Preservation of Anemia Control and Weekly ESA Dosage After Conversion from PEG-Epoetin Beta to Darbepoetin Alfa in Adult HD Patients:The TRANSFORM Study

Donck J. et al. Adv Ther. 2014 Nov;31(11):1155-68

Background

• Over 90% of subjects undergoing renal replacement are anaemic in the absence of treatment with an ESA

• ESAs available in the EU can be divided into 3 categories, based on their serum half-life• Recombinant human erythropoietin, or short acting ESAs• Darbeopetin alfa (DA)• Pegylated erythropoietin beta (Peg-EPO)

• Due to the pharmacological characteristics, these three categories of ESA are not interchangeable

ESA: erythropoiesis stimulating agent, rHuEPO: human recombinant erythropoietin

Tsakiris. Nephron 2000;85(Suppl 1):2-8Macdougall. Sem Nephrol 2000; 20:375-81Egrie et al. Exp Hematol 2003;31:290-299

Rationale

• There is very little published literature on switch from pegylated erythropoietin beta to darbepoetin alfa

• A single published study from Switzerland with limited sample size and follow-up indicated that an equimolar conversion ratio conferred a 22% dose decrease post-switch with no loss of Hb control

• TRANSFORM looked at dialysis patients whose treatment had been switched from intravenous (IV) methoxy polyethylene glycol-epoetin beta (peg-EPO) to IV darbepoetin alfa (DA)

• Data obtained from this study are intended to contribute to filling a literature gap and to provide a robust source of information for physicians

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68Meier et al. J Am Soc Nephrol. 2010;21:211 (Abstract TH-PO441)

Objectives

• Primary objective • To describe the time course of haemoglobin concentration in EU

haemodialysis patients switched from IV peg-EPO to IV DA

• Secondary objectives• To describe other parameters related to clinical management of

anaemia• Peg-EPO and darbepoetin alfa doses over time• Dose ratio at switch• Hb excursions (<10 g/dL and >12 g/dL)

IV: intravenous, DA: darbepoetin alfa, peg-EPO: pegylated erythropoietin beta

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Study design

• A multi-centre, observational cohort study

• 1027 subjects enrolled

IV Peg-EPO14 weeks’ data prior to

switch to DA

IV DA26 weeks’ data post-commencement of DA

Start End

S = Switch from peg-EPO (i.e. first dose of DA)

-14 26

S

Retrospective data collection

Retrospective / prospective data collection

weeks

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Inclusion and exclusion criteria• Inclusion criteria

• ≥18 years of age• with CKD on haemodialysis and fulfilling the following

• Haemodialysis for ≥26 weeks prior to switch• Peg-EPO treatment for ≥14 weeks immediately prior to switch• Switched from peg-EPO to DA during or after 01 Jan 2011 and received ≥1

dose of DA post-switch• Informed consent has been provided (if applicable)

• Exclusion criteria• Administration of more than 2 doses of an ESA other than peg-EPO in the 7-

14 weeks immediately prior to switch, and/or an ESA other than peg-EPO during the 6 weeks immediately prior to switch

• Chemotherapy during the 14 weeks immediately prior to switch• Major surgery within 14 weeks prior to switch• Red blood cell transfusion within 14 weeks prior to switch

CKD: chronic kidney disease

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Outcome measures

• Primary outcome measure• Haemoglobin concentration at monthly intervals

• Secondary outcome measures• Doses of peg-EPO and DA over time• Dose ratio at switch*• Haemoglobin excursions (<10 g/dL and >12 g/dL)

* Weekly dose equivalent of DA divided by the weekly dose equivalent of peg-EPO at the time of switch

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Disposition of patients

*not mutually exclusive

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Patient characteristics at time of switching

Patients in analysisset (n = 785)

Patient demographics

Age (years)Mean (SD)Median (Q1, Q3)

68.7 (14.3)72.0 (60.0, 79.0)

Gender, female, n (%) 344 (43.8)

Prior renal transplantations, n (%)01≥2

721 (91.8) 52 (6.6) 12 (1.5)

Duration of dialysis (months)Mean (SD)Median (Q1, Q3)

42.9 (40.1)32.0 (16.0, 57.0)

Hemodialysis access, n (%)Arteriovenous fistulaArteriovenous graftPermanent venous catheterTemporary venous catheterOther

606 (77.2) 38 (4.8)124 (15.8) 11 (1.4) 6 (0.8)

Weekly peg-EPO dose (µg),geometric mean (95% CI)

27.83 (26.36, 29.37)

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

The most frequent co-morbidities were hypertension, diabetes, peripheral vascular disease, and coronary artery disease

