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Calcineurin Inhibitors in Kidney Transplantation: Friend of Foe? Michael Casey, MD Sept 16, 2011

Introduction • Calcineurin Inhibitors (CNIs) have been a hotly debated subject for over two decades. • Despite excellent short-term outcomes, longterm outcomes have been disappointing.

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Deceased and Living Donor Renal Graft Survival 16 14

Half-Life (Years)

12 10 8 6 4 2 0 1989

1991

1993

1995

1997

1999

2001

2003

2005

Transplant Year DDTx

LDTx

Adapted from Lodhi et al. Nephrol Dial Transplant. 2011 Jan;26(1):15-7.

Deceased Donor Kidney Transplant Attrition Rates 20

% Attrition

16

12

8

4

0 1989

1994

1999

2004

2009

Transplant Year 0-1 Year

1-3 Years

3-5 Years

5-10 Years

Adapted from Lamb et al. Am J Transplant. 2011 Mar;11(3):450-62.

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What role CNIs play in modern kidney transplantation? • Many clinicians are left bewildered by the numerous studies, sheer amount of data, and ambiguous results. • We will review the key studies to hopefully answer that burning question…

Calcineurin Inhibitors… Friend

Or Foe?

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A Brief History • Early 1970s—Cyclosporine (CSA) was isolated from a soil fungus

Tolypocladium inflatum

Hodge Lab of Systemic Mycology. Viewed 9/12/11. www.plantpath.cornell.edu/labs/hodge/G-tolypocladium.html

A Brief History • Late 1970s—earliest clinical experiences1,2 with CSA reported in a handful of patients – lower rejection rates – better graft survival

1. Calne et al. Lancet. 1978;2:1323-1327. 2. Calne et al. Lancet. 1979;2:1033-1036.

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Improved 1-Year Allograft Survival in CyclosporineTreated Deceased-Donor Kidney Transplant Recipients

Data from Starzl TE, et al. Surg Gynecol Obstet. 1981;153:486-494.

A Brief History • Early 1980s—multicenter RCTs showed better graft survival at 1 year with CSA based regimens1,2 • 1983—the FDA approved CSA

1. Cyclosporin a as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Preliminary results of a European multicentre trial. Lancet. 1982;2:57-60. 2. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med. 1983;309:809-815.

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Nephrotoxicity • Graft survival stagnated which raised concerns that CNI toxicity may limit long-term outcomes

Gaston R S CJASN 2009;4:2029-2034

Prevalence of CNI-induced Nephrotoxicity

Nankivell et al. N Engl J Med. 2003;349:2326-2333.

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Efficacy • Three CNI-sparing strategies: 1. CNI withdrawal 2. CNI avoidance 3. CNI minimization

CNI Withdrawal • Definition: CNI withdrawal eliminates CNIs from recipients who have already been transplanted. • This strategy can be subdivided by – Type of immunosuppression regimen – Timing of CNI withdrawal (early or late)

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Early CNI Withdrawal with Sirolimus • The Rapamune Maintenance Regimen study1 looked at early CSA withdrawal • Despite a higher biopsy proven acute rejection (BPAR) rate, the CNI withdrawal group experienced better renal function and graft survival.2

1. Johnson et al. Transplantation. 2001;72:777-786. 2. Oberbauer et al. Transpl Int. 2005;18:22-28.

Early Cyclosporine Withdrawal From a Sirolimus-Based Regimen

More nephrotoxic control regimen

Data from Oberbauer R, et al. Transpl Int. 2005;18:22-28.

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CONCEPT Study Aim: Evaluate conversion from a CSA-based regimen to a SRLbased regimen 3 months after transplantation (n=192)

1 Yr Endpoints

SRL Conversion Group

CNI Maintenance Group

P value

eGFR (mL/min)

68.9

64.4

0.017

BPAR

16.8

8.2

0.071

Better Renal function with CNI withdrawal with SRL Lebranchu Y, et al. Am J Transplant. 2009;9:1115-1123.

