RAPAMUNE®TM

1

RandomizationRandomizationVariableVariable Day* to Day 386 Day* to Day 386

RAPA, CRAPA, Cminmin, TN, TN 0.7650.765

CsA, CCsA, Cminmin, TN, TN 0.2010.201

GenderGender 0.1170.117Increasing Recipient AgeIncreasing Recipient Age 0.1990.199CadaverCadaver 0.8520.852HLA MismatchHLA Mismatch 0.0980.098Increasing Ischemia TimeIncreasing Ischemia Time 0.9190.919Increasing Donor AgeIncreasing Donor Age 0.0260.026# Rejections# Rejections 3131

RandomizationRandomizationVariableVariable Day* to Day 386 Day* to Day 386

RAPA, CRAPA, Cminmin, TN, TN 0.7650.765

CsA, CCsA, Cminmin, TN, TN 0.2010.201

GenderGender 0.1170.117Increasing Recipient AgeIncreasing Recipient Age 0.1990.199CadaverCadaver 0.8520.852HLA MismatchHLA Mismatch 0.0980.098Increasing Ischemia TimeIncreasing Ischemia Time 0.9190.919Increasing Donor AgeIncreasing Donor Age 0.0260.026# Rejections# Rejections 3131

Study 310: Univariate Logistic Regression - RAPA Group

Study 310: Univariate Logistic Regression - RAPA Group

TABLE 8.3E

** Randomization Day for Individual Patient, Approx. Day 90Randomization Day for Individual Patient, Approx. Day 90

RAPAMUNE®TM

23.1A

Study 212Enrolled 19.1% Black Patients

Study 212Enrolled 19.1% Black Patients

Trial 310: 8 patients (1.5%) were black:

– RAPA + CsA 5/215 (2.3%)

– RAPA 2/215 (0.9%)

– Nonrandomized 1/95 (1.1%)

Trial 212: 47 (19.1%) black

– RAPA + CsA 18/97 (18.6%)

– RAPA 15/100 (15%)

– Nonrandomzied 14/49 (28.6%)

Trial 310: 8 patients (1.5%) were black:

– RAPA + CsA 5/215 (2.3%)

– RAPA 2/215 (0.9%)

– Nonrandomized 1/95 (1.1%)

Trial 212: 47 (19.1%) black

– RAPA + CsA 18/97 (18.6%)

– RAPA 15/100 (15%)

– Nonrandomzied 14/49 (28.6%)

RAPAMUNE®TM

3

Study 212: All 13 Eligible Black Patients Successfully Eliminated CsA

Study 212: All 13 Eligible Black Patients Successfully Eliminated CsA

CsA withdrawal arm:

– Enrolled 15

– Eligible for CsA taper 13

• 2 patients with AR

– Completed CsA taper 13

• 3 patients with AR post CsA withdrawal: 35, 64, and 122 days after completing CsA elimination

CsA withdrawal arm:

– Enrolled 15

– Eligible for CsA taper 13

• 2 patients with AR

– Completed CsA taper 13

• 3 patients with AR post CsA withdrawal: 35, 64, and 122 days after completing CsA elimination

RAPAMUNE®TM

4

22.2

10.1

33.3

15.213.3

7.1

33.3

20

0

5

10

15

20

25

30

35

40

Black Non-black Black Non-black

RAPA + CsARAPA

22.2

10.1

33.3

15.213.3

7.1

33.3

20

0

5

10

15

20

25

30

35

40

Black Non-black Black Non-black

RAPA + CsARAPA

%

Study 212: Similar Rates of Acute Rejection at Months 2 and 12

Study 212: Similar Rates of Acute Rejection at Months 2 and 12

N = 18 15 79 85 18 15 79 85N = 18 15 79 85 18 15 79 85

Month 2 Month 12P = NS

RAPAMUNE®TM

5

55.89

50.41

57.78

74.71

67.7164.88

0

20

40

60

80

100

2 6 12

Time, months

Me

an

Ob

se

rve

d V

alu

es

fo

r N

an

kiv

ell

GF

R,

mL

/min

RAPA + CsARAPA

Study 212: Significantly Higher Calculated GFR at Month12 in the RAPA Group, Black PatientsStudy 212: Significantly Higher Calculated GFR at Month12 in the RAPA Group, Black Patients

