# Presentation: 521161

## Oral Rapamycin in Argentina:ORAR Stent Trial

**Rapamycin blood****level > 8 ng/mL****(n = 48)**

**Rapamycin blood ****level < 8 ng/mL****(n = 37)**

**Rodriguez, et al.***** Heart. *****2005;91:1433-1437.**

**118-25**

***P***** = 0.041**

***P***** = 0.031**

## High Rate of Premature Discontinuation of MedicationPhase 3 Trials

| Study | Treatment | Rate of medication discontinuation (%) |
| --- | --- | --- |
| B253 (1 year) | AZA | 28.5 |
|  | Everolimus 1.5 mg | 29.7 |
|  | Everolimus 3.0 mg | 39.8 |
| MYC 1864 (1 year) | MMF | 40.1 |
|  | AZA | 42.7 |
| NR 15880 (5 doses over 50 days) | Anti–IL-2R | 18.2a |
|  | Placebo |  |

**a**** < 4 doses, reported for both arms.**

- qc

## Incidence of ACE/ARB Use Study B253 ITT Population—12-month Analysis

- IVUS back-up - Aug 10th.ppt

**205-22**

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
| Category/grade | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Patients taking any ACE | 116 (54.2) | 127 (60.8) | 128 (60.7) |
| Patients taking any ARB |   52 (24.3) |   62 (29.7) |   63 (29.9) |
| Patients taking anycalcium channel blockers | 152 (71.0) | 147 (70.3) | 146 (69.2) |

- qc

## Efficacy-Related Events at 6 Months Study B253

|  | Patients, n (%) |  |  |  |
| --- | --- | --- | --- | --- |
|  |  | Everolimus |  |  |
| Parameter | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 | P value |
| Acute rejection with HDC | 16 (7.5) | 14 (6.7) | 11 (5.2) | NS |
| Graft loss |   6 (2.8) |   4 (1.9) |   8 (3.8) | NS |
| Death | 12 (5.6) | 13 (6.2) | 14 (6.6) | NS |
| Lost to follow-up |   1 (0.5) | 0 | 0 | NS |
| Antibody-treated acute rejection episode of grade ≥ 3A or associated with HDC | 14 (6.5) | 12 (5.7) |   6 (2.8) | NS |
| Any treated acute rejection episode | 124 (57.9) |   94 (45.0)* | 75 (35.5)** |  |

********P***** = 0.009 1.5 mg vs AZA; ** *****P***** < 0.001 3.0 mg vs AZA**
**Not mutually exclusive.**

**PTT 9.1-5a**

- qc

## Sensitivity for Missed On-Treatment and Discontinuation Biopsies Study 253—ITT Population, 6-month Analysis

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Days from first dose to event**

**0**

**25**

**75**

**125**

**175**

**200**

**50**

**100**

**150**

**AZA**
**Everolimus 1.5 mg**
**Everolimus 3.0 mg**
**Censored**

***P *****= 0.078, 1.5 mg vs AZA**
***P *****= 0.013, 3.0 mg vs AZA**

- qc

## Sensitivity Analysis—Average MIT  for Patients Missing IVUS (Age-matched AZA Outcome Assigned)

| Reason for missing | Treatment | Mean change in average MIT (mm) |  | P value
vs AZA |
| --- | --- | --- | --- | --- |
|  |  | N | Mean |  |
| Any reason | AZA                                                          | 140	0.10 |  |    |
|  | Everolimus 1.5 mg | 137	0.07 |  | 0.010 |
|  | Everolimus 3.0 mg | 142	0.07 |  | 0.011 |
| Renal issue | AZA |   76	0.10 |  |  |
|  | Everolimus 1.5 mg |   85	0.05 |  | 0.027 |
|  | Everolimus 3.0 mg |   81	0.04 |  | 0.007 |
| D/C study med, death, AEs | AZA | 100	0.10 |  |  |
|  | Everolimus 1.5 mg |   95	0.06 |  | 0.015 |
|  | Everolimus 3.0 mg |   99	0.05 |  | 0.002 |

- IVUS back-up - Aug 10th.ppt

**205-21**

**QC**

## Changes in Maximal Intimal Thickness B253 vs 1995 Landmark Prava HTx Trial

**Kobashigawa JA, et al.***** N Engl J Med.***** 1995;333:621-627.**
**Eisen HJ, et al.***** N Engl J Med.***** 2003;349:847-858.**

