John B Hynes Convention Center, Boston, MA July 2006

Transcription

1 HIGHLIGHTS FROM THE 1ST JOINT INTERNATIONAL TRANSPLANT MEETING OF THE WORLD TRANSPLANT CONGRESS John B Hynes Convention Center, Boston, MA July 2006 Boston 2006 Leading scientists and clinicians from around the world converged in Boston, USA, from July 2006 to attend the inaugural joint international transplant meeting of the World Transplant Congress. This meeting marked the first time that members of The Transplant Society, The American Society of Transplant Surgeons, and The American Society of Transplantation have come together to expand the capacity to share new worldwide research and to learn about new discoveries in transplantation medicine. Attendees at this landmark event included physicians, surgeons, research scientists, nurses, organ procurement personnel, and pharmacists in the field of organ transplantation. The presenters at this congress included the most respected and knowledgeable members of this highly specialised area of medicine. This e-newsletter focuses on some of the key data presented for the first time at the World Transplant Congress. This includes 12 month results of the Symphony Study investigating immunosuppression minimization and withdrawal, interim findings from the TranCept study exploring the introduction of CellCept at different time points post transplant, the clinical implications of therapeutic drug monitoring shown in the FDCC and Apomygre studies and the role of gene polymorphisms on MPA pharmacokinetics. Contents 2. Symphony Study Main results 3. Symphony Study MPA pharmacokinetics analysis 4. Symphony Study CellCept + low-dose sirolimus sub-analysis 5. FDCC Trial 6. APOMYGRE Study 7. OptiCept Study 8. Spare the Nephron Study 9. Polymorphisms and MPA exposure 10.Caesar Study Pharmacogenetic analysis 11. The Big Interview Herwig-Ulf Meier Kriesche (The TranCept Study) HOME PRINT EXIT PREVIOUS NEXT 1

2 Concurrent Session: Immunosuppression Trial I Symphony Study - Comparing standard immunosuppression to CellCept, daclizumab and corticosteroids plus either low-dose CsA, tacrolimus or sirolimus in renal transplant recipients CellCept + low-dose tacrolimus reduces CNI burden without compromising safety and efficacy. Link to abstract 49 Henrik Ekberg, Malmö, Sweden, presented results from the Symphony Study, a prospective, randomised, open, comparative study involving 1,645 renal transplant patients. The study was the largest prospective de novo kidney transplant study designed to date, and compared an immunosuppressive regimen comprising normal-dose CsA (target trough level ng/ml), CellCept (1 g bid) and corticosteroids, with one of three regimens comprising daclizumab (2 mg/kg followed by 4 x 1 mg/kg every two weeks), CellCept (1 g bid), and corticosteroids, plus a low-dose of either CsA ( ng/ml), tacrolimus (TAC, 3-7 ng/ml), or sirolimus (SRL, 4-8 ng/ml). The primary objective of the Symphony Study was to determine whether CNI burden could be reduced without adversely affecting safety and efficacy parameters. The primary endpoint was to determine renal function at 12-months post-transplant (measured using Cockcroft-Gault-calculated GFR), and secondary endpoints included 12-month acute rejection rates, 12- month graft survival rates, 12-month patient survival rates, and a 12-month safety analysis. Compared to all other groups, patients receiving low-dose CellCept, TAC, and daclizumab had significantly higher GFR rates, and the lowest incidence of biopsy-proven acute rejection. Graft survival was also significantly higher than in patients receiving normal-dose CsA or low-dose SRL. Calculated GFR (Cockcroft-Gault) Calculated GFR (Cockcroft-Gault) (ml/min) þ= þ< þ< months post-tx Graft and Patient Survival Graft survival (%) þ= þ= months post-tx Normal-dose CsA 93% 94% 89% 89% Patient survival (%) Normal-dose CsA Low-dose CsA Low-dose TAC Low-dose SRL þ=ns 98% 97% 97% 97% 12 months post-tx Low-dose CsA Low-dose TAC Low-dose SRL Biopsy Proven Acute Rejection (ITT, Excluding Borderline) Probability of acute rejection Time (months) % Low-dose SRL 25.8% Normal-dose CsA 24.0% Low-dose CsA 12.3% Low-dose TAC The Symphony Study shows that CellCept + low-dose TAC maximises the function and survival of the transplanted kidney, and protects the patient by providing the optimal balance between efficacy and toxicity available today. Henrik Ekberg HOME PRINT EXIT PREVIOUS NEXT 2

3 Concurrent Session: MPA Pharmacology Symphony Study - Pharmacokinetics of free and total MPA when CellCept administered with low-dose tacrolimus, low-dose cyclosporine, low-dose sirolimus, or standard-dose cyclosporine in renal transplant recipients CsA may inhibit the secretion of MPAG into bile. is Link to abstract 824 Josep Grinyo, Barcelona, Spain, presented a pharmacokinetic sub-analysis of the Symphony Study, involving 83 renal transplant patients. The primary study objective was to assess the differences in the AUC0-12 of MPA and its metabolites among the four Symphony cohorts. C max and t max MPA trough levels were also measured. Patients were randomized to receive either standard CsA (CsA-S), low-dose CsA (CsA-L), low-dose tacrolimus (T-L), or low-dose sirolimus (S-L) in combination with CellCept and corticosteroids. PK sampling was done pre-dose, and at 20, 40, 75 minutes, and 2, 3, 6, 8, 10 and 12 hours post-dose. MPA dose interval AUCs are dose normalized to 1 g. The results are summarised in the following tables: Day 7: Dose-Normalised Pharmacokinetic Parameters All evaluable patients Normal CsA n Median±SD Low CsA n Median±SD Low TAC n Median±SD Low SRL n Median±SD Day 7: Pharmacokinetic Parameters All evaluable patients Normal CsA n Median±SD Low CsA n Median±SD Low TAC n Median±SD MPA (AUC) ± ± ±21.6 Free MPA (AUC) ± ± ±0.62 MPAG (AUC) ± ± ±808 Acyl glucuronide (AUC) Study drug (AUC) Study drug ± ± ± ± ± ±42 (trough levels) ± ± ±2 Low SRL n Median±SD ± ± ± ± ± ±4 Compared with patients on standard-dose CsA, patients on low-dose sirolimus or tacrolimus had higher free MPA, higher total MPA, and lower MPAG. This sub-analysis supports the hypothesis that CsA inhibits MPAG secretion into bile. Further analyses should now investigate correlations of individual time points with MPA AUC 0-12, the clinical relevance of interactions of CsA, tacrolimus, and sirolimus on MPA metabolism, the clinical relevance of total free MPA and acyl glucuronide, and the relationship of acyl glucuronide with GI effects. Josep Grinyo MPA (AUC) ± ± ± ±24.9 Free MPA (AUC) ± ± ± ±0.55 MPAG (AUC) ± ± ± ±1011 Acyl glucuronide (AUC) ± ± ± ±15.6 HOME PRINT EXIT PREVIOUS NEXT 3