Spare-the-Nephron Trial Results Aim: Evaluate the efficacy and safety of early conversion to SRL/MMF compared with CNI/MMF (80% on FK) in kidney allograft recipients (n=299) 2 Year Endpoints

SRL/MMF group

CNI/MMF group

P value

BPAR (%)

9.5

11.3

ND

Allograft loss (%)

2.4

4.0

ND

Δ iothalamate GFR (%)

8.6

3.4

0.54

ND = data not provided

The mean % change from baseline in the primary end point of measured GFR was indistinguishable.

Weir et al. Kidney Int. 2011;79:897-907.

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CONVERT Trial Resultsa Aim: Evaluate the efficacy and safety of late conversion to SRL v. maintenance CNI (n=830 with 2:1 randomization) aOn-therapy

2 year Endpoint

patients with baseline GFR > 40 mL/min

Group A

Group B

P value

GFR (mL/min)

59.9

62.6

P = .009

BPARb

1.6

2.6

NS

98

96.8

NS

99.2

97.8

NS

Allograft

survivalb

Patient survivalb b%

of patients who met composite and individual safety endpoints at 12 months after randomization Note: Enrollment in the 20- to 40-mL/min stratum was halted prematurely due to a higher incidence of safety endpoints in the SRL conversion arm. Schena FP, et al. Transplantation. 2009;87:233-242.

CNI Withdrawal with Sirolimus • These equivocal results plus sirolimus’ side effect profile has limited its use as evidenced by the high withdrawal rates seen in clinical studies and slow acceptance in clinical practice.

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CAESAR Trial Results Aim: Evaluate early CSA withdrawal under MMF-based immunosuppression (n=536)

1 Year Endpoints

CSA Withdrawal Low-dose Group CSA Group

Standard dose CSA group

P value

Mean measured GFR (mL/min/1.73 m2)

50.9

50.9

48.6

NS

Serum creatinine

1.7

1.5

1.6

NS

BPAR (%)

38

25.4

27.5

P = .027a P = .040b

aGroup

A vs Group B A vs Group C Ekberg H, et al. Am J Transplant. 2007;7:560-570. bGroup

CNI Withdrawal with MMF • The Cyclosporine Withdrawal Study Group assessed late CSA withdrawal 12-30 months after Txp • Like the prior study, no difference in graft survival, but more acute rejections were seen in the CSA withdrawal group.

Abramowicz et al. Transplantation. 2005;16:2234-2240.

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CNI Avoidance • Definition: CNI avoidance is the omission of CNIs from a de novo regimen. • In a single center study, Flechner and colleagues saw better renal function in recipients on SRL-MMF compared to CSAMMF.1

1. Flechner et al. Am J Transplant. 2004;4:1776-1785.

CNI Avoidance • But in a subsequent single center study, Larson and colleagues compared SRL/MMF to FK/MMF. • But this time no renal function benefit was seen.

Larson et al. Am J Transplant. 2006;6:514-522.

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ELITE-Symphony Study • The ELITE-Symphony study is the largest ever kidney transplant trial that compared CNIavoidance and CNI-minimization strategies with full-dose CSA/MMF.

Ekberg et al. N Engl J Med. 2007;357:2562-2575.

ELITE-Symphony Study 1 Year Results

Std dose CSA

Low-dose CSA

Low-dose FK

Low-dose SRL

P value*

eGFR (mL/min)

57.1

59.4

65.4

56.7

< 0.001

BPAR (%)^

25.8

24.0

12.3

37.2

< 0.001

Graft survival (%)

89.3

93.1

94.2

89.3

0.01

*P value between low-dose FK and low-dose SRL ^Biopsy proven acute rejections excluding borderline values

Ekberg et al. N Engl J Med. 2007;357:2562-2575.

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Overall Allograft Survival Rates by Discharge Immunosuppressive Regimen for Deceased-Donor Kidney Transplants

Data from Srinivas TR, et al. Am J Transplant. 2007;7:586-594.

CNI Avoidance • Unfortunately, the promise of CNI avoidance with de novo SRL/MMF was not fulfilled. With more acute rejections and poorer graft survival, SRL is discouraged as the primary immunosuppressant in de novo recipients.

