cn-1 everolimus renal safety and efficacy extrapolations, dose recommendations lawrence hunsicker,...

CN-1

EverolimusRenal Safety and

Efficacy Extrapolations,Dose Recommendations

Lawrence Hunsicker, MD

Professor of Medicine and Medical Director of Organ Transplantation

Carver College of Medicine at the University of Iowa

CN-2

Overview

Use of everolimus, together with cyclosporine (CsA) in usual doses, is associated with a significant reduction in kidney function

This effect is closely related to the trough (C0) levels of CsA, but unrelated to the levels of everolimus

Use of everolimus with reduced dose CsA results in calculated creatinine clearance similar to those seen in patients treated with full dose CsA and either AZA or MMF

PK/PD analyses demonstrate everolimus and CsA, at reduced dose after the first month, is effective in preventing cardiac rejection

CN-3

Certican® Proposed Dosage and Administration

Everolimus should be used in an initial dose of 1.5 mg per day in 2 divided doses, but dose adjusted to achieve a target trough level of 3 to 8 ng/mL

Recommended target exposure of CsA in thefirst month is 250 to 400 ng/mL

Exposure to CsA beyond Month 1 should be about

– 175 ng/mL for month 2 - 3


– 100 ng/mL beyond month 6

CN-4

Outline

Review of renal safety data from heart study B253

Role of everolimus and CsA

– PK/PD relationships for renal function Efficacy of reduced-dose CsA in cardiac

transplantation

– PK/PD efficacy heart study B253 Conclusions about safety and efficacy Dosing recommendations

CN-5Mean Creatinine Clearance (Cockcroft-Gault) Over Time—24 MonthsStudy B253

0

20

40

60

80

100

Time, months

Cre

atin

ine

clea

ran

ce (

mL

/min

)

AZAEverolimus 1.5 mgEverolimus 3.0 mg

AZA, nEverolimus 1.5 mg, nEverolimus 3.0 mg, n

122116100

205194206

152140132

Data from PTT 10.3-1b 24 months

BL 12 24

201193190

1

166169153

3

167156152

6

*

**

**** * *

*P < 0.001Error bars = Standard deviation.

CN-6

Renal Function—12 monthsStudy B253

Everolimus

AZA 1.5 mg 3.0 mgn = 145 n = 132 n = 129

Creatinine clearance mean (SD) (mL/min)

65.0 (22.89)

51.7 (19.06)*

51.3 (27.65)*

n = 149 n = 137 n = 131

Creatinine mean (SD) (mg/dL)

1.67 (0.55)

2.06 (0.67)*

2.14 (0.95)*

*P < 0.005 vs AZA

CS-20

CN-7

Outline




transplantation


CN-8Absence of Renal Toxicity of Everolimus MonotherapyStudy 2201—Rheumatoid Arthritis

209-1

Parameter (mean)Placebon = 60

Everolimus 6.0 mgn = 61

Creatinine (mg/dL)

Baseline 0.78 0.78

Week 12 0.81 0.77

Week 24 0.72 0.68

Slide set CPOs.ppt s32

CN-9

Design of Kidney Transplant Studies Studies B201, B251, A2306, A2307

≤ 48 hrs

Everolimus 1.5 mg (B201: n = 194; B251: n = 193)

Everolimus 3.0 mg (B201: n = 198; B251: n = 194)

MMF 2 g (B201: n = 196; B251: n = 196)

101-2

≤ 24 hrsEverolimus 1.5 mg/d (2306: n = 112; 2307: n = 117)

Everolimus 3.0 mg/d (2306: n = 125; 2307: n = 139)

Wk 1 - 4Baseline Week 5 - 12 Month 4 - 12

B201, B251

A2306, A2307a

a With IL-2R monoclonal antibody.

n’s from CSRs

(Standard CsA)

(Reduced CsA)

CN-10

a With IL-2R monoclonal antibody.

Mean CsA Trough Levels and Creatinine Clearance With Conventional or Reduced-Dose CsA Studies B201, B251, A2306, A2307a—ITT 12-month Analysis

B201 B251 A2306 A2307CsA trough levels (ng/mL)

6 months

Everolimus 1.5 mg 173 178 82 64Everolimus 3.0 mg 158 175 83 68MMF 2 g 170 178 — —

12 months


Creatinine clearance (mL/min)


CN-11Heart Study B253—Creatinine Clearance Decrease 30% After Month 1 by CsA and Everolimus Concentrationa

0

20

40

60

80

100

Pat

ien

ts (

%)

< 4 4 - 6 6 - 9 ≥ 9

≤ 180

180 - 230

230 - 280≥ 280

Everolimus exposure (ng/mL)CsA exposure

(ng/m

L)

a Time-weighted average trough until event or censoring.

