FUTURE DIRECTIONS IN TRANSPLANTATION

FUTURE DIRECTIONS IN TRANSPLANTATION Highlights from the XX th International Congress of the Transplantation Society (ICTS) Austria Center, Vienna, Austria 5 10 September 2004 CONTENTS 2 Graft survival CellCept + CsA vs sirolimus + CsA 3 CellCept and gastric ph modulators 4-5 Improving transplant outcomes 6 CellCept, CsA and gastrointestinal risk 7 CellCept and pre-existing diabetes 8 CellCept and daclizumab in heart recipients 9-10 CMV prevention strategies 11 CellCept and steroid-free immunosuppression 12 ROTRF highlights of the first five years VIENNA 2004 Vienna, the capital of Austria, has two million inhabitants and is situated on the banks of the Danube. The influx of visitors from all over the world has made Vienna the most popular tourist destination in Austria. Vienna has a strong heritage in classical music, and was home to Mozart, Beethoven, Schubert and Johann Strauss. The city s Wiener Philharmoniker is one of the world s top orchestras; the Vienna Boys Choir is triumphantly successful wherever it tours, and the Vienna Conservatorium has produced innumerable international award-winners in all musical disciplines. The cultural options in Vienna include more than classical music. Today, Vienna offers theatre, film or dance festivals, opera or operetta and exhibitions. The tradition of dance-hall balls is deeply rooted in Austrian history. Between January and February, during Fasching, the Austrian Carnival, balls are held nearly every weekend all over town, when many revellers dance the Viennese Waltz. The Waltz derives from the 18th century with the advent of a bourgeois society. It is much faster than its modern-day counterparts, and allows for dashing movements by changing the direction of rotation mid-dance ( Linkswalzer and Rechtswalzer ). From 5-10 September 2004, over 5,000 of the world s leading scientists and clinicians converged in Vienna to sample this unique cultural atmosphere and attend the XXth International Congress of the Transplantation Society. This e-newsletter summarises the meeting s key proceedings. 1 This newsletter has been written by an independent medical writer and, as such, does not

Oral Session: Kidney Immunosuppression Comparison of graft survival rates with MMF + CsA and sirolimus + CsA Compared to sirolimus + CsA, MMF + CsA is associated with significantly higher graft survival. H. Meier-Kriesche [CLICK ON NAME FOR ABSTRACT], University of Florida, Gainesville, USA presented a retrospective analysis of the 2003 Scientific Registry of Transplant Recipients (SRTR). Patients were included in the analysis if they had undergone solitary renal transplantation between 1998 and 2003, and were discharged on either mycophenolate mofetil (MMF) + cyclosporine microemulsion (CsA) (n=21,017), or sirolimus (rapa) + CsA (n=1,999). The study objective was to compare the long-term effects of the two regimens on: Graft survival Death-censored graft survival Patient survival Acute rejection Renal function Univariate Kaplan Meier analyses and multivariate Cox regression models were used to compare the relative risks of MMF + CSA and sirolimus + CSA. Subgroup analyses were also conducted for donor type and recipient ethnicity. Multivariate analyses demonstrated that sirolimus + CsA was associated with a significantly higher risk of graft loss, death-censored graft loss, and patient death. The MMF + CsA group also reported lower acute rejection rates (0-12 months: 17.4% vs 20.5%, p=0.002; 1-4 years: 7.2% vs 9.2%, p=0.006), and superior renal function. Only 38.6% of MMF + CsA patients experienced a four-year decline in renal function, compared to 47% of patients in the sirolimus + CsA group. 4-year Death Censored Graft Survival MMF+CsA vs. Sirolimus+CsA Percentage Surviving Grafts (%) 100 90 80 70 60 50 0 P=0.003 1 2 3 Years From Transplant Date Information regarding drug dosing/concentrations is not available in the SRTR; however, findings from this study are likely reflective of the early experience of sirolimus + CSA, when full-dose CSA was utilized. The impact of alternative strategies of sirolimus utilization with reduced CSA exposure or alternative agents on these outcomes should be studied. H. Meier-Kriesche MMF+CsA 87.2% Sirolimus+CsA 83.7% 4 2 This newsletter has been written by an independent medical writer and, as such, does not

Poster Session: Kidney Clinical Effect of gastric ph modulators on MMF pharmacokinetics H2-antagonists, PPIs, and antacids have no effect on MPA exposure. T. Van Gelder [CLICK ON NAME FOR ABSTRACT], Erasmus Medical Center, Rotterdam, The Netherlands presented a retrospective, pharmacokinetic (PK) analysis of mycophenolic acid (MPA) levels recorded during a randomised, double-blind, plasmaconcentration controlled trial. This trial measured the safety and efficacy of oral mycophenolate mofetil (MMF) for the prevention of acute rejection in 141 de novo renal transplant patients receiving maintenance immunosuppressive therapy. The purpose of this sub-analysis was to investigate the effects of gastric ph modulators on MPA exposure. The modulators examined were: H2-antagonists (H2As) proton pump inhibitors (PPIs) antacids Three full 12-hour MPA PK analyses were undertaken on days 3, 7, and 11. Five further abbreviated two-hour analyses were performed on weeks 3, 4, 8, 12, and 20. Use of H2b, PPI, or antacids within 24 hours prior to an analysis was deemed a positive result. MPA exposure over 20 weeks of therapy was not significantly different irrespective of whether the patient received concomitant H2As, PPIs, or antacids. In patients using PPIs, C max was not significantly different in all periods except on days 7, 11, and 21. T max was calculated to be 40 mins in all periods for all groups except in the PPI use group, where it was 75 mins from day 11 onwards. Mean Concentration Over Time by H2-blocker Status on Day 11 Mean Concentration (µg/ml) 12 10 8 6 4 2 0 0.00 H2-blocker (N=102) Non-H2-blocker (N=32) 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 Time of Dosing (Hour) The results of this study suggest that the use of H2As, PPIs, and antacids during MMF therapy, does not have an overall significant impact on MPA exposure. T. Van Gelder 3 This newsletter has been written by an independent medical writer and, as such, does not