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CNI Minimization • Definition: CNI minimization uses reduceddose CNI to limit toxicity. • Two randomized controlled trials – CAESAR – ELITE-Symphony

CAESAR Trial Results Aim: Another arm to evaluate low-dose CSA versus standard dose CSA under MMF-based immunosuppression (n=536)

1 Year Endpoints

CSA Withdrawal Low-dose Group CSA Group

Standard dose CSA group

P value NS

Mean measured GFR (mL/min/1.73 m2)

50.9

50.9

48.6

Serum creatinine

1.7

1.5

1.6

NS

27.5

P = .027a P = .040b

BPAR (%)

aGroup

38

A vs Group B A vs Group C Ekberg H, et al. Am J Transplant. 2007;7:560-570.

25.4

No difference

bGroup

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ELITE-Symphony Study 1 Year Results

Std dose CSA

Low-dose CSA

Low-dose FK* 65.4

eGFR (mL/min)

57.1

59.4

P<.001

P=.001

BPAR^ (%)

25.8

24.0

P<.001

P<.001

Graft survival (%)

89.3

93.1

P=.01

P=.56

Low-dose SRL

12.3 94.2

*Reference group for P values ^Biopsy proven acute rejections excluding borderline values Low-dose FK had better renal function and BPAR rate compared to all other treatment groups. Graft survival was better with low-dose FK compared to standard-dose CSA and low-dose SRL. Ekberg et al. N Engl J Med. 2007;357:2562-2575.

CNI Minimization with Everolimus • With the arrival of everolimus, researchers began to evaluate new CNI minimization strategies • No differences were seen in renal function, rejection rates or graft survival.1,2

1. Chan et al. Transplantation. 2008;85:821-826. 2. Nashan et al. Transplantation. 2004;78:1332-1340.

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CNI Sparing Strategies, In Summary • Given the problems associated with CNI avoidance and uncertain efficacy of CNI withdrawal, CNI minimization is the leading clinical strategy for managing CNI side effects.

LOOKING AHEAD

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Belatacept (Nulojix) • Belatacept is a novel T-cell costimulation blocker • The phase III trials BENEFIT1 and BENEFIT-EXT2 investigated belatacept-based regimens versus a standard cyclosporine regimen.

1. Vincenti et al. Am J Transplant. 2010 Mar;10(3):535-46. 2. Durrbach et al. Am J Transplant. 2010;10:547-557.

BENEFIT: Phase III Study of Belatacept vs Cyclosporine Year 1 primary endpoints[1]

Year 2[2]

Year 3 current analysis[3]

Patients receiving kidney transplant from living or deceased donor (N = 666)

Transplantation

Belatacept More Intense (MI) Regimen Belatacept 10 mg/kg on Days 1, 5, 14, 28, 42, 56, 70, 84, 112, 140, 168; then 5 mg/kg every 4 wks (n = 219) Belatacept Less Intense (LI) Regimen Belatacept 10 mg/kg on Days 1, 5, 14, 28, 56, 84, 112; then 5 mg/kg every 4 wks (n = 226) Cyclosporine 150-300 ng/mL on Days 1-28, then 100-250 ng/mL thereafter (n = 221)  All patients received basiliximab induction, mycophenolate mofetil, and corticosteroids  Cyclosporine-treated patients also received T-cell–depleting agents if delayed graft function anticipated 1. Vincenti F, et al. Am J Transplant. 2010;10:535-546. 2. Larsen CP, et al. Transplantation. 2010;90: 1528-1535. 3. Vincenti F, et al. ATC 2011. Abstract 227.

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The BENEFIT Study: Belatacept-Based Immunosuppression Regimens vs Cyclosporine at 12 Months

Data from Vincenti F, et al. Am J Transplant. 2010;10:535-546.

BENEFIT: Graft Function Similar With Belatacept and Cyclosporine at Year 3  Increased rate of acute rejection observed early with belatacept Outcome at Year 3, %

Belatacept MI (n = 219)

Belatacept LI (n = 226)

Cyclosporine (n = 221)

Patients surviving with functioning graft

92

92

89

Acute rejection through Year 3

24

17

10

 Months 0-24

24

17

9

 Months 24-36

0

0

1

Efficacy failure* through Year 3

32

26

26

*BPAR, graft loss, death, or lost to follow-up. Vincenti F, et al. ATC 2011. Abstract 227.