265-3 DV - AC B253 PKPD draft2.doc

CN-12

Outline




transplantation


CN-13BPAR ISHLT Grade ≥ 3A Rates vs Everolimus ExposureStudy B253

46 44

33

19 22 1924 21

15 16

0

20

40

60

80

100

AZAª < 3 3 - 4 4 - 5 5 - 6 6 - 7 7 - 8 8 - 9 9 - 10 > 10Everolimus trough levels, ng/mL

Pa

tie

nts

wit

h B

PA

R ≥

3A

, %

104-6

BPAR rates by average everolimus trough levelto event or day 450

a At 12 months.

CN-14Percent of Patients Free of BPAR ISHLT Grade ≥ 3A Based on Everolimus Exposure Study B253—Day 1 to 225

Log-rank: Mean exposure < 3 ng/mL is statistically differentLog-rank: Mean exposure < 3 ng/mL is statistically differentfrom 3 to 8 or > 8 ng/mL (from 3 to 8 or > 8 ng/mL (PP < 0.001). < 0.001).

104-9

Everolimus trough levels≥ 8 ng/mL3 - 8 ng/mL< 3 ng/mLAZA

Time after transplantation (days)0 25 50 75 100 125 150 175 200 225

0

20

40

60

80

100

Pat

ien

ts f

ree

of

acu

te r

ejec

tio

n,

%

CN-15BPAR ISHLT Grade ≥ 3A Acute Rejection by CsA and Everolimus Concentrationa

Study B253—Days 15 - 225

0

20

40

60

80

100

Fre

qu

ency

of

BP

AR

(%

)

< 3 3 - 6 6 - 9 ≥ 9

≤ 180180 - 220

220 - 270≥ 270

Everolimus exposure (ng/mL) CsA exposure (n

g/mL)

a Time-weighted average trough until event or censoring.

265-4 DV - AC B253 PKPD draft2.doc

CN-16Rejection by CsA Exposure QuartileDay 1 to Month 1Study B253

0

10

20

30

40

BP

AR

≥ IS

HL

T 3

A (

%)

0-25 26-50 51-75 76-100

Novartis Briefing Book Table 4-11

Quartiles based on CsA exposure

1.5 mg

AZA

3.0 mg

CN-17Rejection by CsA Exposure QuartileMonths 2 to 3Study B253

0

10

20

30

40

BP

AR

≥ IS

HL

T 3

A (

%)

0-25 26-50 51-75 76-100



1.5 mg

AZA

3.0 mg


0

10

20

30

40

BP

AR

≥ IS

HL

T 3

A (

%)

0-25 26-50 51-75 76-100


1.5 mg

AZA

3.0 mg


CN-20Rejection by CsA Exposure QuartileEverolimus 1.5 mg Over Months 2 to 12Study B253

2.3

9.1

3.0

9.14.3

0.0

7.0

0.0

12.1

4.5

17.4

5.9

0

10

20

30

40

50

Months 2 to 3 Months 4 to 6 Months 7 to 12

Quartiles

BP

AR

≥ IS

HL

T 3

A (

%)

Quartile 1Quartile 2Quartile 3Quartile 4

225-1 ac_ci12_rev.rtf

151 126 95232 270 354 186 229 294 149 192 244Median CsAtrough levels(ng/mL)

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

CN-21

Outline




transplantation


CN-22

Summary

The combination of everolimus with standard dose CsA is associated with reduced renal function compared with CsA with AZA or MMF

But reduced dose CsA with either dose of everolimus is associated with excellent renal outcomes, similar to those with CsA and either AZA or MMF

The use of everolimus with lower doses of CsA after month 1 is equally effective in preventing cardiac rejection

CN-23

Conclusions

Renal toxicity is primarily associated with blood levels of CsA

Antirejection efficacy is primarily associated with blood levels of everolimus

It is possible to dose these agents so as to avoid renal toxicity and maintain antirejection efficacy

Thus in the hands of transplant experts, use of everolimus as we have recommended is effective in cardiac transplantation and is safe with respect to the effects on the kidneys

CN-24

Outline




transplantation


CN-25

Dose Recommendation for Everolimus

Initial dose of everolimus is 1.5 mg/day We recommend use of everolimus to achieve

trough concentrations of 3 to 8 ng/mL for the entire posttransplant period

As implied above, therapeutic monitoring of everolimus levels is appropriate

CN-26

Dose Recommendation for CsA

Recommended target exposure of CsA in thefirst month is 250 to 400 ng/mL

Exposure to CsA beyond Month 1 should approximate the median of the lowest exposure quartiles observed over time for study B253



– 100 ng/mL beyond month 6

cn-1 everolimus renal safety and efficacy extrapolations, dose recommendations lawrence hunsicker,...

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