Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro...

Francesco LocatelliDipartimento di Nefrologia, Dialisi e Trapianto di Rene

Ospedale “Alessandro Manzoni” di Lecco

Bari, 19-20 Marzo 2010

XV Convegno del gruppo di studio di Dialisi Peritoneale

EPO receptor EPO receptor

Elliott S, et al. Blood 89: 493-502, 1997Syed RS, et al. Nature 395: 511-516, 1998

Erythropoietin has two erythropoietin receptor binding sites

EPO receptor

Erythropoietin has two erythropoietin receptor binding sites

EPO receptorrHuEPO

Elliott S, et al. Blood 89: 493-502, 1997Syed RS, et al. Nature 395: 511-516, 1998

The ideal ESA

Effective

Safe

Flexible administration route

Less frequent administration schedule

Cheap

Currently available ESAs Recombinant human erythropoietin (rHuEPO)

– Epoetin alfa– Epoetin beta

Long-acting ESAs– Darbepoetin alfa

• Different molecular structure

• Increased biological activity

- CERA• Different mechanism of action

• Different molecular structure

• Increased biological activity

rHuEPO3 N-linked carbohydrate chains

Up to 14 sialic acids 30,400 daltons ~40% carbohydrate

Egrie JC, Browne JK. Nephrol Dial Transplant. 2001;16(suppl 3):3-13

4 N-linked carbohydrate chains Up to 18 sialic acids 33,750 daltons ~46% carbohydrate

NESP 5 N-linked carbohydrate chains

Up to 22 sialic acids 37,100 daltons ~51% carbohydrate

Bio

log

ical

act

ivit

y

Ser

um

hal

f-li

fe

Rec

epto

r b

ind

ing

Biochemical and biological properties of rHuEPO and glycosylation analogs

Hb concentrations at 4-week intervals

7

8

9

10

11

12

13

14

15

Study week

251 5 9 13 17 21 37 49

Hb

(g

/dL

)

37

129

35

128

35

127

33

127

34

123

33

121

31

106 77 51

rHuEPO

NESP

rHuEPO

NESP

Patientnumbers:

Locatelli F et al. Kidney Int 2001; 60: 741-747

- 3 - 2 - 1 0 1 2 3

- 0.54 [ -1.27, 0.19 ]

- 0.56 [ - 1.22, 0.11 ]

PPITT

Group ratio

Once week epoetin beta in HDMean time-adjusted AUC for haematocrit

• Mean [ 90% CI ]

Locatelli et al. Am J Kidney Dis 2002, 40: 119-125

Weeks since withheld dose

9

10

11

12

13

14

15

16

–5 –4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9 10 11–6

Hb

(g

/dL

)Time for Hb to return to 12 g/dL

after dose withheld due to Hb >14 g/dL

rHuEPO (n = 13)

NESP (n = 31)

Locatelli F et al. Kidney Int 2001; 60: 741-747

DA administration Q2W was not associated with an increased frequency of Hb >14 g/dL

Percentage of Hb values >14 g/dL

5

4

3

2

1

0Q2W

(n=153)QW

(n=153)

Mea

n %

of

Hb

val

ues

>

14

g/d

L

1.3

2.6

Locatelli F et al. Nephrol Dial Transplant 2005;20 S.5:MP181

16 (10) 2007

Serum half life of ESAs

3. Dougherty et al. ASCO 20044. Macdougall et al. ASN 2005

Agent Population Mean (± SE)half-life (h)

IV SCEpoetin alfa Healthy volunteers1 6.8 ± 0.6 19.4 ± 2.5

Epoetin beta Healthy volunteers1 8.8 ± 0.5 24.2 ± 2.6

Darbepoetin alfa

Peritoneal dialysis patients2

25.3 ± 2.2 48.8 ± 5.2

C.E.R.A. Healthy volunteers3 133 ± 9.8 137 ± 21.9

Peritoneal dialysis patients4

134 ± 19 139 ± 20

1. Halstenson et al. Clin Pharmacol Ther. 1991:50:702-7122. Macdougall et al. J Am Soc Nephrol. 1999;10:2392-2395

Understanding how C.E.R.A. is different

Receptor bindingproperties

Pharmacokineticproperties

Different pharmacologic profile

C.E.R.A: Dose independent of scheduleCore study, PP population, n=124 (BA16286)

Mean (SE) change in Hb (g/dL) at 6 wk

Locatelli et al. Curr Med Res Opin 2007;23:969–979

n.s.