4 Concurrent Session: mtor Inhibitors Symphony Study CellCept, daclizumab, and steroids plus low-dose sirolimus in the first eight weeks following renal transplantation A safe and effective low-dose sirolimus-containing immunosuppression regimen has yet to be identified. Link to abstract 691 Henrik Ekberg, Malmö, Sweden presented a sub-analysis of the Symphony Study, involving 399 patients randomised to the low-dose sirolimus group (4-8 ng/ml). The sub-study objectives were to determine the practicality of achieving and maintaining these target levels, and to further investigate the regimen-associated clinical outcomes. The chosen sirolimus loading dose was 9 mg/day for the first three days, followed by 3 mg/day thereafter. Trough levels were analysed at weeks 1, 2, 4, and 8, and correlated with clinical outcome. At week 1, 15% of the patients were below, 53% within and 32% above target of between 4-8 ng/ml. Similar percentages were observed at the following measurements for week 8: 10%, 51% and 39%, respectively. Although it could be shown that investigators tried to correct offtarget levels, only 9% of the patients were consistently on target, highlighting that SRL levels are difficult to maintain. The average SRL dosage at week 8 was 2.93 mg. The rate of biopsy proven acute rejections (BPAR - excluding borderline rejection) in low-srl at one year (37%) was significantly higher than in the other groups (12-25%). No clear correlation of SRL levels and efficacy measures (BPAR, treatment failure) but also no clear correlation of SRL levels and toxicities (lymphoceles, triglycerides, wound healing problems) could be identified. Trough Levels of SRL IS trough level (ng/ml) Target range Weeks The chosen dosing scheme was appropriate for reaching the sirolimus target concentration of 4-8ng/mL but it was difficult to stay within this target range, and most patients had levels between 4 and 11 ng/ml. This target was not appropriate for achieving adequate efficacy, but was still associated with toxicity. The study also showed that patients with initial levels below target, did not have an increased risk of AR. There was also no clear correlation of sirolimus levels with treatment failure or toxicity. Therefore, our findings show that a low-toxicity and efficient CNI-free sirolimus-containing regimen has yet to be defined. Henrik Ekberg HOME PRINT EXIT PREVIOUS NEXT 4

5 Concurrent Session: MPA Pharmacology FDCC Trial Comparison of fixed-dose versus concentration-controlled CellCept regimens in de novo renal transplant patients CellCept starting doses should be dependent upon the concurrent CNI. Teun van Gelder, Erasmus MC, Rotterdam, The Netherlands presented results from the FDCC Trial, a prospective randomised study involving 901 renal transplant patients. The study objective was to investigate the potential added benefit of therapeutic drug monitoring (TDM) of CellCept therapy in adult and paediatric de novo renal allograft recipients, in light of the fact that MPA exposure directly correlates with rejection prevention and that significant inter-patient variability of MPA exposure is known to exist. All patients were randomised to receive either fixeddose CellCept therapy (FD; 1 g bid for 30 days then fixed-dose according to centre protocol) or concentration-controlled CellCept therapy (CC). In the CC group, abbreviated AUCs were measured on days 3 and 10, week 4, and months 3, 6, and 12, and were used to predict AUC CellCept doses were adjusted to reach a target value MPA-AUC 0-12 of mg/l*h. Patients also received corticosteroids plus either CsA (n=483) or tacrolimus (n=418). The primary endpoint of the study was treatment failure, via a composite endpoint comprising biopsy-proven acute rejection (BPAR; BANFF grade > 1), patient death, graft loss, or discontinuation of CellCept treatment. Patients with higher MPA exposures experienced fewer acute rejections, but no clear differences in exposure levels between the FD and CC arms were achieved. At twelve months, the incidence of treatment failure was comparable for both groups (FD = 25.7% versus CC = 25.6%). There were also no significant inter-group differences in graft loss, death, and CellCept discontinuation. The incidence of BPAR was similarly low in both groups FD = 14.6% versus CC = 14.7%). Exposure as Box-and-Whisker Plot AUC (mg+h/l) Day 3 Cyclosporin Subpopulation Concentration controlled (CC) Fixed dose (FD) Day 10 Week 4 M 3 M 6 M Tacrolimus Subpopulation Day 3 Day 10 Week 4 M 3 M 6 M 12 There does appear to be a relationship between efficacy and MPA exposure, but in our study, AUCs were very similar in both groups and the proportion of patients reaching target MPA exposure was similar. This could be due to the fact that investigators seemed reluctant to adjust the CellCept dose fully, based on MPA levels. Therefore a difference in efficacy could not be expected. However, our results do suggest that in tacrolimustreated patients, a CellCept starting dose of 2 g/day should be used to evoke optimal MPA exposure and low BPAR incidence, whilst in CsAtreated patients, a CellCept starting dose of 3 g/day would be beneficial. Teun van Gelder Link to abstract 819 HOME PRINT EXIT PREVIOUS NEXT 5

