Darbepoetin scientific information and comparison

ANEMIA IN CKD
STAGE eGFR
(ml/min/1.73m2)
ANEMIA
PREVALENCE
3 30-59 5.2%
4 15-29 44.1%
5 <15 or on dialysis 100%

CAUSES OF ANEMIA IN CKD
 EPO deficiency
 Blood loss
 Shorter RBC life span
 Decreased bone marrow responsiveness to
EPO
 Vitamin deficiencies
 Iron deficiency (poor iron absorption)
 High uremia level
 Chronic inflammation

ANEMIA IN CKD LEADS TO :
 ↓ QOL
 ↓ energy and exercise capacity
 ↓ neurocognitive function
 ↑ mortality (27.3% of all cause
mortality)
 ↑ LVH
 Onset of cardiac events

EFFECT OF ANEMIA ON
CARDIOVASCULAR SYSTEM
 CV disease related mortality is 15 times more in patients with CKD.
 50% of deaths in patients with CKD are due to CV disease.
 LVH is the most common abnormality seen in patients with CKD and
there is a strong correlation between anemia and LVH.
 Tissue hypoxia due to anemia is the principal stimuli triggering the
compensatory changes that stresses the CV system

ERYTHROPOIESIS-STIMULATING
AGENTS
 Erythropoiesis-stimulating agents (ESA) are effective in
achieving and maintaining target haemoglobin levels.
 Traditional ESA include epoetin α and epoetin β.
 Epoetin α and β resemble closely the endogenous molecule
and have similar pharmacokinetics.
 Second-generation ESA include darbepoetin and continuous
erythropoiesis receptor activator (CERA).
Acta Nephrologica 26(3): 137-142, 2012

RECOMBINANT HUMAN
ERYTHROPOIETIN (rHuEPO)
 Although rHuEpo has proven highly effective in treating renal
anaemia, administration two or three times weekly is recommended
for most patients because of its short circulating half-life.
 The chronic nature of the disease and its treatment means that
multiple weekly injections of rHuEpo may be inconvenient for both
patients and healthcare providers.
Asakawa et al. Renal Replacement Therapy (2016) 2:12
J Intern Med 2006; 260: 577–585

DARBEPOETIN ALFA
 The recombinant human erythropoetin, epoetin alfa, was approved by
the FDA in 1993 for the treatment of anemia associated with
chemotherapy.
 Darbepoetin, was created by site-directed mutagenesis and differs from
epoetin at five amino acid positions.
 Darbepoetin was approved by the FDA for the treatment of anemia
associated with chemotherapy in July of 2001.

DESCRIPTION
 Darbepoetin alfa is a erythropoiesis-
stimulating protein that is produced in
Chinese hamster ovary (CHO) cells by
recombinant DNA technology.
 165-amino acid protein : contains 5 N-
linked oligosaccharide chains, whereas
recombinant human erythropoietin
contains 3 chains. The approximate
molecular weight is 37,000 daltons.
 NESP = Novel erythropoiesis stimulating protein-
Darbepoeitin Alfa
 The "X"s in darbepoetin alfa represent the five
amino acid exchange sites that were required to
allow the attachment of two extra N-linked
carbohydrate chains.

STRUCTURAL AND CHARACTERISTIC DIFFERENCE
BETWEEN RECOMBINANT HUMAN
ERYTHROPOIETIN ALFA AND DARBEPOETIN ALFA.
CHARACTERISTICS HUMAN
ERYTHROPOIETIN ALFA
DARBEPOETIN ALFA
Structure 3-linked CHO chains 5-linked CHO chains
Sialic acid 14 sialic acid residues 22 sialic acid residues
Molecular weight 30,400 daltons 38,500 daltons
Carbohydrates 40% 52%
Plasma half life 4-8 hours 24 hours

MECHANISM OF ACTION
 Erythropoietin deficiency is the primary
cause of their anemia.
 Darbepoetin alpha stimulates
erythropoiesis by the same mechanism
as endogenous erythropoietin.
 A primary growth factor for erythroid
development, erythropoietin is
produced in the kidney and released
into the bloodstream in response to
hypoxia.

