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IS THERE ANYTHING BETTER THAN ERYTHROPOIETIN FOR (RENAL) ANEMIA?
Peter Yorgin, MDClinical Director of Pediatric Nephrology
OBJECTIVES Discuss The Concerns Regarding Current
Exogenous Erythropoietin Replacement Therapy
Review The Roles Of Erythropoietin Mimetics and the Inhibitors of Down-Regulation of Erythropoiesis
Explore New Erythropoiesis Stimulating Agents (ESA) Erythropoeitin-mimetics
Hematide CNTO 530 Anti-EPO receptor complex antibodies (Axys Pharmaceuticals)
Fusion proteins EPO-EPO GS-CSF-EPO EPO-CGC EPO-TpC
OBJECTIVES
ANTI-Down Regulators Prolyl hydroxalase inhibitors
FG 2216 FG 4592
GATA inhibitors K-11706 K-7174
HCP inhibitors
Briefly Examine Erythrocyte Replacement Options
LIST OF BESTSELLING DRUGS
Rank 2006 Brand Name(s) Generic Name Sales 2006 (USD millions) Change from
2005 Company(ies)
Disease/Medical Use
First Approval Date
1 Lipitor Atorvastatin 14,385 7% Pfizer Cholesterol Dec-1996
2 Advair, SeretideFluticasone +
Salmeterol6,129 12% GlaxoSmithKline Asthma Aug-2000
3 Plavix, Iscover Clopidogrel 6,057 -5% Bristol-Myers Squibb
Thrombotic events
Nov-1997
4 Nexium Esomeprazole 5,182 12% AstraZenecaGastrointestinal
disordersMar-2000
5 Norvasc Amlodipine 4,866 3% Pfizer Hypertension Jul-1992
6 Remicade Infliximab 4,428 23%
Johnson & Johnson, Schering-Plough
, Mitsubishi Tanabe Pharma
Crohn's disease, Rheumatoid
arthritisAug-1998
7 Enbrel Etanercept 4,379 20% WyethRheumatoid
arthritisNov-1998
8 Zyprexa Olanzapine 4,364 4% Eli Lilly Psychosis Sep-19969 Diovan Valsartan 4,223 15% Novartis Hypertension Dec-1996
10 Risperdal Risperidone 4,183 18% Johnson & Johnson
Psychosis Dec-1993
11 AranespDarbepoetin
alfa4,121 26% Amgen Anemia Jun-2001
12Rituxan,
MabTheraRituximab 3,861 16%
Roche, Genentech, Biogen Idec,
Chugai Pharmaceutical
Non-Hodgkin’s lymphoma
Nov-1997
13 Effexor Venlafaxine 3,722 8% WyethDepression,
Anxiety disordersDec-1993
14Protonix, Pantozol, Pantoloc
Pantoprazole 3,621 4%Wyeth, Altana,
SolvayGastrointestinal
disordersFeb-2000
15 Singulair Montelukast 3,579 20% Merck & Co. Asthma Feb-199816 Seroquel Quetiapine 3,560 23% Astellas Pharma Schizophrenia Sep-1997
17Prevacid, Takepron
Lansoprazole 3,425 3%TAP Pharmaceuticals
, Takeda Pharmaceutical
Gastrointestinal disorders
May-1995
18 Procrit, Eprex Erythropoietin 3,180 -4% Johnson & Johnson
Anemia Dec-199019 Cozaar, Hyzaar Losartan 3,163 4% Merck & Co. Hypertension Apr-199520 Fosamax Alendronate 3,134 -2% Merck & Co. Osteoporosis Sep-1995
http://en.wikipedia.org/wiki/List_of_bestselling_drugs
CONCERNS REGARDING EXOGENOUS ERYTHROPOIETIN
Cost $2 Billion in 2005
USRDS 2005 report
$10,000-20,000 per dialysis patient year
Per patient/year cost $4836. For patients requiring therapy, $10,000/year is common
USRDS 2009 data http://www.usrds.org/reference.htm
$1,840,760,373
CONCERNS REGARDING EXOGENOUS ERYTHROPOIETIN Hyperkalemia
Decreased clearance of potassium (-8.6%) due to the decrease in plasma volume – adust clearances. Buur T., Lundberg M. Clin Nephrol 34(5): 230-5,1990. Schaefer R. M., Schaefer, L. Nephrol Dial Transplant 11 Suppl 281-2,
1996
Hypertension Rise of hematocrit and erythrocyte mass Changes in production or sensitivity to endogenous
vasopressors Alterations in vascular smooth-muscle ionic milieu Dysregulation of production or responsiveness to
endogenous vasodilatory factors A direct vasopressor action of EPO Arterial remodeling through stimulation of vascular cell
growth. Vaziri, N. D. Am J Kidney Dis 33(5): 821-8, 1999.