Scientific Symposium: Improving Transplant Outcomes Does the Choice of Immunosuppression Make a Difference? [page 1 of 2] Clinical outcomes can be improved by reducing PTLD risk and selecting CNI-sparing regimens Innovative MMF-containing immunosuppressive regimens can preserve renal structure and function in a variety of transplant recipients. H. Ekberg, Lund University, Malmö, Sweden; S. Flechner, Cleveland Clinic Foundation, Ohio, USA; and D. Hanto, Beth Israel Deaconess Medical Center, Boston, USA presented data from a number of investigative studies. These data specifically focused on the risks and benefits of calcineurin-sparing regimens, the merits of immunosuppression with sirolimus and mycophenolate mofetil (MMF), and the effects of post-transplant lymphoproliferative disorder (PTLD) on graft and patient survival. Professor Ekberg reviewed recent data which investigated: Calcineurin-inhibitor (CNI) reduction and withdrawal immediately following renal transplantation Cyclosporine (CsA) withdrawal in stable renal transplant patients CNI reduction and withdrawal in renal transplant recipients with chronic allograft nephropathy (CAN) Existing data show that although CsA withdrawal carries a risk of acute rejection, immediate posttransplant reduction of CsA using a regimen of daclizumab and MMF is safe and effective. The ongoing SYMPHONY study will further examine MMF in combination with low-dose tacrolimus and sirolimus. Further studies suggest that in stable renal transplant recipients, CsA withdrawal is associated with moderate risk and moderate benefit, whilst in patients with chronic allograft nephropathy, discontinuation is safe and beneficial. Renal biopsies and dose monitoring of MPA may allow more accurate identification and treatment of patients suitable for CNI dose reduction/withdrawal. Incidence of Acute Rejection After Renal Transplantation Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 H. Ekberg Pre-adaptation CNI necessary Daclizumab CNI (or SRL) MMF Steroids Post-adaptation CNI should be avoided MMF / SRL / CS Daclizumab Placebo 20 40 60 80 100 120 140 160 180 200 Time Post-Transplant (Days) H. Ekberg CONTINUES ON NEXT PAGE 4 This newsletter has been written by an independent medical writer and, as such, does not

Scientific Symposium: Improving Transplant Outcomes Does the Choice of Immunosuppression Make a Difference? [page 2 of 2] Clinical outcomes can be improved by reducing PLTD risk and selecting CNI-sparing regimens [continued from previous page] BACK Professor Flechner then presented several studies which showed that substitution of a CNI-containing regimen with an immunosuppressant regimen which included sirolimus and MMF, leads to improved renal function and comparable acute rejection rates. A Comparison 0f 2-gram MMF (n=160) vs 1-gram MMF (n=100) Dosing in Ab/Sirolimus/Steroid Treated Renal Allograft Recipients MMF (gm/d) 5 4 3 2 1 0 95 14 86 40 86 59 76 62 0.5 mo 1 mo 3 mo 6 mo MMF 2 g MMF 1 g MMF 2 g MMF 1 g MPA (mg/l) MMF 1 g MMF 2 g MMF 1 g MMF 2 g Data show that antibody induction followed by an immunosuppressive regimen of MMF, sirolimus, and steroids, improves renal function and histology compared with CNItreated patients. Further, acute rejection rates are similar between the two groups, and if MMF concentrations are controlled, this is accompanied by a reduction in GI side effects. It is hoped that this concentration may provide for an alternative natural history of renal allograft survival. S. Flechner S. Flechner D. Hanto The final presentation, from Professor Hanto, investigated the hypothesis that the choice of immunosuppressive regimen can significantly affect the development of PTLD and long-term graft and patient survival. MMF Improves Patient Survival After Heart Transplantation UNOS/ISHLT Thoracic Registry Patient Survival (%) 100 90 80 70 60 0 P=0.0012 MMF (N=657) Azathioprine (N=4942) 6 12 18 24 30 Time Post-Transplant (Months) 36 Induction therapy with monoclonal anti-lymphocyte antibodies increases the risk of developing PTLD. With anti-il-2 receptor antibody induction, although PTLD risk is unchanged, it is associated with reduced acute rejection rates and a significant reduction in the risk of graft loss and mortality. Compared to azathioprine, MMF significantly reduces PTLD risk, and MMF-based discharge regimens are associated with increased graft and patient survival, and reduced acute rejection rates. D. Hanto 5 This newsletter has been written by an independent medical writer and, as such, does not

