New trends in immunosuppression

New trends in immunosuppression Focus on adequate MPA exposure in renal transplant recipients Wolfgang Arns Agenda: dose → exposure (PK) → respons...
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New trends in immunosuppression Focus on adequate MPA exposure in renal transplant recipients

Wolfgang Arns

Agenda:

dose → exposure (PK) → response (PD)

• The benefit of MPA exposure early and late after renal transplantation

• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy

Agenda

• The benefit of MPA exposure early and late after renal transplantation

• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy

Incidence of acute rejection at 6 months post-transplant (%)

Mycophenolate not only reduces the rate of early acute rejection… 30

24.7%

25 20

15.5%

p15% or HLA-MM ≥4 or AA

Van Gelder T, in press, post hoc analysis of FDCC

Relationship between MPA exposure and acute rejection

• Full analysis set •

MPA AUC on day 3 vs BPAR in 1st month •



MPA AUC on day 3 vs BPAR in 1st year •



p value = 0.009

p value = 0.006

MPA AUC on day 28 vs BPAR > 1st month •

p value = 0.56

key message

MPA exposure increases with time post-transplant

120

MPA AUC [μg·h/ml]

100

High target AUC ~4 g MMF equivalent

80

60

Intermediate target AUC ~2 g MMF equivalent

40

magic MPA AUC of 30

Low target AUC ~1 g MMF eqivalent*

20

0 0

20

40

60

80

100

120

140

Days post-transplant Hale MD et al. Clin Pharmacol Ther 1998;64:672–83.

*)1 g MMF is eqivalent to 720 mg EC-MPS

As MPA exposure increases with a delay over time, intensified early dosing regimen could be the solution

120

MPA AUC [μg·h/ml]

100

High target AUC ~4 g MMF equivalent 80

60

Intermediate target AUC ~2 g MMF equvalent

40

“magic” AUC Low target AUC ~1 g MMF equivalent

20

0 0

20

40

60

80

100

120

Days post-transplant Hale MD et al. Clin Pharmacol Ther 1998;64:672–83.

140

Optimyze Study • Open-label, prospective, randomized, parallel group pilot study • 3 centers in Germany • Phase 1 Objectives: feasibility to achieve target MPA-AUC (> 40 g*h/mL) and safety of an intensified EC-MPS regimen in 75 patients • Phase 2 Objectives: therapeutic benefit of this regimen in 128 patients Glander P, Sommerer C, Arns W et al, CJASN 2010; 5(4): 503-511 Sommerer C, Glander P, Arns W et al, Transplantation 2011; 91(7): 779-85

Study Design

Intensified

2880 2160 1440 mg / day EC-MPS CsA + Steroids + Basiliximab

Randomization 1:1 1440 mg / day EC-MPS CsA + Steroids + Basiliximab

Standard

0

14

6 months study period

42

180 days

Study Endpoint • Primary efficacy endpoint

Composite of biopsy proven acute rejection (BPAR), graft loss and death at Month 6

• Key safety endpoints Incidences of anemia, leucopenia, gastrointestinal side effects and infections

Mean Daily EC-MPS Dose CsA Dose 3500

mg/d 2880

3000

Standard

Intensified

Day 1-14

6.7 ±1.6

6.4 ± 1.7

Day 15-42

4.4 ± 1.9

4.2 ± 1.9

Day 43-180

3.0 ± 1.2

3.1 ±1.1

2500

2160 2000

1440

1500 1000 500 0 Day 1-14

Day 15- 42

Day 43-180

Standard Intensified

Dosing regimens were applied according to the protocol

MPA-AUC Standard Proposed upper therapeutic exposure (30 mg*h/L)

Target exposure level (40 mg*h/L)

Proposed lower therapeutic exposure (30 mg*h/L)

Almost all patients of the intensified group reached the target MPA-AUC of 30 to 60 µg*h/mL

