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

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

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 –135 ng/mL for month –100 ng/mL beyond month 6

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

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 Data from PTT b 24 months BL * * * * * * * * * *P < Error bars = Standard deviation.

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 < vs AZA CS-20

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

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

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) ≤ 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 Month B201, B251 A2306, A2307 a a With IL-2R monoclonal antibody. n’s from CSRs (Standard CsA) (Reduced CsA)

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 mg Everolimus 3.0 mg MMF 2 g170178—— 12 months Everolimus 1.5 mg Everolimus 3.0 mg MMF 2 g157167—— Creatinine clearance (mL/min) Everolimus 1.5 mg Everolimus 3.0 mg MMF 2 g5469——

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 DV - AC B253 PKPD draft2.doc

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

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

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) Everolimus trough levels ≥ 8 ng/mL ng/mL < 3 ng/mL AZA Time after transplantation (days) Patients free of acute rejection, %

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

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

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

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

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

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

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

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

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

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

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

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 –135 ng/mL for month –100 ng/mL beyond month 6