1. CN-1 Everolimus Renal Safety and Efficacy Extrapolations, Dose Recommendations Lawrence Hunsicker, MD Professor of Medicine and Medical Director of Organ Transplantation Carver College of Medicine at the University of Iowa

2. CN-2 Overview  Use of everolimus, together with cyclosporine (CsA) in usual doses, is associated with a significant reduction in kidney function  This effect is closely related to the trough (C 0 ) levels of CsA, but unrelated to the levels of everolimus  Use of everolimus with reduced dose CsA results in calculated creatinine clearance similar to those seen in patients treated with full dose CsA and either AZA or MMF  PK/PD analyses demonstrate everolimus and CsA, at reduced dose after the first month, is effective in preventing cardiac rejection

3. CN-3 Certican ® Proposed Dosage and Administration  Everolimus should be used in an initial dose of 1.5 mg per day in 2 divided doses, but dose adjusted to achieve a target trough level of 3 to 8 ng/mL  Recommended target exposure of CsA in the first month is 250 to 400 ng/mL  Exposure to CsA beyond Month 1 should be about –175 ng/mL for month 2 - 3 –135 ng/mL for month 4 - 6 –100 ng/mL beyond month 6

4. CN-4 Outline  Review of renal safety data from heart study B253  Role of everolimus and CsA –PK/PD relationships for renal function  Efficacy of reduced-dose CsA in cardiac transplantation –PK/PD efficacy heart study B253  Conclusions about safety and efficacy  Dosing recommendations

5. CN-5 Mean Creatinine Clearance (Cockcroft-Gault) Over Time—24 Months Study B253 AZA, n Everolimus 1.5 mg, n Everolimus 3.0 mg, n 122 116 100 205 194 206 152 140 132 Data from PTT 10.3-1b 24 months BL1224 201 193 190 1 166 169 153 3 167 156 152 6 * * * * * * * * * *P < 0.001 Error bars = Standard deviation.

6. CN-6 Renal Function—12 months Study B253 Everolimus AZA1.5 mg3.0 mg n = 145n = 132n = 129 Creatinine clearance mean (SD) (mL/min) 65.0 (22.89) 51.7 (19.06)* 51.3 (27.65)* n = 149n = 137n = 131 Creatinine mean (SD) (mg/dL) 1.67 (0.55) 2.06 (0.67)* 2.14 (0.95)* *P < 0.005 vs AZA CS-20

7. CN-7 Outline  Review of renal safety data from heart study B253  Role of everolimus and CsA –PK/PD relationships for renal function  Efficacy of reduced-dose CsA in cardiac transplantation –PK/PD efficacy heart study B253  Conclusions about safety and efficacy  Dosing recommendations

8. CN-8 Absence of Renal Toxicity of Everolimus Monotherapy Study 2201—Rheumatoid Arthritis 209-1 Parameter (mean) Placebo n = 60 Everolimus 6.0 mg n = 61 Creatinine (mg/dL) Baseline0.78 Week 120.810.77 Week 240.720.68 Slide set CPOs.ppt s32

9. CN-9 Design of Kidney Transplant Studies Studies B201, B251, A2306, A2307 ≤ 48 hrs Everolimus 1.5 mg (B201: n = 194; B251: n = 193) Everolimus 3.0 mg (B201: n = 198; B251: n = 194) MMF 2 g (B201: n = 196; B251: n = 196) 101-2 ≤ 24 hrs Everolimus 1.5 mg/d (2306: n = 112; 2307: n = 117) Everolimus 3.0 mg/d (2306: n = 125; 2307: n = 139) Wk 1 - 4BaselineWeek 5 - 12Month 4 - 12 B201, B251 A2306, A2307 a a With IL-2R monoclonal antibody. n’s from CSRs (Standard CsA) (Reduced CsA)

10. CN-10 a With IL-2R monoclonal antibody. Mean CsA Trough Levels and Creatinine Clearance With Conventional or Reduced-Dose CsA Studies B201, B251, A2306, A2307 a —ITT 12-month Analysis B201B251A2306A2307 CsA trough levels (ng/mL) 6 months Everolimus 1.5 mg1731788264 Everolimus 3.0 mg1581758368 MMF 2 g170178—— 12 months Everolimus 1.5 mg1441406160 Everolimus 3.0 mg1561217158 MMF 2 g157167—— Creatinine clearance (mL/min) Everolimus 1.5 mg52596567 Everolimus 3.0 mg475564 MMF 2 g5469——