Administration schedule

QW Q3W Q4W

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

-1.00 -0.75 -0.50 -0.25 0.00 0.25 0.50 0.75 1.00

Difference in adjusted group mean Hb (g/dL) change between baseline and evaluation (97.5% CI)

P<0.0001 for all comparisons

PP

0.004

-0.215 0.223C.E.R.A. Q2W

-0.173 0.275

0.051C.E.R.A. Q4W

Non-inferiority limit:C.E.R.A. groups vs epoetin

Primary efficacy analysisC.E.R.A. up to once-monthly as effective as epoetin TIW-QW

Levin NW et al. Lancet 2007, 370 (9596): 1415-1421

ITT-0.213

0.031

0.276

0.025

0.270-0.220

C.E.R.A. Q2W

C.E.R.A. Q4W

IV C.E.R.A. once- and twice-monthly maintains stable Hb over one year

BL 1 2 3 4 5 6 7 8 9 10 11 127

8

9

10

11

12

13

14

15

16

Final visit

4 8 12 16 20 24 28 32 36 40 44 48 52

C.E.R.A. Q2W IV

C.E.R.A. Q4W IV

Epoetin TIW-QW IV

Mean (SD) Hb (g/dL)

Months

Weeks

Levin NW et al. Lancet 2007, 370 (9596): 1415-1421

- 1.00 - 0.75 - 0.50 - 0.25 0.00 0.25 0.50 0.75 1.00

Non-inferiority lower 97.5% CI limit

Difference in mean adjusted Hb versus epoetin (g/dL)

SC C.E.R.A. once-monthly and twice-monthly as effective as epoetin 3x/wk

PROTOS: primary efficacy analysis (PP population)

P < 0.0001 for all comparisons

0.141

- 0.098 0.380C.E.R.A. 1x/2wk

- 0.262 0.217

- 0.022 C.E.R.A. 1x/4wk

Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46

BL 1 2 3 4 5 6 7 8 9 10 11 127

8

9

10

11

12

13

14

15

16

Final visit

Mean (SD) Hb (g/dL)

4 8 12 16 20 24 28 32 36 40 44 48 52

Months

Weeks

C.E.R.A. 1x/2wk

C.E.R.A. 1x/4wk

Epoetin 1-3x/wk

Stable Hb maintenance with once-monthly SC C.E.R.A.

PROTOS: ITT population

Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46

0.180

-0.049 0.408

0.180

- 0.049 0.408

- 1.00 - 0.75 - 0.50 - 0.25 0.00 0.25 0.50 0.75 1.00

Non-inferiority lower 95.0% CI limit

Difference in mean adjusted Hb (g/dL)

P < 0.0001

IV C.E.R.A. twice-monthly as effective as darbepoetin 1x/wk

STRIATA: primary efficacy analysis (PP population)

Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul

31

BL 1 2 3 4 5 6 7 8 9 10 11 127

8

9

10

11

12

13

14

15

16

Final visit

Mean (SD) Hb (g/dL)

4 8 12 16 20 24 28 32 36 40 44 48 52

Months

Weeks

C.E.R.A. 1x/2wk

Darbepoetin 1x/wk

Stable Hb maintenance with twice-monthly IV C.E.R.A.