P = .098P = .0003

TABLE 3.3.3A

N = 15 13 16 14 15 13

RAPAMUNE®TM

6

Study 212: Numerically Lower BP in RAPA Group - Black Patients

Study 212: Numerically Lower BP in RAPA Group - Black Patients

0

40

80

120

160

RAPA + CsA

RAPA

RAPA + CsA 154 89.1

RAPA 137 86.6

Systolic Diastolic

N= 9 7 9 7

P=0.069

P=0.541

RAPAMUNE®TM

7

RAPA + CsA RAPA Fisher’s Exact(N = 97) (N = 100) P value

Patient SurvivalBlack 17 (94.4) 15 (100) 1.000Non-black 77 (97.5) 81 (95.3) 0.683

Graft Survival Black 17 (94.4) 14 (93.3) 1.000Non-black 73 (92.4) 81 (95.3) 0.524

RAPA + CsA RAPA Fisher’s Exact(N = 97) (N = 100) P value

Patient SurvivalBlack 17 (94.4) 15 (100) 1.000Non-black 77 (97.5) 81 (95.3) 0.683

Graft Survival Black 17 (94.4) 14 (93.3) 1.000Non-black 73 (92.4) 81 (95.3) 0.524

Study 212: Patient & Graft Survival (%) By Ethnic Origin: Month 12

Study 212: Patient & Graft Survival (%) By Ethnic Origin: Month 12

RAPAMUNE®TM

8Study 310: No (S.D.) Difference

in CADI Score at 1 YearStudy 310: No (S.D.) Difference

in CADI Score at 1 Year

Inflammation

Fibrosis

Mes Matr Increase

Glomerular Sclerosis

Tubular Atrophy

Intimal Proliferation (VAS)

CADI*

Inflammation

Fibrosis

Mes Matr Increase

Glomerular Sclerosis

Tubular Atrophy

Intimal Proliferation (VAS)

CADI*

RAPA + CsARAPA + CsA RAPARAPA

BaselineBaseline BaselineBaseline12 Months12 Months 12 Months12 Months

0.07 (0.2)

0.33 (0.4)

0.26 (0.3)

0.28 (0.4)

0.07 (0.2)

0.19 (0.3)

1.2 (1.2)

0.07 (0.2)

0.33 (0.4)

0.26 (0.3)

0.28 (0.4)

0.07 (0.2)

0.19 (0.3)

1.2 (1.2)

0.5 (0.4)

1.1 (0.6)

0.5 (0.4)

0.3 (0.4)

0.64 (0.5)

0.46 (0.48)

3.5 (3.4)

0.5 (0.4)

1.1 (0.6)

0.5 (0.4)

0.3 (0.4)

0.64 (0.5)

0.46 (0.48)

3.5 (3.4)

0.03 (0.14)

0.36 (0.5)

0.3 (0.3)

0.3 (0.5)

0.10 (0.3)

0.14 (0.4)

1.2 (1.4)

0.03 (0.14)

0.36 (0.5)

0.3 (0.3)

0.3 (0.5)

0.10 (0.3)

0.14 (0.4)

1.2 (1.4)

0.8 (0.6)

1.1 (0.7)

0.5 (0.4)

0.3 (0.5)

0.6 (0.5)

0.37 (0.5)

3.6 (1.9)

0.8 (0.6)

1.1 (0.7)

0.5 (0.4)

0.3 (0.5)

0.6 (0.5)

0.37 (0.5)

3.6 (1.9)

N = 70N = 70 N = 56N = 56

*Chronic Allograft Damage Index

RAPAMUNE®TM

9

RAPA + CsA RAPABiopsy Yes No Yes No

N 70 117 P* 56 109 P*

Pre-Randomizedcreatinine, µM 142 150 ns 155 148 ns

12 Monthcreatinine, µM 150 163 ns 149 138 ns

Pre-RandomizedGFR, ml/mn 61 58 ns 56 56 ns

12 monthGFR, ml/mn 59 55 ns 61 64 ns

RAPA + CsA RAPABiopsy Yes No Yes No

N 70 117 P* 56 109 P*

Pre-Randomizedcreatinine, µM 142 150 ns 155 148 ns

12 Monthcreatinine, µM 150 163 ns 149 138 ns

Pre-RandomizedGFR, ml/mn 61 58 ns 56 56 ns

12 monthGFR, ml/mn 59 55 ns 61 64 ns

Renal Function (Observed Mean)Patients With Biopsy Vs No BiopsyRenal Function (Observed Mean)

