# Presentation: 752676

## Certican® (everolimus)

**Cardiovascular and Renal Drugs****Advisory Committee Meeting**
**November 16, 2005**

## Certican® (everolimus)Introduction and Regulatory Background

**Mathias Hukkelhoven, PhD**
**Senior Vice President****Global Head, Drug Regulatory Affairs****Novartis Pharmaceuticals Corporation**

## 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**** **

**122-5**

## Certican® Long-term Studies in Heart and Kidney

| de novo                     N = 2532 |  |  |
| --- | --- | --- |
| Heart  | B253N = 634 | 6, 12, 24 months full-dose Neoral®
Open-label extension through 48 months |
| Kidney  | B201, B251, B157N = 1275 | 6, 12, 36 months full-dose Neoral |
| Kidney  | B351N = 19 | Pediatric full-dose Neoral12, 24 months |
| Kidney  | B156N = 111 | Full vs reduced-dose Neoral plus Simulect®12, 36 months |
| Kidney  | A2306N = 237 | Reduced-dose Neoral: everolimus TDM6, 12 months |
| Kidney  | A2307N = 256 | Reduced-dose Neoral plus Simulect: everolimus TDM6, 12 months |

## 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 |  |

## Certican® NDA History

**208-1**

**NDA submissions in kidney and heart**

**Dec 02**

**Oct 03**

**Approvable letter #1 for kidney and heart**

**Approvable letter #2 for kidney and heart**

**Aug 04**

**Feb 04**

**Mar 05**

**Major amendment in support of AC discussions**

**Nov 04**

**End-of-review meeting **

**Response**

## 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 **

## 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**

## 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**

## 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 |

## Novartis Consultants

| Randall C. Starling, MD, MPh | Head, Section of Heart Failure and Cardiac Transplant Medicine
Department of Cardiovascular Medicine, Cleveland Clinic FoundationCleveland, Ohio |
| --- | --- |
| Lee-Jen Wei, PhD | Professor of Biostatistics
Department of Biostatistics
Harvard School of Public Health
Boston, MA |
| Hans B. Lehmkuhl, MD | Senior ConsultantHead of Heart and Lung Failureand Thoracic TransplantationGerman Heart Center Berlin, Germany |