CONCERNS REGARDING EXOGENOUS ERYTHROPOIETIN: CHOIR STUDY
Singh, A. K. et al N Engl J Med 355(20):2085-98, 2006
CONCERNS REGARDING EXOGENOUS ERYTHROPOIETIN
Besarab, A. et al. N Engl J Med 339(9): 584-90, 1998.
ERYTHROPOIETIN BLACK BOX WARNING Erythropoietin Black Box Warning Patients currently using or considering the use of an ESA should know the following:
A higher chance of death and an increased rate of tumor growth were reported in patients with advanced head and neck cancer receiving radiation therapy and in patients with metastatic breast cancer receiving chemotherapy, when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
A higher chance of death was reported and no fewer blood transfusions were received when ESAs were given to patients with cancer and anemia not receiving chemotherapy.
A higher chance of death was reported and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in patients with chronic kidney failure when ESAs were given to maintain hemoglobin levels of more than 12 g/dL.
A higher chance of blood clots was reported in patients who were scheduled for major surgery and given ESAs. ESAs are not approved for treatment of the symptoms of anemia, such as fatigue in patients with cancer, surgical
patients and patients with HIV. If you have any questions you should talk with your health care provider.
Important study results include the following: Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart
attacks, strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels (hemoglobin more than 12 g/dL).
Patients with head and neck cancer receiving radiation therapy had faster tumor growth when ESAs were adjusted to maintain hemoglobin levels higher than 12 g/dL.
Patients with cancer not receiving chemotherapy died sooner and had no fewer blood transfusions when ESAs were given according to the dosing recommendations for cancer patients receiving chemotherapy.
Patients scheduled for orthopedic surgery who received ESAs to reduce blood transfusions during and after surgery had more blood clots than those not given an ESA.
Physicians who prescribe ESAs should consider the important study results above and: Adjust the dose of ESA to maintain the lowest hemoglobin level necessary to avoid the need for
transfusions; Monitor patients' hemoglobin levels to ensure they do not exceed 12 g/dL; Understand that ESAs are given to decrease the chances of receiving transfusions; Understand that ESAs have not been shown to improve the outcomes of chemotherapy treatment (e.g., better tumor
shrinkage, delay in tumor growth or longer time for survival); Consider both the risks of transfusions and those of ESAs when deciding to prescribe an ESA; and Understand that ESAs should not be given to treat the symptoms of anemia, including shortness of breath, dizziness,
fatigue, low energy, or poor quality of lifehttp://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm124262.htm
ACCELERATORS AND INHIBITORS
REGULATION OF ERYTHROPOIESIS: ACCELERATORS (+)
HIF-2a and b
Erythropoietin
Erythropoietin receptor
Hypoxia
More erythrocytes
ESA COMPARISON (ERYTHROPOIETIN-LIKE THERAPY)
Erythropoietin alpha
Erythropoietin beta
Erythropoietin delta
Erythropoietin omega