MECHANISM OF ACTION
 In respond to hypoxia, erythropoietin
interacts with progenitor stem cells to
increase red blood cell (RBC)
production.
 Increased hemoglobin levels are not
generally observed until 2 to 6 weeks
after initiating treatment with
Darbepoetin alpha.

DOSAGE FORMS AND
STRENGTHS
 Single-dose prefilled syringes: 25 mcg/0.42mL, 40 mcg/0.4mL, 60
mcg/0.3 mL

INDICATIONS
DARBEPOETIN ALFA is erythropoiesis-stimulating agent (ESA)
indicated for the treatment of anemia due to:
 Chronic Kidney Disease (CKD) in patients on dialysis and
patients not on dialysis.
 In patients with non-myeloid malignancies where anemia is
due to the effect of concomitantly administered
chemotherapy.
Arensp FDA international pi

DOSAGE AND ADMINISTRATION
 Recommended starting dose for CKD patients on dialysis :
 0.45 mcg/kg intravenously or subcutaneously weekly, or
 0.75 mcg/kg intravenously or subcutaneously every 2 weeks
 Intravenous route is recommended for patients on hemodialysis
 Recommended starting dose for patients with CKD not on dialysis :
 0.45 mcg/kg intravenously or subcutaneously at 4 week intervals
 Recommended starting dose for cancer patients on chemotherapy :
 2.25 mcg/kg subcutaneously weekly, or 500 mcg subcutaneously every 3 weeks

Ref:PI
Lesser incidence of vascular access thrombosis
CKD : Chronic Kidney Disease
QW: Once weekly Q2W : biweekly TIW : Thrice in a week
FEWER PRICKS FOR BETTER
COMPLIANCE

DOSING ADJUSTMENT INSTRUCTION
 CKD:
 • If Hb does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not
increase the dose more frequently than once every 4 weeks
 • If Hb increases >1 g/dL in 2-week period: Reduce dose by ≥25%
 • Inadequate or lack of response over a 12- week escalation period: Discontinue
therapy
 Cancer:
 • If Hb does not increase by >1 g/dL after 4 weeks: Increase to 300 units/kg 3
times/week or 60,000 units weekly
 • If Hb increases >1 g/dL in 2-week period or exceeds target: Withhold dose and
resume with 25% dose reduction if needed
 Inadequate response at 8 weeks: Discontinue Arensp FDA international pi

ADVERSE REACTIONS
 Patients with CKD: Adverse reactions in ≥ 10% of Darbepoetin-
treated patients in clinical studies were hypertension, dyspnea,
peripheral edema, cough, and procedural hypotension.
 Cancer Patients Receiving Chemotherapy: Adverse reactions in ≥ 1%
of Darbepoetin-treated patients in clinical studies were abdominal
pain, edema, and thrombovascular events .

USE IN SPECIFIC POPULATIONS
 Pregnancy category C: Based on animal data, may cause fetal harm.
Pregnancy Surveillance Program is available.
 Nursing Mothers: Exercise caution when Darbepoetin is administered to
a nursing woman.
 Pediatric Use: Safety and efficacy not established in the initial treatment
of anemic patients with CKD, in the transition from another
erythropoietin in patients with CKD who are less than 1 year of age, or
in pediatric patients with cancer.

CONTRAINDICATIONS
 Uncontrolled hypertension
 Pure red cell aplasia (PRCA) that begins after treatment with
darbepoetin alfa or other erythropoietin protein drugs
 Serious allergic reactions to darbepoetin alfa

WARNINGS AND PRECAUTIONS
 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using
Darbepoetin to target a hemoglobin level of greater than 11 g/dL increases the risk
of serious adverse cardiovascular reactions and has not been shown to provide
additional benefit. Use caution in patients with coexistent cardiovascular disease
and stroke.
 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in
Patients With Cancer.
 Hypertension: Control hypertension prior to initiating and during treatment
 Seizures: increases the risk for seizures in patients with CKD. Increase monitoring of
these patients for changes in seizure frequency or premonitory symptoms.