6 Concurrent Session: MPA Pharmacology CellCept Therapeutic Drug Monitoring Comparison of a fixed-dose versus a concentration-controlled regimen in kidney transplant recipients CellCept therapeutic dose monitoring using a Bayesian estimator is safe and effective. Link to abstract 820 Yann Le Meur, Limoges, France, presented results from the APOMYGRE Study, a multicentre, randomised study involving 137 renal transplant patients. The study objective was to compare the effects of MPA exposure using a fixed-dose (FD) and concentration-controlled (CC) CellCept -containing immunosuppressive regimen. All patients received a classical immunosuppressant regimen comprising basiliximab, CsA, CellCept and steroids. The FD group (n=67) received 2 g of CellCept a day. The CC group (n=70) received a CellCept dose adapted to the area under the concentration curve (AUC) of MPA, with a target of 40 mg*h/l. Dose adjustments were directly calculated by the computer program. MPA AUCs were calculated with a Bayesian estimator using a 3-point limited sampling strategy on days 7 and 14, and months 1, 3, 6, and 12. There were significant inter-group differences in MPA AUC during the early post-transplant period. For example, at one month post-transplant, 90% of the CC cohort but only 56% of the FD cohort experienced MPA AUC levels above 30 mg*h/l. At the end of the study, there were no inter-group differences in the rates of patient and graft survival, but when compared to the FD group, there were significantly fewer biopsy proven acute rejections in the CC group (7.7% versus 24.6%, p = 0.02). This improvement in efficacy was achieved in the CC group without a corresponding increase in most adverse events. Indeed, of all the monitored adverse events, only the incidence of herpes simplex was significantly increased in the CC group (FD = 1.5%; CC = 12.3%). MPA Exposure AUC (h,mg/l) Day 7 Day 14 Month 1 CC group FD group Visit Month 3 Month 6 Month 12 Therapeutic dose monitoring for CellCept using a Bayesian estimator is feasible, safe, effective, and a good tool for individualisation. Our results suggest that when in combination with CsA, the initial CellCept dose should be 3 g/day. MPA AUC monitoring should also be carried out. Yann Le Meur HOME PRINT EXIT PREVIOUS NEXT 6

7 Concurrent Session: MPA Pharmacology / Immunosuppression Trials IV OptiCept Study Interim results of monitored CellCept in combination with CNI in renal transplantation Concentration-controlled CellCept with a reduced-level CNI improves renal function when compared to patients on a standard-dose CNI regimen. Link to abstract 822 Link to abstract 1090 Roy Bloom, Philadelphia, USA and Diane Cibrik, Michigan, USA, presented two sixmonth interim analyses of the two-year, open-label, prospective, randomised, multi-centre OptiCept Trial, involving 718 single-organ renal allograft recipients. The study objective was to compare the efficacy, safety, and effects on renal function of maintenance immunosuppression with either concentration-controlled (CC) or fixed-dose (FD) CellCept in combination with a standard- or reduced-level CNI regimen. All patients received either: concentrationcontrolled CellCept and reduced level (RL) CNI (CellCept CC/CNI RL ); concentration-controlled CellCept and standard level (SL) CNI (CellCept CC/CNI SL ); or fixed-dose CellCept (1 g bid) and standard level CNI (CellCept FD/CNI SL ). Troughbased dose adjustments were made in the CellCept CC arms, and abbreviated AUCs were measured for retrospective analysis. Antibody induction and/or corticosteroids were administered according to centre practice. The primary efficacy endpoints included the proportion of patients with biopsy-proven acute rejection (BPAR), graft loss, or death, and mean percent change in calculated GFR (Nankivell equation). Safety endpoints were the incidences of AEs and SAEs. Biopsy-proven acute rejection occurred in 2.2% of the CellCept CC/CNI RL cohort, 9.7% of the CellCept CC/CNI SL cohort, and 3.0% of the CellCept FD/CNI SL group. Graft loss occurred in 2.2% of the CellCept CC/CNI RL group, 1.9% of the CellCept CC/CNI SL group, and 3.0% of the CellCept FD/CNI SL group. Mean percent increase in calculated GFR was higher in the CellCept CC/CNI RL group (27.3 ± 49.1) when compared to the CellCept CC/CNI SL (8.8 ± 27.9) and CellCept FD/CNI SL groups (18.3 ± 39.6). All safety outcomes were similar. % Change from Baseline in GFR Mean Percentage Change (±SD) Tacrolimus: Day 180 CellCept CC /CNI RL CellCept CC /CNI SL CellCept FO /CNI SL Concentration-controlled CellCept and reduced-level CNI appear to provide comparable efficacy and safety to a full-dose CNI regimen with or without MPA monitoring. Complete follow-up of the 718 patients will provide more definitive data supporting this low-cni regimen. Roy Bloom & Diane Cibrik HOME PRINT EXIT PREVIOUS NEXT 7

8 Concurrent Session: Immunosuppression Trials IV Spare the Nephron Interim results of CellCept /sirolimus maintenance therapy after CNI withdrawal in chronic renal transplant recipients CNI-free, CellCept -sirolimus maintenance therapy improves renal function without increasing acute rejection risk. Link to abstract 1084 Link to abstract 1085 Thomas Pearson, Altanta, USA presented two twelve-month interim analyses of the Spare The Nephron Trial, involving 254 renal transplant patients. The study objective was to investigate whether reduced CNI exposure improved renal allograft function in this patient cohort. Two-hundred-and-fifty-four patients maintained on CellCept and a CNI were randomized days after transplantation to receive CellCept (1-1.5 g bid) plus SRL (2-10 mg followed by at least 2 mg/day; trough 5-10 ng/ml) (CellCept /SRL group) or a continuation of their current regimen (CellCept /CNI group). The CNI was discontinued in the CellCept /SRL group. Antibody induction and/or corticosteroids were administered according to individual centre practice. Efficacy endpoints included the proportions of patients with biopsy-proven acute rejection (BPAR), graft loss, and death, and the percent change in measured glomerular filtration rate. At one year, the median percent increase from baseline in measured GFR was 25 for CellCept /SRL and -10 for CellCept /CNI. BPAR was seen in 3/48 (6.3%) CellCept /SRL-treated patients and 7/57 (12.3%) of those receiving CellCept /CNI. Graft loss was experienced by 1/48 (2.1%) of those in the CellCept /SRL group and 3/57 (5.3%) of those in the CellCept /CNI group. No patient in the CellCept /SRL group and 2/57 (3.5%) in the CellCept /CNI group died. Mean % Change in Measured GFR Mean Percentage Change (±SEM) n=37 Baseline to Month 12 n= n=33 These preliminary findings suggest that CellCept - sirolimus maintenance therapy results in low rejection rates, and that there is no increase in the risk of acute rejection after CNI withdrawal. It also appears that the CNI-free CellCept -sirolimus regimen is associated with improvements in renal function, when compared to CNI-CellCept. 1.0 CellCept /SRL CellCept /CNI CellCept /TAC Complete follow-up of the 340 patients will provide a definitive long-term assessment of the influence of these regimens. Thomas Pearson HOME PRINT EXIT PREVIOUS NEXT 8