Darbepoetin Methoxy polyethylene glycol-erythropoietin beta
Brand names
Epogen, Procrit
NeoRecormon DynEPO Epomax Aranesp Mircera
Half life IV: 4-13 hoursSQ: 13-37 hours
IV: 4 - 12 hours SQ: 8-22 hours
IV: 4.7 to 13.2 hours
IV: 10-30 hours
IV: 12-39 hoursSQ: 21-144 hours
SQ: 139-142 hours
FDA Approval
Approved Not approved, Approved in Europe
Not approved in USA, Approved in Europe
Not approved in USA. Approved in Europe
Approved Approved
Source Chinese hamster ovary cells
Chinese hamster ovary cells
Human cell line
Baby hamster kidney cells
Chinese hamster ovary cells
Chinese hamster ovary cells
CONTINUOUS ERYTHROPOIETIN RECEPTOR ACTIVATOR (CERA) METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA (MIRCERA)
AMICUS ARCTOS MAXIMA PROTOS STRIATA RUBRA
Intervention CERA IV1x/2wk
CERA IV1x/2wk
CERA IV 1x/2wkCERA IV 1x/4wk
CERA IV 1x/2wkCERA IV 1x/4wk
CERA IV1x/2wk
CERA IV/SCpre-filledsyringes 1x/2wk
Comparator EPO IV3x/wk
DAR SC 1x/wk
EPO IV1-3x/wk
EPO IV1-3x/wk
DAR IV 1x/wkor 1x/2wk
EPO IV/SC1-3x/wk
Subjects N=181dialysisEPO-naïve
N=324pre-dialysisEPO-naïve
N=673dialysis
N=673dialysis
N=313dialysis
N=336dialysis
Mean baseline Hgb
CERA:9.4 g/dLEPO:9.4 g/dL
CERA:10.2 g/dLDAR:10.2 g/dL
CERA 1x/2wk:12.0 g/dLCERA 1x/4wk:11.9 g/dLEPO: 12.0 g/dL
CERA1x/2wk:11.7 g/dLCERA1x/4wk:11.6 g/dLEPO: 11.6 g/dL
CERA: 12.0 g/dLDAR: 11.9 g/dL
CERA: 12.0 g/dLDAR: 11.9 g/dL
Mean Hgb Result
CERA:12.1 g/dLEPO: 12.0g/dL
CERA:12.3 g/dLDAR:12.2 g/dL
CERA 1x/2wk: 11.9CERA 1x/4wk:11.9 g/dLEPO: 11.9 g/dL
CERA 1x/2wk:11.7 g/dLCERA 1x/4wk:11.5 g/dLEPO: 11.5 g/dL
CERA: 12.1 g/dLDAR: 11.8 g/dL
CERA: 11.9g/dLEPO: 11.8 g/dL
Adapated from http://www.cadth.ca/media/pdf/E0025_Mircera_for_Renal_Anemia_cetap_e.pdf
ADMINISTRATION OF MIRCERA IN CKD PATIENTS TOTREAT ANEMIA WITH A TWICE-MONTHLY SCHEDULE (ARCTOS STUDY)
MacDougall IC, et al. Clin J Am Soc Nephrol 3: 337-347, 2008
MIRCERA VERSUS DARBEPOEITIN ADVERSE EFFECTS
EPO FC MONOMER AND EPO FC DIMER
epo
Fc domain of human IgG
epoepo
Erythroepoeitin Fc monomer
Erythroepoeitin Fc dimer
Full length human erythropoietin
A.J. Bitonti, J.A. Dumont . Advanced Drug Delivery Reviews, 58, 1106–1118, 2006.
In humans, reticulocyte counts increased after receiving the highest dose.
Dumont JA, et al. J Aerosol Med 18: 294-303, 2005.
EPO FC: AFTER SINGLE INHALATION
A.J. Bitonti, J.A. Dumont . Advanced Drug Delivery Reviews, 58, 1106–1118, 2006.
LESS TIGHT BINDING TO THE RECEPTOR INDUCES BETTER ERYTHROPOIESIS
Lacy S.E. et al. J. Immunol. 2008;181;1282-1287
CNTO 530
Bugelski PJ et al. J Biotechnol, 2008, 134, 171–
Fc domain of human IgG4
EMP-1
Linker
• CNTO has no sequence homology with erythropoietin.
• There is a signal peptidase consensus site, an EMP1 sequence, a flexible linker, a human J chain and a human IgG4 Fc domain.
CNTO 530: PHASE 1 STUDY
Bouman-Thio E et al. J Clin Pharmacol. 2008 ,48,1197-207
HEMATIDETM
Hematide is a polyethylene glycolated synthetic peptide with no sequence homology to erythropoietin
The Hematide molecule is PEGylated making it more stable
PEG(Polyethylene
Glycol)
Peptide
Peptide
HEMATIDETM
Single-group open-labeled trial for patients had chronic kidney disease and pure red-cell aplasia or hypoplasia due to anti-erythropoietin antibodies.
