Certican® (everolimus) Tablets Prophylaxis of rejection in heart transplantation

1. Certican® (everolimus) TabletsProphylaxis of rejection in heart transplantation Renata Albrecht, M.D. Steve Gitterman, M.D., Ph.D. Division of Special Pathogen and Transplant Products Office of Antimicrobial Products OND/CDER/FDA

2. Cardiovascular and Renal Drugs Advisory CommitteeNovember 16, 2005 • Standing committee • Experts and consultants • Cardiology, nephrology, transplantation, statistics, clinical pharmacology • Approvable action previously taken • Novartis interested in a public discussion of Certican application and unmet medical need in heart transplantation

3. Agenda • Novartis presentation • Overview of cardiac transplantation • FDA presentation • Questions for committee discussion and vote

4. Certican® NDA 21-628 • Phase 3 comparative studies • Heart study: B253 • Renal studies: B201, B251 • Regimen • “Fixed-dose” everolimus, “full dose” cyclosporine, and steroids • Protocol amended at 12 months due to toxicity

5. Certican® with“full dose” cyclosporine • Approvable letters (see Novartis backgrounder) • Risk outweighs benefit • Novartis proposed labeling • “Certican should not be used long-term together with full doses of cyclosporine.”

6. Question 1 • “Fixed-dose” everolimus and “full-dose” cyclosporine Novartis has presented the results and extensively discussed the use of a ‘fixed-dose’ everolimus regimen with “full-dose” cyclosporine in study B253. Both FDA and Novartis agree that this exact fixed-dose regimen should not be used for the prophylaxis of organ rejection in cardiac transplantation. Do committee members agree with this conclusion?

7. Therapeutic Drug Monitoring (TDM) • Novartis will present proposed dosing regimen in heart transplantation • Everolimus dosing • Cyclosporine dosing • No prospective randomized study of TDM in heart transplantation conducted • Other sources of information • Analyses from “full dose” cyclosporine heart study • Proposed extrapolation from noncomparative kidney TDM studies • Clinical Pharmacology Modeling

8. Question 2 • Therapeutic Drug Monitoring Novartis has proposed an alternative ‘TDM-based’ regimen for the use of everolimus in combination with cyclosporine. The proposed regimen has not been prospectively tested in a cardiac transplantation study. In the absence of a prospective study of this regimen, do committee members believe there is sufficient information available to conclude that the regimen as proposed by Novartis has been demonstrated to be safe and effective for use in heart transplantation?

9. Question 2(continued) • In your discussion, please be specific regarding what information supports the proposed TDM-based regimen. • Please discuss in your answer whether you believe that everolimus has been shown safe and effective for all cardiac transplant recipients. • Alternatively, please discuss whether you believe there are certain subgroups where use should be specifically indicated or specifically restricted.

10. Question 3 • Are Additional Data Needed? If your answer to question #2 is YES, that the proposed TDM-regimen is safe and effective, please comment on what additional information should be obtained regarding everolimus post-approval. Additionally, do you have any recommendations regarding labeling (package insert).

11. Question 4 • What Additional Data Are Needed? If your answer to question #2 is NO, please comment what additional information would be necessary for approval. For example, please comment whether the currently-ongoing European study and/or the planned US cardiac transplantation study would be adequate to demonstrate safety and efficacy. Also comment whether additional data or studies would be necessary.