CONVERSION FROM EPOETIN ALFA TO
DARBEPOETIN IN PATIENTS WITH CKD ON
DIALYSIS
 Due to the longer serum half-life, Darbepoetin alfa is
administered less frequently than epoetin alfa.
 Administer darbepoetin once weekly in patients who were
receiving epoetin alfa 2 to 3 times weekly.
 Administer darbepoetin once every 2 weeks in patients who
were receiving epoetin alfa once weekly.

ESTIMATED DARBEPOETIN STARTING DOSES (MCG/WEEK) FOR
PATIENTS WITH CKD ON DIALYSIS BASED ON PREVIOUS EPOETIN
ALFA DOSE (UNITS/WEEK)
Previous weekly epoetin alpha dose (units/week) Darbepoetin alpha dose(mcg/week)
Adult Pediatric
< 1,500 6.25 *
1,500 to 2,499 6.25 6.25
2,500 to 4,999 12.5 10
5000 to 10,999 25 20
11,000 to 17,999 40 40
18,000 to 33,999 60 60
34,000 to 89,999 100 100
≥90000 200 200

Studies from Europe and United States had shown that
darbepoetin α maintained haemoglobin levels as safely and
effectively as epoetin in dialysis patients at a reduced dosing
frequency and no antibodies to darbepoetin were detected.

Comparison between short and long acting ESAs in Hemodialysis patients
Darbepoetin EPO
No. of dose changes
• Hb variability is less frequent with Darbepoetin group with respect to EPO
Group.
• Fewer dose changes in Darbepoetin group compared to EPO Group.
Darbepoetin EPO
Randomized
prospective open label
study
N=139
(Darbepoetin
:72,EPO:67)
Study duration:24
weeks
Int Urol Nephrol 2014 ;46:453–459
Hb : Hemoglobin , ESA Erythropoetin Stimulating Agents
EPO : Erythropoetin
*
CONSISTENT HB LEVEL IN
DIALYSIS PATIENTS

STAAR Study
52 weeks multicenter study to access the efficacy of Q2W Darbepoetin in CKD patients who
were on rHuEPO before Darbepoetin but not on dialysis
Hb levels were maintained over 52 weeks without a significant change
in darbepoetin dose
Mean Hb concentrations (±SD) by study week
Mean Q2W darbepoetin alfa dose (±SD) by study week
Subgroup analysis
N=524
Study Duration:52 weeks
Am J Nephrol 2006;26:149–156CKD : Chronic Kidney Disease
CONSISTENT HB LEVEL IN CKD PATIENTS
NOT ON DIALYSIS

Comparison between Darbepoetin and Epoetin
for Treatment of Anemia in Hemodialysis Patients
Acta Nephrologica 26(3): 137-142, 2012

Darbepoetin at a reduced dosing frequency for treatment of
anemia in chronic renal insufficiency not yet on dialysis
• NESP administered subcutaneously (starting
dose 0.45µg/kg once weekly)
Multicenter,
randomized, open-
label study.
Patients:
• >=18 years, with
a diagnosis of CRI,
• hemoglobin
concentration11.0
g/dL,
• serum vitamin B12
and folate levels
above the lower
limit of the normal
range, and
• a creatinine
clearance of 30
mL/min
Primary measure of
efficacy:
• Proportion of patients
achieving Hb response
during the 24-week
treatment period,
(defined as an increase
in hemoglobin of 1.0
g/dL from baseline and
a hemoglobin
concentration of 11.0
g/dL).
Safety:
• Adverse events,
laboratory variables
(hematology,
biochemistry, and
• iron status), vital signs,
and antibody formation
to NESP or rHuEPO
Kidney International, Vol. 60 (2001), pp. 741–747
Study drug dose was adjusted by 25% of the starting dose as necessary to achieve a hemoglobin increase of 1.0 g/dL from baseline and to maintain
hemoglobin concentrations within a range of 11.0 to 13.0 g/dL.
If a patient’s hemoglobin increased by 2.0g/dL during any four-week period, study drug doses were reduced by 25% of the starting dose.
If a patient’s hemoglobin concentration increased to 14.0 g/dL, study drug was withheld until the hemoglobin concentration fell below 12.0 g/dL and was
restarted at a dose 25% lower than the previous dose.
• rHuEPO administered subcutaneously (starting
dose 50 U/kg twice weekly).
Randomized to receive NESP or rHuEPO in a 3:1
ratio

