# Presentation: 690125

## EverolimusSafety of Everolimus

**Kenneth Somberg, MD**
**Vice President and Global Head****Clinical Research and Development****Transplantation and Immunology****Novartis Pharmaceuticals**

## Agenda

**Patient disposition**
**Deaths, SAEs, and discontinuations**
**AEs—12-month blinded period emphasized**
**Overall AEs**
**Infections**
**Malignancies**
**Other**
**Laboratory assessments**
**Hematologic**
**Lipids**
**Renal**

## Patient Disposition Study B253—ITT Population, 12-month Analysisa

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
| Patient disposition | AZA n = 214 | 1.5 mg n = 209 | 3.0 mg n = 211 |
| Discontinued treatment prior to 12 monthsa | 61 (28.5) | 62 (29.7) | 84 (39.8) |
| 	Adverse event(s) | 28 (13.1) | 33 (15.8) | 46 (21.8) |
| 	Unsatisfactory therapeutic effect | 15 (7.0) | 14 (6.7) | 2 (0.9) |
| 	Death | 5 (2.3) | 5 (2.4) | 8 (3.8) |
|    Otherb | 13 (6.1) | 10 (4.8) | 28 (13.3) |
| Discontinued study prior to 12 monthsa | 21 (9.8) | 19 (9.1) | 24 (11.4) |

**a**** Time window for 12-month visit was Days 312 to 450.**
**b**** Abnormal laboratory values and test procedure results, protocol violations, lost to follow-up, and withdrawn consent.**

**143-16**

## Safety Comparison BetweenStudy B253—ITT Population, 12- and 24-month Analyses

|  | 12 months |  |  | 24 months |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Everolimus |  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Death, % |   8.4 |   9.1 | 11.4 | 11.2 | 10.0 | 13.7 |
| Nonfatal SAEs, % | 60.3 | 64.6 | 70.6 | 65.4 | 71.8 | 76.8 |
| Discontinuation due to AEs, % | 13.1 | 15.8 | 21.8 | 18.7 | 20.6 | 27.5 |

**QC**

## Primary Causes of Death Study B253—ITT Population, 12-month Analysisa

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209  | 3.0 mgn = 211  |
| Any death | 18 (8.4) | 19 (9.1) | 24 (11.4) |
| Infections |   5 (2.3) |   4 (1.9) | 4 (1.9) |
| Cardiac disease |   2 (0.9) |   3 (1.4) | 3 (1.4) |
| Vascular disease |   3 (1.4) |   1 (0.5) | 4 (1.9) |
| Immune system disorders |   4 (1.9) |   2 (1.0) | 1 (0.5) |
| Multiorgan failure |   1 (0.5) |   2 (1.0) | 3 (1.4) |
| Otherb |   3 (1.4) |   7 (3.3) | 9 (4.3) |

**a**** Cutoff date for all events was day 450.**
**b**** Includes blood, gastrointestinal, nervous system and respiratory disorders, injury and poisoning, neoplasms, and surgical procedures.**

## Cumulative Nonfatal Serious Adverse Events (SAE) in ≥ 3% Study B253—ITT Population, 12-month Analysis

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Any nonfatal SAE | 129 (60.3) | 135 (64.6) | 149 (70.6)* |
| Pericardial effusion | 6 (2.8) | 20 (9.6)* | 16 (7.6)* |
| Cardiac tamponade | 2 (0.9) | 4 (1.9) | 9 (4.3)* |
| Pleural effusion | 2 (0.9) | 3 (1.4) | 9 (4.3)* |
| Cytomegalovirus | 19 (8.9) | 3 (1.4)** | 6 (2.8)* |
| Pneumonia NOS | 5 (2.3) | 13 (6.2) | 14 (6.6)* |
| Anemia NOS | 6 (2.8) | 4 (1.9) | 15 (7.1) |
| Pyrexia | 12 (5.6) | 6 (2.9) | 14 (6.6) |
| Renal impairment NOS | 6 (2.8) | 5 (2.4) | 11 (5.2) |
| Acute renal failure | 9 (4.2) | 10 (4.8) | 9 (4.3) |
| Fluid overload | 6 (2.8) | 6 (2.9) | 7 (3.3) |
| Postoperative wound infection | 5 (2.3) | 7 (3.3) | 4 (1.9) |
| Thrombocytopenia | 0 | 3 (1.4) | 7 (3.3)* |
| Back pain | 0 | 0 | 7 (3.3)* |

********P***** < 0.05 vs AZA; *******P***** < 0.001 vs AZA**

**CSR B253 T 10-7; PYY 10.2-1b**

## InfectionsStudy B253—ITT Population, 12-month Analysis

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209  | 3.0 mgn = 211 |
| Viral | 31.3 | 14.8* | 17.1* |
|    CMV | 21.5 |     7.7* |     7.6* |
| Bacterial | 24.8 |   33.0* |   37.9* |
| Fungal |   8.9 |   7.7 | 11.4 |

**143-30**

********P***** ****< 0.05 vs AZA**

**QC**

## Incidence Rate of Pneumonia by Type of OrganismStudy B253—12-month Analysis

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Any pneumonia event | 13 | 36 | 37 |
| Organism identified | 10 (4.6) | 15 (7.1) | 19 (9.0) |
| Bacterial | 6 (2.8) | 11 (5.2) | 13 (6.1) |
| Viral | 2 (0.9) | 0 | 0 |
| Fungal | 0 | 3 (1.4) | 2 (0.9) |
| PCP | 1 (0.5) | 1 (0.5) | 2 (0.9) |
| Other | 1 (0.5) | 0 | 2 (0.9) |
| No organism identified | 3 (1.4) | 21 (10.0) | 18 (8.5) |
| Discontinuations | 2 (0.9) | 1 (0.5) | 4 (1.8) |
| Death | 0 | 0 | 2 (0.9) |