11. CN-11 Heart Study B253—Creatinine Clearance Decrease 30% After Month 1 by CsA and Everolimus Concentration a CsA exposure (ng/mL) a Time-weighted average trough until event or censoring. 265-3 DV - AC B253 PKPD draft2.doc

12. CN-12 Outline  Review of renal safety data from heart study B253  Role of everolimus and CsA –PK/PD relationships for renal function  Efficacy of reduced-dose CsA in cardiac transplantation –PK/PD efficacy heart study B253  Conclusions about safety and efficacy  Dosing recommendations

13. CN-13 BPAR ISHLT Grade ≥ 3A Rates vs Everolimus Exposure Study B253 104-6 BPAR rates by average everolimus trough level to event or day 450 a At 12 months.

14. CN-14 Percent of Patients Free of BPAR ISHLT Grade ≥ 3A Based on Everolimus Exposure Study B253—Day 1 to 225 Log-rank: Mean exposure 8 ng/mL (P 8 ng/mL (P < 0.001). 104-9 Everolimus trough levels ≥ 8 ng/mL 3 - 8 ng/mL < 3 ng/mL AZA Time after transplantation (days) 0255075100125150175200225 0 20 40 60 80 100 Patients free of acute rejection, %

15. CN-15 BPAR ISHLT Grade ≥ 3A Acute Rejection by CsA and Everolimus Concentration a Study B253—Days 15 - 225 CsA exposure (ng/mL) a Time-weighted average trough until event or censoring. 265-4 DV - AC B253 PKPD draft2.doc

16. CN-16 Rejection by CsA Exposure Quartile Day 1 to Month 1 Study B253 Novartis Briefing Book Table 4-11 Quartiles based on CsA exposure 1.5 mg AZA 3.0 mg

17. CN-17 Rejection by CsA Exposure Quartile Months 2 to 3 Study B253 Novartis Briefing Book Table 4-11 Quartiles based on CsA exposure 1.5 mg AZA 3.0 mg

18. CN-18 Rejection by CsA Exposure Quartile Months 4 to 6 Study B253 Quartiles based on CsA exposure 1.5 mg AZA 3.0 mg Novartis Briefing Book Table 4-12

19. CN-19 Rejection by CsA Exposure Quartile Months 7 to 12 Study B253 Quartiles based on CsA exposure 1.5 mg AZA 3.0 mg Novartis Briefing Book Table 4-13

20. CN-20 Rejection by CsA Exposure Quartile Everolimus 1.5 mg Over Months 2 to 12 Study B253 225-1 ac_ci12_rev.rtf 15112695232270354186229294149192244Median CsA trough levels (ng/mL) Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4

21. CN-21 Outline  Review of renal safety data from heart study B253  Role of everolimus and CsA –PK/PD relationships for renal function  Efficacy of reduced-dose CsA in cardiac transplantation –PK/PD efficacy heart study B253  Conclusions about safety and efficacy  Dosing recommendations

22. CN-22 Summary  The combination of everolimus with standard dose CsA is associated with reduced renal function compared with CsA with AZA or MMF  But reduced dose CsA with either dose of everolimus is associated with excellent renal outcomes, similar to those with CsA and either AZA or MMF  The use of everolimus with lower doses of CsA after month 1 is equally effective in preventing cardiac rejection

23. CN-23 Conclusions  Renal toxicity is primarily associated with blood levels of CsA  Antirejection efficacy is primarily associated with blood levels of everolimus  It is possible to dose these agents so as to avoid renal toxicity and maintain antirejection efficacy  Thus in the hands of transplant experts, use of everolimus as we have recommended is effective in cardiac transplantation and is safe with respect to the effects on the kidneys

24. CN-24 Outline  Review of renal safety data from heart study B253  Role of everolimus and CsA –PK/PD relationships for renal function  Efficacy of reduced-dose CsA in cardiac transplantation –PK/PD efficacy heart study B253  Conclusions about safety and efficacy  Dosing recommendations

25. CN-25 Dose Recommendation for Everolimus  Initial dose of everolimus is 1.5 mg/day  We recommend use of everolimus to achieve trough concentrations of 3 to 8 ng/mL for the entire posttransplant period  As implied above, therapeutic monitoring of everolimus levels is appropriate

26. CN-26 Dose Recommendation for CsA  Recommended target exposure of CsA in the first month is 250 to 400 ng/mL  Exposure to CsA beyond Month 1 should approximate the median of the lowest exposure quartiles observed over time for study B253 –175 ng/mL for month 2 - 3 –135 ng/mL for month 4 - 6 –100 ng/mL beyond month 6