9 Poster Session: Kidney Transplantation Rejection & Immunosuppression Gene polymorphisms partly explain inter-individual variability of CellCept pharmacokinetics and acute rejection incidence Polymorphisms of the UGT1A9 and MRP2 genes affect MPA exposure; polymorphisms of the T3757C gene are associated with higher acute rejection rates. Madelon van Agteren, Erasmus MC, Rotterdam, The Netherlands presented three analyses investigating the association between polymorphisms and MPA exposure. Link to abstract 1215 Link to abstract 1216 Link to abstract 1217 The objective of the analyses was to investigate whether certain polymorphisms could partly explain the extensive inter-patient variability in mycophenolic acid (MPA) pharmacokinetics and/or MPA-associated acute rejection rates. Around three-hundred renal transplant patients entered this substudy of the randomised, controlled trial comparing fixed-dose CellCept versus concentrationcontrolled CellCept (FDCC Study). Abbreviated AUC samples were obtained on days 3 and 10, week 4, and months 3, 6, and 12. The samples were analysed for the presence of known polymorphisms. Treatment failure at 12 months IMPHD T3737C TT non carrier Not TT carrier Total No acute rejection Acute rejection 55/252 (22%) 19/59 (32%) 74/311 (24%) Single nucleotide polymorphisms in the UGT1A9 gene (T275A and C2152T) are associated with lower MPA exposure. These SNPs explain part of the betweenpatient variability in MPA pharmacokinetics. However, the impact of this polymorphism on MPA exposure is modest, compared to the overall variability. The C-3972T polymorphism in the MRP2 gene has a significant, but modest effect on MPA pharmacokinetics in tacrolimus-treated renal transplant patients. This study found no effect of the MRP2 polymorphism in CsA-treated patients, presumably because CsA itself inhibits MRP2. MPA C0 and AUC in carriers vs non carriers T275A MPA C0 and AUC carriers vs non carriers C3972T TRL treated patients C TT TA Day 3 UGT1A9 - T275A Day 10 Week 4 Visit 3 Months 6 Months 12 Months AUC TT TA Day 3 UGT1A9 - T275A Day 10 Week 4 Visit 3 Months 6 Months 12 Months Mean AUC Mean C CC not CC CC not CC Day 3 Day 10 TRL - C3972T Week 4 Visit 3 Months 6 Months 12 Months Possession of at least one C allele at the IMPDH T3757C gene polymorphism shows a trend to a higher incidence of acute rejection after kidney transplantation. Madelon van Agteren HOME PRINT EXIT PREVIOUS NEXT 9

10 Concurrent Session: Rejection - Mechanisms Association of three polymorphisms with acute rejection after kidney transplantation: an exploratory pharmacogenetic analysis of the Caesar Study Three polymorphisms of the MDR1, IL-10, and IMPDH2 genes are associated with higher acute rejection rates in renal transplant recipients. Link to abstract 1020 Josep Grinyo, Barcelona, Spain, presented an exploratory pharmacogenetic analysis of the Caesar Study investigating the association between 19 single nucleotide polymorphisms and biopsy-proven acute rejection (BPAR). Each of these 19 polymorphisms were associated with genes which were thought to affect BPAR (i.e. IMPDH1, IMPDH2, MDR1, MRP2, CYP3A4, CYP3A5, IL-2, IL-10 and TGF ß). Specifically, these genes were involved in mediating the immune response, or in pharmacodynamic or pharmacokinetic aspects of the chosen drug regimen (i.e. CellCept + corticosteroids + standard-, low-, or no-dose CsA). Two-hundred-and-thirty-seven renal transplant patients were investigated. Homozygosity for the IL A allele was associated with nearly 5-fold higher odds of BPAR, presence of at least one IMPDH C allele increased the odds of developing BPAR by nearly 3 times, and presence of the MDR T allele almost doubled the odds of BPAR. No statistically significant interactions among these 3 polymorphisms, or with the different treatment regimens, were detected. Results: Modeling by multivariate analysis Polymorphisms MDR1 C3435T IMPDH2 T3757C IL-10 C-592A Genetic coding T vs C (Additive) TT vs. {CT;CC} AA vs {CC; AC} (recessive) Odds ratio* [Wald 95% CI] 2.07 [1.225;3.49] 2.84 [1.13;7.14] 4.60 [1.42;14.94] *: OR and p-values adjusted on sex, age category and treatment groups effects No interaction with treatment group effects in any of the polymorphisms No interaction with sex or age No interaction between the different polymorphisms p-value in the final model* Variation in genes may be important in understanding the basis of acute rejection. For example, the MDR1 C3435T polymorphism has previously been shown to be associated with differences in expression levels and function of P-glycoprotein and enhanced CsA clearance, whilst the IL A polymorphism has been reported to influence IL-10 transcription levels in vitro. However, these associations still require additional confirmation and their functional link is unclear. In addition, to date, their discriminatory power is too low to be used for individual screening purposes. Josep Grinyo HOME PRINT EXIT PREVIOUS NEXT 10

11 THE BIG INTERVIEW: THE TRANCEPT STUDY Herwig-Ulf Meier-Kriesche, Florida, USA Herwig-Ulf Meier-Kriesche, Florida, USA presented exciting results from the interim results of the four-year TranCept Study, a prospective, multicentre, observational clinical study involving 1777 patients who were switched to an CellCept -containing immunosuppressive regimen more than six months after transplantation. Future Directions caught up with Professor Meier-Kriesche to discover his thoughts on these compelling results. FD: What is the rationale behind the TranCept study? HUMK: There is a wealth of short-term data investigating CellCept s efficacy, but to date, very few large, long-term, studies have been performed. The TranCept study designers sought to rectify that by providing longterm safety and efficacy data in patients who had been switched to CellCept for a variety of reasons, more than six months post-transplant. FD: What is the overall TranCept study design? HUMK: The TranCept study was a prospective, multicentre, observational, non-interventional, one-arm global surveillance study of clinical outcomes, involving 1,777 renal allograft recipients switched at least six-months after renal transplantation to long-term immunosuppressive therapy with CellCept. The principal aim of the study was to document the effects of long-term CellCept treatment on renal function over four years, in four groups who had commenced CellCept at different post-transplant timepoints. All patients had received CNI-based immunosuppression prior to the switch, and all were single organ renal allograft recipients. The main analysis variable was calculated GFR, and this was analysed both in the population as a whole, and in subpopulations which were organised according to post-switch timings and reasonings. For the main analysis, patients were categorised into four main groups: Reasons for CellCept Introduction 100% 75% 50% 25% 0% A B C D All Other Insufficient response/ar Adverse events Renal function decline Group A (n=170) included all patients switched to CellCept between six and 12 months posttransplant Group B (n=205) included all patients switched to CellCept between one and two years posttransplant Group C (n=461) included all patients switched to CellCept between two and five years posttransplant Group D (n=874) included all patients switched to CellCept after five years post-transplant. Continued on next page There is a wealth of short-term data investigating CellCept s efficacy, but to date, very few large, long-term, studies have been performed. Herwig-Ulf Meier-Kriesche HOME PRINT EXIT PREVIOUS NEXT 11

