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CsA Elimination Studies

RAPAMUNE ®. CsA Elimination Studies. Safety. Summary of Safety Assessments. Etiologies of graft loss and death Adverse events, including those related to immunosuppression (infection and malignancy) Blood pressure measurements Laboratory parameters.

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CsA Elimination Studies

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  1. RAPAMUNE® CsA Elimination Studies Safety

  2. Summary of Safety Assessments • Etiologies of graft loss and death • Adverse events, including those related to immunosuppression (infection and malignancy) • Blood pressure measurements • Laboratory parameters

  3. Study 310Equivalent 12 Month Graft Survival RAPA + CsARAPAAll Patients(n = 215)(n = 215)(N = 525) Overall rate (%) 95.8 97.2 89.1 95% CI – 1.4 (– 4.9, 2.1) Graft loss* 2.3 < 1 6.7 Death with functioning graft 1.9 1.9 4.0 Lost to follow-up 0 0 < 1 * Death censored; physical or functional loss of graft. Intent-to-treat population.

  4. Study 310Etiologies of Graft Loss* RAPA + CsARAPA(n = 215)(n = 215) Infection (sepsis) 2 (0.9) 0 Renal fibrosis 1 (0.5) 0 Graft ischemia 1 (0.5) 1 (0.5) Graft vascularthrombosis 1 (0.5) 0 Recurrent disease 0 1 (0.5) * Intent-to-treat analysis at 12 months.

  5. Study 310 Equivalent 12 Month Patient Survival* RAPA + CsARAPAAll Patients(n = 215)(n = 215)(N = 525) Survival (%) 97.2 98.1 94.9 95% CI – 0.9 (– 3.8, 1.9) * Intent-to-treat analysis.

  6. Study 310Etiologies of Patient Death* RAPA + CsARAPA(n = 215)(n = 215) Cardiac arrest 3 (1.4) 1 (0.5) Infection Sepsis 2 (0.9) 2 (0.9) Aspergillosis 1 (0.5) 1 (0.5) * Intent-to-treat analysis at 12 months.

  7. Summary of Safety Assessments • Etiologies of graft loss and death • Adverse events, including those related to immunosuppression (infection and malignancy) • Blood pressure measurements • Laboratory parameters

  8. Study 310: Incidence (%) of Significantly Different Treatment-Emergent Adverse Events* RAPA + CsARAPA(n = 215)(n = 215)P value CsA toxicity 8.8 2.8 .012 Creatinine increase 26.5 15.3 .006 Edema 7.4 2.8 .047 Hypertension 20.0 7.0 <.001 Hyperuricemia 13.5 4.7 .002 Hypokalemia 2.3 8.8 .005 SGOT (AST) increased 3.3 9.8 .010 SGPT (ALT) increased 4.7 14.9 <.001 Thrombocytopenia 4.2 11.2 .010 * Post-randomization.

  9. Study 310Incidence (%) of Infections RAPA + CsARAPAInfection type (n = 215)(n = 215) Sepsis 4.2 3.3 Cytomegalovirus Syndrome 4.7 5.1 Tissue-invasive 1.4 0.9 Pneumonia 5.6 9.3 Herpes simplex 5.6 6.5 Herpes zoster 6.0* 0.5 Urinary tract infection 20.5 26.5 * P = .002

  10. Study 310Similar Incidence (%) of Neoplasia RAPA + CsARAPA(n = 215)(n = 215) Total, n (%) 14 (6.5) 8 (3.7) Skin Non-melanomatous 6 (2.8)* 5 (2.3)* Melanoma 1 (0.5) 0 B-cell lymphoma 1 (0.5) 1 (0.5) Acute myeloid leukemia 1 (0.5) 0 Other Lung 1 (0.5) 0 Oropharynx 1 (0.5) 0 Renal 2 (0.9) 0 Prostate 1 (0.5) 0 Cervix 0 1 (0.5) Colon 0 1 (0.5)** * 2 cases (RAPA + CsA) and 1 case (RAPA) - onset prerandomization. ** Adenomatoid polyp; not malignant.