Subcutaneous injection of HematideTM 0.05 mg per kilogram every 4 weeks.
14 patients were treated with HematideTM for a median of 28 months.
The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter.
Transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions.
Anti-erythropoietin antibodies decreased and became undetectable in six patients.
One developed antibodies against HematideTM. Macdougall, I. C. et al. N Engl J Med 361: 19: 1848-55, 2009.
DOWN-REGULATION OF ERYTHROPOIESIS: INHIBITORS (-)
Fewer erythrocytes
Hypoxia Inducible Factor Inhibition
GATA Inhibitors
HYPOXIA INDUCIBLE FACTOR (HIF) Hypoxia Inducible Factor (HIF) HIF-1, 120kda, in the subfamily
of of transcription factors Regulates erythropoietin gene
transcription There are three HIFs
Hypoxia inducible factor 1 a Hypoxia inducible factor 2 a Hypoxia inducible factor 3 a
HIF-2a seems to be the dominant isoform in regulating erythropoietin production.
Percy MJ, et al. Blood 2008; 111:5400–02.Percy MJ, et al. N. Engl. J. Med. 2008; 358: 162–8.
http://en.wikipedia.org/wiki/File:Protein_HIF1A_PDB_1h2k.png
REGULATION OF HIF
Hypoxia inducible factor 2 a
NORMOXI
A
• Degradation by Von Hipple Lindau Disease protein binding and ubiquination
HYPOXIA
• Translocation to the nucleus, binding with HIF , b
transcription of erythropoietin
PROLYL-HYDROXYLASES
Three prolyl hydroxylases PHD1 PHD2 PHD3
Ascorbate is required for function of the enzymes Maintains iron in its reduced form
These enzymes are inhibited by Hypoxia Iron Cobalt
Epstein ACR, et al Cell 2001; 107: 43–54
NORMOXIA: HIF BONDING TO VON HIPPLE LINDAU DISEASE PROTEIN
HIF-1
HIF-1• Proline
converted to Hydroxyproline by proline hydroxylase
HIF-1• Proline
converted to Hydroxyproline
• Bound to VHL disease protein
Ivan M, et al. Science 2001; 292: 464–8
NORMOXIA: NO ERYTHROPOIETIN TRANSCRIPTION
HIF-1 bound to VHL disease
protein
HIF-1 transported by ubiquitins for
degradation in proteosome
system
Erythropoietin DNA not
transcribed
Salceda, S .et al. J Biol Chem 272(36): 22642-7, 1997.
HYPOXIA
HIFa
HIF a binds to HIF b which translocates
HIF-1 into the nucleus
HIF a and HIF b Bind to the
hypoxia response
elements of the
erythropoietin DNA
NORMOXIA: PROLYL HYDROXYLASES
ProlineHydroxyproline
2-oxyglutarate succinate
Prolyl hydroxylase 2 a
O2 CO2
McNeill LA, et al. Bioorg. Med. Chem. Lett. 2002;12: 1547–50
Hypoxia inducible factor a 2
PROLYL HYDROXYLASES INHIBITORS (ANTI-INHIBITOR)
Polycythemia due to Prolyl hydroxylase gene defects Gene defect of PHD2 in humans
Percy MJ, et al. Proc. Natl. Acad. Sci. USA 2006; 103: 654–9.
Gene defects of PHD1 and PHD3 in mice Minamishima YA, et al. Blood 2008; 111: 3236–44. Takeda K, et al. Blood 2008; 111: 3229–35.
Chuvash polycythemia Ang SO, et al. Nat. Genet 2002; 32: 614–21.
Inhibition of prolyl hydroxylase protein leads to an increase in erythropoietin production
PROLYL HYDROXYLASE INHIBITORS
Prolyl Hydroxylase Inhibitors The use of 2-oxoglutarate mimics
Dimethyloxalylglycine, inhibits the HIF hydroxylases which are associated with induction of HIF and HIF-regulated genes. Jaakkola P, et al. Science 2001; 292: 468–
72.
