1. Features of darbepoetin alfa in the nephrology setting

2. In patients not on dialysis
Module 2 – Achieving and maintaining the Hb target with darbepoetin alfa
In patients not on dialysis

3. Uniform EU label applies to all ESAs
EU label for all ESAs
Hb target: 10–12 g/dl
Avoid sustained Hb >12 g/dl
Treatment of symptomatic anaemia
Restrictive dose titration
Lowest epoetin dose should be used
Hb = haemoglobin
Aranesp SPC Feb 2012, Mircera SPC Nov 2011, NeoRecormon SPC Aug 2011, Epoetin alfa Hexal SPC Apr 2011, Silapo SPC Jun 2011, Eporatio SPC Sep 2010
available at:
Eprex SPC Oct 2011, available at 3

4. The half-life of darbepoetin alfa is long enough to allow extended dosing1,2 but is short enough for customized control of Hb levels3 24
13-28 73
25-53
139
Half-life (hours) 4 5
6,* 7 8
*Peginesatide acetate is currently not approved in the EU
1Agarwal et al. J Intern Med 2006;260:577–85. 2Carrera et al. Nephrol Dial Transplant 2006;21:2846–50. 3Locatelli et al. Kidney Int 2001;60:741–7. 4Eprex® (epoetin alfa) SPC Oct 2011, available at .
5NeoRecormon® (epoetin beta) SPC Aug 2011, available at:
6Omontys (peginesatide) Prescribing Information March 2012, available at:
7Aranesp® (darbepoetin alfa) SPC Feb 2012 , available at: .
8Mircera® (methoxy polyethylene glycol-epoetin beta) SPC Nov 2011, available at:

5. Long enough Convenience Short enough Concern
The half-life of the darbepoetin alfa molecule has the flexibility to regain and maintain Hb control
Long enough
Convenience
Long enough for extended dosing
Short enough for customised control
Short enough for customized control
Short enough
Concern

6. Extended dosing of darbepoetin alfa in CKD patients not on dialysis
Experience with:
Q2W dosing
QM dosing
Needle-stick injury prevention
CKD = chronic kidney disease. QW = weekly. Q2W = every other week. QM = once monthly
Darbepoetin alfa prescribing information:
Correction Phase: HD patients - QW dosing; CKD patients not on dialysis – QW or Q2W SC dosing
Maintenance Phase: HD patients - QW or Q2W dosing; CKD patients not on dialysis – QW, Q2W or QM SC dosing 6

7. Every other week (Q2W) dosing of darbepoetin alfa was effective in CKD patients not on dialysis
Reference
Study description*
Treatment period
Hb study target range
Primary end point
Suranyi et al.
Am J Nephrol 2003;23:106–11
N = 76
EPO naive → Q2W DA
24 weeks
11–13 g/dl
Patients achieving
Hb 11–13 g/dl
Toto et al.
Am J Nephrol 2004;24:453–60
N = 608
Dose of DA,
when Hb ≥11 g/dl
Hertel et al.
Am J Nephrol 2006;26:149–56
N = 524
QW rHuEPO → Q2W DA
52 weeks
≤ 12 g/dl
Mean Hb during
week 20–32
Galle et al.
Nephrol Dial Transplant
2012;27:
N = 4278
Epoetin a, epoetin b, DA QW, DA other
→ DA Q2W / QM SC
12 months
>11
achievement of Hb level >11 g/dl,
absolute Hb level 12 months post-initiation
*Open-label studies
DA = darbepoetin alfa. rHuEPO = recombinant human erythropoietin 7

8. High response rate with Q2W dosing of darbepoetin alfa
Hb response was achieved in 97% of patients (N = 61) completing 24 weeks of treatment
Patients (%)
97% 3% 20 40 60 80
100
Patients within Hb study target range (11–13 g/dl)
Patients outside Hb study target range
Patients were judged to have achieved a Hb response when they reached the Hb target range (11.0–13.0 g/dl).
Suranyi et al. Am J Nephrol 2003;23:106–11 8

9. Mean Hb concentration (g/dl)
Q2W darbepoetin alfa effectively corrected anaemia and maintained stable Hb levels
At time of response the mean (SD) DA dose was 63.5 ± 16.9 μg/Q2W (N = 463*)
Mean Hb concentration (g/dl)
Q2W dose of DA (µg)
Study week 1 3 7 11 13 17 21 23 9 10 12 14 19 15 5 50 40 60 80 90 70
DA dose Hb 30 20
*Patients who completed 24 weeks of DA treatment
Hb response was defined as a Hb range of between 11.0 and 13.0 g/dl for up to 24 weeks
Toto et al. Am J Nephrol 2004;24:453–60 9