***P***** = 0.002**

***P***** = 0.01**

## Incidence Rate of Key Safety Events by Everolimus Trough Ranges Up to Event or Day 450Study B253—Safety Population, 12-month Analysis

|  | Patients, % |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | < 3ng/mL | 3 - 8ng/mL | ≥ 8ng/mL | Everolimus1.5 mg + 3.0 mg | AZA |
| Hypertriglyceridemia | 12.3 | 17.5 | 15.5 | 16.2 | 4.7 |
| Thrombocytopenia | 1.5 | 5.8 | 9.6 | 7.4 | 4.2 |
| ThrombocytopeniaWk3-M12 | 0 | 3.0 | 6.1 | 3.3 | 0.9 |
| Leukopenia | 9.7 | 7.1 | 8.7 | 10.0 | 20.1 |
| Hypercholesterolemia | 66.7 | 63.6 | 66.1 | 64.5 | 45.8 |
| High Cr M3-M12 | 50.0 | 43.3 | 47.9 | 45.5 | 23.4 |
| D/C for any reason | 41.3 | 35.8 | 46.0 | 41.0 | 35.0 |
| Overall safety | 12.3 | 19.2 | 20.7 | 18.6 | 5.6 |

- App 4 PTT4.3-6

**259**

**QC**

## Kaplan-Meier Analysis of Time to First MACE From Day 1 to Month 48ITT Population—48-month Analysis

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**180**

**360**

**540**

**720**

**900**

**1080**

**1260**

**1440**

**1620**

**Survival distribution function**

**Kaplan-Meier Analysis of Time to ****First MACE From Day 1 to Month 48****ITT Population—48-month Analysis**

- ac_mace_km2.doc

**187-1**

**Treatment****	****	****                   Patients at risk/censored**
**AZA (n = 214)****	****167/8****	****148/18****	****87/72**
**Everolimus 1.5 mg (n = 209)****	****164/13****	****152/18****	****94/69**
**Everolimus 3.0 mg (n = 211)****	****160/14****	****147/23****	****83/80**

**AZA**

**Everolimus 1.5 mg**

**Everolimus 3.0 mg**

***P***** = 0.537, 1.5 mg vs AZA**

**Time (days)**

***P***** = 0.500, 3.0 mg vs AZA**

- QC

## All MACE: Day 1 to Month 48

|  | Patients, n (%a) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| All MACE (total) |   56 (28.4) | 49 (27.1) |   48 (24.8) |
|        Graft-related |   44 (22.1) | 31 (16.2) |   38 (19.7) |
|        Non-graft related | 16 (8.7) | 22 (13.4) | 12 (6.3) |
|        Fatal | 10 (5.2) | 7 (4.2) |   9 (5.1) |
|        Nonfatal |   52 (26.7) | 44 (24.6) |   41 (20.9) |

**A patient may be counted in more than one row.**
**a**** Kaplan-Meier rate.**
***P***** = NS for all comparisons, based on log-rank test.  **

- qc

## Efficacy-Related EventsEverolimus 1.5 mg and MMFStudies B201/B251/A2306/A2307—12 months

|  | Everolimus 1.5 mg |  |  |  | MMF | MMF |
| --- | --- | --- | --- | --- | --- | --- |
|  | B201n = 194 | B251n = 193 | A2306n = 112 | A2307n = 117 | B201n = 196 | B251n = 196 |
| Primary composite endpoint | 29.9 | 24.9 | 27.7 | 16.2 | 31.1 | 27.6 |
| Biopsy-proven acute rejection | 23.2 | 19.2 | 25.9 | 13.7 | 24.0 | 24.0 |
| Graft loss | 4.6 | 8.8 | 5.4 | 1.7 | 9.2 | 5.1 |
| Death | 5.2 | 3.1 | 0.9 | 0 | 2.6 | 2.0 |
| Lost to follow-up | 0.5 | 0.5 | 0 | 0.9 | 0.5 | 0.5 |

- 278dv

- NDA 21-560 T1; NDAN Amendment Final SU T2-1

## Reduction of ≥ 50% in CsA Is Associated With Stabilization of Renal Function (CrCl)

**AZA**
**n = 71**

**Everolimus 1.5 mg**
**n = 68**

**Everolimus 3.0 mg**
**n = 63**

**Post-CsA reduction**

**Pre-CsA reduction**

**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).**

- qc

## RAD2411—CsA C0 Target Blood Levels

**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**

- qc

## DispositionStudy B253—6 months

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Discontinued study medication | 42 (19.6) | 46 (22.0) | 61 (28.9) |
| Discontinued study | 13 (6.1) | 15 (7.2) | 15 (7.1) |

## K-M Estimate of Time of Discontinuation of Study Medication at 12 months Study 253—ITT Population, 12-month Analysis

**K-M Estimate of Time of Discontinuation of Study Medication at 12 months**** ****Study 253—ITT Population, 12-month Analysis**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Days from first dose to event**