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BENEFIT: 3-Yr Sustained Improved Renal Function With Belatacept vs Cyclosporine Slope, mL/min/1.73 m2/yr (95% CI) Bela MI +1.043 (0.106 to 1.980) Bela LI +1.229 (0.309 to 2.149) CsA -2.046 (-2.994 to -1.098)

Mean Calculated GFR (95% CI)

100 80 60 40 from CsA 15.1-15.3

20

from CsA 17.5-17.6

from CsA 20.8-21.4

0 0 Pts at Risk, n Belatacept MI Belatacept LI Cyclosporine

3

6

9

214 207 170 180 220 211 185 176 214 201 189 174

12

15

201 174 200 178 199 171

18 21 Month

24

27

30

33

36

167 181 160

191 201 182

165 177 162

169 177 159

169 177 156

186 180 171

167 174 160

Vincenti F, et al. ATC 2011. Abstract 227.

Pooled Data From Phase II/III Belatacept Trials: Adverse Events 

Major safety outcomes generally comparable across belatacept and cyclosporine arms



Incidence of TB slightly higher with belatacept vs cyclosporine therapy

–

–



Infections and CV events most common causes of death (occurring in 1% to 4% of pts)

Limited to areas with high endemicity

PTLD the primary safety concern

PTLD Outcome, n

Belatacept MI (n = 477)

Belatacept LI (n = 472)

Cyclosporine (n = 476)

Total PTLD cases

8

7

3

 CNS

6

3

0

 Renal allograft

2

4

0

 Disseminated

0

0

3

Total deaths due to PTLD

4

4

3

 CNS

3

3

0

 Renal allograft

1

1

0

 Disseminated

0

0

3

Larsen C, et al. ATC 2011. Abstract 228.

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BENEFIT and BENEFIT-EXT: PTLD According to EBV Status 

Further characterization of belatacept-associated PTLD identified 10-fold higher risk of development in EBV-negative vs EBV-positive recipients – Similar frequency of PTLD in EBV-positive belatacept recipients and cyclosporine recipients

Patients, %

Belatacept

Cyclosporine

 EBV negative

8.8

1.75

 EBV positive

0.74

0.25

 EBV negative

5.49

0

 EBV positive

0.49

0

 EBV negative

3.3

1.75

 EBV positive

0.25

0.25

All PTLD

CNS PTLD

Non-CNS PTLD

Larsen C, et al. ATC 2011. Abstract 228.

Belatacept (Nulojix) • Now, 3-year safety data from both trials showed a decrease in PTLD risk with belatacept after 18 months.1 • With no new safety signals and better renal function, the FDA approved belatacept in June 2011 for EBV-positive adult kidney transplant patients.

1. Larsen et al. 2011 American Transplant Congress. Philadelphia, USA. Abstract # 228. Am J Transplant. 2011;11(Suppl 2):99-100.

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Tofacitinib (CP-690,550) • Tofacitinib is a Janus kinase 3 (JAK3) inhibitor that suppresses the signal pathway for many cytokines such as IL-2, 4, 9, 15, 21 • The phase IIB trial was just completed and results were presented at the 2011 ATC

Tofacitinib vs Cyclosporine for de novo Kidney Transplantation Month 3

Tofacitinib 15 mg BID (n = 107)

Transplantation

Patients undergoing immunologically low-/moderate-risk de novo kidney transplantation from deceased donor or HLA-mismatched living donor (N = 322)

Month 6

Month 12

Tofacitinib 10 mg BID

Tofacitinib 15 mg BID (n = 106)

Tofacitinib 10 mg BID

Cyclosporine* (n = 109)

*Targeted to 12-hr whole blood trough levels of 125-400 ng/mL during Months 1-3 and 100-300 ng/mL during Months 4-12. Vincenti F, et al. ATC 2011. Abstract 4.