STRIATA: ITT Population

Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul

31

SC C.E.R.A.: Smooth and steady Hb increase with a high response rate

ARCTOS: ITT population

Response rate (%)

95% CI

C.E.R.A. 1x/2wk 97.5 93.8-99.3

Darbepoetin alfa 1x/wk

96.3 92.1-98.6

Mean (SD) Hb (g/dL)

C.E.R.A. 1x/2wk

Darbepoetin alfa 1x/wk

Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47

BL 1 2 3 4 5 67

8

9

10

11

12

13

14

15

16

Final visitMonthsWeeks 4 8 12 16 20 24

Mean (SD) Hb (g/dL)

BL 1 2 3 4 5 6

7

8

9

10

11

12

13

14

15

16

Final visitMonthsWeeks 4 8 12 16 20 24

C.E.R.A. 1x/2wk

Darbepoetin alfa 1x/wkrHuEPO

Locatelli F et al. Kidney Int 2001; 60: 741-

747

Hb concentrations during 24-week intervals


P < 0.0001

Pat

ien

ts (

%)*

Fewer patients exceed Hb 13 g/dL with C.E.R.A. than with darbepoetin alfaARCTOS: ITT population

*Patients with ≥1 Hb value >13 g/dL during first 8 weeks

C.E.R.A. 1x/2wk Darbepoetin alfa 1x/wk0

10

20

30

40


Decline in Hb after withholding treatment Long C.E.R.A. half-life does not affect Hb decline

following dose interruption – pooled analysis of maintenance studies

Mean (SD) Hb (g/dL)

Safety populations

Epoetin (QW to TIW) or darbepoetin alfa (QW or Q2W) (n=126)

C.E.R.A. Q4W (n=59)

Weeks since treatment interruption (time 0)

Locatelli F. et al Kidney Intern. S. 2008 : Heifets & Dougherty. WCN 2007

-3 -2 -1 0 1 2 3 4 5 610

11

12

13

14

15

16

alfa beta alfa

020

40

60

80

100

120

140

Ho

urs

Epoetin Epoetin Darbepoetin

SCIV

Half life comparison

Halstenson. Clin Pharmacol Ther. 1991;50:702Macdougall. J Am Soc Nephrol. 1999;10:23925

Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167 Abstract M527

Methoxy polyethylene glycol-epoetin beta’s half-life is much longer than that of darbepoetin alfa

137 h vs 38 h when given SC

133 h vs 25 h when given IV

Methoxy polyethlene glycol-epoetin beta

Half life of epoetins

Halstenson. Clin Pharmacol Ther. 1991;50:702 Macdougall. J Am Soc Nephrol. 1999;10:2392

Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167. Abstract M527Woodburn. Blood. 2004;104:2904

*Healthy volunteers†Peritoneal dialysis patients

t½ (hours)

Intravenous

Subcutaneous

Epoetin alfa 6.8* 19.4*

Epoetin beta 8.8* 24.2*

Darbepoetin alfa† 25.3 48.8

3:1

3:1

2:1

Methoxy polyethylene glycol-epoetin beta

130 1331:1

Hematide 75 ~801:1

Nissenson AR et al. J Am Soc Nephrol 5:1517-1529, 1995

Ht response to EPO or placebo in PD patients

* ERI: EPO resistance index

Wei M, et al. Int Urol Nephrol. 2007;39(3):935-40.

Cosa può influenzare la scarsa risposta agli ESAs in DP?

• Sono stati condotti pochi trials sull'uso degli ESA's nei pazienti in dialisi peritoneale

• La via di somministrazione di ESAs in dialisi peritoneale deve, per ragioni pratiche, essere SC

• Le dosi di ESAs necessarie per mantenere livelli di Hb nel range suggerito dalle linee guida in dialisi peritoneale sono ridotte rispetto ai pazienti in emodialisi

ESAs in dialisi peritoneale

1Ling B et al. Clin Nephrol 2005;63:327-34; 2Agarwal AK et al. J Intern Med 2006;260:577-85; 3Disney A et al. Nephrology (Carlton) 2007;12:95-101; 4Sousa American Society of Nephrology 2006; Abstract SA-PO218; 5Hoggard J et al. Curr Med Res Opin 2006;22:2023-30.

Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysis

Reference Open-label study description*

Treatment + evaluation

period

Hb study target range

Primaryendpoint

Ling1 n=98Q2W DA → QM DA

29 weeks 10-12 g/dl % of patients withinHb study target range

Agarwal2 n=152Q2W DA → QM DA

33 weeks 11-13 g/dl % of patientswith Hb ≥11 g/dl

Disney3 n=66Q2W DA → QM DA

33 weeks 10-13 g/dl Maintaining mean Hb ≥10 g/dl

Sousa4 n=71Q2W DA → QM DA

18 months 11-13 g/dl Effectiveness and safetyof DA QM

Hoggard5

n=442QW/Q2W rHuEPO →

QM DA28 weeks 10-12 g/dl

% of patients convertingfrom EA QW who

preferred DA QM at week 21

Limited evidence with once-monthly dosing

DrugAdministration

interval (route of administration)

Target Hb(g/dL)

Population (no. patients

enrolled)Trial design Reference

Epoetin alfa QW, Q2WQ3W, Q4W (SC)

≥11 CKD not on dialysis (n=519)

Randomised Provenzano et al 2005

Darbepoetin alfa

Q4W (SC) 10-12 CKD not on dialysis (n=97)

Single arm, non-randomised

Ling et al 2005

Darbepoetin alfa

Q4W (SC) ≥10 CKD not on dialysis (n=66)


Disney et al 2007

Darbepoetin alfa

Q4W (SC) ≥11 CKD not on dialysis (n=152)


Agarwal et al 2006

Darbepoetin alfa

Q3W, Q4Wa (IV and SC)

10-13 Dialysis patients (n=54)


Jadoul et al 2004

aDosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland

ESAs, erythropoiesis-stimulating agents; Hb, haemoglobin; IV, intravenous; SC, subcutaneous

Limited evidence of efficacy in HD patients for once-monthly darbepoetin alfaa

Patients on darbepoetin alfa Q2W converted to Q3W dosing and, if Hb stable (10-13 g/dL), to Q4W dosinga

522 patients originally recruited

Limited conversion to Q4W dosinga:Of 54 patients entering the study, 36 patients were converted to Q4W dosing

Limited maintenance on Q4W dosinga:Of 36 patients converting to Q4W dosing, 30 patients maintained Hb >10 g/dL over 20 weeks

Jadoul et al. Nephrol Dial Transplant 2004;19:898-903

13.0

12.5

12.0

11.5

11.0

10.5

10.0

9.5

9.0

100

80

60

40

20

0–2 0 4 8 12 16 20 26 30 34 4238

Hb (g/dL) Dose (g/wk)

Study week

Q3W dosing (n=44) Q4W dosinga (n=30)

HbDose

aDosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland

Labelled dosing information on maintenance therapy dosing interval

MIRCERA– Once-monthly maintenance dosing in CKD patients on

dialysis and not on dialysis

Darbepoetin alfa– In HD patients

Once weekly or once every 2 weeks maintenance dosing

In Switzerland in selected HD patients, also once monthly

– In CKD patients not on dialysisStepwise expansion from QW over Q2W to QM for those patients stable on previous dose interval and by doubling the dose

ARANESP, Summary of Product Characteristics, 2006; MIRCERA, Summary of Product Characteristics, 2007

CKD, chronic kidney disease; HD, haemodialysis; QW, weekly; Q2W, every 2 weeks; QM, once monthly

The PATRONUS study: a randomised comparison of the

efficacy and safety of MIRCERA® with darbepoetin alfa using once-monthly dosing in haemodialysis

patients

PATRONUS study objectives

• Primary– To compare the efficacy of once-monthly IV MIRCERA®

with that of darbepoetin alfa* in the maintenance of Hb levels in HD patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance therapy

• Secondary– To assess the safety and tolerability of IV MIRCERA® in HD

patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance treatment

* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.

