RAPAMUNE ® TM 1 Randomization Variable Day* to Day 386 Randomization Variable Day* to Day 386 RAPA, C min, TN0.765 CsA, C min, TN0.201 Gender0.117 Increasing.

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Presentation transcript:

RAPAMUNE ® TM 1 Randomization Variable Day* to Day 386 Randomization Variable Day* to Day 386 RAPA, C min, TN0.765 CsA, C min, TN0.201 Gender0.117 Increasing Recipient Age0.199 Cadaver0.852 HLA Mismatch0.098 Increasing Ischemia Time0.919 Increasing Donor Age0.026 # Rejections31 Randomization Variable Day* to Day 386 Randomization Variable Day* to Day 386 RAPA, C min, TN0.765 CsA, C min, TN0.201 Gender0.117 Increasing Recipient Age0.199 Cadaver0.852 HLA Mismatch0.098 Increasing Ischemia Time0.919 Increasing Donor Age0.026 # Rejections31 Study 310: Univariate Logistic Regression - RAPA Group TABLE 8.3E *Randomization Day for Individual Patient, Approx. Day 90

RAPAMUNE ® TM 2 3.1A Study 212 Enrolled 19.1% Black Patients  Trial 310: 8 patients (1.5%) were black: –RAPA + CsA5/215 (2.3%) –RAPA2/215 (0.9%) –Nonrandomized1/95 (1.1%)  Trial 212: 47 (19.1%) black –RAPA + CsA18/97 (18.6%) –RAPA15/100 (15%) –Nonrandomzied14/49 (28.6%)  Trial 310: 8 patients (1.5%) were black: –RAPA + CsA5/215 (2.3%) –RAPA2/215 (0.9%) –Nonrandomized1/95 (1.1%)  Trial 212: 47 (19.1%) black –RAPA + CsA18/97 (18.6%) –RAPA15/100 (15%) –Nonrandomzied14/49 (28.6%)

RAPAMUNE ® TM 3 Study 212: All 13 Eligible Black Patients Successfully Eliminated CsA  CsA withdrawal arm: –Enrolled15 –Eligible for CsA taper13 2 patients with AR –Completed CsA taper13 3 patients with AR post CsA withdrawal: 35, 64, and 122 days after completing CsA elimination  CsA withdrawal arm: –Enrolled15 –Eligible for CsA taper13 2 patients with AR –Completed CsA taper13 3 patients with AR post CsA withdrawal: 35, 64, and 122 days after completing CsA elimination

RAPAMUNE ® TM 4 % Study 212: Similar Rates of Acute Rejection at Months 2 and 12 N = Month 2Month 12 P = NS

RAPAMUNE ® TM 5 Study 212: Significantly Higher Calculated GFR at Month12 in the RAPA Group, Black Patients P =.098 P =.0003 TABLE 3.3.3A N =

RAPAMUNE ® TM 6 Study 212: Numerically Lower BP in RAPA Group - Black Patients N= P=0.069 P=0.541

RAPAMUNE ® TM 7 RAPA + CsARAPA Fisher’s Exact (N = 97)(N = 100)P value Patient Survival Black17 (94.4)15 (100)1.000 Non-black77 (97.5)81 (95.3)0.683 Graft Survival Black17 (94.4)14 (93.3)1.000 Non-black73 (92.4)81 (95.3)0.524 RAPA + CsARAPA Fisher’s Exact (N = 97)(N = 100)P value Patient Survival Black17 (94.4)15 (100)1.000 Non-black77 (97.5)81 (95.3)0.683 Graft Survival Black17 (94.4)14 (93.3)1.000 Non-black73 (92.4)81 (95.3)0.524 Study 212: Patient & Graft Survival (%) By Ethnic Origin: Month 12

RAPAMUNE ® TM 8 Study 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 + CsA RAPA Baseline 12 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 = 70 N = 56 *Chronic Allograft Damage Index

