) in on Advagraf versus tacrolimus immediate release.ii The study, a retrospective analysis, was conducted by the European Liver Transplant Registry (ELTR), one of the largest and most robust independent registries, that holds data for 98% of conducted in Europe.iii

Whereas for a large number of diseases, such as cancer and diabetes, the standardised mortality rate is falling, for liver disease, mortality rates have been increasing over the past few decades.iv In addition, more than 500 patients are on the UK’s active liver transplant list (as of March 2014), which is a 12% increase since 2013 and 880 transplants have taken place between 2013 and 2014 in the UK.v It is also estimated that over the past 20 years, the number of potential patients in the UK who could benefit from a liver transplant has increased by 90%, whilst the number of available donations has remained the same.vi

Both Advagraf and tacrolimus immediate release are immunosuppressants licensed for the prevention of organ rejection in patients receiving Liver and Kidney transplants. Due to its distinctive pharmacokinetic profile, Advagraf offers patients a more convenient reduced pill intake, as it permits once daily administration, over tacrolimus immediate release which is twice daily.vii

Dr Varuna Aluvihare, Consultant Hepatologist, King’s College, London said: “A graft survival benefit means better patient survival, meaning that for every 13 patients treated with Advagraf, we could potentially save 1 life when compared to people being treated with the usual twice daily tacrolimus. Whilst we do not know the underlying reason for this benefit, it is exciting to speculate that this may due to some benefits inherent in this formulation of tacrolimus, as well as the undoubted fact that patients find it easier to take.”

Andrew Langford from the British Liver Trust said: “We know that, compared to other major diseases, liver disease mortality is increasing at an alarming rate over the past 30 years and is the UK’s third commonest cause of premature death. Although liver transplant is a life saver for some, it is concerning that around a quarter of patients will still die within five years of their transplant.”

“Therefore, the data we are seeing from the ELTR’s real-world study are very significant and an increase in graft survival has important implications for patient survival. In addition, reducing from twice daily to once daily has a positive impact on a person’s quality of life.”

Dr Alan McDougall, Medical Director, Astellas Pharma Ltd UK said: “Astellas are dedicated to delivering innovative and high quality treatments to patients. These real-world data suggest that the once daily formulation of Advagraf, when compared to twice daily immediate release tacrolimus, has the potential to benefit hundreds of liver transplant patients in the UK.”

The benefit was still seen when the propensity score matching (population number n=810) for baseline characteristics was applied and Advagraf continued to demonstrate an observed 8% reduction in graft loss at 3 years vs. tacrolimus immediate release.

About ELTR

The aim of the ELTR study was to assess the effect of early use of Advagraf versus tacrolimus immediate release (twice daily) on long-term transplanted organ survival using real-world ELTR data.ii The European Liver Transplant Registry (ELTR) is one of the largest and most robust registries, representing over 98% of the overall European liver transplant data from 153 centres across 20 countries.iii

The study was a retrospective analysis of liver transplant patients (>18 years old) receiving either Advagraf (n=528) or tacrolimus immediate release (n=3,839) within the first month of transplantation and with a follow-up period of three years.ii Data was collated over a five year period (Jan 2008 – Dec 2012) and the primary outcome measures were transplanted organ survival rates.ii Only those patients whose newly transplanted organ was still functioning at 1 month were included in the analysis.ii

Factors influencing organ survival were identified using univariate and multivariate regression analyses (p<0.05). Differences in organ survival rates between patients receiving Advagraf and those receiving tacrolimus immediate release were assessed by Kaplan-Meier (KM) survival analysis.ii

An 8% organ survival advantage was seen in the Advagraf arm versus tacrolimus immediate release, meaning the newly transplanted organs of patients treated with Advagraf were more likely to still be functioning three years post-transplant compared with those treated with tacrolimus immediate release (88% vs 80%, p=0.01).ii This benefit was still seen when the propensity score matching for baseline characteristics was applied.ii

As with any registry based study, there are a number of limitations that must be considered when interpreting these data. Recognizing this issue the ELTR carried out additional analysis and when patients were matched for baseline characteristics, the significant long-term graft survival advantage was confirmed.i


[i] Improved Survival in Liver Transplant Recipients Receiving Prolonged-Release Tacrolimus in the European Liver Transplant Registry, R. Adam, V. Karam, V. Delvart, P. Trune?ka, D. Samuel, W. O. Bechstein, P. N?mec, G. Tisone, J. Klempnauer, M. Rossi, O. O. Rummo, S. Dokmak, M. Krawczyk, J. Pratschke, O. Kollmar, K. Boudjema, M. Colledan, B. G. Ericzon, G. Mantion, U. Baccarani, P. Neuhaus, A. Paul, P. Bachellier, F. Zamboni, R. Hanvesakul, P. Muiesan and all contributing centers and the European Liver Intestine Transplant Association (ELITA), American Journal of Transplantation, DOI: 10.1111/ajt.13171, published online 19 February 2015.

[ii] Adam R et al. The European Liver Transplant Registry (ELTR): Improved Survival Outcomes in De Novo Liver Transplantation with Tacrolimus Prolonged Release (Advagraf). Poster A435 presented at the World Transplant Congress (WTC), July 2014

[iii] European Liver Transplant Registry Centers. Available at http://www.eltr.org/spip.php?page=centers Last accessed January 2015

[iv] Williams et al Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis The Lancet, Volume 384, Issue 9958, 29 November-5 December 2014, Pages 1953-1997

[v] NHS Blood and Transplant. Organ Donation and Transplantation Activity Report 2013/14. Available at http://www.organdonation.nhs.uk/statistics/transplant_activity_report/. Last accessed January 2015

[vi] NHS Choices, Liver Transplantation http://www.nhs.uk/conditions/Liver-transplant/Pages/Introduction.aspx Last accessed January 2015

[vii] European Medicines Agency. Advagraf EPAR Summary for the Public available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000712/WC500022235.pdf; Last accessed January 2015

Source: Astellas Pharma Limited