Everolimus Benefit/Risk Assessment

1. EverolimusBenefit/Risk Assessment Howard J. Eisen, MD Thomas J. Vischer Professor of MedicineChief, Division of CardiologyDrexel University College of Medicine

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 inheart 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

3. Concentration-Controlled Everolimus With Reduced CsA in Heart TransplantationStudy 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

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

5. Everolimus 1.5 mg and 3.0 mg/day Reduced Efficacy Failure andAcute 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.

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 1- 48 months, an outcome of cardiac allograft vasculopathy, was significantly lower in the everolimus 1.5 mg treatment arm compared to AZA

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

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

9. Optimization of Everolimus Treatment With Therapeutic Drug MonitoringBenefit/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

10. Overall ConclusionBenefit/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