Patients With Biopsy Vs No Biopsy

* P: Yes versus No < .05

RAPAMUNE®TM

10Study 310: Nonrandomized Patients (Ninety-Five Discontinued Prior to

Randomized at Month 3)

Study 310: Nonrandomized Patients (Ninety-Five Discontinued Prior to

Randomized at Month 3)

Reasons for Discontinuation

– 70 (74%) adverse event

– 12 (13%) unsatisfactory response, efficacy

– 13 (13.6%) other causes

Reasons for Discontinuation

– 70 (74%) adverse event

– 12 (13%) unsatisfactory response, efficacy

– 13 (13.6%) other causes

RAPAMUNE®TM

11Study 310

Adverse Events Leading to Discontinuation Prior to Randomization at Month 3

Study 310Adverse Events Leading to Discontinuation

Prior to Randomization at Month 3

Event Number of Pts.

Infection and sepsis 10

Surgical complication 8

HUS 7

Thrombosed artery/vein 6

ATN 5

Hyperlipidemia 5

Thrombocytopenia 5

Event Number of Pts.

Infection and sepsis 10

Surgical complication 8

HUS 7

Thrombosed artery/vein 6

ATN 5

Hyperlipidemia 5

Thrombocytopenia 5

Event Number of Pts.

Elevated LFTs 4

Pneumonia/pneumopathy 4

Renal dysfunction 4

Cardiovascular 3

CsA toxicity 3

Leukopenia 3

Other 3

Event Number of Pts.

Elevated LFTs 4

Pneumonia/pneumopathy 4

Renal dysfunction 4

Cardiovascular 3

CsA toxicity 3

Leukopenia 3

Other 3

HUS = Hemolytic uremic syndrome.ATN = Acute tubular necrosis.LFTs = Liver function tests.

RAPAMUNE®TM

12Study 310: 70% of Patients With Acute Rejection Prerandomization – Eventually

Randomized

Study 310: 70% of Patients With Acute Rejection Prerandomization – Eventually

Randomized

12 out of 95 (13%) non-randomized patients

– 9 mild/moderate acute rejection

– 1 severe acute rejection

– 1 graft loss

– 1 increased creatinine

70% of patients with acute rejection pre-randomization were eventually randomized

12 out of 95 (13%) non-randomized patients

– 9 mild/moderate acute rejection

– 1 severe acute rejection

– 1 graft loss

– 1 increased creatinine

70% of patients with acute rejection pre-randomization were eventually randomized

RAPAMUNE®TM

13Study 310Nonrandomized Patients: Other causes of

discontinuation

Study 310Nonrandomized Patients: Other causes of

discontinuation

Other causes of discontinuation (n=13)

– 4 (4 %) patient request

– 4 (4%) protocol violation

– 3 (3%) other medical event

– 2 (2%) protocol stipulations

Other causes of discontinuation (n=13)

– 4 (4 %) patient request

– 4 (4%) protocol violation

– 3 (3%) other medical event

– 2 (2%) protocol stipulations

RAPAMUNE®TM

14

Study 310: No Rejections in RAPA Group: 12-24 MonthsStudy 310: No Rejections in RAPA Group: 12-24 Months

RAPAMUNE®TM

15

Renal Function at 12 Months Predicts Long Term Graft Survival

Renal Function at 12 Months Predicts Long Term Graft Survival

105,743 renal transplant recipients from the UNOS/OPTN database between 1988 and 1998

Creat. 12 Mos Creat. 6 to 12 Mos Graft t1/2

(mg/dL) (mg/dL) (yrs)

<1.5 <0.3 11.6<1.5 >0.3 9.9>1.5 <0.3 8.9>1.5 >0.3 6.0

105,743 renal transplant recipients from the UNOS/OPTN database between 1988 and 1998

Creat. 12 Mos Creat. 6 to 12 Mos Graft t1/2

(mg/dL) (mg/dL) (yrs)

<1.5 <0.3 11.6<1.5 >0.3 9.9>1.5 <0.3 8.9>1.5 >0.3 6.0

Johnson CP et al. Am J Transplantation, 2001; 1 (Suppl 1): 146.

