Everolimus Renal Safety and Efficacy Extrapolations, Dose Recommendations

1
EverolimusRenal Safety and Efficacy
Extrapolations,Dose Recommendations

• Lawrence Hunsicker, MD
• Professor of Medicine and Medical Director of
  Organ TransplantationCarver College of Medicine
  at the University of Iowa

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

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
• 135 ng/mL for month 4 - 6
• 100 ng/mL beyond month 6

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

5
Mean Creatinine Clearance (Cockcroft-Gault) Over
Time24 MonthsStudy B253
Data from PTT 10.3-1b 24 months









BL
12
24
1
3
6
AZA, n Everolimus 1.5 mg, n Everolimus 3.0 mg, n
122 116 100
205 194 206
152 140 132
201 193 190
166 169 153
167 156 152
P 6
Renal Function12 monthsStudy B253
CS-20
P 7
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

8
Absence of Renal Toxicity of Everolimus
MonotherapyStudy 2201Rheumatoid Arthritis
209-1
Slide set CPOs.ppt s32
9
Design of Kidney Transplant Studies Studies
B201, B251, A2306, A2307
101-2
ns from CSRs
B201, B251
Everolimus 1.5 mg (B201 n 194 B251 n 193)
(Standard CsA)
Everolimus 3.0 mg (B201 n 198 B251 n 194)
48 hrs
MMF 2 g (B201 n 196 B251 n 196)
A2306, A2307a
Everolimus 1.5 mg/d (2306 n 112 2307 n
117)
(Reduced CsA)
24 hrs
Everolimus 3.0 mg/d (2306 n 125 2307 n
139)
Wk 1 - 4
Baseline
Week 5 - 12
Month 4 - 12
a With IL-2R monoclonal antibody.
10
Mean CsA Trough Levels and Creatinine Clearance
With Conventional or Reduced-Dose CsA Studies
B201, B251, A2306, A2307aITT 12-month Analysis
a With IL-2R monoclonal antibody.
11
Heart Study B253Creatinine Clearance Decrease
30 After Month 1 by CsA and Everolimus
Concentrationa
265-3
DV - AC B253 PKPD draft2.doc
CsA exposure (ng/mL)
a Time-weighted average trough until event or
censoring.
12
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

13
BPAR ISHLT Grade 3A Rates vs Everolimus
ExposureStudy B253
104-6
BPAR rates by average everolimus trough levelto
event or day 450
a At 12 months.
14
Percent of Patients Free of BPAR ISHLT Grade
3A Based on Everolimus Exposure Study B253Day 1
to 225
104-9
100
80
60
Patients free of acute rejection,
Everolimus trough levels 8 ng/mL 3 - 8
ng/mL 40
20
0
0
25
50
75
100
125
150
175
200
225
Time after transplantation (days)
Log-rank Mean exposure statistically differentfrom 3 to 8 or 8 ng/mL
(P 15
BPAR ISHLT Grade 3A Acute Rejection by CsA and
Everolimus ConcentrationaStudy B253Days 15 -
225
265-4
DV - AC B253 PKPD draft2.doc
CsA exposure (ng/mL)
a Time-weighted average trough until event or
censoring.
16
Rejection by CsA Exposure QuartileDay 1 to Month
1Study B253
Novartis Briefing Book Table 4-11
AZA
3.0 mg
1.5 mg
Quartiles based on CsA exposure
17
Rejection by CsA Exposure QuartileMonths 2 to
3Study B253
Novartis Briefing Book Table 4-11
AZA
3.0 mg
1.5 mg
Quartiles based on CsA exposure
18
Rejection by CsA Exposure QuartileMonths 4 to
6Study B253
Novartis Briefing Book Table 4-12
AZA
3.0 mg
1.5 mg
Quartiles based on CsA exposure
19
Rejection by CsA Exposure QuartileMonths 7 to
12Study B253
Novartis Briefing Book Table 4-13
AZA
3.0 mg
1.5 mg
Quartiles based on CsA exposure
20
Rejection by CsA Exposure QuartileEverolimus 1.5
mg Over Months 2 to 12Study B253
225-1
ac_ci12_rev.rtf
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
151
126
95
232
270
354
186
229
294
149
192
244
Median CsA trough levels(ng/mL)
21
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

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

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

24
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

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

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
• 175 ng/mL for month 2 - 3
• 135 ng/mL for month 4 - 6
• 100 ng/mL beyond month 6