1. Maurizio Salvadori Careggi University Hospital, Florence Italy
EC-MPS is associated with superior efficacy outcomes compared to MMF in de novo kidney transplant patients: A pooled analysis
Maurizio Salvadori Careggi University Hospital, Florence Italy
On behalf of Klemens Budde, Herwig Holzer, Giovanni Civati, Bjørn Lien and Wolfgang Arns 1

2. Background
Poor tolerability leads to MMF dose reduction or discontinuation in up to 70% of patients1,2
MPA dose changes are associated with:
Increased risk of acute rejection2,3
Increased risk of graft loss2,4
Enteric-coated mycophenolate sodium (EC-MPS) delays release of MPA vs MMF5, which may improve tolerability6
Data from large, prospective, comparative studies are still limited, and a pooled analysis of 12-month data from 4 prospective, multicenter trials was performed to compare efficacy with EC-MPS vs MMF in de novo kidney transplant recipients
1. Knoll GA et al. J Am Soc Nephrol 2003; 14: Pelletier RP. Clin Transplant 2003; 17:
3. Tierce JC et al. Clin Transplant 2005; 19: Bunnapradist S. Transplantation 2006; 82:
5. Arns W. Clin Transplant 2005; 19: Chan L et al. Transplantation 2006; 81: 1290–1297 2

3. Study design & patient numbers
EC-MPS N
MMF N
Induction therapy
End date
Criteria for MPA dose change
ERLB3011
Double-blind
213
210
Permitted as per center practice
2001
Decreased platelets, WBCs or neutrophils
ERLB24052,3
Open-label
1076 –
Permitted, as per subprotocols
2005
Leucopenia or neutropenia
RADB2014
196 No
Decreased platelets, WBCs or neutrophils Increased cholesterol or triglycerides
RADB2515
2002
Decreased platelets, WBCs or ANC Increased cholesterol or triglycerides
B301: 44% patients (half IL-2, Half others)
MYPROMS: % patients de novo, % patients induction; % patients IL-2
All patients received CsA and all study protocols included corticosteroid therapy EC-MPS dose was 1440mg/day & MMF dose was 2000mg/day (considered bioequivalent)
1. Salvadori M et al. Am J Transplant 2004; 4: Data on file, Novartis Pharma AG 3. Legendre C et al. Transplant Proc 2007; 39: Vitko S et al. Transplantation 2004; 78: Lorber MI et al. Transplantation 2005; 80: 3

4. Similar inclusion/exclusion criteria
Maximum age (years)
Donor type
Donor age (years)
Other key exclusion criteria
ERLB3011 75
Any unless asystolic*
Any
PRA >50%
ERLB24052,3
10-65
PRA >20-50%**
RADB2014 65
Any*
Induction therapy
RADB2515
CIT >40 hours DGF >48 hours post-tx
Add PRA and other characteristics mentioned in the slide
Other than HLA-idential living-related donors ** Maximum threshold varied between subprotocols
1. Salvadori M et al. Am J Transplant 2004; 4: Data on file, Novartis Pharma AG 3. Legendre C et al. Transplant Proc 2007; 39: Vitko S et al. Transplantation 2004; 78: Lorber MI et al. Transplantation 2005; 80: 4

5. Baseline characteristics by study
ERLB301
ERLB2405
RADB201
RADB251
Recipient age (years) Mean (SD) Range
47 (12) 18-72
48 (12) 17-76
46 (12) 18-71
43 (12) 16-68
Male recipient (%)
66%
71%
67%
White recipient (%)
88%
90%
87%
68%
Diabetes (%)
16%
11% 6%
24%
PRA >10% (%) 3% 5% 7%
Donor age ≥50 years (%)
41%
45%
39%
23%
Deceased donor (%)
84%
81%
91%
46%
Cold ischemia time, median (range) (h)
17 (0-39)
15 (0-42)
17 (0-42)
4 (0-38)
Induction (%)
26%
73% 0% 5 5