RAPAMUNE®TM

16

On therapy analysis using the criteria of Johnson CP et al. Am J On therapy analysis using the criteria of Johnson CP et al. Am J Transplantation, 2001; 1 (Suppl 1): 146.Transplantation, 2001; 1 (Suppl 1): 146.

Creat. 12 Mos Creat. 12 Mos Creat. 6 to 12 Mos Creat. 6 to 12 Mos RAPA+CsARAPA+CsA RAPARAPA(mg/dL)(mg/dL) (mg/dL)(mg/dL) (%)(%) (%) (%)

<1.5<1.5 <0.3<0.3 34.634.6 60.760.7

<1.5 <1.5 >0.3 >0.3 2.62.6 0.0 0.0

>1.5 >1.5 <0.3 <0.3 40.040.0 28.828.8

>1.5 >1.5 >0.3 >0.3 23.223.2 10.410.4

On therapy analysis using the criteria of Johnson CP et al. Am J On therapy analysis using the criteria of Johnson CP et al. Am J Transplantation, 2001; 1 (Suppl 1): 146.Transplantation, 2001; 1 (Suppl 1): 146.

Creat. 12 Mos Creat. 12 Mos Creat. 6 to 12 Mos Creat. 6 to 12 Mos RAPA+CsARAPA+CsA RAPARAPA(mg/dL)(mg/dL) (mg/dL)(mg/dL) (%)(%) (%) (%)

<1.5<1.5 <0.3<0.3 34.634.6 60.760.7

<1.5 <1.5 >0.3 >0.3 2.62.6 0.0 0.0

>1.5 >1.5 <0.3 <0.3 40.040.0 28.828.8

>1.5 >1.5 >0.3 >0.3 23.223.2 10.410.4

Study 310: Predicted Long Term Graft Survival Better with RAPAStudy 310: Predicted Long Term Graft Survival Better with RAPA

CMH: CMH: PP = 0.001 = 0.001

RAPAMUNE®TM

17

Slope of 1000/CreatinineAll Data Between 6 and 24 Months

Slope of 1000/CreatinineAll Data Between 6 and 24 Months

Slope 95% CI of slope P-value*

RAPA + CsA –0.013 (–0.017, –0.008) < .001

RAPA 0.008 (0.004, 0.013) < .001

Difference –0.021 (–0.027, –0.014) < .001(RAPA + CsA – RAPA)

Slope 95% CI of slope P-value*

RAPA + CsA –0.013 (–0.017, –0.008) < .001

RAPA 0.008 (0.004, 0.013) < .001

Difference –0.021 (–0.027, –0.014) < .001(RAPA + CsA – RAPA)

*Significant *Significant PP-value indicates non-zero change over time.-value indicates non-zero change over time.

RAPAMUNE®TM

18

Slope of 1000/CreatinineAll Data Between 12 and 24 Months

Slope of 1000/CreatinineAll Data Between 12 and 24 Months

Slope 95% CI of slope P-value*

RAPA + CsA –0.015 (–0.021, –0.009) < .001

RAPA 0.003 (–0.004, 0.009) .420

Difference –0.018 (–0.026, –0.009) < .001(RAPA + CsA – RAPA)

Slope 95% CI of slope P-value*

RAPA + CsA –0.015 (–0.021, –0.009) < .001

RAPA 0.003 (–0.004, 0.009) .420

Difference –0.018 (–0.026, –0.009) < .001(RAPA + CsA – RAPA)

*Significant *Significant PP-value indicates non-zero change over time.-value indicates non-zero change over time.