10. Q2W dosing of darbepoetin alfa remained steady over time
Mean Hb concentration (g/dl)
Mean DA dose (µg/wk)
Hertel et al. Am J Nephrol 2006;26:149–56

11. Geometric Mean Weekly Dose (95% CI), µg/wk
Q2W/QM darbepoetin alfa effectively corrected anaemia and maintained stable Hb levels in ESA-prior as well as ESA-naive patients not on dialysis
ESA-prior patients
ESA-naive patients
Mean Hb conc. (95% CI), g/dL
Geometric Mean Weekly Dose (95% CI), µg/wk
Months Before/After Initiation
10.0
10.5
11.0
11.5
12.0
12.5 10 15 20 25 -6 -5 -4 -3 -2 -1 P I 1 2 3 4 5 6 7 8 9 11 12
Full Analysis Set (n=2193) Hb
ESA dose
DA dose Hb
DA dose
In the prior ESA subgroup, mean Hb increased before initiation and continued to increase immediately after initiation, then decreased and stabilized at around the 7- to 9-month interval. Increasing Hb levels corresponded to a reduction in the geometric mean weekly ESA dose at initiation compared with pre-initiation dosing with no dose penalty in the post-initiation period.
Mean Hb levels were maintained in the prior-ESA sub-group with no dose increase.
Full Analysis Set (n=2085)
Q2W = bi-weekly. QM = monthly. ESA = erythropoiesis stimulating agent. DA = darbepoetin alfa.
P = immediately prior to initiation. I = at initiation.
Galle et al. Nephrol Dial Transplant 2012;27:

12. Treatment and evaluation period
Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysis
Reference
Study description*
Treatment and evaluation period
Hb study target (g/dl)
Primary endpoint
Ling et al.
Clin Nephrol 2005;63:327–34
N = 97
Q2W DA → QM DA
29 weeks
10-12
proportion of patients maintaining Hb study target range
Agarwal et al.
J Intern Med 2006;260:577–85
N = 152
33 weeks
11-13
proportion of patients with Hb ≥ 11 g/dl during the evaluation period
Disney et al.
Nephrology 2007;12:95–101
N = 66
10-13
proportion of patients maintaining
mean Hb ≥ 10 g/dl during the evaluation period
Galle et al.
Nephrol Dial Transplant
2012;27:
N = 4278
Epoetin a, epoetin b, DA QW, DA other
→ DA Q2W / QM SC
12 months
>11
achievement of Hb level >11 g/dl,
absolute Hb level 12 months post-initiation
Hoggard et al.
Curr Med Res Opin
2006;22:
N = 442
QW/Q2W Epoetin α → QM DA
28 weeks
Patient preference at week 21 for QM DA versus previous QW Epoetin α
*Open-label studies

13. Patients could be safely and effectively switched from Q2W to QM dosing of darbepoetin alfa
Hb concentration was maintained within the target range in 85% (95% CI = 78% – 93%) of patients who completed the study period of 29 weeks
Baseline versus evaluation period:
Mean Hb level remained stable (11.1 ± 0.6 g/dl versus 11.1 ± 0.7)
DA monthly dose was similar (88.7 ± 49.9 µg versus 86.6 ± 78.8 µg)
Patients (%)
Ling et al. Clin Nephrol 2005;63:327–34 13

14. Darbepoetin alfa (mg/month)
Switch from Q2W to QM darbepoetin alfa allowed stable Hb levels and steady dose
76% (95% CI: 68%; 83%) of patients achieved mean Hb ≥11 g/dl during evaluation
(n = 150*) 9 10 11 12 13 14 BL 1
Study week
Hb (g/dl) 5 17 21 25 29 33
Mean (SE) 50
150
250
Study month
Darbepoetin alfa (mg/month) 2 3 4 6 7 8
Median (95% CI)
200
100
*Patients who received at least one dose of DA
Agarwal et al. J Intern Med 2006;260:577–85 14

15. Darbepoetin alfa dose (mg/month)
Q2W dosing of darbepoetin alfa could be safely and effectively extended to the QM regimen
83% of patients had mean Hb ≥10 g/dl during the evaluation (n=66*)
QM DA treatment was safe and well-tolerated
Study week
Darbepoetin alfa dose (mg/month) 25 50 75
100
125
150
Hb (g/dl) 14 13 12 11 10 BL 5 9 17 21 29 1 33 Hb
Dose
*Patients who received at least one dose of DA
Disney et al. Nephrology 2007;12:95–101 15

