# Presentation: 674203

## EverolimusEfficacy Results of Study B253 in De Novo Heart Transplantation 

**Jeffrey Hosenpud, MD**
**Clinical Professor of Medicine****University of Wisconsin**

## Study ObjectivesStudy B253

**Primary objective****To compare efficacy of everolimus 1.5 and ****3.0 mg versus AZA in *****de novo***** heart transplant patients in the first 6 months following heart transplantation**

**108-3**
**QC**

## Primary Efficacy EndpointStudy B253

**Composite efficacy endpoint at 6 months was the freedom from: **
**Biopsy-proven acute rejection ISHLT ****grade ≥ 3A**
**Acute rejection associated with hemodynamic compromise**
**Graft loss/retransplantation**
**Death**
**Lost to follow-up**

**108-48**
**QC**

## ISHLT Grading System for Acute Heart Rejection

| Standardized cardiac biopsy grading |  |
| --- | --- |
| Grade | Histopathologic findings |
| 0 | No rejection |
| 1 (1A or 1B) | A = Focal (perivascular or interstitial) infiltrate without necrosis |
|  | B = Diffuse but sparse infiltrate without necrosis |
| 2 | One focus only with aggressive infiltration and/or focal myocyte damage |
| 3 (3A or 3B) | A = Multifocal aggressive infiltrates and/or myocyte damage |
|  | B = Diffuse inflammatory process with necrosis |
| 4 | Diffuse aggressive polymorphous ± infiltrate ± edema, ± hemorrhage, ± vasculitis, with necrosis |

- ISHLT Website

**Billingham ME, et al. *****J Heart Trans*****. 1990;9:587-593.**

## Secondary Efficacy ObjectivesStudy B253

**Secondary objectives**
**Composite efficacy endpoint at 12 and 24 months**
**Individual components of composite endpoint at 6, 12, and 24 months**
**Allograft vasculopathy at 12 and 24 months as measured by IVUS**

**108-3**

## Study DesignStudy B253

**Transplant****surgery**

**Baseline **

**≤ ****72 hr**

**Everolimus 1.5 mg + CsA + steroids (n = 209)**

**Everolimus 3.0 mg + CsA + steroids (n = 211)**

**AZA 1 - 3 mg/kg/day + CsA + steroids (n = 214)**

**Study phase, 2 years**

**102-7**
**QC**

**Randomization (N = 634)**
**First dose of everolimus**
**Day 1 **

**Scheduled 6-, 12-, and  24-month analyses**

**Randomized, double-blind, double-dummy, 52 centers**
**Everolimus and CsA given twice daily, AZA once daily**
**Renal Amendment: > 85% reached 2-year endpoint**

## Dose Selection of Everolimus and CyclosporineStudy B253

**Everolimus dose was based on **
**Dose finding in kidney studies **
**PK/PD modeling in primates**
**Dose-response relationships for sirolimus in kidney transplantation **
**Cyclosporine trough adjusted by local assay to maintain C****min**** ranges:**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Time (months)**

**250 - 400****ng/mL**

**200 - 350****ng/mL**

**100 - 300 ng/mL**

**QC**

## Protocol Assessments Visit and Biopsy ScheduleStudy B253

**Surveillance endomyocardial biopsies performed at every study visit—consistent with standard of care**
**Additional endomyocardial biopsies for suspected acute rejection **
**Patients who discontinued study medication were  followed up at 3, 6, 12, and 24 months **

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Time (months)**

**QC**

## Efficacy and Safety AnalysesStudy B253

**Efficacy analyses were conducted on all randomized patients**
**Safety analyses were conducted on all randomized patients receiving at least 1 dose of study medication**
**Lab analyses performed while on treatment**

| Analyses | Events up to |
| --- | --- |
| 12-month efficacy  | Day 381  |
| 12-month safety | Day 450 |
| 24-month efficacy and safety | Day 810 |

**QC**

- Pg 34 CSR

## DemographicsStudy B253—ITT Population

|  |  | Everolimus |  |
| --- | --- | --- | --- |
| Recipients | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Age, yr (mean ± SD) | 50.5 ± 11.5 | 51.2 ± 11.2 | 52.1 ± 10.8 |
| Male, n (%) | 182 (85.0) | 166 (79.4) | 171 (81.0) |
| Race |  |  |  |
| 	Black, n (%) | 13 (6.1) | 21 (10.0) | 11 (5.2) |
| CMV, n (%) 	 |  |  |  |
|    Donor+/Recipient– | 37 (17.3) | 36 (17.2) | 48 (22.7) |
| CAD, n (%) at baseline | 68 (31.8) | 78 (37.3) | 84 (39.8) |
| Diabetes, n (%)  | 36 (16.8) | 35 (16.7) | 49 (23.2) |
|  |  |  |  |