RAPAMUNE®TM

19Study 310 Histologic Grade of First Biopsy Confirmed-

Acute Rejection by Grade: 12 Months

Study 310 Histologic Grade of First Biopsy Confirmed-

Acute Rejection by Grade: 12 Months

Grade ofGrade of NonrandomizedNonrandomizedPeriodPeriod rejectionrejection RAPA + CsARAPA + CsA RAPARAPA RAPA + CsA RAPA + CsA P-vP-value*alue*

Pre-Pre- MildMild 12/20 (60.0)12/20 (60.0) 10/22 (45.5) 10/22 (45.5) 9/27(33.3) 9/27(33.3)randomizationrandomization Moderate (2a) Moderate (2a) 3/20 (15.0) 3/20 (15.0) 4/22 (18.2) 4/22 (18.2) 7/27 (25.9)7/27 (25.9)

Moderate (2b) Moderate (2b) 4/20 (20.0) 4/20 (20.0) 6/22 (27.3) 6/22 (27.3) 5/27 (18.5)5/27 (18.5) .336.336SevereSevere 1/20 (5.0)1/20 (5.0) 2/22 (9.1) 2/22 (9.1) 6/27 (22.2)6/27 (22.2)

Post-Post- MildMild 5/6 (83.3) 5/6 (83.3) 14/21 (66.7) 14/21 (66.7) --randomizationrandomization Moderate (2a) Moderate (2a) 1/6 (16.7) 1/6 (16.7) 6/21 (28.6) 6/21 (28.6) -- .421.421

Moderate (2b) Moderate (2b) -- 1/21 (4.8) 1/21 (4.8) --

Follow upFollow up MildMild 2/3 (66.7) 2/3 (66.7) - - 3/7 (42.9)3/7 (42.9)Moderate (2b) Moderate (2b) 1/3 (33.3) 1/3 (33.3) - - 2/7 (28.6)2/7 (28.6) --

Severe Severe -- - - 2/7 (28.6)2/7 (28.6)

TotalTotal MildMild 19/29 (65.5) 19/29 (65.5) 24/43 (55.8) 24/43 (55.8) 12/34 (35.8)12/34 (35.8)Moderate (2a) Moderate (2a) 4/29 (13.8) 4/29 (13.8) 10/43 (16.3) 10/43 (16.3) 7/34 (20.6)7/34 (20.6) .514.514Moderate (2b) Moderate (2b) 5/29 (17.2) 5/29 (17.2) 7/43 (16.3) 7/43 (16.3) 7/34 (20.6)7/34 (20.6)

Severe Severe 1/29 (3.4) 1/29 (3.4) 2/43 (4.7) 2/43 (4.7) 8/34 (23.5)8/34 (23.5)

Grade ofGrade of NonrandomizedNonrandomizedPeriodPeriod rejectionrejection RAPA + CsARAPA + CsA RAPARAPA RAPA + CsA RAPA + CsA P-vP-value*alue*

Pre-Pre- MildMild 12/20 (60.0)12/20 (60.0) 10/22 (45.5) 10/22 (45.5) 9/27(33.3) 9/27(33.3)randomizationrandomization Moderate (2a) Moderate (2a) 3/20 (15.0) 3/20 (15.0) 4/22 (18.2) 4/22 (18.2) 7/27 (25.9)7/27 (25.9)

Moderate (2b) Moderate (2b) 4/20 (20.0) 4/20 (20.0) 6/22 (27.3) 6/22 (27.3) 5/27 (18.5)5/27 (18.5) .336.336SevereSevere 1/20 (5.0)1/20 (5.0) 2/22 (9.1) 2/22 (9.1) 6/27 (22.2)6/27 (22.2)

Post-Post- MildMild 5/6 (83.3) 5/6 (83.3) 14/21 (66.7) 14/21 (66.7) --randomizationrandomization Moderate (2a) Moderate (2a) 1/6 (16.7) 1/6 (16.7) 6/21 (28.6) 6/21 (28.6) -- .421.421

Moderate (2b) Moderate (2b) -- 1/21 (4.8) 1/21 (4.8) --

Follow upFollow up MildMild 2/3 (66.7) 2/3 (66.7) - - 3/7 (42.9)3/7 (42.9)Moderate (2b) Moderate (2b) 1/3 (33.3) 1/3 (33.3) - - 2/7 (28.6)2/7 (28.6) --