  11. Summary of Safety Assessments • Etiologies of graft loss and death • Adverse events, including those related to immunosuppression (infection and malignancy) • Blood pressure measurements • Laboratory parameters

  12. RAPA + CsA RAPA Study 310Improved Mean Blood Pressure (mmHg) n= 189 182 119 25 * n= 188 182 119 25 * * * * * * * * mmHg n= 178 163 106 20 n= 179 163 107 21 Randomization Randomization * P < .05

  13. Study 310: Reduced Requirement for Combination Anti-Hypertensive Regimens: Percent of Patients at 12 Months* Drugs (n)RAPA + CsARAPA 0 8.0 10.9 1 25.1 32.1 2 28.9 34.5 3 24.1 17.0 4 9.1 3.6 5 4.3 1.8 6 0.5 0 * CMH P = .013 (row mean score difference).

  14. Summary of Safety Assessments • Etiologies of graft loss and death • Adverse events, including those related to immunosuppression (infection and malignancy) • Blood pressure measurements • Laboratory parameters

  15. Study 310: Similar Use of Lipid-Lowering Agents* Pre-Treatment On-Therapy n= 41 32 7 39 35 3 179 156 51 180 158 53 P = N.S. * Cumulative data.

  16. Study 310: Similar Fasting Cholesterol Values 14 RAPA + CsA RAPA 450 (n = 156) (n = 143) 12 400 10 350 300 8 Mean Fasting Cholesterol, mg/dL 250 Mean Fasting Cholesterol, mmol/L 6 200 150 4 100 2 50 0 0 Month 12

  17. RAPA + CsA RAPA Study 310: Similar Mean FastingHDL- and LDL-Cholesterol Values * ULN n= 137 136 85 19 * n= 125 121 102 80 ULN n= 132 141 83 17 n= 141 144 85 18 Randomization Randomization * P < .05ULN = upper limit of normal.

  18. Study 310: Similar Fasting Triglyceride Values

  19. RAPA + CsA RAPA Study 310: Mean ALT/SGPT and AST/SGOT Values ULN n= 175 158 110 22 ULN n= 175 157 106 22 * * * * * * * n= 178 175 118 25 n= 177 175 119 25 Randomization Randomization * P < .05ULN = upper limit of normal.

  20. TABLE 10.4.2.4C Study 310: Randomized Patients With at Least 1 SGPT Value Greater Than 5 Times the Upper Limit of Normal (SGPT  275 IU/L) Therapy GroupPatient No. Time Slot Value (IU/L) Cause of Elevated Liver Enzymes RAPA + CsA (12 Months) 3505 Month 4 670* Hepatitis B 3814 Months 4-7 347 - 804* Hepatitis B reactivation 5807 Month 3 301 Etiology undetermined 6110 Months 3-5, 7 323 - 770* Increased liver enzymes since d7 6912 Month 5 555* Hepatitis B core antigen positive 7202 Month 8 332 Etiology undetermined RAPA (12 Months) 3821 Month 5 297 Hepatitis B 4102 Month 5 377 Etiology undetermined 8506 Month 4 460 CMV Hepatitis 8512 Month 12 539 - 680* Hepatitis (drug-induced) 8708 Months 4, 5 297 - 322 Hepatitis (drug-induced) * Values greater than 10 times the normal values (ALT/SGPT  550 IU/L).

  21. RAPA + CsA RAPA Study 310: Mean WhiteBlood Cell and Platelet Counts ULN ULN n= 183 182 122 25 n= 183 181 120 25 * * * * * n= 180 163 111 22 n= 180 163 111 22 LLN LLN Randomization Randomization * P < .05ULN = upper limit of normal.LLN = lower limit of normal.