Poster Session: Immunosuppression Clinical CsA dose reduction is not associated with increased GI side effects or the need for sub-optimal MMF dosing An immunosuppressant combination of full-dose MMF and reduced-dose CsA is not associated with increased risk of GI adverse events. H. Kreis [CLICK ON NAME FOR ABSTRACT], Hôpital Necker, Paris, France presented a two-year, multicentre, open-label, prospective, randomised study of 158 renal transplant patients. The study objective was to compare the efficacy and safety of mycophenolate mofetil (MMF) + reduced-dose cyclosporine microemulsion (rcsa) versus MMF + standard-dose cyclosporine (scsa). A post-hoc analysis was also performed to compare the incidence of gastrointestinal adverse events (GI AEs) between the two groups. Immediately following transplantation, daclizumab, MMF, steroids and CsA were administered to all patients for eight weeks. Patients were then randomised to receive either scsa (N=80) or rcsa (N=78). Mean MMF doses were comparable between the two groups (1.91±0.24 g/day (rcsa) vs 1.94±0.33 g/day (scsa)). Target trough CsA blood levels for the scsa group were 150-200 ng/ml (W9-M12) and 100-150 ng/ml (M12-M24). For the rcsa group, these levels were adjusted to 100-150 ng/ml (W9-W12), 75-100 ng/ml (W12-M12) and <75 ng/ml (M12-M24). During the two-year follow-up, the overall incidence of GI adverse events was comparable between groups (57.0% (rcsa) vs 56.3% (scsa)). Diarrhoea occurred in 15.2% of patients in the rcsa group and 5.0% in the scsa group. None of these episodes led to withdrawal. Lowering cyclosporine doses in patients taking MMF 2g/day is not associated with an overall increase in gastrointestinal adverse events. Although diarrhoea was more frequent in patients taking reduced CsA, most cases were mild to moderate and all resulted in a complete recovery. Other GI events were comparable between the two groups. In this two-year study, MMF at a dose of 2g/day appears to be safe and well tolerated in the vast majority of patients, including those with a reduced dose of CsA. This study strengthens the feasibility of using long-term MMF-based immunosuppressive regimens with CsA minimalisation. H. Kreis Gastrointestinal Adverse Events, W8-W104 Adverse Events Overall gastrointestinal system disorders Gastrointestinal disorders, diarrhoea, abdominal pain Others: Constipation Dyspepsia Gastritis NOS Gastroduodentitis Intestinal obstruction NOS Nausea Vomiting NOS Gingival disorders Standard CsA Dose (N=80) 45 (56%) 15 (19%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 4 (5%) 23 (29%) Reduced CsA Dose (N=79) 45 (57%) 19 (24%) 1 (1%) 3 (4%) 2 (2%) 1 (1%) 4 (5%) 18 (23%) p-value 0.9 0.4 6 This newsletter has been written by an independent medical writer and, as such, does not

Oral Session: Kidney Immunosuppression Impact of diabetic status on MPA exposure MMF maintains its efficacy in patients with pre-existing diabetes. T. Van Gelder [CLICK ON NAME FOR ABSTRACT], Erasmus Medical Center, Rotterdam, The Netherlands presented a retrospective, pharmacokinetic (PK) analysis of mycophenolic acid (MPA) levels recorded during a randomised, double-blind, plasma-concentration controlled trial which measured the safety and efficacy of oral mycophenolate mofetil (MMF) for the prevention of acute rejection in 141 de novo renal transplant patients receiving maintenance immunosuppressive therapy. The trial was designed to investigate the relationship between PK parameters (MPA AUC, MPA C predose, and MPA C max ) and clinical outcome after kidney transplantation. This sub-analysis was undertaken to determine whether pre-existing diabetes mellitus impacts on MPA exposure in renal transplant recipients. Three full 12-hour MPA PK analyses were undertaken on days 3, 7, and 11. Five further abbreviated two-hour analyses were performed on weeks 3, 4, 8, 12, and 20. Diabetic status was determined based on medical history and/or reported use of anti-diabetics at study entry. People with diabetes (n=15) and people without diabetes (n=126) were compared using repeated measures in a linear mixed effects model. Log transformed AUC 0-12 and C max were compared adjusting for treatment group, sex, age, donor age, and average daily dose of MMF, cyclosporine, and corticosteroids. MPA exposure over 20 weeks of therapy was not significantly different in the people with diabetes and without diabetes groups. MPA AUC 0-12 increased over time in both patient groups, almost doubling by week 12 (diabetic arm: day 7 = 28.1±13.2 mgh/l, week 12 = 48.0±23.1 mgh/l; non-diabetic arm: day 7 = 29.4±17.8 mgh/l, week 12 = 51.3±30.1 mgh/l). The study showed that AUC 0-12 was not significantly different at any period, whilst C max was not significantly different for all periods except days 7 and 11. Mean Concentration Over Time by Diabetic Status Day 11 Mean Concentration (µg/ml) 18 16 14 12 10 8 6 4 2 Diabetics (N=13) Non-diabetics (N=121) 0 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 Time of Dosing (Hour) Exposure to mycophenolic acid after administering mycophenolate mofetil is not significantly different in people with or without diabetes. Our sub-analysis shows that C max and T max are not significantly different after day 11 post-transplant in people with or without diabetes. T. Van Gelder 7 This newsletter has been written by an independent medical writer and, as such, does not

Oral Session: Heart Clinical Trials Daclizumab in combination with MMF and steroids in cardiac transplant recipients Daclizumab induction reduces acute rejection rates and does not affect overall mortality. J. Morris [CLICK ON NAME FOR ABSTRACT], ProSanos Corporation, La Jolla, USA presented a retrospective, placebo-controlled, three-year study involving cardiac transplant recipients sourced from the US Scientific Registry of Transplant Recipients. Patients were included in the study if they satisfied the following criteria: recipients of transplantation performed in the United States between January 1998 and October 2003 recipients of discharge therapy comprising mycophenolate mofetil (MMF), cyclosporine (CsA), and corticosteroids The study objective was to compare outcomes in cardiac transplant recipients treated with daclizumab (n=684) with those receiving no induction therapy (n=2,525). Primary study endpoints were defined as patient death from any cause and, specifically, infectious death. Secondary endpoints included rejection within the first year post-transplant (acute rejection), cardiovascular death, and malignant death. All outcomes were evaluated at 6 months, 12 months, and 3 years post-transplant. The distribution of patient demographics, donor characteristics, and recipient transplant procedure details was similar for the daclizumab and the non-induction groups. Patients on daclizumab had no increased risk of death due to any cause, infectious death, cardiovascular death, or malignant death compared to non-induction recipients at any time point studied (6 and 12 months, and 3 years post-transplant). Patients receiving daclizumab had a lower incidence of acute rejection at 6 months (p=0.005) and 12 months (p<0.001) compared to non-induction patients; the adjusted risk for acute rejection at 12 months was also lower in daclizumab-treated patients (HR=0.77; CI=0.67, 0.89). Any Treated Early and Late Acute Rejection* Acute Rejection (0-6 months) Acute Rejection (0-12 months) Late Acute Rejection (0-3 years) *proportions from Kaplan-Meier analysis Daclizumab (N=684) 15.8% 39.2% 50.8% No Induction (N=2525) Our results showed that patients receiving daclizumab induction experienced significantly fewer incidences of acute rejection compared to patients who did not receive induction therapy. This was accompanied by a significantly lower adjusted risk for post-transplant rejection over time. J. Morris 20.6% 47.1% 54.3% p-value 0.0053 0.0002 0.0064 Cox Regression HR=0.77 p=0.013 HR=0.77 p<0.001 HR=0.83 p=0.006 8 This newsletter has been written by an independent medical writer and, as such, does not