Severe Severe -- - - 2/7 (28.6)2/7 (28.6)

TotalTotal MildMild 19/29 (65.5) 19/29 (65.5) 24/43 (55.8) 24/43 (55.8) 12/34 (35.8)12/34 (35.8)Moderate (2a) Moderate (2a) 4/29 (13.8) 4/29 (13.8) 10/43 (16.3) 10/43 (16.3) 7/34 (20.6)7/34 (20.6) .514.514Moderate (2b) Moderate (2b) 5/29 (17.2) 5/29 (17.2) 7/43 (16.3) 7/43 (16.3) 7/34 (20.6)7/34 (20.6)

Severe Severe 1/29 (3.4) 1/29 (3.4) 2/43 (4.7) 2/43 (4.7) 8/34 (23.5)8/34 (23.5)

TABLE 9.3.2.1C

** Between randomized groupsBetween randomized groups

RAPAMUNE®TM

20

Study 310: Decreasing Doses of CsA in RAPA Group With Time to First RejectionStudy 310: Decreasing Doses of CsA in

RAPA Group With Time to First Rejection

Days Post-transplant

0 30 60 90 120 150 180 210 240 270 300 330 360 390

CsA

Co

nce

ntr

atio

n n

g/m

l

0

50

100

150

200

250

300%

Prim

ary Acu

te Graft R

ejection

0

5

10

15

20

25

30Mean CsA Troughs RAPARAPA Acute rejectionRAPA + CsA Acute rejection

TABLE 9.3.2.1A

RAPAMUNE®TM

21Study 310

Thirty-One Patients Discontinued at the3 Month Visit (Days 75-140)

Study 310Thirty-One Patients Discontinued at the

3 Month Visit (Days 75-140)

10 (32%) Adverse event (3 HUS, 2 poor wound healing, 2 hyperlipidemia, 1abdominal LFTs,1 surgical complication, 1 pain)

6 (19%) Acute rejection/unsatisfactory response

5 (16%) Creatinine > 4.5 mg/dL

5 (16%) Renal dysfunction/dialysis

3 (10%) Patient non-compliance

2 (7%) Patient request

10 (32%) Adverse event (3 HUS, 2 poor wound healing, 2 hyperlipidemia, 1abdominal LFTs,1 surgical complication, 1 pain)

6 (19%) Acute rejection/unsatisfactory response

5 (16%) Creatinine > 4.5 mg/dL

5 (16%) Renal dysfunction/dialysis

3 (10%) Patient non-compliance

2 (7%) Patient request

RAPAMUNE®TM

22TABLE 10.4.2.1.2C

RAPA + CsARAPA + CsA RAPARAPA ANCOVAANCOVATime Time (n = 215)(n = 215) (n = 215)(n = 215) P P valuevalue

Month 1Month 1 4.32 4.32 0.040.04 4.34 4.34 0.04 0.04 --(211)(211) (210)(210)

Month 2Month 2 4.17 4.17 0.04 0.04 4.22 4.22 0.04 0.04 --(208)(208) (197)(197)

Month 3Month 3 4.13 4.13 0.04 0.04 4.09 4.09 0.04 0.04 .158 .158(186)(186) (191)(191)

Month 6Month 6 4.11 4.11 0.04 0.04 3.86 3.86 0.03 0.03 < .001< .001(185)(185) (182)(182)

Month 9Month 9 4.09 4.09 0.04 0.04 3.82 3.82 0.04 0.04 < .001< .001(184)(184) (165)(165)

Month 12Month 12 4.07 4.07 0.04 0.04 3.77 3.77 0.04 0.04 < .001< .001(185)(185) (163)(163)

Month 15Month 15 4.09 4.09 0.04 0.04 3.84 3.84 0.04 0.04 < .001< .001(153)(153) (146)(146)

Month 18Month 18 4.22 4.22 0.05 0.05 3.98 3.98 0.04 0.04 < .001< .001(119)(119) (110)(110)

Month 24Month 24 4.31 4.31 0.14 0.14 3.86 3.86 0.11 0.11 .004 .004(24)(24) (22)(22)