RAPAMUNE ® TM 9 RAPA + CsARAPA BiopsyYesNoYesNo N70117P*56109P* Pre-Randomized creatinine, µM142150ns ns 12 Month creatinine, µM150163ns ns Pre-Randomized GFR, ml/mn6158 ns ns 12 month GFR, ml/mn5955ns 61 64ns RAPA + CsARAPA BiopsyYesNoYesNo N70117P*56109P* Pre-Randomized creatinine, µM142150ns ns 12 Month creatinine, µM150163ns ns Pre-Randomized GFR, ml/mn6158 ns ns 12 month GFR, ml/mn5955ns 61 64ns Renal Function (Observed Mean) Patients With Biopsy Vs No Biopsy *P: Yes versus No <.05

RAPAMUNE ® TM 10 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 11 Study 310 Adverse Events Leading to Discontinuation Prior to Randomization at Month 3 EventNumber of Pts. Infection and sepsis10 Surgical complication8 HUS7 Thrombosed artery/vein6 ATN5 Hyperlipidemia5 Thrombocytopenia5 EventNumber of Pts. Infection and sepsis10 Surgical complication8 HUS7 Thrombosed artery/vein6 ATN5 Hyperlipidemia5 Thrombocytopenia5 EventNumber of Pts. Elevated LFTs4 Pneumonia/pneumopathy4 Renal dysfunction4 Cardiovascular3 CsA toxicity3 Leukopenia3 Other3 EventNumber of Pts. Elevated LFTs4 Pneumonia/pneumopathy4 Renal dysfunction4 Cardiovascular3 CsA toxicity3 Leukopenia3 Other3 HUS = Hemolytic uremic syndrome. ATN = Acute tubular necrosis. LFTs = Liver function tests.

RAPAMUNE ® TM 12 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 prerandomization 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 prerandomization were eventually randomized

RAPAMUNE ® TM 13 Study 310 Nonrandomized 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: Months

RAPAMUNE ® TM 15 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 t 1/2 (mg/dL)(mg/dL)(yrs) > > ,743 renal transplant recipients from the UNOS/OPTN database between 1988 and 1998 Creat. 12 Mos  Creat. 6 to 12 Mos Graft t 1/2 (mg/dL)(mg/dL)(yrs) > > 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 Transplantation, 2001; 1 (Suppl 1): 146. Creat. 12 Mos  Creat. 6 to 12 MosRAPA+CsARAPA (mg/dL)(mg/dL)(%) (%) > > > > On therapy analysis using the criteria of Johnson CP et al. Am J Transplantation, 2001; 1 (Suppl 1): 146. Creat. 12 Mos  Creat. 6 to 12 MosRAPA+CsARAPA (mg/dL)(mg/dL)(%) (%) > > > > Study 310: Predicted Long Term Graft Survival Better with RAPA CMH: P = 0.001

RAPAMUNE ® TM 17 Slope of 1000/Creatinine All Data Between 6 and 24 Months Slope95% CI of slopeP-value* RAPA + CsA–0.013(–0.017, –0.008)<.001 RAPA0.008(0.004, 0.013)<.001 Difference–0.021(–0.027, –0.014)<.001 (RAPA + CsA – RAPA) Slope95% CI of slopeP-value* RAPA + CsA–0.013(–0.017, –0.008)<.001 RAPA0.008(0.004, 0.013)<.001 Difference–0.021(–0.027, –0.014)<.001 (RAPA + CsA – RAPA) *Significant P-value indicates non-zero change over time.

RAPAMUNE ® TM 18 Slope of 1000/Creatinine All Data Between 12 and 24 Months Slope95% CI of slopeP-value* RAPA + CsA–0.015(–0.021, –0.009)<.001 RAPA0.003(–0.004, 0.009).420 Difference–0.018(–0.026, –0.009)<.001 (RAPA + CsA – RAPA) Slope95% CI of slopeP-value* RAPA + CsA–0.015(–0.021, –0.009)<.001 RAPA0.003(–0.004, 0.009).420 Difference–0.018(–0.026, –0.009)<.001 (RAPA + CsA – RAPA) *Significant P-value indicates non-zero change over time.