**0**

**100**

**300**

**500**

**200**

**400**

**AZA**
**Everolimus 1.5 mg**
**Everolimus 3.0 mg**
**Censored**

- qc

## Everolimus B253 Biopsy Compliance

|  | Patients, n |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Day |  |  | Month |  |  |  |  |  |  |
| Treatment group | 7 | 14 | 28 | 2 | 3 | 6 | 9 | 12 | 18 | 24 |
| Evaluable patientsa |  |  |  |  |  |  |  |  |  |  |
| 	AZA | 213 | 212 | 211 | 208 | 205 | 201 | 200 | 198 | 192 | 186 |
| 	Everolimus 1.5 mg | 208 | 205 | 204 | 200 | 198 | 197 | 194 | 192 | 190 | 188 |
| 	Everolimus 3.0 mg | 211 | 211 | 209 | 204 | 202 | 200 | 195 | 190 | 187 | 181 |
| Patients without biopsy |  |  |  |  |  |  |  |  |  |  |
| 	AZA | 33 | 12 | 11 | 21 | 14 | 22 | 35 | 42 | 57 | 75 |
| 	Everolimus 1.5 mg | 22 | 13 | 13 | 18 | 14 | 22 | 41 | 44 | 58 | 73 |
| 	Everolimus 3.0 mg | 17 | 14 | 15 | 25 | 25 | 37 | 47 | 50 | 74 | 85 |

**a Evaluable patients are all patients with functioning graft.**
**Patients who reached endpoint based on results of biopsy are not counted.**

- email 10/11/0 Protocol CRAD001 B253

- 250

## Cyclosporine Whole Blood Trough Level (ng/mL) During Visit WindowDHZB Series vs Dosing in Study B253

- Everolimus data collection Table 4.1

- 248-5

**Dr. Hans Lehmkuhl, personal communication.**

**Everolimus 1.5 mg (B253)**

**DHZB series**

## Serum Creatinine (Change From Baseline)DHZB Series

**n = **

**35**

**35**

**35**

**35**

**35**

**30**

**19**

**11**

- Everolimus data collection Table 6.1

- 248-8

**Dr. Hans Lehmkuhl, personal communication.**

## Efficacy 6 months Follow-upDHZB Series

**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

- 248-14

|  | Study B253 patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus  |  |
| Parameter | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Biopsy-proven acute rejection ≥ grade 3A |   89 (41.6) |       58 (27.8)*,+ |      40 (19.0)** |

********P***** = 0.003 vs AZA; *******P***** < 0.001 vs AZA; ****+*****P *****< 0.05 everolimus 1.5 mg vs everolimus 3.0 mg**

## Baseline Renal Function and Creatinine Clearance of < 29 mL/min at 12 monthsStudy B253

**Baseline Renal Function and Creatinine Clearance of < 29 mL/min at 12 months****Study B253**

**0**

**100**

**200**

**300**

**400**

**500**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Time posttransplant (days)**

**1st quartile**
**2nd quartile**
**3rd quartile**
**4th quartile**
**Censored**

**Excludes patients with CrCl at baseline < 29 mL/min.**

***P *****< 0.0001 by log-rank test**

- DV - New slides.doc from Kevin Mange 11-02-05

**268-3**

- qc

## Baseline Renal Function and Primary EfficacyStudy B253

**Baseline Renal Function and ****Primary Efficacy****Study B253**

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Time posttransplant (days)**

**Excludes patients with CrCl at baseline < 29 mL/min.**

***P *****= 0.38 by log-rank test**

- DV - New slides.doc from Kevin Mange 11-02-05

**268-2**

**1st quartile**
**2nd quartile**
**3rd quartile**
**4th quartile**
**Censored**

- qc

## Baseline Renal Function and Creatinine Clearance < 29 mL/min at 12 monthsStudy B253—Everolimus 1.5 mg

**Baseline Renal Function and Creatinine Clearance < 29 mL/min at 12 months****Study B253—Everolimus 1.5 mg**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Time posttransplant (days)**

**268-7**

**0**

**100**

**200**

**300**

**400**

**500**

**Excludes patients with CrCl at baseline < 29 mL/min.**

- ac_risk_RF_km1

- DV - New slides.doc from Kevin Mange 11-02-05

**1st quartile**
**2nd quartile**
**3rd quartile**
**4th quartile**
**Censored**

- qc

## Baseline Renal Function and Creatinine Clearance < 29 mL/min at 12 monthsStudy 253—AZA

**Baseline Renal Function and Creatinine Clearance < 29 mL/min at 12 months****Study 253—AZA**

**0**

**0.25**

**0.50**

**0.75**

**1.00**

**Survival distribution**

**Time posttransplant (days)**

**268-6**

**0**

**100**

**200**

**300**

**400**

**500**

**Excludes patients with CrCl at baseline < 29 mL/min.**

- ac_risk_RF_km1

- DV - New slides.doc from Kevin Mange 11-02-05

- qc