RAPA + CsARAPA + CsA RAPARAPA ANCOVAANCOVATime Time (n = 215)(n = 215) (n = 215)(n = 215) P P valuevalue

Month 1Month 1 4.32 4.32 0.040.04 4.34 4.34 0.04 0.04 --(211)(211) (210)(210)

Month 2Month 2 4.17 4.17 0.04 0.04 4.22 4.22 0.04 0.04 --(208)(208) (197)(197)

Month 3Month 3 4.13 4.13 0.04 0.04 4.09 4.09 0.04 0.04 .158 .158(186)(186) (191)(191)

Month 6Month 6 4.11 4.11 0.04 0.04 3.86 3.86 0.03 0.03 < .001< .001(185)(185) (182)(182)

Month 9Month 9 4.09 4.09 0.04 0.04 3.82 3.82 0.04 0.04 < .001< .001(184)(184) (165)(165)

Month 12Month 12 4.07 4.07 0.04 0.04 3.77 3.77 0.04 0.04 < .001< .001(185)(185) (163)(163)

Month 15Month 15 4.09 4.09 0.04 0.04 3.84 3.84 0.04 0.04 < .001< .001(153)(153) (146)(146)

Month 18Month 18 4.22 4.22 0.05 0.05 3.98 3.98 0.04 0.04 < .001< .001(119)(119) (110)(110)

Month 24Month 24 4.31 4.31 0.14 0.14 3.86 3.86 0.11 0.11 .004 .004(24)(24) (22)(22)

Study 310: Lower Mean SerumPotassium (mmol/L) Levels Following

Cyclosporine Withdrawal

Study 310: Lower Mean SerumPotassium (mmol/L) Levels Following

Cyclosporine Withdrawal

RAPAMUNE®TM

23

Months

0 3 6 9 12 15 18 21 24

SR

L (

ng

/ml)

Imm

un

oas

say

0

5

10

15

20

25

30

RAPA+CsARAPA

Randomization 4

8

12

16

20

24

0

SR

L (n

g/m

l) LC

-MS

or -U

V

8.29 mg

2.15 mg

6.05 mg

2.05 mg

Study 310: Mean Sirolimus Troughs/Levels and Doses Through 24 Months

Study 310: Mean Sirolimus Troughs/Levels and Doses Through 24 Months

RAPAMUNE®TM

24Study 310: Lower Serum Creatinine Following CsA Elimination - Completers

Through 24 Months

Study 310: Lower Serum Creatinine Following CsA Elimination - Completers

Through 24 Months

N = 143

N = 144

* P < 0.01

Mean Creatinine24 Month Completers Only

Months

0 3 6 9 12 15 18 21 24

µm

ol/

L

50

75

100

125

150

175

200

225

250

mg

/dL

1.0

1.5

2.0

2.5

RAPA + CsARAPA

Randomization

* * * * * * * * * * * * **

RAPAMUNE®TM

25

(Immunoassay)

Study 310: PK-PD Analysis Confirms Flexibility of the RAPAMUNE - CsA

Combination

Study 310: PK-PD Analysis Confirms Flexibility of the RAPAMUNE - CsA

Combination

RAPAMUNE®TM

26

Studies 207 Plus 210: Lipid Levels vs RAPA Trough Concentrations

Studies 207 Plus 210: Lipid Levels vs RAPA Trough Concentrations

RAPAMUNE®TM

27

Weeks

0 8 16 24 32 40 48 56 64 72 80 88 96 104

SG

PT

/AL

T

0

10

20

30

40

50

60

70

80

90

CsARAPA

Mean SGPT/ALT

Studies 207 Plus 210 SGPT Values

Studies 207 Plus 210 SGPT Values

RAPAMUNE®TM

28

Weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Tro

ug

h B

loo

d S

RL

(n

g/m

l)

0

10

20

30

40

50P

latelets (G/l)

0

50

100

150

200

250

300

350

400

Trig

lycerides (m

M)

0

1

2

3

4

5

6

7

Mean PlateletsMean Trough Blood SRL

Mean Triglycerides

Study 207Study 207Concentration - EffectConcentration - Effect