16. % patients with Hb >11 g/dL
70% of CKD patients not on dialysis achieved Hb level >11 g/dl with extended (Q2W/QM) darbepoetin alfa dosing
% patients with Hb >11 g/dL
The proportion of patients with Hb >11 g/dL at initiation and at 10–12 months was comparable in the prior ESA group (71% vs. 70%) and increased in the ESA-naïve group (19% vs. 72%).
The post-initiation Hb level increase resulted in an increase in the proportion of patients with Hb levels >11 g/dL from 342/1842 (19%) at initiation to 1359/1885 (72%) for Months 10–12.
Galle et al. Nephrol Dial Transplant 2012;27:

17. Hb target was achieved with QM darbepoetin alfa in the majority of CKD patients not on dialysis
% of patients
Hb study target range
1Agarwal et al. J Intern Med 2006;260:577–85
2Disney et al. Nephrology 2007;12:95–101
3Ling et al. Clin Nephrol 2005;63:327–34
4Galle et al. Nephrol Dial Transplant 2012;27: 17

18. 96% of patients preferred QM darbepoetin alfa
Mean Hb level remained stable between baseline (11.4 g/dl) and the end of the study (11.2 g/dl)
N = 319
Patient response (%)
Hoggard et al. Curr Med Res Opin 2006;22:2023–30 18

19. (90% power, 5% significance level)
Correcting anaemia by darbepoetin alfa QM in CKD patients not on dialysis: Design of a randomised phase III study ( )
Primary Objective: To determine whether the efficacy of once monthly (QM) dosing of darbepoetin alfa is non-inferior to that of once every 2 week (Q2W) dosing for the correction of anemia in subjects with CKD not on dialysis
≥ 18 years of age
Clinically stable
eGFR mL/min/1.73 m2
Hb < 10 g/dL at two consecutive measurements
Adequate iron stores (TSAT≥15%)
Darbepoetin alfa Q2W
1:1 randomisation
Double-blind to dose and dosing interval
Target Hb = 10.0 – 12.0 g/dL and ≥ 1.0 g/dL above baseline
Initiation dose: 0.75 µg/kg Q2W or 1.5 µg/kg QM
Non-inferiority margin: -0.5 g/dL
Darbepoetin alfa QM
N ~ 334
(90% power, 5% significance level)
The aim of this randomized, double-blind, non-inferiority, active-controlled, phase III study was to determine whether QM DA dosing was non-inferior to dosing every 2 weeks (Q2W) when treating anaemia in patients with CKD-ND.
The study was conducted at 95 centres in Europe, Australia and Mexico.
To be eligible for the study, patients must:
– be 18 years of age or older
– have a diagnosis of CKD (estimated glomerular filtration rate [eGFR] of 15–59 mL/min/1.73 m2)
– be clinically stable
– have had two consecutive screening Hb values < 10.0 g/dL (taken ≥ 7 days apart)
– have adequate iron stores (transferrin saturation [TSAT] ≥ 15%*)
– be available for protocol-required study visits.
Patients were excluded from the study if they met any of the following criteria:
– erythropoiesis-stimulating agent use in the12-week period before enrolment
– uncontrolled hypertension (diastolic blood pressure > 100 mmHg or systolic blood pressure > 170 mmHg)
– cardiovascular condition in the 12-week period before enrolment
– malignancy in the 5-year period before enrolment (except localized basal or squamous cell carcinoma of the skin, or cervical intraepithelial neoplasia)
– red blood cell transfusions in the 12-week period before enrolment
– systemic haematological disease.
• Patients were randomized 1:1 to receive DA Q2W or QM for 33 weeks. Those randomized to the DA QM study group received placebo injections Q2W to maintain the study blind.
• Hb concentrations were measured every 2 weeks; TSAT was measured every 4 weeks.
• Patients were treated to achieve target Hb levels of 10–12 g/dL and a ≥ 1 g/dL increase from baseline. Patients were then given the corresponding pre-filled syringe based on a range of doses.
Initial DA doses were 0.75 μg/kg and 1.5 μg/kg for the Q2W and QM
groups, respectively.
• The primary endpoint was change in Hb levels between baseline and the evaluation period (weeks 29–33). Non-inferiority between dosing regimens in the correction of anaemia was to be concluded if the lower limit of the two-sided 95% confidence interval (CI) for the least-squares mean difference between treatments (QM − Q2W) was above −0.5 g/dL.
• Additional endpoints included:
– achieving both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL
– the time to achieve both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL
– DA doses over the duration of the study
– safety data
Titration weeks 1 -28
Evaluation weeks 29-33
Primary Endpoint:
Hb change between baseline and the evaluation period (weeks 29-33)
Other Endpoints:
- achieving both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL
- the time to achieve both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL
- Darbepoetin alfa doses over the duration of the study
- Safety data
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