  22. Study 310: Safety Summary • Equivalent patient and graft survival • RAPA + CsA group: increased incidence of CsA toxicity, increased creatinine, edema, hypertension, hyperuricemia • RAPA group: increased incidence of hypokalemia, increased SGOT/SGPT, thrombocytopenia • Similar rates of infection and malignancy • Improved blood pressure following CsA elimination • Comparable lipid profiles, WBC’s and platelet counts

  23. Study 212 Similar 12 Month Graft Survival RAPA + CsARAPANonrandomized(n = 97)(n = 100)(N = 49) Overall rate (%) 92.8 95.0 75.5 95% CI – 2.2 (– 8.9, 4.5) Graft loss* 4.1 1.0 14.3 Death with a functioning graft 3.1 4.0 8.2 Lost to follow-up 0 0 2.0 * Death censored; physical or functional loss of graft.

  24. Study 212Etiologies of Graft Loss* RAPA + CsARAPA(n = 97)(n = 100) Acute rejection 1 (1.0) 1 (1.0) ATN/DGF 1 (1.0) 0 HUS** 2 (2.1) 0 * Intent-to-treat analysis at 12 Months; death censored. **HUS = Hemolytic uremic syndrome.

  25. Study 212 Similar 12 Month Patient Survival* RAPA + CsARAPANonrandomized (n = 97)(n = 100)(n = 49) Survival (%) 96.9 96.0 89.8 95% CI 0.9 (– 4.3, 6.1) * Intent-to-treat population.

  26. Study 212Etiologies of Patient Death* RAPA + CsARAPA(n = 97)(n = 100) Cardiovascular cardiac arrest 2 (2.1) 1 (1.0) heart failure 0 1 (1.0) unspecified 0 1 (1.0) Infection (encephalitis) 1 (1.0) 0 Pulmonary edema 0 1 (1.0) * Intent-to-treat population.

  27. Study 212: Treatment Emergent Adverse Events (%) RAPA + CsARAPAAdverse Event, % (n = 97)(n = 99)*P value Hypertension 46.4 30.3 .027 Dyspnea 20.6 9.1 .027 Edema 14.4 3.0 .005 Hypervolemia 12.4 4.0 .039 Hypomagnesemia 12.4 4.0 .039 Thrombocytopenia 14.4 28.3 .023 Hypokalemia 13.4 25.3 .046 Diarrhea 11.3 25.3 .016 Liver function tests abnormal 7.2 17.2 .048 Atrial fibrillation 1.0 8.1 .035 * 1 patient did not receive drug.

  28. Study 212 Atrial Fibrillation Incidence in Study 212 Not Observed in Other Studies Treatment Incidence (%) Comments Study 212 (N=246)RAPA + CsA 1.0 Age: 49y; Duration: 1 d(n=1) Outcome: resolved with treatment Relationship: not related RAPA 8.1Age: 51 to 68y; Duration 1 to 58d(n=8) Outcome: resolved with treatment P = .035 Relationship: not related Study 310 (N=525)RAPA + CsA 1.9 P = N.S.RAPA 3.7 Studies 301/302 (N=1296)RAPA 2mg/CsA 3.6 P = N.S.RAPA 5mg/CsA 3.1AZA/CsA 3.1Placebo/CsA 1.6

  29. Study 212: Similar Incidence (%)of Infections at Month 12* RAPA + CsARAPAInfection Type (n = 97)(n = 100) Sepsis 7.2 6.0 Cytomegalovirus syndrome 4.1 5.0 tissue-invasive 1.0 2.0 Pneumonia 9.3 7.0 Pneumocystis carinii pneumonia 0 1.0 Herpes simplex 13.4 11.0 Herpes zoster 5.2 4.0 Urinary tract infection 33.0 36.0 Wound infection 7.2 7.0 Epstein-Barr virus 0 2.0 P = N.S.* Intent-to-treat population at 12 months.

  30. Study 212: Incidence (%) ofMalignancy at Month 12 RAPA + CsARAPA(n = 97)(n = 100) Total 0 4.0 Non-melanomatous skin cancer 0 2.0 PTLD (presumed) 0 1.0 Renal cell carcinoma (native kidney) 0 1.0 PTLD = Post-transplant lymphoproliferative disease.