- ac_pneumoniaa3.sas 02NOV05  12:51

- qc

## Cumulative Neoplasms Study B253—ITT Population, 12-month Analysis

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209  | 3.0 mgn = 211 |
| Malignant | 7 (3.3) | 14 (6.7) | 8 (3.8) |
| 	Posttransplant 	lymphoproliferative disease | 3 (1.4) | 3 (1.4) | 4 (1.9) |
| 	Skin | 1 (0.5) | 9 (4.3) | 3 (1.4) |
| 	Prostate cancer | 3 (1.4) | 2 (1.0) | 0 |
| 	Cervical adenocarcinoma | 0 | 0 | 1 (0.5) |
| Benign | 4 (1.9) | 3 (1.4) | 5 (2.4) |

## Cumulative Wound Complications Study B253—ITT Population, 12-month Analysis

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Lymphocele | 2 (0.9) |  10 (4.8)* |      9 (4.3)* |
| Wound dehiscence | 1 (0.5) |   4 (1.9) |   4 (1.9) |
| Wound drainage | 0 | 0 |   4 (1.9) |
| Incisional hernia | 4 (1.9) | 18 (8.6)* | 8 (3.8) |

**150**

********P***** < 0.05**

## Hematologic Abnormalities Based on Notable RangesStudy B253—12-month Analysis

|  |  |  |  | Everolimus |  |
| --- | --- | --- | --- | --- | --- |
| Laboratory test  | Notable (abnormal) values  |  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| Hemoglobin  | Low | < 7.0 g/dL  |   8 (3.8)  |  6 (2.9)  | 16 (7.7)c  |
| Leukocytes (total)  | Low  | < 2.8 × 109/L  |    43 (20.2) | 16 (7.8)a |  26 (12.4)b  |
|  | High | > 16 × 109/L  |   87 (40.8)  |  71 (34.5)  |  78 (34.5) |
| Neutrophils  | Low  | < 1.5 × 109/L  | 17 (8.0)  |   3 (1.5)a  |    6 (2.9)b  |
| Platelet count  | Low  | Day 1 to 28: ≤ 50 × 109/L  |   9 (4.2)  | 15 (7.3)  | 16 (7.7)  |
|  |  | After Week 4: ≤ 75 × 109/L  |  |  |  |

- Novartis briefing book T 5-10

**a**** Everolimus 1.5 mg vs AZA; ****b**** Everolimus** **3.0 mg vs AZA; and ****c**** Everolimus** **1.5 mg vs Everolimus** **3.0 mg (*****P***** < 0.05, based on 95% binomial confidence intervals). **

**QC**

## TriglyceridesStudy B253—ITT Population, 12- and 24-month Analyses

**Baseline**

**Month 12**

**Month 24**

**AZA, n****	****210****	****151****	****114**
**Everolimus 1.5 mg, n****	****202****	****140****	****103**
**Everolimus 3.0 mg, n****	****209****	****132****	****96**

********P***** < 0.001 vs AZA**
**Error bars = Standard deviation. On-treatment analysis.**

**PTT 10.3-1b**

*****

*****

*****

*****

## Total, LDL, and HDL CholesterolStudy B253—ITT Population, 12- and 24-month Analyses

**Baseline**

**Month 12**

**Month 24**

**AZA, n****	****210****	****151****	****114**
**Everolimus 1.5 mg, n****	****202****	****140****	****103**
**Everolimus 3.0 mg, n****	****209****	****132****	****96**

********P***** < 0.005 vs AZA**
**Error bars = Standard deviation. On-treatment analysis.**

**PTT 10.3-1b**

*****

*****

*****

*****

**Total**

**LDL**

**HDL**

## MACE SummaryStudy B253—Month 1 to 48 

|  | Patients, n (%)a |  |  |
| --- | --- | --- | --- |
|  |  | Everolimus |  |
|  | AZAn = 214 | 1.5 mgn = 209 | 3.0 mgn = 211 |
| All MACE (total) |   43 (22.8) | 32 (19.3) | 32 (17.5) |
|        Graft-related |   33 (17.4) |  19 (10.4)* | 25 (13.6) |
|        Non–graft-related | 14 (7.8) | 15 (10.2) | 8 (4.4) |
|        Fatal | 10 (5.2) | 6 (3.7) | 7 (4.2) |
|        Nonfatal |   39 (21.1) | 27 (16.6) | 26 (14.0) |

**A patient may be counted in more than one row.**
**a**** Percent based on Kaplan-Meier rate. **
********P***** = 0.052 based on log-rank test**

## Summary of Safety

**Incidence of AEs and SAEs were similar between 1.5 mg everolimus and AZA groups but higher with 3.0 mg everolimus compared with AZA **
**Everolimus is associated with**
**Significantly lower incidence of CMV infections**
**Higher incidence of bacterial infections **
**The incidence of malignancy was similar across all groups**

**NS151**

## Summary of Safety

**Similar changes in LDL cholesterol and HDL cholesterol were observed in all arms, but higher triglyceride levels were observed in the everolimus arms**
**Fewer adverse events for MACE among everolimus-treated patients**

**NS151**