20. Baseline characteristics were not different in the QM and Q2W groups (I/II)
Darbepoetin alfa
Q2W
(N = 175) QM
(N = 180)
Total
(N = 355)
Female – n(%)
107 (61.1)
104 (57.8)
211 (59.4)
Race – n (%)
134 (94.4)
138 (89.6)
272 (91.9)
White / Caucasian
166 (94.9)
163 (90.6)
329 (92.7)
Black / African American
1 (0.6)
1 (0.3)
Other
9 (5.1)
16 (8.9)
25 (7.0)
Age (years) – mean (SD)
68.4 (14.1)
66.3 (15.2)
67.3 (14.7)
Range, years
20 – 90
19 – 92
Weight (kg) - mean (SD)
77.2 (18.6)
75.2 (16.9)
76.2 (17.8)
Range, kg
39 – 142
38 – 125
Primary aetiology of CKD – n (%)
Diabetes mellitus
69 (39.4)
79 (43.9)
148 (41.7)
Hypertension
44 (25.1)
41 (22.8)
85 (23.9)
Glomerulonephritis
7 (4.0)
13 (7.2)
20 (5.6)
Urological disease
6 (3.4)
4 (2.2)
10 (2.8)
Polycystic kidney disease
3 (1.7)
6 (1.7)
Other / unknown
46 (26.3)
40 (22.2)
86 (24.2)
In total, 355 patients were enrolled (Q2W: n = 175; QM: n = 180) and comprised the full analysis set used to report safety data.
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

21. Baseline characteristics were not different in the QM and Q2W groups (II/II)
Darbepoetin alfa
Q2W
(N = 175) QM
(N = 180)
Total
(N = 355)
Medical history – n (%)
Cardiovascular disease
167 (95.4)
172 (95.6)
339 (95.5)
Endocrine or metabolic disease
127 (72.6)
131 (72.8)
258 (72.7)
Hb concentration, g/dL – mean (SD)
9.13 (0.61)
9.11 (0.70)
9.12 (0.65)
Range, g/dL
6.2 – 9.9
5.2 – 9.9
Hb category – n (%)
<8.0 g/dL
8 (4.6)
14 (7.8)
22 (6.2)
≥8.0 to <9.0 g/dL
43 (24.6)
36 (20.0)
79 (22.3)
≥9.0 to <9.5 g/dL
69 (39.4)
72 (40.0)
141 (39.7)
≥9.5 to <10.0 g/dL
55 (31.4)
58 (32.2)
113 (31.8)
eGFR, mL/min/1.73 m2 – mean (SD)
25.9 (9.1)
28.3 (11.1)
27.1 (10.2)
Range, mL/min/1.73 m2
13 – 59
13 – 66
TSAT, % – mean (SD)
27.8 (14.2)
28.9 (13.6)
28.4 (13.9)
Range, %
4 – 94
15 – 97
4 - 97
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

22. Darbepoetin alfa QM dosing was non-inferior to Q2W dosing in correcting CKD anaemia
Change in haemoglobin from baseline to evaluation
Hb, g/dL (95% CI)
Non-inferiority margin
Primary efficacy analysis set
Darbepoetin alfa
Q2W (N = 142)
QM (N = 154)
Treatment difference (QM-Q2W)
Adjusted mean change (SE) in Hb, g/dL
2.16 (0.09)
1.97 (0.08)
-0.19 (0.12)
95% CI
1.98, 2.33
1.80, 2.14
-0.43, 0.05
Patients achieving a Hb level ≥ 10.0 g/dL and an increase from baseline ≥ 1.0 g/dL
At any time, n (%)
139 (97.9)
151 (98.1)
290 (98.0)
95.5, 100
95.9, 100
96.4, 99.6
During the evaluation period, n (%)
131 (92.3)
142 (92.2)
273 (92.2)
87.9, 96.7
88.0, 96.4
89.2, 95.3
The mean change (95% CI) in Hb from baseline to evaluation at weeks 29–33 was 2.16 g/dL (1.98, 2.33) for the Q2W group and 1.97 g/dL (1.80, 2.14) for the QM group, when adjusted for baseline Hb.
The adjusted mean (95% CI) difference in Hb change (QM − Q2W) was −0.19 g/dL (−0.43, 0.05), which demonstrated that QM dosing was non-inferior to Q2W dosing.
Most patients (Q2W: 97.9%; QM: 98.1%) achieved both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL at any time point during the study.
ANCOVA model adjusted for baseline Hb
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