Cont..
Results
A hemoglobin response (defined as an increase of 1.0 g/dL from baseline and a
concentration11.0 g/dL) was achieved by 93% (95% CI, 87 to 97%) of patients
receiving NESP during the 24-week treatment period.
Similarly, 92%(95%CI, 78 to 98%) of patients achieved a response in the rHuEPO
group.
Mean hemoglobin concentrations at
four-week intervals.
The shaded area indicates target range.
Symbols are the patients receiving:
(DOT) recombinant human erythropoietin
(rHuEPO);
(Triangle) novel erythropoiesis
stimulating protein (NESP).
Abbreviations are:
E, number of patients receiving rHuEPO;
N, number of patients receiving NESP.

Treatment of anemia with darbepoetin alfa administered
de novo once every other week in chronic kidney
disease.
© Copyright
Fresenius Kabi
AG
Objective: To evaluate extending the dosing interval of darbepoetin alfa to once every other week
administration for the treatment of anemia in patients with chronic kidney disease (CKD) not requiring
dialysis who were naive to rHuEPO therapy.
• Multi-center, open-label study.
• 76 rHuEPO-naïve patients were enrolled to
receive darbepoetin alfa (0.75 microg/kg)
once every other week for up to 24 weeks.
• Doses were titrated to achieve and maintain
a hemoglobin target of 11-13 g/dl.
RESULTS:
• 97% of patients completing 24 weeks of treatment
achieved a hemoglobin response.
• The median time to response was 5 weeks (range 1-
25 weeks).
• The median darbepoetin alfa dose at the time of
response was 60 microg (range 30-130 microg).
• Darbepoetin alfa was safe and well tolerated, and
no antibodies to darbepoetin alfa were detected.
CONCLUSION: These results demonstrate the utility of darbepoetin alfa administered once every other week in rHuEPO-
naive CKD patients. This new treatment paradigm may allow for more widespread management of anemia in patients with
CKD.
Am J Nephrol. 2003 Mar-Apr;23(2):106-11.

Darbepoetin alfa administered to achieve and maintain target
hemoglobin levels for 1 year in EPO-naive patients with CKD-ND.
© Copyright
Fresenius Kabi
AG
OBJECTIVE: To assess the efficacy and safety of every-other-week darbepoetin alfa therapy in treating anemia
and maintaining hemoglobin levels for 1 year in patients with chronic kidney disease (CKD) who were not
undergoing dialysis and who had not previously received erythropoesis-stimulating proteins (ESPs).
PATIENTS AND METHODS:
• Multicenter 52-week study,
• Patients with CKD who were not receiving dialysis (creatinine
clearance < or =70 mL/min or estimated glomerular
filtration rate [GFR] < or =60 mL/min).
• Patients not receiving ESPs, had hemoglobin concentrations
<11 g/dL, and had transferrin saturation of 20% or higher
during screening.
• Patients initiated every-other-week darbepoetin alfa therapy
at 0.75 microg/kg, with the dose subsequently titrated to
maintain hemoglobin levels not to exceed 12 g/dL.
RESULTS:
• The least squares mean evaluation Hb concentration
was 11.54 g/dL and the change from baseline was 1.6
g/dL
• The mean (SD) every-other-week darbepoetin alfa dose
during evaluation was 44.5 (33.7) mcg.
• Darbepoetin alfa was well tolerated throughout the
study period
CONCLUSION: Darbepoetin alfa initiated every other week safely and effectively treated anemia and
maintained hemoglobin for 1 year in patients with CKD who were not undergoing dialysis and who were not
receiving prior ESP therapy.
Am J Nephrol. 2006;26(2):149-56.

