Oral Rapamycin in Argentina: ORAR Stent Trial

1
Oral Rapamycin in ArgentinaORAR Stent Trial
118-25
P 0.031
P 0.041
Rapamycin bloodlevel 8 ng/mL(n 48)
Rapamycin blood level Rodriguez, et al. Heart. 2005911433-1437.
2
High Rate of Premature Discontinuation of
MedicationPhase 3 Trials
qc
a 3
Incidence of ACE/ARB Use Study B253 ITT
Population12-month Analysis
IVUS back-up - Aug 10th.ppt
205-22
qc
4
Efficacy-Related Events at 6 Months Study B253
qc
PTT 9.1-5a
P 0.009 1.5 mg vs AZA P AZA Not mutually exclusive.
5
Sensitivity for Missed On-Treatment and
Discontinuation Biopsies Study 253ITT
Population, 6-month Analysis
qc
1.00
0.75
Survival distribution
0.50
AZA Everolimus 1.5 mg Everolimus 3.0 mg Censored
0.25
P 0.078, 1.5 mg vs AZA P 0.013, 3.0 mg vs AZA
0
0
25
75
125
175
200
50
100
150
Days from first dose to event
6
Sensitivity AnalysisAverage MIT for Patients
Missing IVUS (Age-matched AZA Outcome Assigned)
IVUS back-up - Aug 10th.ppt
205-21
QC
7
Changes in Maximal Intimal Thickness B253 vs
1995 Landmark Prava HTx Trial
P 0.002
P 0.01
Kobashigawa JA, et al. N Engl J Med.
1995333621-627. Eisen HJ, et al. N Engl J Med.
2003349847-858.
8
Incidence Rate of Key Safety Events by Everolimus
Trough Ranges Up to Event or Day 450Study
B253Safety Population, 12-month Analysis
259
QC
App 4 PTT4.3-6
9
Kaplan-Meier Analysis of Time to First MACE From
Day 1 to Month 48ITT Population48-month Analysis
187-1
QC
ac_mace_km2.doc
1.0
0.9
P 0.537, 1.5 mg vs AZA
P 0.500, 3.0 mg vs AZA
0.8
Survival distribution function
0.7
AZA
Everolimus 1.5 mg
0.6
Everolimus 3.0 mg
0.5
0
180
360
540
720
900
1080
1260
1440
1620
Time (days)
Treatment Patients at
risk/censored AZA (n 214) 167/8 148/18 87/72 Eve
rolimus 1.5 mg (n 209) 164/13 152/18 94/69 Evero
limus 3.0 mg (n 211) 160/14 147/23 83/80
10
All MACE Day 1 to Month 48
qc
A patient may be counted in more than one row. a
Kaplan-Meier rate. P NS for all comparisons,
based on log-rank test.
11
Efficacy-Related EventsEverolimus 1.5 mg and
MMFStudies B201/B251/A2306/A230712 months
278dv
NDA 21-560 T1 NDAN Amendment Final SU T2-1
12
Reduction of 50 in CsA Is Associated With
Stabilization of Renal Function (CrCl)
qc
Post-CsA reduction
Pre-CsA reduction
AZA n 71
Everolimus 1.5 mg n 68
Everolimus 3.0 mg n 63
From repeated measures analysis, all slopes of
estimated CrCl before CsA reduction were
significantly different from 0 (P 0.002). The
slope of estimated CrCl after CsA reduction in
the everolimus 3.0 mg group is significantly
different from 0 (P 0.002). All changes in
slopes of estimated CrCl (before and after CsA
reduction) were significantly different from 0 (P
0.045).
13
RAD2411CsA C0 Target Blood Levels
qc

• CsA dosing with MMF
• Mo 1, 2 200 - 350 ng/mL
• Mo 3, 4 200 - 300 ng/mL
• Mo 5, 6 150 - 250 ng/mL
• Mo 7 - 12 100 - 250 ng/mL

• CsA dosing with everolimus
• Mo 1 200 - 350 ng/mL
• Mo 2 150 - 250 ng/mL
• Mo 3, 4 100 - 200 ng/mL
• Mo 5, 6 75 - 150 ng/mL
• Mo 7 - 12 50 - 100 ng/mL

• Targets agreed by EU health authorities
• Bridging local clinical practices
• Allow for lower CsA levels in everolimus arm

14
DispositionStudy B2536 months
15
K-M Estimate of Time of Discontinuation of Study
Medication at 12 months Study 253ITT
Population, 12-month Analysis
qc
1.00
0.75
Survival distribution
0.50
AZA Everolimus 1.5 mg Everolimus 3.0 mg Censored
0.25
0
0
100
300
500
200
400
Days from first dose to event
16
Everolimus B253 Biopsy Compliance
250
email 10/11/0 Protocol CRAD001 B253
a Evaluable patients are all patients with
functioning graft. Patients who reached endpoint
based on results of biopsy are not counted.
17
Cyclosporine Whole Blood Trough Level (ng/mL)
During Visit WindowDHZB Series vs Dosing in
Study B253
248-5
Everolimus 1.5 mg (B253)
DHZB series
Everolimus data collection Table 4.1
Dr. Hans Lehmkuhl, personal communication.
18
Serum Creatinine (Change From Baseline)DHZB
Series
248-8
Everolimus data collection Table 6.1
n
35
35
35
35
35
30
19
11
Dr. Hans Lehmkuhl, personal communication.
19
Efficacy 6 months Follow-upDHZB Series
248-14

• 0 graft loss
• 0 death
• 3/30 ISHLT grade 3A rejection through 6 months
  (all prior to Month 3)

Everolimus data collection Table 7.2
P 0.003 vs AZA P everolimus 1.5 mg vs everolimus 3.0 mg
20
Baseline Renal Function and Creatinine Clearance
of DV - New slides.doc from Kevin Mange 11-02-05
268-3
qc
1.00
0.75
Survival distribution
0.50
1st quartile 2nd quartile 3rd quartile 4th
quartile Censored
0.25
P 0
0
100
200
300
400
500
Time posttransplant (days)
Excludes patients with CrCl at baseline mL/min.
21
Baseline Renal Function and Primary
EfficacyStudy B253
DV - New slides.doc from Kevin Mange 11-02-05
268-2
qc
1.00
0.75
Survival distribution
0.50
1st quartile 2nd quartile 3rd quartile 4th
quartile Censored
0.25
P 0.38 by log-rank test
0
0
50
100
150
200
250
300
350
400
Time posttransplant (days)
Excludes patients with CrCl at baseline mL/min.
22
Baseline Renal Function and Creatinine Clearance
1.5 mg
268-7
ac_risk_RF_km1
DV - New slides.doc from Kevin Mange 11-02-05
qc
1.00
0.75
Survival distribution
0.50
1st quartile 2nd quartile 3rd quartile 4th
quartile Censored
0.25
0
0
100
200
300
400
500
Time posttransplant (days)
Excludes patients with CrCl at baseline mL/min.
23
Baseline Renal Function and Creatinine Clearance
268-6
ac_risk_RF_km1
DV - New slides.doc from Kevin Mange 11-02-05
qc
1.00
0.75
Survival distribution
0.50
0.25
0
0
100
200
300
400
500
Time posttransplant (days)
Excludes patients with CrCl at baseline mL/min.