**103-6**
**QC**

**No significant differences among treatment groups.**

- PTT 7-4.1 / 7.4-3

## Median Daily Dose of Study Medication Study B253—Day 1 to Month 12

| Medication/treatment group |  |  |
| --- | --- | --- |
|  | n | Median |
| AZA (mg/kg) | 214 | 1.7 |
| Everolimus 1.5 mg | 209 | 1.5 |
| Everolimus 3.0 mg | 211 | 2.8 |

**PTT 8.1-3 B253 CSR 12 mo**

**QC**

## Cyclosporine Trough ConcentrationsaStudy B253 

**a**** Central laboratory measurements.**
**Error bars represent standard deviation.**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Time (months)**

**250 - 400****ng/mL**

**200 - 350****ng/mL**

**100 - 300 ng/mL**

**QC**

**AZA**

**Everolimus 1.5 mg**

**Everolimus 3.0 mg**

**CsA target**

## Standardization of Patient CareStudy B253

|  | Patients, % |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| HMG CoA reductase inhibitor | 89.7 | 90.0 | 90.5 |
| PCP prophylaxis | 91.1 | 85.2 | 89.6 |
| CMV prophylaxis | 66.3 | 62.2 | 64.4 |
| Antihypertensive agent | 97.7 | 98.1 | 97.2 |
| Induction antibody therapy (poly/monoclonal) | 50.9 | 49.8 | 48.3 |

**PTT 8.209 / 8.2-8**

**QC**

## Efficacy Endpointa at 6 months Study B253

***P***** < 0.001**

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

**a**** Biopsy-proven rejection ISHLT grade ≥ 3A or rejection with hemodynamic compromise or graft loss or death or lost to follow-up.**

|  | n | Events | RR |
| --- | --- | --- | --- |
| AZA | 214 | 100 | — |
| Everolimus 1.5 mg | 209 |   76 | 0.778 |
| Everolimus 3.0 mg | 211 |   57 | 0.578 |

**Table 9-1**

**QC**

## Efficacy Related Eventsa at 6 months Study B253

**a**** Not mutually exclusive, except for ‘Lost to follow-up’.**
********P***** = 0.003 vs AZA; *******P***** < 0.001 vs AZA; ****+*****P *****< 0.05 everolimus 1.5 mg vs everolimus 3.0 mg**

**CSR B253 P 14**

|  | 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)** |
| Acute rejection with HDC | 16 (7.5) | 14 (6.7) | 11 (5.2) |
| Graft loss |   6 (2.8) |   4 (1.9) |   8 (3.8) |
| Death | 12 (5.6) | 13 (6.2) | 14 (6.6) |
| Lost to follow-up |   1 (0.5) | 0 | 0 |

**DV**

## Efficacy Endpointa at 12 and 24 months Study B253

**n = 209**

**n = 214**

**n = 211**

***P***** < 0.001**

***P***** = 0.02**

**12 months**

**a Biopsy-proven rejection ISHLT grade ≥ 3A or rejection with hemodynamic compromise or graft loss or death or lost to follow-up (2 patients).**

**n = 209**

**n = 214**

**n = 211**

***P***** < 0.001**

***P***** = 0.016**

**24 months**

**DV**

## Freedom From Efficacy Failure Through 24 monthsStudy B253—Kaplan-Meier Analysis

**Freedom From Efficacy Failure ****Through 24 months****Study B253—Kaplan-Meier Analysis**

**Study duration (days)**

**100**

**90**

**80**

**70**

**60**

**50**

**40**

**Estimate (%)**

**0**

**90**

**180**

**270**

**360**

**450**

**540**

**630**

**720**

**810**

**3.0 mg vs AZA:****	****HR = 0.53, *****P***** < 0.0001**
**1.5 mg vs AZA:****	****HR = 0.73, *****P***** = 0.021**
**3.0 mg vs 1.5 mg:****	****HR = 0.729, *****P *****= 0.0395**

**QC**

**Everolimus 1.5 mg (n = 209)**

**Everolimus 3.0 mg (n = 211)**

**AZA (n = 214)**

## Survival* Through 24 monthsStudy B253—Kaplan-Meier Analysis

**60**

**40**

**0**

**20**

**80**

**90**

**50**

**30**

**10**

**70**

**Survival* Through 24 months****Study B253—Kaplan-Meier Analysis**

**Study duration (days)**

**95% CIs and number of patients at risk shown at 3, 6, 12, and 24 months.*****Freedom from graft loss/death/lost to follow-up through 24 months.**

**0**

**90**

**180**

**270**

**360**

**450**

**540**

**630**

**720**

**810**

**Estimate (%)**

**QC**

**Everolimus 1.5 mg (n = 209)**

**AZA (n = 214)**

**Everolimus 3.0 mg (n = 211)**

## ConclusionsStudy B253

**Study B253 is the first blinded, randomized clinical trial in heart transplantation to show a significant efficacy benefit for a new immunosuppressive agent**
**Everolimus, as part of an immunosuppressive regimen in heart transplantation, significantly reduces acute rejection**
**Efficacy benefit persists to 24 months posttransplant**
**No survival differences between treatment arms**

**QC**