Rapamune ®

1. Rapamune® Cyclosporine Withdrawal in Renal Transplantation Advisory Committee 1/24/02 Rosemary Tiernan, MD, MPH

2. Consumer Safety Officer Chemistry Reviewers Immunology Reviewer Clinical Pharmacologists Pharmacotoxicologists Biostatistical Reviewers Medical Officer Medical Team Leader Matthew Bacho Mark Seggel, PhD Norman Schmuff, PhD Shukal Bala, PhD Kofi Kumi, PhD Funmi Ajayi, PhD Steven Kunder, PhD Kenneth Hastings, Dr.PH Cheryl A. Dixon, PhD Karen M. Higgins, ScD Rosemary Tiernan, MD,MPH M. Cavaillé-Coll, MD, PhD FDA Review Team

3. FDA Perspective: Rapamune® • Background • Design of Clinical Studies • Efficacy • Safety • Questions to the Advisory Committee

4. Basis of Initial Approval (1999) • Two randomized, double blind phase III studies (301 and 302) comparing Rapamune, 2mg and 5mg, to azathioprine or placebo • Non-inferiority with respect to 12-month patient and graft survival • Significant reduction in the incidence of rejection at 6-months • Decreased renal function at 12 months observed

5. Phase 4 Commitment (1) • Report long-term follow-up safety and efficacy data from studies 301 and 302 • Data pertaining to GFR and serum creatinine will be included as follow-up information. • These data should be collected throughout the entire duration of the study whether or not patients remain on study drug.

6. Phase 4 Commitment (2) • Evaluate the optimum therapeutic concentration range for sirolimus and the value of reduced cyclosporine concentrations in combination with sirolimus.

7. Proposed Labeling Change • Consideration of cyclosporine withdrawal at 2 to 4 months after transplantation • Concentration controlled sirolimus at 15 to 25 ng/mL (immunoassay) when used without cyclosporine

8. Studies to Support Labeling Change • Study 310 • open label, non-IND study in Europe, Canada, and Australia • randomization at month 3 • Study 212 • open label study in US and Europe • randomization days 2 to 7

9. Sirolimus Dosing • In the cyclosporine withdrawal arm, the dosage of sirolimus increased after withdrawal and adjusted to maintain whole blood concentrations • Study 310: 20 to 30 ng/mL. • Study 212: 10 to 20 ng/mL.

10. Strengths and Weaknesses • Strengths • Cyclosporine concentrations • Quality of sirolimus concentration control • Quality of follow-up • Weaknesses • Open-label study designs • Under-representation of US transplant population • Time of randomization

11. Efficacy Considerations • Patient population • Discontinuations during treatment through month 12 • Patient and graft survival at 12 months • Acute rejection after cyclosporine withdrawal • Renal function at 12 months

12. Patient Population Study 310 • High risk transplant recipients were not randomized to cyclosporine maintenance or withdrawal ~ Banff Grade III acute rejection episode or vascular rejection 4 weeks before random assignment ~ Dialysis dependency ~ Serum creatinine > 400 µmol/L ~ Inadequate renal function (in the opinion of the investigator) to support CsA elimination

13. Patient Population Study 212 • Patients with adequate renal function (as determined by the investigator) were randomly assigned, within 48 hours after transplantation to cyclosporine maintenance or withdrawal. • Patients whose ATN/DGF had not resolved by day 7 after transplantation were not randomized.

14. Discontinuations During Treatment throughMonth 12 * Fisher’s Exact

15. Reasons for DiscontinuationStudy 310

16. Patient and Graft Survival * Difference: ( Rapa + CsA )- Rapa 95% Confidence Interval based on Normal approximation with continuity correction

17. Acute Rejection Following CsA Withdrawal * Fisher’s Exact

18. Renal Function at 12 Months • GFR and Serum Creatinine • Analysis of all patients with a functioning graft at 12 months including those who discontinued study drug • Small amount of missing data • Overall, renal function is better for the cyclosporine withdrawal arm • For those with a rejection, renal function is reduced

19. GFR (mL/min) at 12 Months* * For those with a functioning graft at 12 months. Mean (SE) and p-value for ANCOVA adjusting for baseline and center.

20. Serum Creatinine (mol/mL) at 12 Months* * For those with a functioning graft at 12 months. Mean (SE) and p-value for ANCOVA adjusting for baseline and center. **One pt. who had outlying value of 960 was excluded.

21. GFR (mL/min) at 12 Months*By Rejection Status * For those with a functioning graft at 12 months. Mean (SE). Rejection pre- or post-randomization.

22. Serum Creatinine (mol/L) at 12 Months* By Rejection Status * For those with a functioning graft at 12 months. Mean (SE). Rejection pre- or post-randomization. **One pt. who had outlying value of 960 was excluded.

23. Safety considerations • Exposure • Adverse event profile from the original NDA • Adverse Events studies 310 and 212

24. Study Dose Mean +SD (n) Range 301 2 mg 8.59 + 4.01 (226) 4.5 - 14 301 5 mg 17.3 + 7.35 (219) 10 - 28 310 2 mg 10.8 + 3.9 (204) 6.5 - 15 310 (no CsA) TDM dosing 23.3 + 5.1 (200) 16.9 - 29.6 Mean Sirolimus Trough Concentration (ng/ml)

25. Analytical Issues • Immunoassay was utilized to determine trough concentrations in clinical trials • Applicant is proposing a validated HPLC methodology for TDM • Samples will be sent to specific laboratories for analysis

26. Treatment-emergent Adverse Events>20 % in the Rapamune NDA (1999) Adverse events with a statistically significant increased incidence in Rapamune 5 mg vs 2 mg : • fever • diarrhea • anemia • leukopenia • thrombocytopenia • hyperlipidemia

27. Treatment-emergent Adverse Events > 5% and <20 % in the Rapamune NDA (1999) Adverse events with a statistically significant increased incidence in Rapamune 5 mg vs 2 mg: • chills - skin ulcer • face edema - lymphocoele • hypotension - tachycardia • hypokalemia - insomnia • increased LDH - epistaxis

28. Liver Function Tests (LFT’s) • HBV/HCV data not available on all patients • Increased incidence of elevated LFT’s in the RAPA vs the RAPA-CsA treatment arms of both studies

29. Infection and malignancy • Infection • Majority of study patients were at lower risk to develop CMV • Differences in the incidence of herpes zoster and fungal dermatitis • Malignancy • No detectable differences in the treatment arms related to malignancy and PTLD

30. Summary • Risks • Surge of early mild rejection • Higher exposure to sirolimus associated with certain adverse events • Benefit • Less cyclosporine-associated toxicities • Mean renal function improved for those without rejection

31. Questions for the Advisory Committee#1 • Do the data presented support the effectiveness and safety of cyclosporine withdrawal and concentration-controlled sirolimus 2 to 4 months after kidney transplantation, in patients treated initially with a regimen of sirolimus, cyclosporine and corticosteroids?

32. Questions for the Advisory Committee#1 • If yes, should this consideration be restricted to a particular sub-population? Conversely, is there a particular sub-population for whom cyclosporine withdrawal should not be considered? • If no, what additional studies would be needed to support such a maintenance regimen?

33. Questions for the Advisory Committee#2 • What additional phase 4 studies would you recommend?

34. Questions for the Advisory Committee#3 • Do you have any comments or recommendations regarding study design and/or endpoints for controlled clinical trials intended to support the safety and efficacy of maintenance immunosuppressive regimens in renal transplantation?