Intensified

IMPDH Activity Standard

Intensified

The intensified regimen led to a significantly stronger inhibition of IMPDH post transplantation

Efficacy Endpoint

p=0.017

20

n=11

Patients (%)

Intensified

17

15

10

5

n=3 n=2 3

n=1 2

Death

5

n=2

n=2

33

3

Graft Loss

Standard

BPAR

Efficacy Endpoint: BPAR Grading

Standard

Intensified

Total

n=65

n=63

n=128

BANFF IA

7 (10.8%)

1 (1.6%)

8 (6.5%)

BANFF IB

2 (3.1%)

0

2 (1.6%)

BANFF IIA

1 (1.5%)

0

1 (0.8%)

BANFF IIB

1 (1.5%)

1 (1.6%)

1 (0.8%)

Number of biopsies

62

47

109

Patients with biopsies

37

29

66

BANFF Klassifikation n (%)

12 months data

IMPDHAEC (µmol*s-1*mol-1) *h

What´s about TDM of MPA exposure: PK-PD-modeling MPA-AUC vs IMPDH-AEC

MPA-AUC mg*h/L

IMPDH activity µmol*s-1*mol-1

What´s about TDM of MPA exposure: PK-PD-modeling single MPA vs single IMPDH 150

125

EC50 1.24 to 1.76 μg/mL

100

75

E= (Emax*C)/(EC50+C) 50

Above a certain threshold increased MPA exposure leads not to more IMPDH suppression.

25

EC-MPS has the potential for a longer exposure.

0

5

10

15

20

25

30

35

40

45

50

MPA-concentration [µg/mL]

No difference was found in calculated EC50 values during the first 3 weeks day 3: 1.24 mg/L [95% CI: 0.59-1.89]; day 10: 1.76 mg/L [95% CI: 1.06-2.97] day 21: 1.44 mg/L [95% CI: 0.89-2.0]).

Need for more data from larger cohorts to validate the safety and efficacy of this concept • prospectively defined fixed effect meta analysis model • Two 6 month, randomized, parallel group, open label, multicenter studies with almost identical design Intensified EC-MPS

2880 mg/d 2160 mg/d

n=213

1440 mg/d EC-MPS CsA + Steroids +/- anti-IL2R induction

Randomization at kidney Tx

Standard EC-MPS

n=219

1440 mg/d EC-MPS CsA + Steroids +/- anti-IL2R induction

Day 0

Day 14

Day 42

CsA; cyclosporine; EC-MPS: enteric-coated mycophenolate sodium; RTx: renal transplant

Day 180 42

EC-MPS dosing • The mean daily EC-MPS doses showed close adherence to the planned regimens in both groups 3500 2763

Mean (SD) (mg/day)

3000

Safety population 2122

2500 2000

1982

1399 1411

1456

1389

1354

1369

1500

1359

1326 1276

1252 1260

1000 500 0 1-14

15-28

EC-MPS: enteric-coated mycophenolate sodium

29-42

43-56

57-84

Days (post-transplantation)

85-120

121-180

43

MPA exposure (AUC0-12h) • Median MPA exposure was ~33-47% higher in the Intensified EC-MPS dose group in the first 6-weeks post-transplant • 80.5% achieved target MPA-AUC by Day 3 in Intensified group PK population

50.8 42.9

44.3

42.7

43.8

42.5

44.3

39.8 33.5 30.9

36.3

28.7

AUC: Area under the curve at steady state

44

Primary efficacy endpoint: Treatment failure • 5% (p=ns) less treatment failure (BPAR, graft loss or death at Month 6) in Intensified group • significantly lower (5.5%) BPAR rates in Intensified group p=0.11

Percentage of patients

22.4% 19.3% 17.4% 13.8%

15

10

p=0.034

ITT population

25

20

Intensified Standard

n=38 n=50

n=30 n=43

5

n=5

2.3%

n=8 3.6%

n=3 n=3 1.4% 1.3%

0 Treatment failure

BPAR*

Graft Loss*

Death*

Study endpoints * Components of treatment failure

45

IMPDH based mycophenolate dosing MPA predose

N=52

IMPDH inhibition

N=52

ns

Criticism: Only 720 mg/day EC-MPS dosing with either TAC or CSA!