Scientific Symposium: Beyond Prevention of CMV [page 1 of 2] Antiviral prophylaxis offers more than prevention of CMV disease Anti-CMV prophylaxis is cost-effective, prevents the reactivation of other opportunistic viruses, and reduces the incidence of post-transplant lymphoproliferative disorder and renal allograft rejection. A. Humar, Toronto General Hospital, Toronto, Canada; M. Pescovitz, Indiana University, Indianapolis, IN, USA; and F. Oppenheimer, Hospital Clinic I Provincial de Barcelona, Barcelona, Spain presented data from a number of investigative studies of anticytomegalovirus (anti-cmv) prophylactic regimens. These data specifically focused on the reactivation of opportunistic viruses, the incidence of post-transplant lymphoproliferative disorder (PTLD), and the relative cost-effectiveness of the prophylactic regimens, in solid organ transplant recipients. Firstly, Dr Humar presented results from a recent double-blind trial in which he had investigated the incidence and clinical relevance of: non-β herpesviruses such as human herpesvirus (HHV-8), Varicella Zoster virus (VZV) and Epstein-Barr virus (EBV) polyomaviruses adenovirus other human herpesviruses such as HHV-6 and HHV-7 This analysis has highlighted the absence of HHV-8 and VZV DNAemia during the first year post-transplant. In contrast, EBV DNAemia was common; however, prophylaxis with valganciclovir may have prevented higher levels of EBV replication. Polyomavirus DNAemia occurred in both renal and nonrenal transplant patients. Adenovirus DNAemia was also relatively common. Finally, the incidence of significant HHV-6 and HHV-7 DNAemia appears lower than previously reported for CMV D + /R SOT patients not receiving anti-cmv prophylaxis. A. Humar Level of EBV DNAemia Patients (%) 10 8 6 4 2 0 A. Humar > 999 copies/ml > 1999 copies/ml Level of EBV DNAemia Valganciclovir Oral ganciclovir All patients > 4999 copies/ml CONTINUES ON NEXT PAGE 9 This newsletter has been written by an independent medical writer and, as such, does not

Scientific Symposium: Beyond Prevention of CMV [page 2 of 2] Antiviral prophylaxis offers more than prevention of CMV disease [continued from previous page] BACK Professor Pescovitz then presented data which examined whether CMV prophylaxis could reduce the risk of PTLD and/or the incidence of renal allograft rejection. Patients from 23 centers in the US were included into this case-controlled study. PTLD Risk With Days on Antiviral Model Risk Ratio 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Acyclovir Ganciclovir 0 15 30 45 60 75 90 105 120 Days on Antiviral The results of this study provide support for the role of ganciclovir in reducing the risk of PTLD during the first year of transplant. For every 30 days of ganciclovir treatment, risk of PTLD was reduced by 41% (odds ratio=0.71; 95% CI= 0.51 0.99). Ganciclovir use was independent of other predictors of PTLD. These may include negative EBV serostatus, history of rejection or prior non-lymphoma malignancies. Antiviral prophylaxis, and particularly ganciclovir, at the time of transplantation, was strongly associated with lower risk of early rejection. After adjusting for other risk factors, acyclovir and ganciclovir reduced the risk of early rejection by 53% and 75% respectively, although prophylaxis was not associated with a reduction in late rejections. Finally, Dr Oppenheimer presented costeffectiveness data which compared the following CMV-controlling strategies: sequential intravenous ganciclovir + induction + oral ganciclovir maintenance oral valganciclovir prophylaxis alone Total Cost of Anti-CMV Prophylaxis Cost category Pharmacological treatment Treatment with anti-cytomegalovirus immunoglobulin Total cost of drug administration Catheter culture Adverse events associated with catheter use Total cost of treatment M. Pescovitz M. Pescovitz F. Oppenheimer Cost of Sequential Ganciclovir ( ) 2983.39 313.73 401.45 13.64 3.30 3715.51 Cost of Valganciclovir ( ) 3295.90 Cost Difference Between Groups 312.51-312.73-401.45-13.64-3.30 3295.90-419.61 Criteria for determining which drug to use for CMV prophylaxis in solid organ transplant patients includes efficacy, safety, convenience, and cost. Valganciclovir has proven efficacy and safety and a convenient once-daily dosing regimen. In addition, this pharmaco-economic analysis indicates that the administration of valganciclovir prophylaxis in high-risk D + /R patients is more cost effective than sequential ganciclovir prophylaxis an estimated saving of 420 per patient. In lung and liver transplant patients, these savings are even greater, averaging 742 and 1,320 respectively. F. Oppenheimer 10 This newsletter has been written by an independent medical writer and, as such, does not