  31. Study 212: Safety Summary • Equivalent patient and graft survival • RAPA + CsA group: increased incidence of hypertension, dyspnea, edema, hypervolemia, hypomagnesemia • RAPA group: increased incidence of thrombocytopenia, hypokalemia, diarrhea, increased SGOT/SGPT, atrial fibrillation • Similar rates of infection and malignancy • Similar lipid profiles, WBC’s and platelet counts

  32. Study 310Patient Disposition by Month 12 % d/c Enrolled (N=525) Nonrandomized (n=95) Randomized 1:1 at Month 3 (n=430) 18.1% 3 RAPA (n=215) RAPA + CsA (n=215) d/c (n=58) d/c (n=38) Primary Endpoint at Month 12 36.4% 12

  33. Study 310: Similar Incidence of Discontinuations (%) at  Month 15 Nonrandomized Randomized Reason for RAPA + CsARAPADiscontinuation (Month 12) (n/n = 95/95)(n/n = 38/215)(n/n = 58/215) Adverse event 74.0 14.017.0 Acute rejection 13.0 2.0 5.0 Other 13.0 2.0 6.0 Total 100.0 18.0 27.0* Discontinuations ( Month 15)**(n/n = 59/215)(n/n = 65/215) Adverse event 20.0 20.0 Acute rejection 4.0 5.0 Other 3.0 5.0 Total 27.0 30.0 * P = .027 (RAPA + CsA vs RAPA). ** P = N.S. (RAPA + CsA vs RAPA).

  34. Study 310: Treatment of Patients Discontinued from the RAPAMUNE Group Converted Therapy* n = 58 (%) Corticosteroids 43 (81)CsA 29 (55)Tacrolimus 14 (26)MMF 16 (30)RAPAMUNE 10 (19) • No acute rejections • 3 Deaths • 2 Graft losses * Each patient may be receiving > 1 therapy.MMF = mycophenolate mofetil.

  35. Study 310: Successful Elimination of Cyclosporine in 92.6% of Patients* 50% 90% * Intent-to-treat analysis.

  36. Study 212Patient Disposition by Month 12 % d/c Enrolled (N=246) Randomized 1:1 within 7 Days (n=197) Nonrandomized (n=49) RAPA (n=100) RAPA + CsA (n=97) d/c (n=25) d/c (n=20) Patient Survival Graft Survival at Month 12 29.7% 12

  37. Study 212 Discontinuations (%) by Month 12 Nonrandomized* Postrandomization Reason for RAPA + CsARAPADiscontinuation (n/n = 28/49)(n/n = 20/97)(n/n = 25/99) Adverse event 41.0 12.0 12.0 Acute rejection 6.0 5.0 4.0 Other 10.0 3.0 10.0 Total 57.0 20.0 26.0 P = N.S. * 49 patients not randomized (48 ATN/DGF; 1 acute rejection).

  38. Study 212Successful Elimination of Cyclosporine RAPAMUNEPatients Eligible for CsA Withdrawalby Month 2 (n=82) RAPAMUNEAll Randomized Patients (n=100) 93% 76%

  39. Safety Summary (I) • Studies 310 and 212 confirm the beneficial safety profile of RAPAMUNE-based therapy following CsA elimination • Excellent patient and graft survival • Similar rates of infection and malignancy • Significantly lower rates of CsA-related adverse events • Significant and sustained improvement in blood pressure in patients in Study 310 • The overall RAPAMUNE safety profile is similar to that observed when it is administered as a fixed 2 mg dose in combination with CsA

  40. Safety Summary (II) • Rates of discontinuation from study medication were similar to other recent immunosuppressive registration trials • Reasons for early discontinuation were typical, with few due to acute rejection • Alternate maintenance therapies were utilized for patients discontinued from the studies • Cyclosporine was successfully eliminated in the majority of patients in the RAPAMUNE group

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