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Tofacitinib Arms Noninferior vs Cyclosporine Arm for Month 6 BPAR Rate Outcome, %

Tofacitinib 15 mg Months 1-3 (n = 107)

Tofacitinib 15 mg Months 1-6 (n = 106)

Cyclosporine (n = 109)

BPAR at Month 6

12.4

16.1

17.7

Clinical BPAR at Month 6

7.1

11.4

9.0

 First BPAR with grade IIB/ III acute/active cellular rejection

1.9

3.7

4.6

 First BPAR with grade II/III antibody-mediated rejection

0

0

3.7

1.5

0

4.5

Kaplan-Meier estimates of outcomes at Month 12

 Repeat rejection

Vincenti F, et al. ATC 2011. Abstract 4.

Significantly Higher GFR at Months 6 and 12 With Tofacitinib vs Cyclosporine GFR Outcome, mL/min

Tofacitinib 15 mg Months 1-3 (n = 107)

Tofacitinib 15 mg Months 1-6 (n = 106)

Cyclosporine A (n = 109)

 Month 6

73.6*

67.4†

57.2

 Month 12

64.7†

64.6†

53.9

MDRD eGFR at Month 12 (LOCF)[2]

64.6‡

64.3‡

Nankivell eGFR at Month 12 (LOCF) [2]

75.4‡

75.6‡

66.9

Nankivell eGFR at Month 12 (imputed LOCF)[2]

71.5‡

72.6‡

64.8

Least square mean of measured GFR[1]

53.9

*P < .0001 vs cyclosporine. †P < .01 vs cyclosporine. ‡P < .05 vs cyclosporine. 1. Vincenti F, et al. ATC 2011. Abstract 4. 2. Tedesco Silva H, et al. ATC 2011. Abstract 225.

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Significantly Lower Incidence of CAN in Tofacitinib Arms vs Cyclosporine Arm Outcome, %

Tofacitinib 15 mg Months 1-3 (n = 107)

Tofacitinib 15 mg Months 1-6 (n = 106)

Cyclosporine A (n = 109)

CAN at Month 12

23.9*

25.0*

48.3

Increase in CAN score > 0 from implantation to Month 12

22.7*

26.5

45.1

Increase in Banff chronicity score from baseline to Month 12

44.2

39.3*

60.4

*P < .05 vs cyclosporine.

Tedesco Silva H, et al. ATC 2011. Abstract 225.

Higher Incidence of Adverse Events With Tofacitinib vs Cyclosporine Safety Outcome

Tofacitinib 15 mg Months 1-3 (n = 107)

Tofacitinib 15 mg Months 1-6 (n = 106)

Cyclosporine (n = 109)

 Serious infection

37.0

44.5

25.3

 CMV disease (including CMV syndrome)

13.3

19.5

4.5

 BKV nephropathy

3.7

2.8

0.9

 Months 0-12

1

2

0

 > Month 12

0

2

0

Events by Month 12, %

PTLD, n

Vincenti F, et al. ATC 2011. Abstract 4.

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Sotrastaurin and Alefacept • Two agents that may not make the cut are sotrastaurin—a protein kinase C inhibitor—and alefacept—a T-cell costimulation blocker. • Two trials of sotrastaurin investigating CNI withdrawal and avoidance strategies were halted prematurely due to lack of efficacy.1,2 • A phase II trial of alefacept with a CNI minimization strategy failed to show noninferiority of its primary outcome—BPAR rate.3 1. Budde et al. Am J Transplant. 2010;10:571-581. 2. Friman et al. Am J Transplant. 2011;11:1444-1455. 3. Bromberg et al. 2011 American Transplant Congress. Abstract #533.

Conclusion • Presently, CNI-based regimens remain transplantation’s proven standard. • Given CNIs’ many toxicities, namely nephrotoxicity, CNIs are unfortunately a necessary evil.

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Conclusion • Past attempts to create CNI-sparing regimens have fallen short of expectations. • However, some new agents, specifically belatacept and tofacitinib, hold promise and may have the potential to achieve sustained CNI-free regimens.

Calcineurin Inhibitors…

Neither Friend

Nor Foe

But Frienemies!

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