Darbepoetin alfa administered once monthly (QM) maintains Hb
concentrations in patients with CKD.
OBJECTIVE: To evaluate the effect of extending the darbepoetin alfa dosing interval to once
monthly in patients with chronic kidney disease (CKD) not receiving dialysis.
PATIENTS AND METHODS:
• Mlticenter, open-label study of 97 patients with CKD
ND.
• Patients receiving stable subcutaneous doses of
darbepoetin alfa once every two weeks were converted
to once monthly for 29 weeks.
• The proportion of patients who successfully maintained
hemoglobin concentrations between 10.0 and 12.0 g/dl
and the mean dose were evaluated.
• Safety measurements (e.g. adverse events, laboratory
parameters, blood pressure) and sero-reactivity were
assessed.
RESULTS:
• Hemoglobin concentration was maintained within
the target range in 79% of all patients receiving
darbepoetin alfa and in 85% of patients who
completed study period.
• The safety profile for monthly darbepoetin alfa
administration was comparable with that previously
observed with more-frequent administration.
CONCLUSION: Patients with CKD who are clinically stable on darbepoetin alfa administered
once every two weeks can be safely and effectively converted to darbepoetin alfa administered
once monthly. Clin Nephrol. 2005 May;63(5):327-34.

Darbepoetin alfa administered once monthly for the
maintenance of Hb concentrations in patients with CKD-
OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in
maintaining haemoglobin (Hb) 11.0-13.0 g/dL in subjects with chronic kidney disease (CKD) not receiving dialysis
and previously treated with darbepoetin alfa every other week (Q2W).
SUBJECTS: Open-label study
subjects >=18 years of age
GFR >=15 and <=60 Ml/min/1.73 m(2), had Hb 11.0-
13.0 g/dL, and were receiving Q2W darbepoetin alfa.
DESIGN:
Subjects were switched to QM darbepoetin alfa
therapy for 28 weeks; the QM dose was titrated to
maintain Hb levels.
Primary end-point: proportion of subjects maintaining
Hb > or =11.0 g dL(-1) during the final 8 weeks of the
study (evaluation phase).
Secondary end-points:
Hb concentration during evaluation, darbepoetin alfa
dose during the study, adverse events, laboratory
parameters, and blood pressure.
RESULTS:
• Mean Hb >=11.0 g/dL (during evaluation was achieved by
76% of the 150 subjects who received at least one dose of
darbepoetin alfa
• Mean (SD) Hb during evaluation was 11.71 (0.92) g/dL.
• 85% of 129 subjects who completed the study had Hb
>=11.0 g/dL during evaluation.
• The dose of darbepoetin alfa over the study period was
124.4 mug.
CONCLUSION: Darbepoetin alpha administered QM maintained Hb in patients
with CKD not receiving dialysis.
J Intern Med. 2006 Dec;260(6):577-85

High target hemoglobin with ESAs has advantages in the renal
function of CKD-ND patients.
OBJECTIVE: We investigated the long-term effects of maintaining high hemoglobin (Hb) on renal function in
patients with chronic kidney disease not on dialysis.
SUBJECTS:
• Hb < 10 g/dL and serum creatinine (Cr) 2-6
mg/dL)
• Randomized to either
• a high Hb group (N = 161, 11.0 ≤ Hb <
13.0 g/dL) receiving darbepoetin alfa or
• a low Hb group (N = 160, 9.0 ≤ Hb < 11.0
g/dL) with epoetin alfa,
• Stratified according to baseline Hb and
serum Cr levels, comorbidity of diabetes,
and study centers.
• Primary endpoints: doubling of serum Cr,
initiation of dialysis, renal transplantation, or
death.
RESULTS:
• Three-year cumulative renal survival rates were 39.9% and 32.4%
in the high and low Hb groups, respectively.
• The estimated hazard ratio for the high versus the low Hb group
was 0.71, the risk reduction was 29% in the high Hb group.
• Incidences of serious adverse cardiovascular events did not differ
significantly between the high and low Hb groups (3.1% and 4.4%,
respectively).
• No safety issues were noted in either group.
CONCLUSION: Maintaining higher Hb levels with darbepoetin alfa better preserved renal
function in patients with chronic kidney disease not on dialysis.
Ther Apher Dial. 2012 Dec;16(6):529-40