6. Baseline characteristics by treatment
EC-MPS (N=1289)
MMF (N=602)
Age, mean (SD) (years)
48 (12)
46 (12)
Male recipient (%)
846 (66%)
413 (69%)
White recipient (%)
1160 (90%)
491 (82%)
Diabetes (%)
147 (11%)
98 (16%)
PRA >10% (%) 5% 4%
Donor age ≥50 years (%)
44%
35%
Deceased donor (%)
82%
73%
Cold ischemia time, median (range) (h)
15 (0-42)
Induction (%)
832 (65%)
57 (9%) 6 6

7. Statistical methods (1)
Logistic regression analyses of EC-MPS vs. MMF with three approaches:
Stepwise, expert driven and propensity scores
Covariates used:
Recipient sex, age, and race (white or other)
Diabetes at baseline (yes/no)
Donor type (deceased/living)
Donor age (<50 / ≥50 years)
PRA (≤ 10% / >10%)
Cold ischemia time
Induction therapy (yes/no) 7 7

8. Statistical methods (2)
Propensity score analyses
Considered the most appropriate approach
Performed to reduce the potential bias that arose from non-randomization and the associated imbalances
Only one head-to-head randomized trial
Variation on the start date between trials
Most EC-MPS patients enrolled in later years
Relative weight of the different trials
Larger number of patients from ERL 2405 trial
Imbalance of patient characteristics for some variables 8 8

9. Propensity Scoring Approach
Published approach for observational (non-randomized) data
Propensity scores calculated = probability of being assigned to EC-MPA based on all covariates
Data split into 5 equal-sized blocks of “similar patients” based on ranked propensity scores
Blocks are fitted into the logistic model as a covariate

10. Immunosuppression EC-MPS (N=1289) MMF (N=602)
MPA dose (g/day), mean (SD)
Month 6
1.84 (0.32)*
1.87 (0.25)
Month 12
1.79 (0.41)*
1.85 (0.33)
Months 0-12
1.82 (0.37)*
1.86 (0.29)
CsA dose (mg/kg/day), mean (SD)
4.6 (1.7)
4.7 (1.7)
3.2 (1.1)
3.5 (1.2)
Steroid dose (mg/day), median (range)
0.12 (0-25.4)
0.13 (0-1.2)
0.10 (0-25.4)
0.10 (0-2.4)
* MMF dose equivalents, with EC-MPS 1440mg considered bioequivalent to MMF 2000mg

11. EC-MPS vs MMF: Efficacy Univariate analysis
EC-MPS (N=1289)
MMF (N=602)
P-value
Month 6
BPAR
243 (18.9%)
142 (23.6%)
0.017
Graft loss
41 (3.2%)
31 (5.1%)
0.039
Death
12 (0.9%)
7 (1.2%)
0.638
BPAR, graft loss or death
285 (22.1%)
166 (27.6%)
0.010
Month 12
260 (20.2%)
147 (24.4%)
0.037
45 (3.5%)
37 (6.1%)
0.009
16 (1.2%)
14 (2.3%)
0.084
308 (23.9%)
174 (28.9%)
0.020
BPAR, biopsy-proven acute rejection

12. EC-MPS vs MMF: Efficacy Logistic analysis (propensity score approach)
Effect of treatment: EC-MPS versus MMF
Odds ratio
95% CI
P-value
Month 6
BPAR
0.71
0.53, 0.95
0.020
Graft loss
0.51
0.28, 0.94
0.032
Death
0.67
0.21, 2.11
0.493
BPAR, graft loss or death
0.68
0.52, 0.89
0.006
Month 12
0.74
0.56, 0.98
0.037
0.50
0.28, 0.87
0.015
0.44
0.17, 1.13
0.088
0.70
0.53, 0.91
0.008
BPAR, biopsy-proven acute rejection

13. Composite endpoint at 12 months: Comparing approaches
Analysis of BPAR, graft loss or death at 12 months
Odds ratio (EC-MPS vs MMF) with 95% CI
Univariate
Stepwise
ED1: All data
ED2: No induction
Propensity
ED: Expert Driven
Stepwise Odds Ratio estimated at age 47 13 13