12 THE BIG INTERVIEW: THE TRANCEPT STUDY Continued from page 11 Similarly, the four main categories for CellCept introduction were: Renal function decline Adverse events Insufficient response / acute rejection Other. FD: What is the study s primary endpoint? HUMK: The primary endpoint of the TranCept study was the evolution of GFR. In general, over time, one would see a deterioration of renal function, and we wanted to see whether the introduction of CellCept during different post-transplant periods, would help to stabilise or reverse this gradual decline. FD: What results were presented at the WTC? HUMK: At WTC, I presented the results of an interim analysis, carried out in February 2006 when 1,256 patients had reached one-year follow-up. The total number of patients included in this analysis was 1,710. FD: What did these results show? HUMK: There was a significant overall improvement in renal function associated with the switch to CellCept. Before CellCept s introduction, there was a continued decline in renal function, but from the moment CellCept was introduced, there was a stabilisation of renal function over the subsequent four-year period. In addition, in the sub-group of patients in whom CNIs were withdrawn or reduced, renal function improved significantly. FD: Were these results surprising? HUMK: When we consider the other interventional trials performed to date, we would have expected the observed improvement in renal function. The most surprising aspect of this trial however, is that these improvements occur at any post-transplant time-point. In addition, one finding that was not surprising, but which was equally important, is that the acute rejection rates with these CellCept - containing regimens were extremely low (2.5% in the whole population and 2.4% in patients with renal function decline and CNI reduction or withdrawal). FD: Are these results likely to change clinical practice? HUMK: The patients who are likely to benefit most from these results are transplant recipients at relatively low-risk of acute rejection, who are taking CNI-containing immunotherapy and are experiencing CNI-associated nephrotoxicity. GFR Evolution: Breakpoint Analysis GFR difference from baseline (ml/min) All patients Time from CellCept introduction (years) Slope by Reason for CellCept Introduction Change in caluclated GRF (ml/min) Tolerability / AEs 6 Time from CellCept introduction (years) 8 Regression lines with breakpoint at CellCept introduction Slope change: p< Regression line without breakpoint GFR decrease no post-switch CNI reduction GFR decrease post-switch CNI reduction or withdrawal All patients (including other subgroups) CellCept introduction 4 The patients who are likely to benefit most from these results are transplant recipients at relatively low-risk of acute rejection. Herwig-Ulf Meier-Kriesche Link to abstract 578 HOME PRINT EXIT PREVIOUS NEXT 12

13 [49] SYMPHONY COMPARING STANDARD IMMUNOSUPPRESSION TO LOW-DOSE CYCLOSPORINE, TACROLIMUS OR SIROLIMUS IN COMBINATION WITH MMF (CellCept ), DACLIZUMAB AND CORTICOSTEROIDS IN RENAL TRANSPLANTATION. H Ekberg, H Tedesco-Silva, A Demirbas, S Vitko, B Nashan, A Gurkan, R Margreiter, C Hugo, J Grinyo, U Frei, Y Vanrenterghem, P Daloze, P Halloran. Lund Univ, Malmoe, Sweden; Federal Univ, Sao Paulo, Brazil; Akdeniz Univ, Antalya, Turkey; IKEM, Prague, Czech Republic; Medizinische Hochschule, Hannover, Germany; SSK Tepecik Hospital, Izmir, Turkey; Universitaetsklinik, Innsbruck, Austria; Univ Hospital, Erlangen, Germany; Ciutat Universitaria de Bellvitge, Barcelona, Spain; Virchow-Klinikum, Berlin, Germany; KU Leuven, Leuven, Belgium; Notre-Dame Hospital, CHUM Montreal, Canada; Univ of Alberta, Edmonton, Canada. Introduction: SYMPHONY is a trial comparing standard immunosuppression versus 3 regimens with low-dose or no CNI in de-novo single-organ renal transplant patients over 1 year. Methods: In this prospective, randomized, open study with 4 parallel arms, 1645 patients in 15 countries were randomized to standard immunosuppression with normal-dose cyclosporine (CsA, target trough level ng/ml for 3 months, ng/ml thereafter), MMF 1g bid and corticosteroids, or to one of three regimens consisting of daclizumab induction (2mg/kg followed by 4x1mg/kg every 2 weeks), MMF (1g bid) and corticosteroids potentiated by a low-dose of either CsA ( ng/ml), tacrolimus (TAC, 3-7ng/ml) or sirolimus (SRL, 4-8ng/ml). Primary objective was to determine renal function (GFR calculated with Cockcroft-Gault) at 12 months. Secondary endpoints were biopsy proven acute rejection (BPAR) rate, patient and graft survival rates, treatment failure, GFR time course and safety. Results: Differences in GFR and BPAR were statistically significant among the 4 groups (p<0.0001). The low-dose TAC group was significantly superior to all other groups with respect to GFR and BPAR (p<0.01) and to normal-dose CsA and low-dose SRL for graft survival (pair-wise p<0.05). N GFR (12 mo) GFR (12 mo) BPAR (6 / 12 mo) Graft survival (12 mo) Patient survival (12 mo) (ITT) median [ml/min] mean + SD [ml/min] [%] [%] [%] Normal-dose CsA / Low-dose CsA / Low-dose TAC / Low-dose SRL / Conclusion: Immunosuppression consisting of daclizumab induction, MMF, low-dose TAC and corticosteroids provides the most optimal balance between efficacy (control of acute rejection) and toxicity (preserving graft function and graft survival). 13