FibroGen Developed oral medications based on
small molecule inhibitors of hypoxia induciblefactor-prolyl hydroxylase FG 2216 FG 4592
Proline
2-oxyglutarate
Prolyl hydroxylase 2 a
O2 CO2
UNLIKE RHUEPO, FG-2216 MITIGATES CKD ANEMIA WITHOUT EXACERBATING HYPERTENSION IN 5/6TH NEPHRECTOMY (NX) MODEL
Ligation of left renal artery to infarct 2/3 of kidney with simultaneous Nx of right kidney
Anemia allowed to develop for 5 wks followed by treatment for 3 wks
100
150
200
250
Langsetmo I., et al. (2005) JASN 16:481A
11
12
13
14
15
16
17
18
Weeks of Dosing0 1 2 3
0 1 2 3
Systo
lic B
lood
Pre
ssu
re(m
m H
g)
Hem
og
lob
in(g
/dL)Sham + Vehicle
Nx + Vehicle
Nx + rHuEPO
Nx + FG-2216
ORAL HIF-PHI ELEVATE HEMOGLOBIN (HB) AND MITIGATE ANEMIA OF CHRONIC DISEASE
Normal Animals Anemia of Chronic Disease
HIF-PHI and darbepoetin enhance Hb in normal animals HIF-PHI elevate Hb in anemic animals with chronic
inflammation No parenteral iron required for HIF-PHI effect
Hb
Diff
ere
nce f
rom
Veh
icle
(g
/dL)
14.4
19.0
14.1
19.8
19.5
9.5 13.5
13.7
10.1
9.6
-1
0
1
2
3
4
5
6
7
Vehicle FG-2216 FG-4592 Darbepoetin IV Iron Vehicle FG-2216 FG-4592 Darbepoetin IV Iron
Langsetmo I, et al. (2005) JASN 16:481A and Klaus S, et al. (2005) JASN 16: 49A
FG-2216 ELICITS ENDOGENOUS EPO IN NEPHRIC AND ANEPHRIC DIALYSIS PATIENTS
Time After Dosing (hrs)0 4 8 12 24
Age-Matched Healthy Volunteersa
7.5 (2.6)
11.5 (4.5)
70.0 (36.6)
90.0 (40.8)
55.3 (30.2)
Remnant Kidney Dialysis Patients
47.6 (82.8)
46.0 (49.0)
136.1 (130.9)
250.0 (225.7)
304.0 (269.7)
Anephric Dialysis Patientsb
7.4 (7.0)
17.5 (14.1)
42.0 (27.9)
52.9 (30.3)
44(22.2)
a Healthy normal volunteers and remnant kidney dialysis patients were age-matched.b One patient was accidentally under-dosed with ~4mg/kg b.w.
Data indicate mean plasma EPO level (U/L) (SD) after single dose of FG-2216 (20 mg/kg)
Both nephric and anephric dialysis patients exhibit time-dependent increases in EPO
EPO in anephric patients assumed to be hepatic-derived
Group
Bernhardt W.M., et al. (2007) JASN 18:515A
WHERE IS ERYTHROPOIETIN PRODUCED?
Koury S.T. et al. Blood 1991 77: 2497-2453.
ROBUST HEMOGLOBIN RESPONSE TO FG-2216 (N=142)
Mean H
b C
hange f
rom
Base
line (
g/d
L)
Weeks of Therapy
Placebo (N=14) 375 mg (N=26) 625 mg (N=52) 1250 mg (N=50)P values indicate a significant difference compared to the placebo group: p ≤ 0.05; **p ≤ 0.001; ***p < 0.0001
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4 8 15
*
*
*
**
***
******
Provenzano R., et al. (2008) American Journal of Kidney Diseases; April;Vol. 51, Issue 4, Page B80
FG-4592 REDUCES LIVER HEPCIDIN EXPRESSION IN ANEMIA INDUCED BY CHRONIC INFLAMMATION (2-WEEK DATA)
Liver RNA isolated 6 hours after last dose of FG-4592 Significant increase in hepcidin expression due to inflammation FG-4592 reduces hepcidin expression in normal animals and
animals with ACD
Rela
tive H
ep
cid
inExp
ressio
n
0
1
2
3
4
Vehicle VehicleFG-4592 FG-4592
Normal Animals Anemia ofChronic Disease
Klaus S, et al. (2005) JASN 16: 49A
CONCERNS REGARDING PROLYL HYDROXYLASE INHIBITORS
Activating HIF and such hydroxylase inhibitors seem to closely mimic the gene expression response to hypoxia.
