CR-1 Everolimus Benefit/Risk Assessment Howard J. Eisen, MD Thomas J. Vischer Professor of Medicine Chief, Division of Cardiology Drexel University College of Medicine

CR-2 Adjunctive Therapy in Heart Transplantation  A significant unmet medical need remains –Acute rejection –CAV  Only CsA and MMF are approved in heart transplantation –Azathioprine (AZA) first adjunct widely used in heart transplantation –MMF approved as noninferior to AZA in efficacy –Sirolimus and tacrolimus used without label guidance –No drug approved for heart transplant since 1998 –Everolimus is first in class for this indication

CR-3 Concentration-Controlled Everolimus With Reduced CsA in Heart Transplantation Study A2411  Randomized non-inferiority study  Study arms –Trough-controlled everolimus (3 to 8 ng/mL) with tapering CsA (50 to 100 ng/mL by month 7) –MMF with standard CsA  Endpoints –Primary: Renal function at 6 months –Secondary: ISHLT grade ≥ 3A rejection at 6 and 12 months  N = 176 (end of enrollment March 2006)  12 month analysis available 2Q 07

CR-4 Concentration-Controlled Everolimus With Reduced CsA in Heart Transplantation Study A2310—Phase 3  Randomized non-inferiority  Study arms –Everolimus (trough 3 to 8 ng/mL) with tapering CsA (50 to 100 ng/mL by month 7) –Everolimus (trough 6 to 12 ng/mL) with tapering CsA (50 to 100 ng/mL by month 7) –MMF 3 g/daily with standard CsA  Endpoints –Primary: Composite efficacy at 12 months –Secondary: Renal function at 12 months IVUS parameters at 12 months  N = 630 (enrolled over 24 months)  Study start November 2005; 1-year analysis 1Q 09

CR-5 Everolimus 1.5 mg and 3.0 mg/day Reduced Efficacy Failure and Acute Rejection  Acute rejection accounts for substantial morbidity and mortality during the first year after transplantation  Everolimus 1.5 mg and 3.0 mg/day significantly reduced acute rejection compared with AZA throughout the study period.

CR-6 Everolimus Reduced CAV in the IVUS Substudy  CAV is a major cause of mortality late after transplant affecting 50% of all patients 5 years after surgery  No established treatment for CAV  Everolimus 1.5 mg and 3.0 mg/day significantly reduced cardiac allograft vasculopathy as defined by IVUS compared with AZA at 12 and 24 months  The incidence of non-fatal graft-related MACE at months, an outcome of cardiac allograft vasculopathy, was significantly lower in the everolimus 1.5 mg treatment arm compared to AZA

CR-7 Safety Results Summary  Malignancy –No increase in malignancy relative to AZA  Infection –Bacterial infections were increased but manageable –CMV infections decreased  Lipids –Total cholesterol and triglycerides increased but HDL and LDL values were similar overall

CR-8 Renal Safety  Renal function –Significantly lower mean creatinine clearance values were observed with everolimus + full-dose CsA –No further reductions in mean CrCl observed after Month 12 for all groups (no progressive renal dysfunction) –Exposure-response analyses demonstrated the critical role of CsA in risk for renal dysfunction –Efficacy for everolimus preserved after CsA reduction

CR-9 Optimization of Everolimus Treatment With Therapeutic Drug Monitoring Benefit/Risk Assessment  Adjusting everolimus whole blood trough concentrations in the range of 3 to 8 ng/mL allows physicians to ensure beneficial outcomes  Exposure-effect analysis supports reducing CsA dosing to safely improve renal function and maintain efficacy

CR-10 Overall Conclusion Benefit/Risk Assessment—Everolimus  Everolimus has demonstrated significant benefit vs AZA in acute rejection and cardiac allograft vasculopathy, which are known risks for reduced survival  Everolimus, like all immunosuppressive therapy used clinically in transplantation, has significant side effects that are manageable by transplant professionals  Given the unmet medical need, improved outcomes justify the tradeoff for an acceptable risk