14 [824] PHARMACOKINETICS OF TOTAL AND FREE MYCOPHENOLIC ACID (MPA) WHEN MYCOPHENOLATE MOFETIL (CellCept ) IS ADMINISTERED WITH LOW-DOSE TACROLIMUS, LOW-DOSE CYCLOSPORINE, LOW-DOSE SIROLIMUS OR STANDARD-DOSE CYCLOSPORINE IN RENAL TRANSPLANTATION. RESULTS OF THE SYMPHONY PK SUBSTUDY. J Grinyo, H Ekberg, F Oppenheimer, J Plumed, G Rodriguez, D Hernandez, D Kuypers, M Brunet. Ciutat Univ de Bellvitge, Barcelona, Spain; Lund Univ, Malmoe, Sweden; Hosp Clinic i Provincial, Barcelona, Spain; HU La Fe, Valencia, Spain; Hosp Virgen del Rocio, Sevilla, Spain; Hosp Univ de Canarias, La Laguna, Tenerife, Spain; Univ of Leuven, Leuven, Belgium; Centre de Diagnostic Biomedic, Barcelona, Spain. Purpose: MMF (CellCept ) co-administration with cyclosporine (CsA) results in lower MPA exposure compared with tacrolimus or sirolimus probably due to inhibition of biliary secretion of MPA-glucoronide (MPAG) by CsA, subsequently decreasing enterohepatic recirculation of MPA. This PK substudy of the SYMPHONY trial compared systemic exposure of MPA and MPAG when 2g of MMF was combined with low-dose CNI, sirolimus or standard CsA and expanded these observations to non-protein bound (free) MPA. Methods: Patients from 15 sites in Spain and Belgium were entered in the PK substudy and randomized to receive either standard CsA (CsA-S), low-dose CsA (CsA-L), low-dose tacrolimus (T-L), or low-dose sirolimus (S-L) in combination with MMF and corticosteroids. PK sampling was done predose, 20, 40, 75 min, 2, 3, 6, 8, 10 and 12 hours post dose. MPA dose interval AUCs are dose normalized to 1 g. MPAG is expressed as MPA equivalents. Results: The PK results for day 7 post transplant are summarized in the table. AUC total ** AUC free ** MPAG* CsA-S (n=13) CsA-L (n=17) T-L (n=15) S-L (n=21) Values (mean + SEM) are in µ g*h/ml. * p<0.05; ** p<0.01 (Kruskal-Wallis global test) Conclusion: 7 days after transplantation, patients on low-dose sirolimus or tacrolimus had higher free MPA, total MPA and lower MPAG exposures compared to patients receiving CsA, regardless if standard or low-dose. Patients receiving low-dose CsA had significantly higher MPA and lower MPAG exposures compared to patients receiving standard-dose CsA, supporting the hypothesis that CsA inhibits MPAG secretion into bile. This substudy showed for the first time that compared to CsA, MMF co-administration with tacrolimus or sirolimus results in higher dose-corrected exposure to the free, pharmacologically active, fraction of MPA. 14

15 [691] LOW-DOSE SIROLIMUS IN THE FIRST 8 WEEKS FOLLOWING RENAL TRANSPLANTATION ACCOMPANIED BY DACLIZUMAB INDUCTION, MMF (CellCept ) AND STEROIDS: THE EXPERIENCE OF THE SYMPHONY STUDY. H Ekberg, F Vincenti, H Tedesco da Silva, P Daloze, T Pearson. Lund Univ, Malmoe, Sweden; UC, San Francisco; Federal Univ, Sao Paulo, Brazil; Notre-Dame Hospital, CHUM Montreal, Canada; Emory Univ, Atlanta. Introduction: The randomized, open-label trial SYMPHONY compared standard immunosuppression (cyclosporine - CsA -, MMF 2g/day and steroids) with 3 regimens with daclizumab induction and low-doses of either cyclosporine (low-csa), tacrolimus (low-tac) or sirolimus (low-srl) in 1645 de-novo renal transplant patients over one year. In the low-srl arm the target trough level was 4-8 ng/ml. How well such levels could be reached and maintained and the clinical outcomes were among the open questions. Methods: The SRL loading dose was 9 mg/day for the first 3 days post-transplant, followed by 3 mg/day and adjusted to maintain through levels between 4-8 ng/ml. In the 399 evaluable patients we analyzed the time course of SRL trough levels at week 1, 2, 4 and 8 and correlated them with selected clinical outcomes. Results: SRL levels: At week 1 (first mandatory measurement), 15% of the patients were below, 53% within and 32% above target. Similar percentages were observed at the following measurements (week 8: 10%, 51% and 39%, respectively). Less than 4% of the patients were constantly above or below target, pointing to a correct reaction to off-target levels. The average SRL dosage was 2.93 mg at week 8. Outcomes: the rate of biopsy proven acute rejections (BPAR - excluding borderline rejection) in low-srl at one year (35%) was higher that in the other groups (12-25%). The increase in BPAR emerged mainly after week 8. No clear correlation of SRL levels with BPAR rate, total cholesterol, triglycerides and wound healing problems (slightly more common than in the other groups) could be identified. Patients with initial levels below target did not seem to be at an undue risk of future rejections. Discussion: We estimate that the addition of low-srl to a CNI-free regimen consisting of daclizumab induction, MMF and steroids conferred an absolute reduction in BPARs of about 15% based on previous studies. The protection over the first 8 weeks was comparable to that of low-csa, but thereafter it was inferior to all other tested drugs regimens. The proposed initial dosing regimen and adaptation strategy were appropriate given the variability of levels in this clinical setting. The room for increasing SRL immunosuppression should be evaluated against the specific SRL toxicity profile. 15