23. Hb achieved over time was similar in the QM and Q2W groups
Mean Hb, 95% CI (g/dL)
Number of subjects
Q2W (n):
142
141
140
139
138
137
136
QM (n):
154
153
152
151
149
150
148
146
Of the 355 patients enrolled, 142 patients and 154 patients had at least one evaluable Hb measurement during the evaluation period and comprised the primary efficacy analysis set for the Q2W and QM subgroups, respectively.
Study week
Baseline Hb is the mean of week -2 and -1 screening values
Hb within 90 days of a transfusion are excluded.
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

24. Comparable proportion of patients achieved a Hb level ≥10 g/dL and a Hb increase ≥1 g/dL from baseline to the evaluation period
Time to first achievement to Hb level ≥10 g/dL
and a Hb increase ≥1 g/dL from baseline
(week) 12 8 4
Q2W
(n = 142) QM
(n = 154) 2 10 6
Proportion of patients (%)
120 80 40
Q2W
(n = 142) QM
(n = 154) 20
100 60
97.9
98.1 5 5
A similarly high level of attainment of both a Hb level ≥ 10.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL during the evaluation period was noted for both treatment groups.
The median (Q1, Q3) time to attaining these levels was similar in both groups: 5 weeks (3, 7) in the Q2W group and 5 weeks (3, 9) in the QM group.
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

25. Weight-adjusted weekly DA dose
Greater darbepoetin alfa weekly doses were used in the QM group than in the Q2W group
Weight-adjusted weekly DA dose
(µg/kg/week)
0.4
0.3
0.2 1
Time (months) 3 5 7 9 11 13 15 17 21 23 25 27 29 31
0.1
Q2W (n = 154)
QM (n = 142) 19
Number of subjects at risk:
Q2W:
QM:
154
153
151
150
142
141
139
140
137
Geometric mean (95% CI) weight-adjusted weekly equivalent DA dose over the evaluation period was 0.20 (0.17, 0.24) μg/kg/week for the Q2W group and 0.27 (0.23, 0.32) μg/kg/week for the QM group.
The use of greater weekly doses of DA in the QM group than in the Q2W group reflects the findings of other clinical trials comparing Q2W and QM dosing regimens of epoetin alfa in CKD-ND populations and peg-EPO in dialysis populations.
Data are presented as geometric mean ± 95% confidence interval.
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

26. Similar safety outcomes were reported with Q2W and QM dosing regimens
Darbepoetin alfa
Full Analysis Set
Q2W
(N = 175)
n (%) QM
(N = 180)
Total
(N = 355)
All treatment emergent adverse events
129 (73.7)
126 (70.0)
255 (71.8)
Serious adverse events
52 (29.7)
54 (30.0)
106 (29.9)
Leading to discontinuation of investigational product
10 (5.7)
7 (3.9)
17 (4.8)
Serious
7 (4.0)
4 (2.2)
11 (3.1)
Non-serious
4 (2.3)
3 (1.7)
7 (2.0)
Leading to discontinuation from study
2 (1.1)
9 (2.5)
6 (3.4)
1 (0.6)
2 (0.6)
Fatal adverse events
5 (2.8)
12 (3.4)
Events of interest
81 (46.3)
76 (42.2)
157 (44.2)
Safety profiles were similar between groups. Darbepoetin alfa was well tolerated and similar safety outcomes were seen with Q2W and QM dosing regimens.
Ferenczi et al. ERA-EDTA 2013 poster, MP211. Abstract available at:

27. SureClick™ improved self-administration, perceived competence and satisfaction in non-dialysed CKD patients
% of patients
Score (scale of 0-36)
Score (scale of 1-7)
p<0.001
24% increase
30% increase
p<0.0001
p<0.0001
National, multicenter, prospective, observational study, including CKD-ND patients with stable Hb, treated for ≥6 months with DA via pre-filled syringes.
Patients have been switched to SureClick® (n=132)
Change from pre-filled syringes to SureClick® has significantly increased self-administration (from 47.7% at baseline to 74.2% at last visit, p<0.001).
Change from pre-filled syringes to SureClick® has significantly increased perceived competence on a 1-7 scale from 4.3% at baseline to 5.6% at last visit, change=1.3 (30%), p<0.05.
Change from pre-filled syringes to SureClick® has significantly increased staisfaction on a 0-36 ATSQ-S scale (36 – maximal satisfaction), from 25.5 at baseline to 31.6 at last visit, change=6.2 (24%), p<0.05.
The use of SureClick® for administering DA is associated with a significant increase of satisfaction and competence among CKD-ND patients. The use of SureClick® enables 3 out of 4 patients to self- administer DA.
Bonafont et al. Nefrologia 2013;33:

28. Security and convenience with needle-stick prevention
Needle-stick injuries affect more than 3 million health-care workers every year, putting them at serious risk of acquiring a blood-borne pathogen1
Using needle-stick prevention devices has been shown to reduce needle-stick injuries by 83%2
SureClick™ improves self-administration, perceived competence and satisfaction in non-dialysed CKD patients3
1Prüss-Ustün et al. Am J Ind Med. 2005;48:482–90
2http://
3Bonafont et al. Nefrologia 2010;30(Suppl1):55 28

29. In patients on haemodialysis
Module 2 – Achieving and maintaining the Hb target with darbepoetin alfa
In patients on haemodialysis

30. Treatment + evaluation period
Extended dosing of darbepoetin alfa was effective in CKD patients on haemodialysis
Reference
Study description
Treatment + evaluation period
Hb study target range
Primary end point
Tolman et al.
J Am Soc Nephrol 2005;16:1463–70
N = 162
TIW EB → QW DA / QW EB
9 months
11–12
Study drug dose
at 9 months
Mann et al.
Clin Nephrol 2007;67:140–8
N = 5520 (pooled)
QW EA / EB → Q2W DA
24 weeks
10–13
Change in Hb between baseline and evaluation
Carrera et al.
Nephrol Dial Transplant 2006;21:2846–50
N = 105
QW DA IV → Q2W DA IV
12 months
11–13
Change in Hb between the switch from QW to Q2W DA
Rottembourg et al.
Clin Nephrol
2011;75(3):242-50
N = 6104
Epoetin a, b, DA, no ESA → Q2W DA
11–13*
10–12+
Hb concentration 12 months after initiation of DA Q2W
BIW = twice a week. CKD = chronic kidney disease. EB = epoetin beta. Hb = haemoglobin. QW = once a week. Q2W = every other week. TIW = three times a week. IV = intravenous.
*Before 2008
+After 2008 30

31. 20% dose decrease after switching from SC epoetin beta TIW to SC DA QW
Epoetin beta SC doses increased by 24% after switching from TIW to QW dosing
µg/kg/wk
IU/kg/wk
1.2
1.0
0.8
0.6
0.4
Mean weekly treatment dose
240
200
160
120 80
0.0
9.0
10.0
11.0
12.0
13.0 1 2 3 4 5 6 7 8 9
Months Hb
Dose
Epoetin beta (EB)
Darbepoetin alfa
N=81
Mean Hb concentration (g/dl, 95% CI)
SC = subcutaneous
Tolman et al. J Am Soc Nephrol 2005;16:1463–70 31

32. Q2W darbepoetin alfa treatment maintained Hb values with no change in the mean dose
Hb values and darbepoetin alfa dosages remained stable over time, independent of the route of administration
Study week
Mean blood Hb value (g/dl) (±SD)
Mean weekly dosage (μg/kg/wk) (±SD) 6 7 8 9 10 11 12 13 14 -2 2 4 16 18 20 22 24
0.4
0.8
1.2
1.6
2.0 Hb
Dose
Hb-IV
Hb-SC
Dose-IV
Dose-SC
N = 1088*
* Patients who received at least one dose of DA IV = intravenous
Mann et al. Clin Nephrol 2007;67:140–8 32

33. Mean Hb concentration and DA dose remained stable after switch to Q2W DA
The median weekly dose of DA was 30 µg at baseline, at the end of treatment period 1 (TP1), and at the end of treatment period 2 (TP2)
Mean Hb (d/dL)
Carrera et al. Nephrol Dial Transplant 2006;21:2846–50 33