Oral Session: Kidney Humoral Response MMF, tacrolimus, and daclizumab induction is an effective steroid-free immunosuppressive regimen Steroid-free immunosuppression with MMF + tacrolimus + daclizumab improves cholesterol levels, glucose profile, and bone mineral density. K. Budde [CLICK ON NAME FOR ABSTRACT], University Hospital Charité, Berlin, Germany presented a six-month, openlabel, randomised, multicentre study involving 538 renal transplant recipients. The study objectives were: to compare the efficacy and safety of a steroid-free regimen with a standard-steroid regimen (mycophenolate mofetil (MMF) + tacrolimus + daclizumab vs MMF + tacrolimus + steroids) and to investigate the effects of this steroid-free regimen on: blood cholesterol glucose disorders bone mineral density (BMD) In both treatment groups, tacrolimus doses were adjusted from 0.1 mg/kg (pre-operatively) tapered to trough levels of 5-10 ng/ml (days 43-183). MMF was administered at a dose of 2 g/day for the first 14 days and 1g/day thereafter. In the steroid-containing arm, i.v. steroid doses were reduced from 500 mg (day 0) tapered to 5 mg (day 43 onwards). In the steroidfree arm, a dose of 1 mg/kg daclizumab was given on day 0 and day 14. There were 278 evaluable patients in the steroid-containing arm and 260 patients in the steroid-free arm. The incidence of biopsy-proven acute rejection was 16.5% in both treatment arms, and the incidence of corticosteroid-resistant acute rejection was 4.7% in the steroid-containing group and 5.0% in the steroid-free group, p=ns. There were no significant differences between the two groups in terms of patient survival, graft loss, and creatinine clearance. However, compared to the steroid-containing group, patients in the steroidfree group reported significant improvements in mean total cholesterol and a lower incidence of new-onset diabetes mellitus (-0.19±1.29 mmol/l vs +0.19±1.33 mmol/l; p=0.005 and 0.4% vs 5.4%; p=0.001 respectively). Steroid-free patients also reported relative improvements in BMD. Total Cholesterol (mean changes from baseline) mmol/l 2.0 1.5 1.0 0.5 0.0-0.5-1.0-1.5-2.0 * Completers Std. Steroids (N=198) Steroid-free (N=185) Day 0 Month 3 Month 6* Our results indicate that steroid-free immunosuppression with MMF, tacrolimus, and daclizumab induction, is as efficacious as a standard steroid-containing regimen. Moreover, the steroid-free regimen offers advantages in terms of improved recovery of bone mineral density, lower total cholesterol, and almost eliminates the need for long-term insulin therapy. This study therefore suggests a reduced cardiovascular risk profile for renal transplant recipients when receiving tacrolimusbased steroid-free therapy. K. Budde P=0.046 P=0.051 P=0.005 11 This newsletter has been written by an independent medical writer and, as such, does not

XXTH INTERNATIONAL CONGRESS OF THE TRANSPLANTATION SOCIETY 2004 Scientific Symposium: Roche Organ Transplantation Research Foundation (ROTRF) 5th Anniversary Symposium Highlights of Scientific Progress Successful landmark studies facilitate ROTRF s future success Additional five-year funding from Roche drives launch of new grant category. These ROTRF-funded studies include: Two types of grant are now available: Controlling immunity through CTLA-4 and other regulatory pathways Jeffrey Bluestone, University of California, San Francisco, USA Conventional Research Grants For research projects relevant to solid organ transplantation Clinical Research Grants For clinical research projects (e.g. projects proposing work with human clinical material, organ transplant patients, human organ preservation, human transplant pathology, and other human transplant problems) that will have a significant impact in the clinical setting in the near future Mesenchymal stem cells as facilitators of transplant tolerance Amelia Bartholomew, University of Illinois, Chicago, USA Mechanisms of graft destruction in the absence of cognate recognition between the graft and T cells Michel Braun, Université Libre de Bruxelles, Brussels, Belgium All would-be grantees were advised to submit a letter of intent to the organisation by 1 October 2004. Further details can be found at: www.rotrf.org Vascular endothelial growth factor in acute and chronic rejection David Briscoe, Harvard Medical School, Boston, USA During the seminar, it was announced that in addition to its initial five-year grant of 25 million Swiss Francs, F. Hoffmann-La Roche had pledged a further 25 million Swiss Francs to fund ROTRF-commissioned research for the next five years. This newsletter has been written by an independent medical writer and, as such, does not Applications and Grants Worldwide North America <47% of applications Europe (inc. former Soviet Union and Israel) <43% of applications Asia and The Middle East <2% of applications South America <1% of applications Africa >1% of applications at least one application ever received no application received Australia >5% of applications Tolerance through haematopoietic cell transplantation with co-stimulation blockade Thomas Wekerle, Medical University of Vienna, Vienna, Austria 12 M. Sykes and J-P Soulilou, Board of Trustees, ROTRF highlighted a number of ground-breaking, ROTRF-funded studies from the past five years. HOME The ROTRF is proud to announce the launch of an initiative to fund more clinical research projects that promise to have a significant impact in the clinical setting in the near future. J-P Soulilou PRINT EXIT