Darbepoetin Alfa is as effective as epoetin for the
Treatment of Anemia in Hemodialysis Patients at a
reduced dosing frequency.
© Copyright
Fresenius Kabi
AG
0.24
0.11
0
0.05
0.1
0.15
0.2
0.25
0.3
Darbepoetin alfa Epoetin alfa
MeanchangeinHblevelsfrom
baselinetoevaluation
Epoetin three times
weekly vs darbepoetin alfa
once weekly
Design: randomized, double-blind, noninferiority study
Methods:
Patients with CKD >= 18 years, clinically stable, and on hemodialysis therapy for
at least 12 weeks, administered stable IV epoetin alfa therapy three times weekly
for a minimum of 8 weeks and have a mean baseline hemoglobin concentration
of 9.5 to 12.5 g/dL. To ensure adequate iron stores to support erythropoiesis,
transferrin saturation was required to be 20% or greater
Patients receiving epoetin therapy were randomized to continue epoetin
administered intravenously (IV) three times weekly (n=338) or change to
darbepoetin alfa administered IV once weekly (n=169).
Primary end point: change in hemoglobin level between baseline and the
evaluation period (weeks 21 to 28)
Results: The safety profile of darbepoetin alfa was similar to that of epoetin, and
no antibody formation to either treatment was detected.
Conclusion: These results show that darbepoetin alfa maintains hemoglobin
concentrations as effectively and safely as epoetin in patients with CKD, but with a
reduced dosing frequency. Am J Kidney Dis. 2002 Jul;40(1):110-8.

ANEMIA POST RENAL
TRANSPLANT
 Darbepoetin alfa has also been evaluated as a treatment option for anemia
after transplantation.
 Pankewycz and colleagues in a prospective study have shown correction of
anemia in 60% post transplant patients at 3 months.
 A retrospective study (n=129) demonstrated that Administering darbepoetin
alfa in the first week following renal transplant reduces anaemia incidence
during the first month without increase cardiovascular events.

ANEMIA POST RENAL
TRANSPLANT
 In a small study (n=20) subcutaneous darbepoetin alfa 200μg was given every
2 weeks to the patients with post stem-cell transplantation anemia.
Darbepoetin was found to be effective without any major safety concerns.
 In an observational, single centre study among renal transplant patients,
darbepoetin corrected anemia both in previously treated as well as EPO naïve
patients. It was found to be well tolerated.

COMPARISON WITH CERA
 20 CKD patients at the pre-dialysis stage who had been administered DA for over
24 weeks were randomly assigned to receive subcutaneous CERA or DA once
every four weeks during 48 weeks.
 In both groups, the rate of achievement of target Hb level changed from 70% to
100% in weeks 0 to 48, with no significant difference between the groups.
 There was no significant difference in the levels of estimated glomerular filtration
rate and iron status between both groups.
 Results suggest that subcutaneous administration of DA or CERA once every four
weeks to predialysis patients has similar effects on achievement of target Hb levels

POINTS TO REMEMBER
 Efficacious in patients converting from previous once-weekly (QW)
erythropoietic therapy with recombinant human erythropoietin(rHuEPO),
and in those naive to erythropoietic therapy.
 Less dosage frequency compared to rHuEPO due to threefold longer serum
half life and greater biological activity.
 More preferred for “pre-dialysis” and “maintenance therapy” in CKD Patients
with anemia.

POINTS TO REMEMBER
 It gives slow and steady rise in Hb and maintains target levels while EPO
gives fast rise.
 Increases convenience & better treatment compliance
 Recently published cochrane review concluded that CERA has little or no
effects on patient-centred outcomes compared with darbepoetin alfa for
adults with CKD.

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