34. Months before / after Conversion
Hb and weekly ESA dose remained stable after switch to darbepoetin alfa Q2W in HD patients
Mean Hb (g/dL) Hb
Dose
Weekly dose (µg/wk)
9.0
9.5
10.0
10.5
11.0
11.5
12.0
12.5
13.0 -6 -5 -4 -3 -2 -1 P C 1 2 3 4 5 6 7 8 9 10 11 12 15 20 25 30 35 40 45
There was a steady decrease in the ESA dose over the 6 months before initiation. At initiation, a substantial drop in dose was observed. Patients initiated DA Q2W at a geometric mean (95% CI) dos eof ug (46.56 – 48.21); that is a weekly equivalent dose of ug/week (23.28 – 24.10), which is a reduction from the regimen received immediately before DA Q2W initiation.
From initiation to 12 months, the ESA dose appeared to steadily increase, although it remained lower than the ESA dose just prior to initiation. At month 12, the geometric mean ESA dose was ug/week (26.12 – 27.49).
Note: Hb level each month is defined as the single closest value in a ±2 week analysis time window and at conversion in a -8 week analysis time window. n=
3500
4029
4363
4522
4589
4632 -
5195
4610
4756
4622
4591
4531
4430
4300
4381
4271
4131
4132
3822
4182
4450
4630
4802
4923
5007
5000
5318
5314
5281
5231
5165
5071
4991
4881
4797
4710
4604
4488
4365
Months before / after Conversion
Hb = haemoglobin. DA = darbepoetin alfa. HD = haemodialysis. P = Prior to Conversion, C = At Conversion.
200: 1 conversion ratio
Adapted from: Rottembourg et al. Clin Nephrol 2011;75:242–50. 34

35. Months before / after Conversion
Hb remained stable and weekly ESA dose decreased after switch to darbepoetin alfa Q2W in PD patients Hb
Dose
Weekly dose (µg/wk)
Mean Hb (g/dL)
9.0
9.5
10.0
10.5
11.0
11.5
12.0
12.5
13.0 -6 -5 -4 -3 -2 -1 P C 1 2 3 4 5 6 7 8 9 10 11 12 15 20 25 30 35 40 45 n=
362
441
489
529
520
504 -
702
541
530
542
511
510
492
506
471
481
426
487
534
567
604
646
655
654
741
738
730
721
711
700
692
676
660
644
631
612
Subgroup analyses were completed for dialysis modality, administration route in HD patients, and vascular access type in HD patients. In all subgroups, there is a similar pattern of change both in
Hb: increase until initiation followed by return to a similar level by month 6, and
dose: reduction immediately after initiation followed by an increase but not a return to pre-initiation level by month 12.
PD pateints generally had a lower dose and slightly higher Hb than HD patients.
Note: Hb level each month is defined as the single closest value in a ±2 week analysis time window and at conversion in a -8 week analysis time window
Months before / after Conversion
Hb = haemoglobin. DA = darbepoetin alfa. PD = peritoneal dialysis. P = Prior to Conversion, C = At Conversion.
200: 1 conversion ratio
Adapted from: Rottembourg et al. Clin Nephrol 2011;75:242–50. 35

36. In paediatric patients with chronic renal failure
Module 2 – Achieving and maintaining the Hb target with darbepoetin alfa
In paediatric patients with chronic renal failure

37. Darbepoetin alfa was studied in paediatric patients with chronic renal failure (CRF)
Reference
Study description*
Treatment period
Hb study target range
Primary
end point
André et al.
Pediatr Nephrol 2007;22:708–14
N = 39 (11–18 yrs)
ESA naive  QW DA**
BIW/TIW rHuEPO  QW DA***
QW rHuEPO  Q2W DA***
6 months
11–13 (g/dl)
Mean dose of DA to achieve and maintain Hb levels of 11–13 g/dl
Warady et al.
Pediatr Nephrol 2006;21:1144–52
N = 124 (1–18 yrs)
BIW/TIW rHuEPO  BIW/TIW rHuEPO
BIW/TIW rHuEPO  QW DA
QW rHuEPO  Q2W DA
28 weeks
10–12.5 (g/dl)
Comparing the efficacy of DA with that of rHuEpo
* Open label studies ** Not on dialysis *** 79.3% on dialysis
BIW = twice a week. DA = darbepoetin alfa. ESA, = erythropoiesis-stimulating agents. Hb = haemoglobin. QW = once a week. Q2W = every other week. rHuEPO = recombinant human erythropoietin. TIW = three times a week Dose conversion ratio: 100 (200) IU rHuEPO  0.42 (1) µg DA
DA doses were determined based on the cumulative rHuEpo dose during the previous 1-week or 2-week periods 37

38. Switched patients* (n = 29)
In paediatric CRF patients switched to DA, the Hb level increased by month 3 and stabilised by month 6
Hb (g/dl) DA dose (µg/kg/week)
Naive patients* (n = 10)
0.5
1.0
1.5
Months
Dose (µg/kg/week) 8 10 12 14
Hb (g/dl)
Mean and SD
Switched patients* (n = 29)
Dose (µg/kg/week)
*Patients between 11 and 18 years of age
CRF = Chronic Renal Failure
André et al. Pediatr Nephrol 2007;22:708–14 38

