Minimizing the risk of chronic allograft dysfunction main challenge in planning the immunosuppresive

1
Minimizing the risk of chronic allograft
dysfunction main challenge in planning the
immunosuppresive regimen post renal
transplantation

• Erich Pohanka
• Akh Linz, Austria

2
CAN is a leading cause for renal transplant
graft failure
Death or graft failure ()
50
40
30
20
10
0
CAN
Death with functioning graft
Recurrent primary disease
Acute rejection
Hyperacuterejection
Vascular
Technical problems
Non-compliance
Other
2
Campbell S et al. ANZdata Registry 2007
3
Causes of graft loss in kidney transplantation

• Death with functioning graft
• CV disease
• Malignancy
• CAN / IFTA
• CNI nephrotoxicity
• Infections
• Smooth muscle proliferation

3
CAN, chronic allograft nephropathy IFTA,
interstitial fibrosis and tubular atrophy CV,
cardiovascular
4
CAN / IFTA a non-specific descriptive entity
defined by pathology
GBM double contours
Interstitial fibrosis and tubular atrophy
Arteriolar hyalinosis
Arteriolosclerosis
4
CAN, chronic allograft nephropathy IFTA,
interstitial fibrosis and tubular atrophy GBM,
glomerular basement membrane
Fletcher JT et al. Pediatric Nephrol
200924146571
5
Multiple factors contribute to early CAN / IFTA
Allo-immunity
CNI toxicity
Donor factors
Polyoma-virus CMV
Interstitial fibrosisandtubular atrophy
I/R-injury
Hypertension
Recurrent disease
Chronic obstruction
De novo DM
CAN, chronic allograft nephropathy IFTA,
interstitial fibrosis and tubular atrophy CNI,
calcineurin inhibitor CMV, cytomegalovirus
I/R, ischaemia / reperfusion DM, diabetes
mellitus
5
6
Choice of immunosuppressant can influence
long-term outcomes
Drug
Long-term outcomes
Efficacy
Prevention of AR
Cancer
CVD
CAN