14. Effect of treatment: EC-MPS versus MMF
EC-MPS vs MMF: SAEs & serious infections Logistic analysis (propensity score approach)
Effect of treatment: EC-MPS versus MMF
Odds ratio
95% CI
P-value
Month 6
SAEs
1.21
0.96, 1.53
0.115
Serious infections
1.08
0.82, 1.43
0.592
Month 12
1.11
0.88, 1.40
0.387
1.01
0.77, 1.32
0.955

15. SAEs at 12 months: Comparing approaches
Analysis of SAEs at 12 months
Odds ratio (EC-MPS vs MMF) with 95% CI
Univariate
Stepwise
ED1: All data
ED2: No induction
Propensity
ED: Expert Driven 15 15

16. Summary
Results from this pooled analysis of >1800 de novo kidney transplant patients indicate:
Significant improvement in efficacy outcomes with EC-MPS vs MMF at both months 6 and 12
BPAR, graft loss & death
Higher rates of serious adverse events at month 6 with EC-MPS, but no differences at month 12
Uni- and multivariate results consistent with the propensity score analyses
These findings should be confirmed in large, randomized, prospective studies comparing EC-MPS vs MMF in de novo kidney transplantation 16

17. Thank You
To all the investigators from studies ERLB301, ERLB2405, RADB201 and RADB251

18. Maurizio Salvadori Careggi University Hospital, Florence Italy
EC-MPS is associated with superior efficacy outcomes compared to MMF in de novo kidney transplant patients: A pooled analysis
Maurizio Salvadori Careggi University Hospital, Florence Italy
On behalf of Klemens Budde, Herwig Holzer, Giovanni Civati, Bjørn Lien and Wolfgang Arns 18

19. BACK-UP SLIDES

20. Propensity Scoring Approach
Published approach for observational (non-randomized) data
Propensity scores calculated = probability of being assigned to EC-MPA based on all covariates
Data split into 5 equal-sized blocks of “similar patients” based on ranked propensity scores
Logistic model fitted with terms for block and treatment group (no evidence of treatment by block interaction)

21. 2 new approaches Basic “expert driven” model fitted to following
populations:
All data (N=1853; NEC-MPA=1259; NMMF=594)
Excluding Induction (N= 990; NEC-MPA= 450; NMMF=540)
Excluding ERL2405 (N= 800; NEC-MPS= 206; NMMF=594)
Study ERLB301 only (N= 410; NEC-MPS= 206; NMMF=204)
Induction Therapy (N= 863; NEC-MPS= 809; NMMF = 54)
Propensity Scoring Approach

22. Deceased, living-related (HLA MM) or living-unrelated donor
ERLB301
ERLB2405
RADB201
RADB251
Inclusion criteria
Deceased, living-related (HLA MM) or living-unrelated donor ●
Exclusion criteria
Maximum recipient age (y) 75 65
Donor age range
10-65
Asystolic donor
Multiorgan transplant
Previous renal transplant
Previous non-renal transplant
Positive T-cell crossmatch
ABO incompatibility
Maximum permitted PRA %
>50%
>20-50%
Thrombocytopenia (<75,000)
Absolute neutrophils <1,500
Leukopenia (<2,500)
Cold ischemia >40 hours
Delayed graft function >40 h
Use of induction therapy

23. All results: Propensity scoring approach
Propensity score analysis of all endpoints at 6 and 12 months
Odds ratio (EC-MPS vs MMF) with 95% CI

24. Results from propensity approach
Effect of treatment: EC-MPS versus MMF
Odds ratio
95% CI
P-value
Month 6
BPAR
0.71
0.53, 0.95
0.020
BPAR, graft loss or death
0.68
0.52, 0.89
0.006
Serious adverse events
1.21
0.96, 1.53
0.115
Month 12
0.74
0.56, 0.98
0.037
0.70
0.53, 0.91
0.008
1.11
0.88, 1.40
0.387

25. BPAR at 12 months: Comparing approaches
Analysis of BPAR at 12 months Odds ratio (EC-MPS vs MMF) with 95% CI 25 25

26. SAEs at 12 months: Comparing approaches
Analysis of SAEs at 12 months Odds ratio (EC-MPS vs MMF) with 95% CI 26 26

27. SAEs at 6 months: Comparing approaches
Analysis of SAEs at 6 months Odds ratio (EC-MPS vs MMF) with 95% CI