RAPAMUNE ® TM 19 Study 310 Histologic Grade of First Biopsy Confirmed- Acute Rejection by Grade: 12 Months Grade ofNonrandomized PeriodrejectionRAPA + CsARAPA RAPA + CsA P-value* Pre-Mild12/20 (60.0)10/22 (45.5) 9/27(33.3) randomizationModerate (2a) 3/20 (15.0) 4/22 (18.2) 7/27 (25.9) Moderate (2b) 4/20 (20.0) 6/22 (27.3) 5/27 (18.5).336 Severe1/20 (5.0)2/22 (9.1) 6/27 (22.2) Post-Mild 5/6 (83.3)14/21 (66.7) - randomizationModerate (2a) 1/6 (16.7) 6/21 (28.6) Moderate (2b) -1/21 (4.8) - Follow upMild 2/3 (66.7)- 3/7 (42.9) Moderate (2b) 1/3 (33.3)- 2/7 (28.6)- Severe -- 2/7 (28.6) TotalMild 19/29 (65.5) 24/43 (55.8) 12/34 (35.8) Moderate (2a) 4/29 (13.8) 10/43 (16.3) 7/34 (20.6).514 Moderate (2b) 5/29 (17.2) 7/43 (16.3) 7/34 (20.6) Severe 1/29 (3.4) 2/43 (4.7) 8/34 (23.5) Grade ofNonrandomized PeriodrejectionRAPA + CsARAPA RAPA + CsA P-value* Pre-Mild12/20 (60.0)10/22 (45.5) 9/27(33.3) randomizationModerate (2a) 3/20 (15.0) 4/22 (18.2) 7/27 (25.9) Moderate (2b) 4/20 (20.0) 6/22 (27.3) 5/27 (18.5).336 Severe1/20 (5.0)2/22 (9.1) 6/27 (22.2) Post-Mild 5/6 (83.3)14/21 (66.7) - randomizationModerate (2a) 1/6 (16.7) 6/21 (28.6) Moderate (2b) -1/21 (4.8) - Follow upMild 2/3 (66.7)- 3/7 (42.9) Moderate (2b) 1/3 (33.3)- 2/7 (28.6)- Severe -- 2/7 (28.6) TotalMild 19/29 (65.5) 24/43 (55.8) 12/34 (35.8) Moderate (2a) 4/29 (13.8) 10/43 (16.3) 7/34 (20.6).514 Moderate (2b) 5/29 (17.2) 7/43 (16.3) 7/34 (20.6) Severe 1/29 (3.4) 2/43 (4.7) 8/34 (23.5) TABLE C *Between randomized groups

RAPAMUNE ® TM 20 Study 310: Decreasing Doses of CsA in RAPA Group With Time to First Rejection Days Post-transplant CsA Concentration ng/ml % Primary Acute Graft Rejection Mean CsA Troughs RAPA RAPA Acute rejection RAPA + CsA Acute rejection TABLE A

RAPAMUNE ® TM 21 Study 310 Thirty-One Patients Discontinued at the 3 Month Visit (Days )  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 22 TABLE C RAPA + CsARAPAANCOVA Time (n = 215)(n = 215)P value Month   (211)(210) Month   (208)(197) Month   (186)(191) Month   0.03<.001 (185)(182) Month   0.04<.001 (184)(165) Month   0.04<.001 (185)(163) Month   0.04<.001 (153)(146) Month   0.04<.001 (119)(110) Month   (24)(22) RAPA + CsARAPAANCOVA Time (n = 215)(n = 215)P value Month   (211)(210) Month   (208)(197) Month   (186)(191) Month   0.03<.001 (185)(182) Month   0.04<.001 (184)(165) Month   0.04<.001 (185)(163) Month   0.04<.001 (153)(146) Month   0.04<.001 (119)(110) Month   (24)(22) Study 310: Lower Mean Serum Potassium (mmol/L) Levels Following Cyclosporine Withdrawal

RAPAMUNE ® TM mg 2.15 mg 6.05 mg 2.05 mg Study 310: Mean Sirolimus Troughs/Levels and Doses Through 24 Months

RAPAMUNE ® TM 24 Study 310: Lower Serum Creatinine Following CsA Elimination - Completers Through 24 Months N = 143 N = 144 * P < 0.01

RAPAMUNE ® TM 25 (Immunoassay) 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

RAPAMUNE ® TM 27 Studies 207 Plus 210 SGPT Values

RAPAMUNE ® TM 28 Study 207 Concentration - Effect