Prednisolone CNIs Everolimus / sirolimus MPA

6
CNI, calcineurin inhibitor MPA, mycophenolic
acid AR, acute rejection CAN, chronic
allograft nephropathy CVD, cardiovascular disease
7
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
7
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
8
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
8
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
9
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
9
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
10
Target CsA levels (ng/mL) in early everolimus
trials
C0 C0 C2 C2 C0 C0 C2
standard low
Everolimus B156 A2306 A2307 MMF B201 B25
1 M02ART
Month 412 125250 50100 350450 350450 100
300 1003006001000
Month 3 125250 50100 550650 350450 10030
0 10030012001400
Month 1 150300 75125 10001400 500700 150
400 200350 16002000
10
aTarget C0 starting Month 6, 50100 ng/mL for
Months 4 and 5CsA, cyclosporin MMF,
mycophenolate mofetil
11
Everolimus with CsA minimisation provides similar
efficacy when compared with standard CsA
Study B156 12-month efficacy
Efficacy failure ( patients)
BPAR( patients)
Creatinine clearance (mL/min)
p0.012
p0.007
StandardCsA
LowCsA
StandardCsA
LowCsA
StandardCsA
LowCsA
Data from 1 year post-transplant. Efficacy
failure acute rejection, death, graft loss or
loss to follow-up
11
Nashan B et al. Transplantation 200478133240
CsA, cyclosporin BPAR, biopsy-proven acute
rejection
12
A2309 investigating the potential of everolimus
for CNI minimisation
Randomisation 1st dose of study drug (Day 1)
Everolimus 1.5 mg/day (C0 38 ng/mL) low CsA,
n277
CsA C0 100200 ng/mL
CsA C075150 ng/mL
CsA C050100 ng/mL
CsA C02550 ng/mL
Transplant surgery Basiliximab steroids
Everolimus 3.0 mg/day (C0612 ng/mL) low CsA,
n279
lt24 h
CsA C0100200 ng/mL
CsA C075150 ng/mL
CsA C050100 ng/mL
CsA C02550 ng/mL
MPA 1440 g/day standard CsA, n277
CsA C0200300 ng/mL
CsA C0 100250 ng/mL
Time (months)post-transplantation
Month 24
Day 5
Month 4
Month 2
Month 6
Month 12 Primary analysis
All patients were administered basiliximab
within 2 hours pre-transplantation and 4 days
thereafter. Oral steroids administered
according to local practice throughout the
trialFrom Day 5 onwards, CsA (microemulsion)
dose adjustments were made based on CsA C0
12
CNI, calcineurin inhibitor CsA, cyclosporin
MPA, mycophenolic acid
13
ASSET (study A2426) investigating the potential
of everolimus for minimising tacrolimus
Transplant Day 0
1st dose of everolimuslt24 hours
Very low tacrolimus
Everolimus (target C0 38 ng/mL) tacrolimus
(target C0 1.53.0 ng/mL) steroids
IL2RA
Low tacrolimus
Everolimus (target C0 38 ng/mL) tacrolimus
(target C0 47 ng/mL) steroids
Month 12
Month 3
Day 1
13
IL2RA, interleukin 2 receptor antagonist bid,
twice a day
14
ASSET everolimus facilitates tacrolimus
minimisation1
ASSET tacrolimus C0 levels
Tacrolimus C0 (ng/mL)
16
Very low tacrolimus (n109)Low tacrolimus (n119)
14
12
10
8
6
4
2
0
Month 3
Month 4
Month 6
Month 9
Month 12
Time
Tacrolimus C0 levels were 50 lower than in the
Symphony study at 12 months2
14
1. Vitko S et al. Presentation at ESOT 2009 2.
Ekberg H et al. N Engl J Med 2007357256275
Safety population
15
Everolimus and very low tacrolimus had clinically
meaningful improvement in renal function
ASSET cGFR over 12 months
Very low tacrolimus (n92)Low tacrolimus (n105)
cGFR (MDRD formula)(mL/min/ 1.73m2)
90
80
p0.362
p0.150
p0.236
p0.081
p0.008
p0.029
70
60
50
40
? 5.34
30
20
10
0
3
4
6
9
12
Time (months)
1-sided a level 0.025 cGFR, calculated
glomerular filtration rate MDRD, modification
of diet in renal disease
15
Vitko S et al. Presentation at ESOT 2009
16
ASSET everolimus with very low tacrolimus
demonstrated no compromise in efficacy
No. of patients who have not experienced any of
the efficacy events nor been censored for any of
the efficacy events at the beginning of the
analysis period non-inferiority, upper CI lt8
ap0.0014
16
tac, tacrolimus CI, confidence intervalBPAR,
biopsy-proven acute rejection
Vitko S et al. Presentation at ESOT 2009
17
ASSET everolimus is associated with reduced
incidence of NODM
ASSET incidence of NODM
No. of patients with NODM
ns
8 (8.6)
2 (2.7)
Very low tacrolimus (n75)
Low tacrolimus (n93)
17
Safety populationNODM, new-onset diabetes
mellitus ns, not significant
Vitko S et al. Presentation at ESOT 2009
18
Zeus Study - Design
Month 0 4.5
Stepwise conversion (2 weeks)
Anti IL-2R Cyclosporine EC-MPS CS
Month 4.5
Everolimus EC-MPS CS
Cyclosporine EC-MPS CS
CsA trough level 100-150 ng/ml
Everolimus trough level 6-10 ng/ml
Anti IL-2R Basiliximab, EC-MPS
Enteric-Coated Mycophenolate Sodium, CS
Corticosteroids
19

• Primary Endpoint Renal Function
• Absolute Values at Month 12

plt0,0001
80
10.6 ml/min
60
71.9
GFR Nankivell (ml / min)
61.3
40
20
Cyclosporine Everolimus
n 145
n 155
No significant difference at baseline
20
Secondary Endpoint Treatment Failure
Secondary efficacy variables showed comparable
outcomes for the Everolimus and Cyclosporine
groups at Month 12
21

• Renal Function
• Absolute values at Month 12

plt0,0001
80
60
GFR Nankivell (ml / min)
61.3
71.9
59.8
69.9
40
20
n 145
n 155
n 5
n 15
Patients who suffered from BPAR
All randomized patients
Better renal function in Everolimus patients with
BPAR compared to CsA/EC-MPS control group
22
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
22
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
23
Everolimus with reduced CNIreduced incidence of
CMV infection
Study B201 CMV infection1,2
Incidence()
p0.001
p0.001
EVL lowCsA
MPA standard CsA
EVL lowCsA
MPA standard CsA
12 months
36 months
Infection reported as adverse eventCNI,
calcineurin inhibitor CMV, cytomegalovirus
EVL, everolimus CsA, cyclosporin MMF,
mycophenolate mofetil
23
1. Vitko S et al. Transplantation
200478153240 2. Vitko S et al. Am J
Transplant 20055252130
24
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
24
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
25
Antiproliferative effects of PSIs blocking the
mTOR pathway
Growth factors IGF-1, VEGF, ErbB, IL-2
PTEN
Oxygen, energy and nutrients
mTOR
Ras/Raf pathway kinases
4E-BP1
elF4E
S6
Protein production
IGF-1, insulin-like growth factor 1VEGF,
vascular endothelial growth factorIL-2,
interleukin 2 mTOR, mammalian target of
rapamycineIF4E, eukaryotic translation
initiation factor 4E4E-BP1, eIF4E-binding
protein 1
25
Angiogenesis
Cell growth
Cell division
26
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
26
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
27
Contents