[O8*] SIROLIMUS IN COMBINATION WITH CYCLOSPORINE MICROEMULSION VERSUS MYCOPHENOLATE MOFETIL WITH CYCLOSPORINE MICROEMULSION IS ASSOCIATED WITH DECREASED GRAFT SURVIVAL IN RENAL TRANSPLANT RECIPIENTS, INDEPENDENT OF ETHNICITY AND DONOR TYPE [P230] THE EFFECT OF GASTRIC PH MODULATORS ON THE PHARMACOKINETICS OF MYCOPHENOLATE MOFETIL (MMF) IN DE NOVO RENAL TRANSPLANT PATIENTS H.-U. Meier-Kriesche 1, B. J. Steffen 2, A. H. Chu 2, J. J. Loveland 2, V. Gotz 2, R. D. Gordon 3, J. A. Morris 2, B. Kaplan 1. 1 University of Florida, Gainesville, Florida, USA; 2 ProSanos Corporation, La Jolla, California, USA; and 3 Roche Laboratories Inc., Nutley, New Jersey, USA. Van Gelder T 1, Pescovitz MD 2, Elzein H 3, Hamzeh F 3. 1 Erasmus Medical Center, Rotterdam, The Netherlands; 2 Indiana University, Indianapolis, IN, USA; and 3 Roche Laboratories, Nutley, NJ, USA. Aims: This retrospective analysis of the 2003 Scientific Registry of Transplant Recipients (SRTR) was designed to evaluate the association between sirolimus (Rapa) + cyclosporine microemulsion (CSA) treatment vs. mycophenolate mofetil (MMF) + CSA in graft survival in adult primary renal transplant (tx) patients. Methods: A retrospective analysis of the 2003 Scientific Registry of Transplant Recipients (SRTR) was performed on patients who underwent solitary renal transplantation between 1998 and 2003 who were discharged on either MMF+CSA (n = 21,017) or Rapa+CSA (n = 1,999). Primary endpoints were graft survival, death-censored graft survival (DCGS), and patient death. Univariate Kaplan-Meier analyses and multivariate Cox regression models correcting for demographic and clinical covariates were used to estimate the relative risks for Rapa+CSA vs. MMF+CSA-treated patients reaching study endpoints. Subgroup analyses were conducted for donor type and recipient ethnicity. An interaction analysis was conducted for ethnicity. Results: In univariate analyses, Rapa+CSA was associated with significantly lower 4-year graft survival (74.6% vs. 79.3%, p=0.0021) and DCGS (83.7% vs. 87.2%, p=0.0029) vs. MMF+CSA; differences in patient death were not statistically significant (86.1% vs. 88.5%, p=0.077). In the multivariate analysis, Rapa+CSA was associated with a significantly increased risk for graft loss, death-censored graft loss, and patient death, as displayed in Table 1. Results for graft loss are presented by recipient ethnicity in Table 2. Similar results were obtained when analyzing subgroups of cadaveric donor vs. living donor tx (not shown). Table 1. Cox Regression for the Association of Rapa+CSA * and Endpoints Endpoint Hazard 95% CI P-Value Ratio Graft loss 1.21 1.07-1.37 0.003 Death-censored graft loss 1.20 1.02-1.41 0.026 Patient death 1.24 1.04-1.46 0.013 *Reference MMF+CSA Table 2. Cox Regression for Drug-Ethnicity Interaction and Graft Loss Drug-Ethnicity Combination Hazard 95% CI P-Value Ratio Rapa+CSA African American 1.93 1.56 2.37 <0.001 MMF+CSA African American 1.52 1.40-1.66 <0.001 Rapa+CSA Caucasian/ 1.18 1.01-1.38 0.037 all other *Reference MMF+CSA Caucasian/all other Conclusions: In summary, Rapa+CSA was associated with significantly worse graft survival compared to MMF+CSA, especially in African American recipients. Death-censored graft survival and patient survival were also significantly worse in patients discharged on Rapa+CSA. Information regarding drug dosing/concentrations is not available in the SRTR; however, findings from this study are likely reflective of the early experience of Rapa+CSA, when full-dose CSA was utilized. The impact of alternative strategies of Rapa utilization with reduced CSA exposure or alternative agents on these outcomes should be studied. Background: Compared to most other immunosuppressive drugs, there are few known drug interactions with MMF. With increased interest in monitoring mycophenolic acid (MPA) plasma concentrations, detection of drug interactions with MMF becomes more clinically relevant. In this retrospective analysis, we investigated the effect of the use of gastric ph modulators (H2 blockers H2b, proton pump inhibitors PPI, or antacids) on MPA exposure in 141 de novo renal transplant patients treated with MMF. Methods: Three full MPA pharmacokinetic (PK) profiles (0 to 12 hours) were done on days 3, 7, and 11; and five abbreviated (0 to 2 hours) PK profiles were done on Weeks 3, 4, 8, 12, and 20. Use of H2b, PPI, or antacids within 24 hours prior to the PK day was considered positive use. Groups defined by the type of gastric ph modulator were compared using repeated measures in a linear mixed effects model. Log transformed AUC 0-12, and Cmax were compared, adjusting for treatment group, sex, age, donor age, and average daily dose of MMF, cyclosporine and corticosteroids. The ratio of the least squares of the means (LSM) and the 90% confidence interval (C.I.) were compared to the (0.8, 1.25) equivalency range. Individual time concentration points were also compared. Results: The MPA exposure over 20 weeks of therapy, expressed as AUC 0-12, was not significantly different in patients with and without concomitant use of H2b, PPI, or antacids. In patients using PPIs, C max was not significantly different in all periods except on days 7, 11, and 21. MPA AUC 0-12 (mg.h/l) by Use of Gastric ph Modulators During MMF Therapy PH Subgroup Day Week Week Ratio of 90% Modulator 7 4 12 LSM C.I. Mean±SD H2b Y (n=104) 28±17 44±29 48±27 0.99 0.93-1.06 N (n=37) 33±19 46±29 59±34 PPI Y (n=28) 25±15 35±25 43±24 0.89 0.83-0.96 N (n=113) 30±18 47±30 53±30 Antacid Y (n=41) 30±17 40±24 54±28 0.97 0.91-1.04 N (n=96) 29±18 47±31 50±30 T max was 40 mins in all periods for all groups except in the PPI use group, where it was 75 mins from day 11 onward. Conclusions: The data suggest that H2-blockers, antacids, or PPIs did not have a significant effect on MPA exposure as measured by AUC. Patients using PPIs had delayed C max from day 11 onwards. C max was not different for H2b and antacid groups. 13 This newsletter has been written by an independent medical writer and, as such, does not BACK

