Data presented at the 22nd International Congress of The Transplantation Society provides further direction to transplant doctors to test the immunosuppression drug levels of patients who are most at risk of rejecting their transplanted organ. The data, a follow-up analysis of the FDCC* study of 901 kidney transplant recipients, shows that the active component in CellCept, mycophenolic acid (MPA), should be measured in 'at risk'** patients. [i]

"By measuring the dependable levels of MPA we identified that patients with less than 30mg*h/l were more likely to reject their organ in the first month after transplantation and this trend was even more pronounced in 'at risk' patients," commented Dr. Teun van Gelder, Internist-Nephrologist, Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. "Therapeutic drug monitoring (TDM), as the measure is known, allows doctors to alter the dose of CellCept and deliver the optimal immunosuppression needed to prevent rejection. We're now seeing an increased interest and acceptance of TDM in clinical practice to ensure more transplants are successful," he added.

Immunosuppressive therapy is life-sustaining and lifelong for most transplant patients. Finding the best possible balance between providing sufficient immunosuppression to prevent rejection whilst minimising the side effects associated with the use of more toxic anti-rejection drugs, such as calcineurin inhibitors (CNIs) and steroids, is a key goal in transplant medicine.

The introduction of CellCept containing regimens has allowed doctors to reduce the dosage of these more toxic drugs, but some patients may need higher doses of CellCept to prevent organ rejection. [ii]

Annually, it is estimated that 70,000 transplants are carried out world-wide [iii], but over 130,000 people are currently on the transplant waiting list. [iv], [v] This underscores the importance of preventing any unnecessary loss of a transplanted organ.

** 'At risk' patients are generally considered to have:1

- Delayed function of the transplanted organ
- Second or third transplantation
- Raised levels (>15%) of naturally circulating defence antibodies, which play a role in initiating rejection
- Low donor/recipient compatibility

The FDCC study findings are supported by the results of two similar trials investigating low-dose CNI or CNI-free CellCept based regimens. The OptiCept trial found that a reduced level of CNI with a therapeutic monitored dose of CellCept is not inferior to that of a fixed-dose of CellCept and the standard-dose of CNI. [vi] The Spare the Nephron study showed that a CellCept-based regimen in combination with sirolimus is associated with improved renal function when compared with the CellCept-based regimen in combination with CNIs; this improvement was seen without increasing the risk of acute rejection. [vii]

The FDCC Study1 (*Fixed-dose versus concentration-controlled CellCept regimens)

The FDCC study was conducted to determine the value of TDM for CellCept in CNI-containing regimens. The randomised controlled study compared fixed-dose versus concentration-controlled CellCept regimens for kidney transplant patients. Patients were treated with CellCept, corticosteroids and either ciclosporin (n = 488) or tacrolimus (n = 413).

A post-hoc, exploratory analysis was performed to study the relationship between MPA plasma concentrations and the incidence of acute rejection in high versus low risk renal transplant patients.

In the full study population an MPA-AUC0-12 below 30 mg*h/L on day three after transplantation was associated with a significant risk of developing acute rejection in the first month (11.4% risk compared to 6.4% in patients with MPA-AUC0-12 above 30 mg*h/L [p = 0.018]). A total of 491 patients (54%) were classified as high risk. In high risk patients the difference in rejection incidence (14.6% vs 7.9%) was comparable to the whole study population. In low risk patients there were similar rejection rates above and below 30 mg*h/L (5.5% vs 4.4%).

The authors concluded the results support the recommendation to perform TDM for CellCept in selected patient populations.

Therapeutic Drug Monitoring [viii]

Therapeutic drug monitoring is the measurement of specific drugs at set intervals in order to maintain a relatively constant concentration of the medication in the bloodstream. Each person absorbs, metabolises, utilises, and eliminates drugs at different rates according to their age, general state of health, genetic makeup, and the interference of other medications that they are taking. This rate may change over time and vary from day to day. Therapeutic drug monitoring follows these changes and allows physicians to adjust the dose of specific drugs to keep the patient within the desired therapeutic range.

Roche in Transplantation

Roche is strongly committed to improving the long-term outcomes of transplantation and enhancing the quality of life of transplant recipients. Roche, as leader in this field, has developed innovative therapies that improve graft and post-transplant health: CellCept is the cornerstone of low toxicity immunosuppressant therapies. CellCept, the largest selling branded immunosuppressive in North America, offers both physicians and patients the possibility of an effective long-term immunosuppressive regimen with low toxicity. Valcyte was developed for the prevention of cytomegalovirus (CMV), a dangerous viral infection associated with transplantation. Oral Valcyte has displaced oral and intravenous ganciclovir as the gold standard for the management of CMV in immunocompromised patients. In addition, Roche supports basic research in transplantation with its funding of the independent Roche Organ Transplantation Research Foundation (ROTRF), which directly supports innovative research projects attracting new researchers with novel scientific ideas to meet unmet medical needs in solid organ transplantation.

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world's biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people.

The full CellCept Summary of Product Characteristics (SmPC) is available at rocheuk.

All trademarks used or mentioned in this release are protected by law.

CellCept is licensed for a fixed dosing regimen in renal transplantation (2g/day) and a routine therapeutic drug monitoring (TDM) of patients on CellCept is not within the product license.

Roche

References

[i] Van Gelder et al. Mycophenolic acid plasma concentrations and acute rejection rate in high risk versus low risk renal transplant patients receiving mycophenolate mofetil. International Congress of the Transplantation Society, Sydney, August 2008, Abstract 109

[ii] De Fijter et al. Concentration-controlled systemic exposure provides improved safety after CNI or MMF withdrawal. American Transplant Congress, San Francisco, May 2007, Abstract 238

[iii] World Health Organisation. Human organ and tissue transplantation, report by the Secretariat. Geneva: World Health Organisation, May 2003.

[iv] Organ donation and transplantation policy options at EU level. Brussels: European Commission consultation document, June 2006. Available at here. (Accessed 24 July 2008)

[v] United Network for Organ Sharing: Organ Donation and Transplantation. US Transplant Data. Available here. (Accessed 24 July 2008)

[vi] Pearson et al. Efficacy and Safety of Mycophenolate Mofetil (MMF)/Sirolimus (SRL) Maintenance Therapy after Calcineurin Inhibitor (CNI) Withdrawal in Renal Transplant Recipients: Final Results of the Spare-the-Nephron (STN) Trial. American Transplant Congress, Toronto, May 2008, Abstract 129.

[vii] Gaston et al. Opticept Trial: Efficacy and Safety of Monitored MMF in Combination with CNI in Renal Transplantation at 12 Months. American Transplant Congress, Toronto, May 2008, Abstract 526.

[viii] Lab Tests Online. Therapeutic Drug Monitoring. Avaialble here. (Accessed 04 August 2008).

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View drug information on CellCept; Valcyte.

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