16 [819] A PROSPECTIVE, RANDOMISED STUDY COMPARING FIXED DOSE VS CONCENTRATION CONTROLLED MMF (CellCept ) REGIMENS FOR DE NOVO PATIENTS FOLLOWING RENAL TRANSPLANTATION (THE FDCC TRIAL). Teun van Gelder, Helio Tedesco Silva, Hans de Fijter, Klemens Budde, Dirk Kuypers, Gunnar Tyden, Aleksander Lohmus, for FDCC Study Group. Erasmus MC, Rotterdam, Netherlands; Sao Paulo, Brazil; Leiden, Netherlands; Berlin, Germany; Leuven, Belgium; Stockholm, Sweden; Tartu, Estonia. Introduction. MMF is effective in the prevention of acute rejection following solid organ transplantation, at fixed dose. Several studies have shown a relationship between MPA plasma concentrations and the likelihood of acute rejection after renal transplantation (rtx). A randomized trial comparing Fixed Dose therapy with Concentration Controlled (FDCC-trial) MMF therapy was designed to study the contribution of therapeutic drug monitoring (TDM) to CellCept treatment. Methods. A total of 901 de novo rtx patients, from 65 centers in 19 countries, were randomized 1:1 to either fixed dose MMF therapy (FD), or concentration controlled MMF therapy (CC). All patients were treated with a calcineurin inhibitor, and corticosteroids. In the CC group abbreviated AUCs (3 samples within the first 2 hours after administration) were measured on day 3, day 10, week 4 and months 3, 6 and 12 and used to predict the AUC MMF dose was adjusted to reach a target value for MPA-AUC 0-12 between 30 and 60 mg/l*hr. Preliminary 6 month outcome data are presented in this abstract. Results. Patients treated with cyclosporine (CsA; n = 483) or tacrolimus (TRL; n = 418) were evenly distributed over the CC ( n = 449) and FD group (n = 452). Preliminary 6 month data on all 901 patients are available. The incidence of biopsy proven acute rejection (BPAR), was 59/449 (13.1%) in CC patients vs 61/452 (13.5%) in FD patients (p = 0.94). Adverse events were equally distributed among the two groups. Leukopenia was more frequent in the CC group (15.7%) compared to the FD group (10.5%) patients (p = 0.03). The percent of patients reaching the AUC 0-12 h target window of 30 and 60 mg/l*hr was not higher in the CC group compared to the FD group: at day 3 CC = 50% vs FD = 49%, at day 10 CC = 53% vs FD = 56%, at week 4 CC = 63% vs FD = 62% and at month 6 CC = 69% vs FD = 58%. Conclusion. Preliminary data show that MMF dose adjustments based on the limited number of abbreviated AUCs used in the FDCC study, were not able to increase the % of patients reaching early target MPA exposure. The incidence of BPAR at 6 months was not different between CC and FD patients. At WTC full 12 month outcome data will be available. 16

17 [820] THERAPEUTIC DRUG MONITORING OF MMF (CellCept ): A RANDOMIZED MULTICENTER STUDY COMPARING CONCENTRATION CONTROLLED VERSUS FIXED DOSE IN KIDNEY TRANSPLANT RECIPIENTS. Yann Le Meur, Matthias Büchler, Sylvie Lavaud, Isabelle Etienne, Pierre-François Westeel, Antoine Thierry, Sophie Caillard, Florence Villemain, Catherine Allard, Lionel Rostaing, Eric Thervet, Jean-Christophe Szelag, Jean-Philippe Rérolle, Guy Touchard, Pierre Marquet. Department of Nephrology, University Hospital, Limoges; Tours; Reims; Rouen; Amiens; Poitiers; Strasbourg; Angers; Caen; Toulouse; H pital Necker, Paris, France. MMF is currently administered according to a fixed dosing regimen but accumulating data suggests that therapeutic drug monitoring (TDM) of its active metabolite mycophenolic acid (MPA) may optimize its efficacy and tolerance. Methods: We conducted a randomized study in 11 French centres and included 137 kidney transplant recipients (PRA< 50%) receiving a classical immunosuppressant regimen with basiliximab, Csa, MMF and steroids. The fixed dose group (FD, 67 patients) received 2 g of MMF a day. The concentration controlled group (CC, 70 patients) received a MMF dose adapted to the area under the concentration curve (AUC) of MPA, with a target of 40 h.mg/l. Dose adjustment were directly calculated by the computer program. MPA AUCs were calculated with a Bayesian estimator using a 3-point limited sampling strategy on day 7,14, and month 1,3,6,12 in both groups (values not communicated to the physicians in the FD group). Results: One year data of 130 patients (65 each goup) is presented. Mean AUCs were significantly higher in the CC group on day 14, M1 and M3 (34 vs 27, 45 vs 34 and 45 vs 37 h.mg/l; p<0.01) due to an increased daily dose of MMF to reach the predefined target: 2.7g at D14, 2.9g at M1 and 2.3g at M3. At M6, MPA AUCs and daily dose of MMF were similar in both groups. Patient anf graft survival were identical in the two groups. There were less biopsy proven acute rejections in the CC group (5 vs 16, p = 0.02). There were no differences in terms of bacterial infections (43 CC vs 49 FD), CMV infections (23 vs 27) GI adverse events (27 vs 24) leukopenia (34 vs 32) or anaemia (57 vs 53). Conclusion: TDM for MMF using a Bayesian estimator is feasible, effective and safe in renal transplant patients and leads to an increased MMF dose up to M6. One year results showed less rejection with no increase of infections or GI and hematological side effects in the CC group. 17

18 [822] OPTICEPT TRIAL: INTERIM RESULTS OF 6-MONTH EFFICACY AND SAFETY OF MONITORED MYCOPHENOLATE MOFETIL (CellCept ) IN COMBINATION WITH CNI IN RENAL TRANSPLANTATION. Roy Bloom, Robert Naraghi, Diane Cibrik, Michael Angelis, Shamkant Mulgoankar, Bruce Kaplan, Robert Gaston, Robert Gordon. University of Pennsylvania, Philadelphia, PA; NIT, Los Angeles, CA; University of Michigan, Ann Arbor, MI; Translife/Florida Hospital, Orlando, FL; Saint Barnabas Medical Center, Livingston, NJ; University of Illinois, Chicago, IL; UAB, Birmingham, AL; Roche, Nutley, NJ. Purpose: To compare the efficacy and safety in renal transplant recipients of maintenance immunosuppression with either a concentration-controlled or fixed-dose MMF (CellCept ) regimen in combination with standard or reduced level calcineurin inhibitor (CNI). Methods: In a 2-year open-label, prospective, randomized, multicenter study, 718 single-organ renal allograft recipients received either: 1) concentrationcontrolled MMF and reduced level CNI (MMF CC /CNI RL ); 2) concentration-controlled MMF and standard level CNI (MMF CC /CNI SL ); or 3) fixed-dose MMF (1 g BID) and standard level CNI (MMF FD /CNI SL ). Trough-based dose adjustments were made in the MMF CC arms; abbreviated AUCs were measured for retrospective analysis. Antibody induction and/or corticosteroids were administered according to center practice. The primary endpoints included the proportion of patients with biopsy-proven acute rejection (BPAR), graft loss, or death, and mean percent change in calculated GFR (Nankivell equation). Safety endpoints were the incidences of AEs and SAEs. No testing of statistical significance was performed in this interim analysis. Results: 6-month interim data were available for 297 patients randomized to receive MMF CC /CNI RL (93), MMF CC /CNI SL (103), and MMF FD /CNI SL (101). Baseline characteristics were similar among groups. Median MPA AUC was g hr/ml in the 3 groups on day 3, on day 10, and at month 6. BPAR occurred in 2/93 (2.2%) MMF CC /CNI RL, 10/103 (9.7%) MMF CC /CNI SL, and 3/101 (3.0%) MMF FD /CNI SL patients. Graft loss occurred in 2/93 (2.2%) MMF CC /CNI RL, 2/103 (1.9%) MMF CC /CNI SL, and 3/101 (3.0%) MMF FD /CNI SL. Mean percent increase in calculated GFR was higher with MMF CC /CNI RL ( ) vs. MMF CC /CNI SL ( ) and MMF FD /CNI SL ( ). Safety outcomes were similar. Conclusions: These findings suggest that maintenance immunosuppression with MMF CC /CNI RL provides comparable results to full dose CNI with or without MPA monitoring as carried out in this trial. Longer follow-up of enrolled patients is needed to firmly assess the benefits of trough-based MMF monitoring in renal allograft recipients. 18