[O281] IMPACT OF DIABETIC STATUS ON MYCOPHENOLIC ACID (MPA) EXPOSURE USING MYCOPHENOLATE MOFETIL (MMF) IN DE NOVO RENAL TRANSPLANT PATIENTS [O412] DACLIZUMAB VERSUS NO INDUCTION THERAPY, IN COMBINATION WITH CYCLOSPORINE MICROEMULSION, MYCOPHENOLATE MOFETIL, AND CORTICOSTEROIDS, IS ASSOCIATED WITH DECREASED ACUTE REJECTION IN CARDIAC TRANSPLANT RECIPIENTS AND NO OBSERVED INCREASE IN MORTALITY Van Gelder T 1, Pescovitz MD 2, Elzein H 3, Hamzeh F 3. 1 Erasmus Medical Center, Rotterdam, The Netherlands; 2 Indiana University, Indianapolis, IN, USA; and 3 Roche Laboratories, Nutley, NJ, USA. J. A. Morris 1, J. A. Kobashigawa 2, K. M. David 1, A. H. Chu 1, B. J. Steffen 1, R. D. Gordon 3. 1 ProSanos Corporation, La Jolla, California, USA; 2 University of California, Los Angeles, Los Angeles, California, USA; and 3 Roche Laboratories Inc., Nutley, New Jersey, USA. Aims: Individualization of MMF therapy has been advocated to minimize the incidence of acute rejection. Pre-existing disease state may contribute to the variability in MPA exposure. This is a retrospective analysis of the impact of pre-existing diabetes on MPA exposure in kidney transplant patients. Methods: 141 kidney transplant patients had three full MPA pharmacokinetics (PK) profiles (0 to 12 hours) on days 3, 7, and 11; and five abbreviated (0 to 2 hours) PK profiles on Weeks 3, 4, 8, 12, and 20. Diabetic status was determined based on medical history and / or reported use of anti-diabetics at study entry. Diabetics and non-diabetics were compared using repeated measures in a linear mixed effects model. Log transformed AUC 0-12 and C max were compared adjusting for treatment group, sex, age, donor age, and average daily dose of MMF, cyclosporine, and corticosteroids. The ratio of the least squares of the means (LSM) and the 90% confidence interval (C.I.) were compared to the (0.8, 1.25) equivalency range. Individual time concentration points were also compared. Results: AUC 0-12 increased over time in both diabetic and nondiabetic patients, almost doubling by Week 12. MPA exposure during 20 weeks of therapy, expressed as MPA AUC 0-12, was not significantly different in the diabetic and non-diabetic groups. Selected MPA AUC 0-12 (mg.h/l) by Diabetic Status Sub Statistic Day Day Week Week Ratio of 90% group 7 21 4 12 LSM C.I. Diabetic Mean 28.1 36.6 43.9 48.0 (n=15) S.D. 13.2 20.0 28.2 23.1 Non-Diabetic Mean 29.4 42.8 44.4 51.3 (n=126) S.D. 17.8 26.0 29.3 30.1 1.02 0.93 to 1.12 C max was not significantly different for all periods except for days 7 and 11. However, AUC 0-12 was not significantly different for all periods. Conclusion: The data suggest that pre-existing diabetic status does not influence MPA exposure as measured by AUC 0-12 after MMF administration to kidney transplant patients. MPA AUC's were similar in all groups including days 7 and 11. Aims: In a recently reported randomized, placebo-controlled study, an increased risk of mortality was observed at 6 and 12 months post-cardiac transplant in patients receiving daclizumab in combination with cyclosporine microemulsion (CSA), mycophenolate mofetil (MMF). The present study further investigated the safety profile of daclizumab in cardiac transplant recipients utilizing a large United States registry of cardiac transplant patients treated with daclizumab versus no induction therapy. Methods: Data on all adult cardiac transplants performed in the United States between January 1998 and October 2003 in patients who received mycophenolate mofetil, cyclosporine, and corticosteroids at hospital discharge were accessed from the Scientific Registry of Transplant Recipients. Patients were divided into 2 groups based on induction treatment: daclizumab (n=684) and no induction (n=2525). Outcomes were evaluated at 6 months, 12 months, and 3 years post-transplant. Univariate Kaplan-Meier and multivariate Cox proportional hazard models correcting for covariates were used to evaluate the relative risks of treatment on safety and efficacy outcomes. Multivariate analyses were corrected for potential confounding covariates, including donor cause of death, recipient pre-transplant serum creatinine, hospitalization status at the time of transplant (i.e., in the intensive care unit [ICU], hospitalized, but not in the ICU, or not hospitalized), on life support pre-transplant, degree of HLA matching, recipient and donor body mass index, donor female into recipient male, recipient race, donor age, cold ischemia time, cytomegalovirus status, and recipient age. Patient death from any cause and, specifically, infectious death, at 6 and 12 months were the primary study endpoints. Secondary endpoints included rejection within the first year post-transplant (acute rejection), cardiovascular death, and malignant death. Results: The distribution of patient demographics, donor characteristics, and recipient transplant procedure details was similar for the daclizumab and the no-induction groups. Patients on daclizumab had no increased risk of death due to any cause, infectious death, cardiovascular death, or malignant death compared to no-induction therapy patients at any time point studied (6 and 12 months, and 3 years post-transplant). Patients given daclizumab had a lower incidence of acute rejection at 6 months (p=0.005) and 12 months (p<0.001) compared to no induction patients; the adjusted risk for acute rejection at 12 months was also lower in daclizumab-treated patients (HR=0.77; CI=0.67, 0.89). Conclusions: In cardiac transplant patients, daclizumab does not result in increased mortality at 6 months, 12 months, or 3 years post-transplant compared to no induction therapy, and is associated with a lower incidence of acute rejection at 6 and 12 months post-transplant. Some of the increased mortality observed in the previous clinical trial may have been due to a higher incidence of severe infections in daclizumab patients resulting from concomitant use of antilymphocyte antibody therapy. Longer follow-up is needed to understand the long-term outcomes of cardiac transplant patients treated with interleukin-2 antagonists and antibody induction therapy. 14 This newsletter has been written by an independent medical writer and, as such, does not BACK