• Everolimus characteristics and mode of action
• Protection against acute rejection
• Maintain efficacy
• Reduce nephrotoxicity CNI minimisation or
  elimination
• Protection against CMV / BKV infection
• Antiproliferative effects
• Effect on CAN
• Potential cardiovascular benefits
• Antitumour effects
• Management of adverse events

27
CNI, calcineurin inhibitor CMV, cytomegalovirus
BKV, BK virus CAN, chronic allograft nephropathy
28
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
28
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
29
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
29
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
30
Antiproliferative effects of everolimusameliorate
chronic allograft nephropathy
Control (28 weeks)
Everolimus (1228 weeks)
Normal glomeruli, mild tubular dilation-atrophy
and normal artery after 28 weeks
Glomerulosclerosis, tubular atrophy, interstitial
fibrosis and vasculopathy (insert) after 28 weeks
30
Preclinical data from transplanted Lewis rats
receiving everolimus (0.5 mg/kg/day) or vehicle
by daily gavage (control)
Lutz J et al. Transplantation 20037650815
31
PSIs antiproliferative effects in stents

• Everolimus eluting stents prevent restenosis of
  the artery following a stent procedure
• Everolimus inhibits in-stent neointimal growth in
  the coronary vessels following stent implantation
  due to its antiproliferative properties

After bioabsorbable everolimus-eluting stent
Before stent
1. Grube E et al. Circulation 200410921682171
2. Tsuchiya Y et al. Am J Cardiol
20069846493. Beijk MA, Piek JJ. Expert Rev
Med Devices 200741121 4. SPIRIT I trial
investigators. Circulation 2005112(Suppl 2)abs
26165. Ormiston JA et al. Catheter Cardiovasc
Interv 20076912831
31
PSI, proliferation signal inhibitor
32
Chronic allograft vasculopathy is a significant
issue in transplantation
12 months
Baseline
Maximal intimal thickness 0.3 mm
Maximal intimal thickness 1.1 mm
32
Eisen HJ et al. N Engl J Med 200334984758
33
Everolimus reduces the incidence of CAV at 12
months in cardiac transplant patients
Study B253 cardiac allograft vasculopathy
Incidenceof CAV ()
100
90
80
p0.045
70
60
52.8
50
35.7
40
30
20
10
0
Azathioprine standard CsA
Everolimus low CsA
33
CAV, cardiac allograft vasculopathy CsA,
cyclosporin
Eisen HJ et al. N Engl J Med 200334984758
34
Everolimus significantly reduces coronary-artery
intimal proliferation in cardiac transplant
recipients
Study B253 change in maximal intimal thickness
Azathioprine standard CsA
Everolimus1.5 mg/day standard CsA
Everolimus3.0 mg/day standard CsA
Mean (standard deviation) change in maximal
intimal thickness from baseline to 12 monthsCsA,
cyclosporin
34
Eisen HJ et al. N Engl J Med 200334984758
35
Everolimus reduces the incidence of MACE 4 years
post-transplant in cardiac transplant recipients
Study B253 incidence of MACE
Incidenceof MACE ()
18
15.28
16
14
12
8.70
10
8.57
8
6
4
2
0
Azathioprine standard CsA
Everolimus1.5 mg/day standard CsA
Everolimus3.0 mg/day standard CsA
35
MACE, major adverse cardiac event CsA,
cyclosporin
Eisen HJ. Nephrol Dial Transplant 200621(Suppl
3)iii9iii13
36
Proliferation Signal Inhibitors qualities to
improve long-term outcomes
CNI minimisation or elimination prevents
nephrotoxicity
PSI
Protects against opportunistic CMV infection
36
CNI, calcineurin inhibitor CMV,
cytomegalovirus PSI, proliferation signal
inhibitor
37