19 [1090] OPTICEPT TRIAL: INTERIM ANALYSIS OF RENAL FUNCTION AFTER 6 MONTHS OF MONITORED MYCOPHENOLATE MOFETIL (CellCept ) IN COMBINATION WITH CNI IN RENAL TRANSPLANTATION. Diane Cibrik, Robert Naraghi, Roy Bloom, Michael Angelis, Shamkant Mulgoankar, Bruce Kaplan, Robert Gaston, Dharmesh Patel. University of Michigan, Ann Arbor, MI; NIT, Los Angeles, CA; University of Pennsylvania, Philadelphia, PA; Translife/Florida Hospital, Orlando, FL; Saint Barnabas Medical Center, Livingston, NJ; University of Illinois, Chicago, IL; UAB, Birmingham, AL; Roche, Nutley, NJ. Purpose: To compare renal function in renal transplant recipients receiving maintenance immunosuppression with either a concentration-controlled or a fixed-dose mycophenolate mofetil regimen in combination with a standard or reduced level calcineurin inhibitor (CNI). Methods: In a 2-year open-label, prospective, randomized, controlled, multicenter study, 718 single-organ renal allograft recipients received either: 1) concentration-controlled MMF (CellCept ) and reduced level CNI (MMF CC /CNI RL ); 2) concentration-controlled MMF and standard level CNI (MMF CC /CNI SL ); or 3) fixed-dose MMF (1 g BID) and standard level CNI regimens (MMF FD /CNI SL ). Trough-based dose adjustments were made in the MMF CC arms; AUCs were collected for retrospective analysis. Antibody induction and/or corticosteroids were administered according to center practice. Renal function endpoints included mean percent changes in calculated glomerular filtration rate (GFR; Nankivell equation), serum creatinine (SCr) level, and calculated creatinine clearance (CrCl) (Cockroft-Gault). No testing of statistical significance was performed in this interim analysis. Results: Treatment group characteristics and renal function endpoints were similar at baseline. Of the 297 patients randomized, biopsy-proven acute rejection occurred in 2/93 (2.2%) MMF CC /CNI RL, 10/103 (9.7%) MMF CC /CNI SL, and 3/101 (3.0%) MMF FD /CNI SL. Six-month interim data were available for 260 patients randomized to receive MMF CC /CNI RL (81), MMF CC /CNI SL (92), and MMF FD /CNI SL (87) (Table). Mean Percent Change in Renal Function: Baseline to Month 6 Endpoint MMF CC /CNI RL MMF CC /CNI SL MMF FD /CNI SL Calculated GFR SCr Calculated CrCl Conclusions: These 6-month interim analyses suggest that concentration-controlled MMF combined with reduced level CNI provides better renal function than the concentration-controlled or standard dose MMF combined with standard level CNI regimens. Complete follow-up of the 718 patients will provide a more definitive long-term assessment of these regimens on renal function. 19

20 [1084] SPARE-THE-NEPHRON (STN) TRIAL: INTERIM ANALYSIS OF RENAL FUNCTION AFTER 12 MONTHS OF MYCOPHENOLATE MOFETIL (CellCept )/SIROLIMUS MAINTENANCE THERAPY AFTER CALCINEURIN INHIBITOR WITHDRAWAL IN RENAL TRANSPLANT RECIPIENTS. Ravinder Wali, Thomas C Pearson, Hamid Shidban, Anita Patel, Laurence Chan, Robert Gordon. University of Maryland, Baltimore, MD; Emory, Atlanta, GA; NIT, Los Angeles, CA; Henry Ford Hospital, Detroit, MI; University of Colorado, Denver, CO; Roche, Nutley, NJ. Purpose: To compare the effect on renal function of maintenance immunosuppression with mycophenolate mofetil and sirolimus (SRL) to that of MMF (CellCept ) and a calcineurin inhibitor (CNI) in renal allograft recipients. Methods: In a 2-year open-label, prospective, randomized, controlled, multicenter study, 254 of 340 planned patients maintained on MMF and a CNI were randomized days after transplantation to either MMF (1-1.5 g BID) plus SRL (2-10 mg followed by at least 2 mg/day; trough 5-10 ng/ml) and to discontinue the CNI (MMF/SRL) or to continue their current regimen (MMF/CNI). Antibody induction and/or corticosteroids were administered according to individual center practice. The primary endpoint was the percent change in measured glomerular filtration rate (GFR; cold iothalamate). Additional renal endpoints included calculated GFR (Nankivell equation), serum creatinine (SCr), and calculated creatinine clearance (CrCl; Cockroft- Gault). No testing of statistical significance was performed in this interim analysis. Results: 48 patients receiving MMF/SRL and 57 receiving MMF/CNI (cyclosporine, n=11; tacrolimus [TAC], n =46) completed 1 year of follow-up. Mean time posttransplant to randomization was d for the MMF/SRL group and d for the MMF/CNI group. Treatment groups were similar at baseline for all reported renal function endpoints. Mean Percent Change in Renal Function From Baseline to Month 12 After Randomization Endpoint MMF/SRL MMF/CNI MMF/TAC Measured GFR Calculated GFR SCr Calculated CrCl At 1 year, the median percent increase from baseline in measured GFR was 25 with MMF/SRL vs. -10 with MMF/CNI. Conclusions: Based on 1-year interim analyses, it appears that MMF/SRL after CNI withdrawal improves renal function when compared with MMF/CNI. Minimal, if any, positive change from baseline in measured GFR was observed in the overall MMF/CNI group with even less change in those receiving TAC. Complete follow-up of the 340 patients will provide a more definitive long-term assessment of these regimens on renal function. 20