CAD: coronary artery disease, TIA: transient ischaemic attack, MI: myocardial infarction,HF: heart failure, PVD: peripheral vascular disease

CAD

Stroke TIA M

IHF

Hyperte

nsion

PVD

Diabete

s

Malig

nancy

None0

20

40

60

80

100

24

5 5 814

76

25

39

138

% o

f p

atie

nts

Mean age (SD): 68.7 (14.3) Gender, female (%): 344 (43.8)

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Hb concentration at time of switching

Hb concentration (g/dL)Patients in analysis set

(n = 785)

Mean (SD) 11.15 (1.10)

Categories, n (%)

<10 108 (13.8)

≥10 to <12 475 (60.5)

≥12 186 (23.7)

Missing 16 (2.0)

Donck et al. Adv Ther. DOI 10.1007/s12325-014-0161-5. Published online 01 November 2014

Dose ratio at switch and month 6

Peg-EPO DA

At switch At month 6

Mean weekly dose (µg/week)

n 768 775 769

Geometric mean (95% CI) 27.83 (26.36, 29.37) 29.99 (28.39, 31.68) 25.57 (24.14, 27.09)

Dose ratio

n 785 770

Geometric mean (95% CI) 1.06 (1.01, 1.11) 0.88 (0.83, 0.93)

Dose-ratio categories, n (%)

<0.8 174 (22.2) 285 (37.0)

>0.8–1.2 310 (39.5) 240 (31.2)

>1.2 301 (38.3) 245 (31.8)

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

N= 725 766 769 763 755 749 754 739 742

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Following the switch to DA, there was an initial linear rise in Hb to month 3 which returned to pre-switch levels by month 6

Month -3 Month -2 Month -111.0

11.2

11.4

11.6

Switch

Hae

mo

glo

bin

(g

/dL

), 9

5% C

I

Hb values within 90 days of a transfusion are excluded, CI: confidence interval

DAPeg-EPO

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

N= 740 779 783 782 778 780 779 777 769

Despite an initial higher dose post-switch, the DA dose declined by month 4 and stabilized around the pre-switch level by month 6

Month -3 Month -2 Month -120

25

30

35

Mea

n w

eek

ly d

ose

, g

eom

etri

c m

ean

, 95

%

CI

(ug

/wee

k)

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Switch

DAPeg-EPO

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Higher dose ratio (>1.2) at switch resulted in a temporarily increased mean Hb

Month -3 Month -2 Month -110.8

11.0

11.2

11.4

11.6

11.8

12.0

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Switch

Mea

n H

b,

95%

CI

(mg

/dL

)

Hb values within 90 days of a transfusion are excluded

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Dose ratio at switch: <0.8 0.8 – 1.2 >1.2

Despite the differences in dose ratios at switch, the mean DA dose became similar in all 3 dose groups by month 4

Month -3 Month -2 Month -115

20

25

30

35

40

45

Mea

n w

eek

ly d

ose

, g

eom

etri

c m

ean

, 95

%

CI

(ug

/wee

k)

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Switch

DAPeg-EPO

Dose ratio at switch: <0.8 0.8 – 1.2 >1.2

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

N= 132 139 123 140 107 92 108 96 115

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Hb excursions <10 g/dL tended to generally be lower in the post-switch period compared to the pre-switch period

Switch

% o

f p

atie

nts

, 95

% C

I

DAPeg-EPO

Month -3 Month -2 Month -10

5

10

15

20

25

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

N= 228 228 195 181 230 260 256 218 208

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Hb excursions >12 g/dL tended to be higher during the middle of the post-switch period compared topre-switch, but dropped to a lower level by month 6

Switch

% o

f p

atie

nts

, 95

% C

I

DAPeg-EPO

Month -3 Month -2 Month -10

10

20

30

40

Adapted from: Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

Summary and Conclusions

• Overall, stable Hb concentrations were maintained over the post-switch period, with Hb values at month 6 for patients receiving DA very similar to those in the month pre-switch when patients were receiving peg-EPO.• Across all three dose-ratio subgroups, mean monthly Hb converged within

the range of 11.1–11.5 g/dL

• Switching patients at dose ratios >1.2, and administration of almost the double of their pre-switch doses resulted in an initial linear haemoglobin increase.

• Despite the initial difference in dose level at switch, the mean dose became similar in the 3 dose ratio switch groups by month 4 and was maintained to month 6.

• Haemoglobin excursions <10 g/dL tended to generally be lower in the post-switch than in the pre-switch period.

• Haemoglobin excursions >12 g/dL tended to be higher during the middle of the post-switch period compared to pre-switch, but dropped to a lower level by month 6.

Donck J et al. Adv Ther. 2014 Nov;31(11):1155-68

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