Inhibition of endothelial and cancer
cellproliferation by PSI
38
Stallone et al. NEJM, 2005
39
Everolimus is an approved treatment for
metastatic renal cell carcinoma RECORD study
Everolimus (n272)
Probability()
100
Placebo (n138)
Log-rank plt0.001
80
Hazard ratio 0.30 95 CI 0.22,
0.40 Progression-free survival Everolimus
median 4.0 months Placebo median 1.9 months
60
40
20
0
12
10
8
6
4
2
0
Months
Everolimus doubles progression-free survival
39
CI, confidence interval
Motzer R et al. Lancet 200837244956
40
Reduced incidence of de novo malignancies
withmTORi / PSIs compared with CNI-containing
regimens
ap0.041 for de novo malignancies and p0.011
forde novo non-skin solid malignancies vs CsA /
Tac alone bplt0.0001 for de novo malignancies and
p0.0125 forde novo non-skin solid malignancies
vs CsA / Tac alone mTORi, mammalian target of
rapamycin inhibitor PSI, proliferation signal
inhibitor CNI, calcineurin inhibitor CsA,
cyclosporin Tac, tacrolimus
40
Kauffman H et al. Transplantation 20058088389
41
Conclusions PSIs are a multifaceted approach to
help improve long-term outcomes
Proliferation Signal Inhibitors
41
CNI, calcineurin inhibitor CMV, cytomegalovirus
42
Overview of PSI adverse events
Most adverse events can be managed with adequate
dose interventions
42
ARB, angiotensin receptor blocker
Pascual J. Transplant Rev 2006201-18
43
Time points for initiating PSIs
De novo
Late conversion
Early conversion
Month 1
Month 26
gt6 months
Time post-transplantation
43
PSI, proliferation signal inhibitor
44
Lessons learned from late conversion the
sirolimus renal conversion trial (CONVERT)
Group 1 Conversion to sirolimus within 24 h of
randomisation (n555)
Transplant surgery6120 monthsprior
to randomisation
CsA / Tac MMF / Aza steroids for at least 12
weeks prior to randomisation
Group 2 Continuation ofCNI-based regimen (n275)
Duration of study (months)
0
48
21 randomisation in groups 1 and 2
44
CsA, cyclosporin Tac, tacrolimus MMF,
mycophenolate mofetil Aza, azathioprine CNI,
calcineurin inhibitor
Schena F et al. Transplantation 20098723342
45
CONVERT trial GFR improves after conversion to
PSI only in patients with good renal function
All patients with baseline gt40 mL/min
GFR(mL/min)
100
80
p0.056
p0.006
plt0.001
p0.009
64.7
63.6
63.4
61.7
62.6
61.3
61.9
61.1
61.2
59.9
60
40
20
0
Baseline
Month 6
Month 12
Month 18
Month 24

• Values adjusted for baseline by analysis of
  covariance
• GFR, glomerular filtration rate PSI,
  proliferation signal inhibitor, CNI, calcineurin
  inhibitor

45
Schena F et al. Transplantation 20098723342
46
CAN / IFTA develops frequently and early after
renal transplantation
100
Patients
75
50
Grade I Grade II Grade III
25
0
0
2
4
6
8
10
Years after transplantation
0 (120)
78 (114)
56 (92)
34 (70)
20 (48)
16 (29)
No. ofpatients
90 of patients have grade 1 CAN in year 1
46
CAN, chronic allograft nephropathy IFTA,
interstitial fibrosis and tubular atrophy
Nankivell BJ et al. N Engl J Med 2003349232633
47
Measures for early detection of CAN

• All renal transplant recipients
• Patients at a high risk

Monitor every month during the first year
post-transplant, then 3 monthly

Absolute serum creatinine Change of serum
creatinine () Estimated GFR Slope of change of
calculated GFR Slope of 1/serum creatinine Other
indications of renal change Proteinurie Deteriorat
ion of blood pressure
Gold standard used in research protocols
Measured GFR Protocol biopsy
Recognise the clinical syndrome
Recurrent glomerulonephritis Renal artery
stenosis Ureteric obstruction BK virus nephropathy
Test new non-interventional tests
Ultrasound biopsy
Histology physiology
Other causes
CAN (tubular atrophy interstitial
fibrosis) OR CAN CNI nephrotoxicity CAN
transplant vasculopathy CAN sub-clinical
rejection CAN chronic antibody-mediated
rejection (including CTG, DSAb, C4d)
Test novel interventional strategies
THERAPEUTIC INTERVENTION
JM Campistol et al Clin Transplant 200923769
48
Suspicion of CAN/IFTA by Monitoring

• Absolute serum creatinine
• gt 1,8 mg/dL (or gt 130 mmol/L)
• Absolute GFR
• lt 50 ml/min
• Change of serum creatinine
• Irreversible rise of 30 at 6 month post
  transplant
• Increase of 0,3 mg/dL (or 20 mmol/L) measured 3 x
  over 3 months
• 15-20 rise over one year
• Change of GFR
• 10 deterioration over 3 months

49
The challenge is to improve long-term graft
survival
49
CNI, calcineurin inhibitor
50
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