Rapamune®

Cyclosporine Withdrawal in Renal Transplantation

Advisory Committee 1/24/02

Rosemary Tiernan, MD, MPH

FDA Review Team

Consumer Safety OfficerChemistry Reviewers

Immunology ReviewerClinical Pharmacologists

Pharmacotoxicologists

Biostatistical Reviewers

Medical OfficerMedical Team Leader

Matthew Bacho Mark Seggel, PhDNorman Schmuff, PhDShukal Bala, PhDKofi Kumi, PhDFunmi Ajayi, PhDSteven Kunder, PhDKenneth Hastings, Dr.PHCheryl A. Dixon, PhDKaren M. Higgins, ScDRosemary Tiernan, MD,MPHM. Cavaillé-Coll, MD, PhD

FDA Perspective: Rapamune®

Background Design of Clinical Studies Efficacy Safety Questions to the Advisory Committee

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

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.

Phase 4 Commitment (2)

Evaluate the optimum therapeutic concentration range for sirolimus and the value of reduced cyclosporine concentrations in combination with sirolimus.

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

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

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.

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

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

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

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.

Discontinuations During Treatment

through Month 12

Rapa +CsA

Rapa p-value*

Study 310 38/21517.7%

58/21527.0%

0.027

Study 212 20/9720.6%

25/10025.0%

0.499

* Fisher’s Exact

Reasons for DiscontinuationStudy 310

Reason

Rapa +CsA

(n = 215)

Rapa

(n=215)

Total 38 (18) 58 (27)

Adverse EventUnsatis. ResponsePatient RequestProtocol ViolationOther

30 (14)4 (2)3 (1)

1 (<1)0

37 (17)10 (5)6 (3)4 (2)

1 (<1)

Patient and Graft Survival

Rapa +CsA

Rapa Diff95% CI*

Study 310 206/21595.8%

209/21597.2%

-1.4(-5.3, 2.5)

Study 212 90/9792.8%

95/10095.0%

-2.2(-9.9, 5.5)

* Difference: ( Rapa + CsA )- Rapa95% Confidence Interval based on Normal approximation with continuity correction

Acute Rejection Following CsA Withdrawal

Rapa +CsA

Rapa p-value*

Study 310 9/2154.2%

21/2159.8%

0.035

Study 212 6/976.2%

14/10014.0%

0.098

* Fisher’s Exact

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

GFR (mL/min) at 12 Months*

Rapa +CsA

Rapa p-value

Study 310 56.1 (1.32)n=191

60.8 (1.35)n=190

<0.0001

Study 212 56.5 (2.01)n=89

66.0 (2.01)n=89

<0.0001

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

Serum Creatinine (mol/mL) at 12 Months*

Rapa +CsA

Rapa p-value

Study 310 160.5 (4.3)n=198**

147.0 (4.7)n=198

<0.0001

Study 212 167.3 (9.2)n=89

136.0 (5.3)n=89

0.0001

* 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.

GFR (mL/min) at 12 Months*By Rejection Status

Non-Rejectors Rejectors

Study Rapa +CsA Rapa Rapa + CsA Rapa

310 57.0 (1.41)n=169

64.2 (1.43)n=150

48.9 (3.6)n=22

48.0 (2.74)n=40

212 58.2 (2.14)n=74

70.9 (1.91)n=70

47.9 (5.15)n=15

47.7 (4.05)n=19

* For those with a functioning graft at 12 months. Mean (SE). Rejection pre- or post-randomization.

Serum Creatinine (mol/L) at 12 Months* By Rejection Status

Non-Rejectors Rejectors

Study Rapa +CsA Rapa Rapa + CsA Rapa

310 157.0 (4.5)n=176

135.7 (4.5)n=157

189.0 (11.3)n=22**

190.2 (12.7)n=41

212 153.7 (7.0)n=74

123.5 (4.7)n=70

234.5 (38.7)n=15

181.9 (13.2)n=19

* 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.

Safety considerations

Exposure Adverse event profile from the original

NDA Adverse Events studies 310 and 212

Mean Sirolimus Trough Concentration (ng/ml)

16.9 - 29.623.3 + 5.1 (200) TDM dosing

310 (no CsA)

6.5 - 1510.8 + 3.9 (204)2 mg310

10 - 2817.3 + 7.35 (219)5 mg301

4.5 - 14 8.59 + 4.01 (226)2 mg301

RangeMean +SD (n) DoseStudy

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

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

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

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

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

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

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?

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?

Questions for the Advisory Committee#2

What additional phase 4 studies would you recommend?

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?