[O429] STEROID-FREE IMMUNOSUPPRESSION WITH DACLIZUMAB, TACROLIMUS AND MMF IS EFFICACIOUS AND IMPROVES CHOLESTEROL, GLUCOSE AND BONE MINERAL DENSITY THE CARMEN STUDY [P743] LOWERING CYCLOSPORINE DOSE IS NOT ASSOCIATED WITH AN INCREASED RISK OF GASTRO-INTESTINAL ADVERSE EVENTS NOR THE NEED FOR DOSAGE DECREASE OF MYCOPHENOLATE MOFETIL K. Budde 1, H.-H. Neumayer 1, L. Rostaing 2, D. Cantarovich 3, G. Mourad 4, P. Rigotti 5 and the CARMEN Study Group. 1 University Hospital Charité, Berlin, Germany; 2 Hopital de Rangueil, Toulouse, France; 3 Nantes University Hospital, Nantes, France; 4 Hopital Lapeyronie, Montpellier, France; 5 University of Padua, Padua, Italy. H. Kreis 1, T. Miloradovich, G. Mourad, O. Cointault, F. Berthoux, M. Delahousse, E. Cassuto, J-M. Chalopin, D. Glotz, Y. Lebranchu, C. Legendre, P. Merville, J-L. Touraine, P. Vialtel, P. Wolf, B. Moulin and R. Purgus. 1 Renal Transplantation, Hopital Necker, Paris, France. Aims: This open, randomized, multicenter, 6-month study evaluated the efficacy and safety of a steroid-free regimen based on daclizumab, tacrolimus and MMF (Dac) in comparison with a standard tacrolimus, MMF and steroid (Steroid) regimen in renal transplant recipients. Methods: In both treatment groups, patients received 0.1 mg/kg tacrolimus pre-operatively (Day 0). The initial oral tacrolimus dose was 0.2 mg/kg/day; subsequent doses were adjusted to trough levels of 10-20 ng/ml (Days 1-21), 10-15 ng/ml (Days 22-41), and 5-10 ng/ml (Days 43-183). The MMF dose was 2 g/day for the first 14 days and 1g/day thereafter in both arms. In the Steroid arm, patients received 500 mg i.v. steroids on Day 0, 125 mg on day 1, and then 20 mg (Days 2-14) tapered to 5 mg (Day 43 onwards). In the Dac arm, steroid administration was restricted to a single dose of 500 mg i.v. on Day 0. A dose of 1 mg/kg daclizumab was given on Day 0 and on Day 14. Results: There were 278 evaluable patients in the Steroid arm and 260 patients in the Dac arm (ITT) from 47 centers in 6 European countries. Patient baseline characteristics were similar in the two groups. In the Steroid group, 90.6% vs. 82.3% of Dac patients completed the study; 8.6% of Steroid and 16.5% of Dac patients were withdrawn. The incidence of biopsy-proven acute rejection was 16.5% in both treatment arms, the incidence of corticosteroid-resistant acute rejection was 4.7% for Steroid and 5.0% for Dac patients, p=ns. In total 8 patients died, 3 in the Steroid group and 5 in the Dac group. In the Steroid group 12 grafts (4.3%) were lost compared to 21 graft losses (8.1%) in the Dac arm, p=ns. Mean calculated creatinine clearance was 53.6 ml/min (Steroid) vs. 52.0 ml/min (Dac). Importantly, treatment groups differed with respect to mean change in total cholesterol from Day 0 to Month 6 (+0.19±1.33 mmol/l vs. -0.19±1.29 mmol/l; p=0.005) and new-onset diabetes mellitus defined as need for insulin >30 days (5.4% vs. 0.4%; p=0.001) for Steroid vs. Dac, respectively. Bone mineral density also worsened in the Steroid group in all areas measured whereas improvements in some areas were observed with Dac. Conclusion: Tacrolimus allows for steroid-free immunosuppression with MMF after daclizumab induction. This regimen is highly efficacious and reduces the changes in glucose metabolism, total cholesterol and bone mineral density observed with a tacrolimus steroid-containing regimen. Aims: It has been demonstrated that the variation of mycophenolate mofetil (MMF, CellCept ) daily dose is associated with a worse outcome after renal transplantation. On the other hand, there is a known pharmacological interaction between cyclosporine (CsA) and MMF. In CsA sparing immunosuppressive protocols, the CsA dose decrease may therefore lead to higher MMF exposure and an increased risk of occurrence of MMF-related adverse events. We described here the evolution of MMF dosage and gastrointestinal (GI) tolerability in a multicenter, open-label, randomized, study comparing the efficacy and safety of a reduced CsA (rcsa) versus a standard CsA (scsa) regimen. Methods: After receiving daclizumab, MMF, steroids and CsA for 8 weeks after transplantation, patients were randomly allocated to receive either scsa (n=80) or rcsa (N=78). The target trough blood levels of CsA were 150-200 (W9-12) and 100-150ng/ml (M12-M24) in the scsa group vs. 100-150 (W9-W12), 75-100 (W12-M12) and <75ng/ml (M12-M24) in the rcsa group. Results: Demographic patterns were similar in both groups. Throughout the study, more than 80 % of patients in both groups received a daily dose of 2 g of MMF (Table) rcsa (n=78) scsa (n=80) 1-YEAR (n=68) (n=73) Mean MMF Dose SD (g/d) 1.91±0.24 1.94±0.33 NS MMF Dose 2g/d (pts,%) 59 (86.8%) 66 (90.4%) NS 2-YEAR FOLLOW-UP VISIT (M24): (n=62) (n=71) Mean MMF Dose SD (g/d) 1.85±0.40 1.93±0.31 NS MMF Dose 2g/d (pts,%) 52 (83.9%) 64 (90.1%) NS BPAR 11.5% 10.0% NS GI adverse events 57.0% 56.3% NS During 2-year follow-up, overall incidence of GI adverse events was comparable between groups. Diarrhoea occurred in 15.2% patients in rcsa and 5.0% in scsa, and none of these episodes led to withdrawal. Conclusions: In this 2-year randomised, prospective, multicenter study associating daclizumab, MMF, CsA and steroids in de novo renal transplant recipients, lowering CsA in patients treated with MMF 2 g daily is not associated with an increase of GI adverse events and MMF daily dose of 2 g/d can be maintained safely in the large majority of patients. 15 This newsletter has been written by an independent medical writer and, as such, does not BACK

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