Raggi MC et al, Transplantation 2010; 90(12): 1536-41

If fixed dose is the right answer: Does one size fits all? The role of body weight in the Singapore experience.

12 mg/kg BW → AUC 45 mg·h/L

Yau W-P et al, NDT 2007; 22,:3638-3645

The value of MPA predose TDM revisited @ 1 month

@ 1 year

Miura M et al, TDM 2011; 33: 295-302

Conclusion

• The introduction of mycophenolate has improved transplant outcome in short and longterm use. • Dose reduction in mycophenolate therapy is associated with lower outcome. In comparison to MMF: EC-MPS is bioeqivalent in equimolar dosing, but has superior tolerability that allows higher dosing with increased MPA exposure. • High exposure of MPA from the very early beginning at transplantation has a great impact on transplant outcome. EC-MPS gives the opportunity for safe intensified dosing strategy according to the optimyze concept.

Agenda

• The benefit of MPA exposure early and late after renal transplantation

• EC-MPS in comparison to MMF • High MPA exposure from the very early beginning • The value of MPA in maintenance therapy „MPA based immunosuppression“

Design of the ZEUS study Month 0 – 4.5

Anti IL-2R + Cyclosporine + EC-MPS + CS

Month 4.5

Stepwise conversion (2 weeks)

Cyclosporine + EC-MPS + CS CsA trough level 100-150 ng/ml

Everolimus + EC-MPS + CS Everolimus trough level 6-10 ng/ml

After Month 12, patients were included in an observational follow up.

Anti IL-2R = Basiliximab, EC-MPS = Enteric-Coated Mycophenolate Sodium, CS = Corticosteroids

Renal Function Adjusted Values (Group (LS-)Means from ANCOVA model, 95% CI) 80

Everolimus N=154

< 0.0001

0.0002

< 0.0001

+6.5 [3.1, 10.0]

70

+7.8 ml/min (ml / min)

GFR Nankivell

GFR Slope ml/min

< 0.0001

60

-1.1 [-4.8, 2.5] Cyclosporin N=146

ITT Population

50

40 Rando.

M6

M9

M12

M24

Renal function maintains over a period of 24 month

Renal Function Adjusted Values (Group (LS-)Means from ANCOVA model, 95% CI)

80

Everolimus< 0.0001

< 0.0001

< 0.0001

GFR Slope ml/min

< 0.0001

+9.0 [4.4, 13.6] 70 (ml / min)

GFR Nankivell

N=154

60

+10.4 ml/min -1.5 [-6.5, 3.6]

Cyclosporin N=146

Per Protocol Population

50

40 Rando.

M6

M9

M12

M24

Renal function maintains over a period of 24 month

The influence of de novo HLA antibodies: Patients on risk – enhancing immunosuppression 100 neg/neg (550) 89%

90 pos/pos (86)

p1g/day

-20 primary non-responders (lack of efficacy, new onset of proteinuria) -10 secondary non-responders (side effects)

In the second year post transplantation about 40% of all transplanted patients are on PSI-based therapy – they will have a clear long term benefit for better renal function.

Overview: de novo immunosuppression immunological status

1.TP/PRAact ≤10% ¹)

low risk

Basiliximab Prednison Cyclosporine Mycophenolate

>1TP u./o. PRAact ≥10%

medium risk

Thymoglobuline Prednison Tacrolimus Mycophenolate

¹) PRAmax≥10% → XM+ → ATG induction

PRAact ≥80%

high risk

Plasma Exchange Rituximab Prednison Tacrolimus Mycophenolate