39. Hb change between baseline and evaluation period
In paediatric CKD patients switched to DA, Hb concentrations remained stable
∆Hb (DA): 0.15 (0.23) g/dl
Study week
Mean Hb (g/dl)
12.0
11.5
11.0
10.5 5 10 15 20 25
End of study
Baseline
n = 59
n = 27
Hb change between baseline and evaluation period
∆Hb (rHuEPO): −0.16 (0.31) g/dl
∆Hb: Mean change (SE)
Warady et al. Pediatr Nephrol 2006;21:1144–52 39

40. Incidence of injection site pain was similar with rHuEPO and darbepoetin alfa
Incident of Injection pain (%)
Warady et al. Pediatr Nephrol 2006;21:1144–52 40

41. Label extension for darbepoetin alfa – Paediatric patients with chronic renal failure
Hb target: 10–12 g/dl
Avoid sustained Hb >12 g/dl
Treatment of symptomatic anaemia
Restrictive dose titration
Lowest darbepoetin dose should be used
For patients aged between 11 and 18 years Treatment of patients younger than 1 year of age has not been studied
Aranesp SPC Feb 2012, available at: 41

42. Paediatric patients with chronic renal failure – Correction phase
If Hb >12 g/dl, consider dose reduction. If Hb continues to increase, reduce dose by ~25%. If after dose reduction Hb continues to increase, withhold dose temporarily. Re-initiate with ~25% lower dose.
Hb increases <1 g/dl
in four weeks dose:
Dose increase ~25%
Hb increases >2 g/dl
Dose reduction ~25%
Hb not to exceed
12 g/dl
Paediatric patients with chronic renal failure ≥11 years Initial dose: 0.45 μg/kg SC/IV QW Patients not on dialysis: 0.75 μg/kg SC Q2W
Aranesp SPC Feb 2012, available at: 42

43. Paediatric patients with chronic renal failure – Maintenance phase
Paediatric patients ≥ 11 years
Patients on dialysis:
QW / Q2W darbepoetin alfa
Q2W dose should be equivalent to twice the previous QW dose
Patients not on dialysis:
Q2W  QM darbepoetin alfa*
QM dose should be equivalent to twice the previous Q2W dose
rHuEPO BIW/TIW  darbepoetin alfa QW**
rHuEPO QW  darbepoetin alfa Q2W**
Hb should be monitored every 1 or 2 weeks
Same route of administration should be used
*Once the Hb target has been achieved
**Dose of darbepoetin alfa (μg/week & μg/2 weeks) can be determined by dividing the total weekly dose of r-HuEPO (IU/week) by 240
Aranesp SPC Feb 2012, available at: 43

44. Summary: Patients achieved and maintained Hb targets with darbepoetin alfa
Patients not on dialysis
Q2W dosing of darbepoetin alfa successfully achieves Hb targets in ESA-naive patients and effectively maintained it when patients were switched from rHuEPO to Q2W DA1-4
QM DA is safe and effective in CKD patients by maintaining the target Hb levels in over 70–85% of the patients with a stable dose requirement4-7
Use of SureclickTM improves convenience and satisfaction for patients and offers benefits to the health-care professionals by reducing the risk of needle-stick injuries8-10
Patients on haemodialysis
Switch from rHuEPO (TIW/BW/QW) to less frequent dosing with SC or IV darbepoetin alfa (QW/Q2W) is effective in maintaining Hb levels11-14
Children are able to maintain target Hb levels at extended dosing intervals while receiving darbepoetin alfa15-16
1Suranyi et al. Am J Nephrol 2003;23:106–11. 2Toto et al. Am J Nephrol 2004;24:453–60. 3Hertel et al. Am J Nephrol 2006;26:149–56.
4Galle et al. Nephrol Dial Transplant 2012;27: Agarwal et al. J Intern Med 2006;260:577–85. 6Disney et al. Nephrology 2007;12:95–101.
7Ling et al. Clin Nephrol 2005;63:327–34. 8http:// 9Hoggard et al. Curr Med Res Opin 2006;22:2023–30.
10Bonafont et al. Nefrologia 2010;30(Suppl1):55. 11Tolman et al. J Am Soc Nephrol 2005;16:1463–70. 12Mann et al. Clin Nephrol 2007;67:140–8. 13Carrera et al. Nephrol Dial Transplant 2006;21:2846–50. 14Rottembourg et al. Clin Nephrol 2011;75(3):242–50.
15André et al. Pediatr Nephrol 2007;22:708–14. 16Warady et al. Pediatr Nephrol 2006;21:1144–52. 44

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