Evaluation (wk 50-53)

4 weeks 26 weeks 26 weeks

Screening period

Darbepoetin alfa1x/2 weeks

(n=245)

Darbepoetin alfa1x/week

Darbepoetin alfa*1x/month

Primary end point

MIRCERA®

1x/month(n=245)

MIRCERA®

1x/month

R

PATRONUS compared once-monthly MIRCERA® and darbepoetin alfa maintenance treatment

R, randomisation


• Primary end point: superiority assessment of the difference in the proportion of responders between groups– Responders are patients with an average Hb decrease

from baseline of <1.0 g/dL and an average Hb >10.5 g/dL during evaluation

• Study was powered to detect an absolute difference of 15% in the primary end point between the 2 treatment groups– Assumed 60% of patients would respond to MIRCERA®

vs 45% to darbepoetin alfa

• Target Hb range: 11–13 g/dL

PATRONUS primary end point


Analysis population

• Primary efficacy analysis used the intent-to-treat population, defined as all randomised patients– In case of withdrawals, the last Hb value in the second treatment

period was used for the Hb assessment (last value carried forward)

– To correct for any increase in Hb caused by RBC transfusion, the Hb values measured within 3 weeks after a transfusion were replaced by the Hb value measured immediately before the transfusion

• Safety population included all patients who received >1 dose of MIRCERA® or darbepoetin alfa

RBC, red blood cell


Darbepoetin alfa to MIRCERA® dose conversion schedule

Weekly darbepoetin alfa dose

(g/week)

MIRCERA® starting dose(g/month)

<40 120

40–80 200

>80 360


Darbepoetin alfa starting doses

4 weekbaseline period

Two changes needed:

Week 1 Week 27

26 weeks 26 weeks

Double Week 25 dose

Double Week – 1 dose


PATRONUS: A multicentre, multinational trial Country Patients enrolled

France 95

Italy 86

Spain 80

Canada 65

Germany 33

Belgium 31

UK 22

Portugal 21

Australia 15

Austria 15

Switzerland 11

Finland 9

Denmark 7

Total 490


Baseline patient characteristicsMIRCERA®

n=245

Darbepoetin alfa

n=245 Male, n (%) 148 (60) 156 (64)

Race, n (%)Caucasian 233 (95) 225 (92) Black 5 (2) 12 (5)Other 7 (3) 8 (3)

Mean age, years (SD) 66.2 (13.6) 65.5 (13.9)

Mean weight, kg (SD) 72.3 (15.1) 73.8 (16.9)

Mean baseline Hb, g/dL (SD) 12.09 (0.56) 12.07 (0.55)

Mean time since first dialysis, years (SD) 4.20 (5.92) 4.15 (5.55)

Dosing

Median darbepoetin alfa dose at weekbefore randomisation, g (IQR) 30.0 (20-40) 20.0 (15-40)

Median study drug dose in month 1, g/month (IQR) 120.0 (120-200) 100 (60-160)

SD = standard deviation; IQR = Interquartile Range

Once-monthly MIRCERA® exhibited a superior response rate compared with once-monthly

darbepoetin alfa*

CI, confidence interval

Res

pons

e ra

te (

%)

64.1%

40.4%

*

Primary end point

*P<0.0001

®

64.1%

40.4%


Once-monthly MIRCERA® shows a 59% higher likelihood of response compared with once-monthly darbepoetin alfa*

Primary end point

−0.75 1.00 1.25 1.50 1.75 2.0

Relative risk of response at evaluation for MIRCERA® vs darbepoetin alfa

1.59*

1.901.33

Superiority limit:MIRCERA® vs darbepoetin alfa

*P<0.0001


Med

ian

Hb

valu

e (g

/dL)

