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Certican® (everolimus)

Cardiovascular and Renal DrugsAdvisory Committee Meeting

November 16, 2005

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Certican® (everolimus)

Introduction and Regulatory Background

Mathias Hukkelhoven, PhD

Senior Vice PresidentGlobal Head, Drug Regulatory Affairs

Novartis Pharmaceuticals Corporation

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Certican® Clinical Development Program Most comprehensive clinical development program

in transplantation

– 25 trials(1 heart, 7 kidney, 17 clin-pharm)

• Approximately 3000 patients enrolled, 1800 patients treated

• 220 investigators worldwide Phase 3 heart study B253

– 634 patients

– Follow-up at 6, 12, 24, and 48 months

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Certican® Long-term Studies in Heart and Kidney

de novo N = 2532

Heart B253N = 634

6, 12, 24 months full-dose Neoral®

Open-label extension through 48 months

Kidney B201, B251, B157N = 1275

6, 12, 36 months full-dose Neoral

Kidney B351N = 19

Pediatric full-dose Neoral12, 24 months

Kidney B156N = 111

Full vs reduced-dose Neoral plus Simulect®

12, 36 months

Kidney A2306N = 237

Reduced-dose Neoral: everolimus TDM6, 12 months

Kidney A2307N = 256

Reduced-dose Neoral plus Simulect: everolimus TDM6, 12 months

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Certican® Global Registration

Total country approvals in kidney and heart 48

1200 patients on commercial drug

• 75% are heart transplant patients

Sweden reference state—kidney and heart approvals Jul 2003

Recommended approvals by 15 of 17 EU member states

Dec 2003

Approval by 10 new EU member states Dec 2004

Australia, South Africa, Switzerland, South America (9), Central America (6), Israel

2003 - 2005

Japan—new drug application submitted—heart Jun 2005

3 countries have not approved Certican—Canada, Ireland, United Kingdom

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Certican® NDA History

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NDA submissions in kidney and heart

Dec 02

Oct 03

Approvable letter #1 for kidney and heart

Approvable letter #2 for kidney and heartAug 04

Feb 04 Mar 05

Major amendment in support of AC discussions

Nov 04

End-of-review meeting

Response

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Overall Objectives

Review the primary efficacy and safety data from the Certican® (everolimus) pivotal study in heart transplantation (B253)

Provide dosing recommendations for everolimus in combination with Neoral®

Present data that support a favorable benefit-risk profile for everolimus in heart transplantation

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Certican® Proposed Indication

Certican® (everolimus) is indicated for the prophylaxis of organ rejection in adult patients receiving a heart transplant

It is recommended that Certican be used concurrently with Neoral® and corticosteroids

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Certican® Proposed Dosage and Administration

The pivotal heart study evaluated fixed doses of

everolimus at 1.5 mg per day and 3.0 mg per day

Initial dose regimen of 1.5 mg per day in 2 divided doses (BID) adjusted to target trough level of 3 to 8 ng/mL

Certican should be used with reduced doses of cyclosporine after the first month

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Today’s Agenda

Introduction and Regulatory background

Mathias Hukkelhoven, PhD

Challenges and Opportunities In Cardiac Transplantation

Howard J. Eisen, MD

Efficacy Results (B253) Jeffrey Hosenpud, MD

IVUS Results (B253) Jon A. Kobashigawa, MD

Safety Kenneth A. Somberg, MD

Renal Safety and Dose Recommendations

Lawrence Hunsicker, MD

Benefit/Risk Assessment Howard J. Eisen, MD

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Novartis Consultants

Randall C. Starling, MD, MPh Head, Section of Heart Failure and Cardiac Transplant MedicineDepartment of Cardiovascular Medicine, Cleveland Clinic FoundationCleveland, Ohio

Lee-Jen Wei, PhD Professor of BiostatisticsDepartment of BiostatisticsHarvard School of Public HealthBoston, MA

Hans B. Lehmkuhl, MD Senior ConsultantHead of Heart and Lung Failureand Thoracic TransplantationGerman Heart Center Berlin, Germany