14.0

12.0

10.0

8.0

7.0

MIRCERA® (median, IQR)Darbepoetin alfa (median, IQR)

Baseline 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks (of trial treatment)

16.0

Evaluation (wk 50-53)

15.0

9.0

13.0

11.0

Only once-monthly MIRCERA® maintained Hb levels during the second 26-week treatment period

Darbepoetin alfa dose increased by >30% during the second 26-week treatment

period

• The median MIRCERA® dose was virtually unchanged during the second 26-week treatment period whereas darbepoetin alfa substantially increased by 35%

Median (IQR) treatment dose, g/month

MIRCERA®

n=211 Darbepoetin alfa

n=219

Week 27 200 (120-313) 150 (80-280)

Months 11 and 12 196 (120-351) 225 (106-400)

Secondary end point

0% +35%


150

125

100

75

50

25

0

−25

−50

Tri

al tr

ea

tme

nt d

ose

ch

ang

e (%

)

7 8 9 10 11 12

MIRCERA (median, IQR)Darbepoetin alfa (median, IQR)

Months (of trial treatment)

MIRCERA® dose was unchanged during the second 26-week treatment period

Secondary end point


Most safety parameters were similar between the two PATRONUS study groups

• Similar incidence of AEs in both study arms– higher rate of constipation with MIRCERA®

• Most common AEs in both arms were hypertension (14.7 vs 10.7%), procedural hypotension (8.6 vs 11.1%) and nasopharyngitis (10.2 vs 8.2%)

• Fewer withdrawals with MIRCERA® than with darbepoetin alfa

MIRCERA®, n (%)n=245

Darbepoetin alfa, n (%)n=244

AEs 222 (90.6) 217 (88.9)

SAEs 99 (40.4) 94 (38.5)

AEs leading to withdrawals 3 (1.2) 7 (2.9)

Withdrawals 58 (23.7) 96 (39.3)

Withdrawals due to insufficient response 10 (4.1) 48 (19.7)

Deaths* 14 (5.7) 14 (5.7)

AEs, adverse event; SAEs, serious adverse events *includes 3 patients who died after withdrawal due to other events


SAEs (>5% in either group) were comparable between study groups in PATRONUS

MIRCERA®

n=245n (%)

Darbepoetin alfa

n=244 n (%)

All body systems 99 (40.4) 94 (38.5)

Infections and infestations 29 (11.8) 27 (11.1)

Injury, poisoning and procedural complications

26 (10.6) 18 (7.4)

Cardiac 16 (6.5) 16 (6.6)

Vascular 14 (5.7) 16 (6.6)

Gastrointestinal 11 (4.5) 16 (6.6)

Nervous system 7 (2.9) 13 (5.3)

Neoplasms 10 (4.1) 5 (2.0)

Metabolism and nutrition 10 (4.1) 4 (1.6)

Respiratory, thoracic and mediastinal 4 (1.6) 7 (2.9)


Clinical Nephrology, Vol 73 – n 2/2010 (94-103)

ConclusionsMIRCERA® was shown to be superior to darbepoetin alfa as once-monthly treatment in the dialysis setting

– Significantly more patients responded with MIRCERA® compared with darbepoetin alfa

– MIRCERA® maintained Hb levels within a tight target range during the second 26-week treatment period

– Mean Hb levels for patients receiving darbepoetin alfa fell to below the lower target (11 g/dL) over the same 26-week period, despite substantial dose increases

This is the first large, randomised, prospective head-to-head study that has shown one ESA to offer superior efficacy compared with another

Carrera F et al. WCN 2009 Milano, poster M558


Hb (or at least high levels) vs ESA (or at least high levels)

ESA

Hb

Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro...

Documents

Transcript of Francesco Locatelli Dipartimento di Nefrologia, Dialisi e Trapianto di Rene Ospedale “Alessandro...