May impact a wider family of 2-oxoglutarate-dependent dioxygenases might also be inhibited by such molecules, are often themselves transcriptionally regulated by hypoxia and have increasingly characterized roles in histone and DNA modification.
Death by acute liver failure in one patient
ERYTHROPOIETIN RECEPTOR EFFECTS
Jak-2
GATA
INB
Ras
RAF
GTP
Mek
Erk
RSK
C-fos
C-JunSTAT5
Epo
EpoRSHIP
NFKb
VDAC
NFKb
mitochondiaSTAT5
STAT5
STAT5
STAT5
GATA INHIBITORS
GATA inhibits erythropoietin (Epo) promoter activity
GATA-specific inhibitors to improve Epo production.
K-11706 Oral administration of K-11706 increased
hemoglobin and serum Epo concentrations, reticulocyte counts and numbers of erythroid colony-forming unit (CFU-E) in a mouse model. Nakano Y. et al. Blood 104(13) 4300-4307, 2004.
K-7174 K7174 was able to abrogate the reduction in
hemoglobin caused by IL-1β, and TNF-α. Imagawa S. et al. FASEB J Sep;17(12):1742-4, 2003.
GATA INHIBITORS: K-7174
CAN ERYTHROCYTES BE REPLACED?
OXYGEN-CARRIER PRODUCTSCATEGORY PRODUCT TYPE MW (DALTONS)
Perfluorocarbons OxygentTM Perfluroctylbromide
450-500
Hemoglobin-based oxygen carriers
HemAssistTM Diaspirin-crosslinkied human hemoglobin
65,000
HemopureTM Polymerized bovine hemoglobin
250,000
PolyhemeTM Pryidoxylated glutaradehyde-polymerized hemoglobin (human)
150,000
HemospanTM Maleimide-actived polyethylene-glycol-modified hemoglobin (human)
95,0000
Hemoglobin vesicles
OxygenixTM Hemoglbin containing liposomes (OXY-0301)
Unpublished
PERFLUROCARBONS Advantages
The oxygen release from PFCs to tissue is almost complete in the presence of a high PO2 gradient between arterial blood and tissue.
Extension of acute normovolemic anemia (hematocrit 21% to 8%) without signs of impaired tissue oxygenation or compromised myocardial contractility
Risks Restricted to low dosages
because studies have indicated that PFC emulsion droplets are rapidly taken up by the reticuloendothelial system and subsequently cause immunosuppression
Adverse Effects Increased rate of
neurological complications? Phase III trials discontinued Increased incidence of
postoperative ileus, Flu-like symptoms, fever,
headache,nausea, and myalgia
HEMOGLOBIN-BASED CARRIERS
HemAssist™ (Baxter Healthcare)
Used for treatment of severe trauma or hemorrhagic shock
Demonstrated increased rates of 24-hour and 48-hour mortality.
PolyHeme™ (Northfield Labs Inc.)
Proved to be an effective resuscitation fluid in 171 patients suffering from massive hemorrhage.
HEMOGLOBIN BASED CARRIERS Hemopure™; (Biopure
Corp.) In hemorrhagic shock,
Hemopure is effective and improved outcome.
Concerns Vasoconstriction
augmented release of endothelin, and
stimulation of endothelin receptors and adrenoreceptors
Hemospan™ (Sangart Inc)
Proven to provide sufficient tissue oxygenation at the microcirculatory level in an experimental model of hemorrhagic shock without causing vasconstriction.
Finished testing in phases I and II, and phase III hospital trial.
HEMOPURE
HEMOPURE: POLYMERIC BOVINE HEMOGLOBIN
Levy J.H. et al. J Thorac Cardiovasc Surg 2002;124:35-42
HEMOSPAN (MP4OX)
http://www.sangart.com/products/mp4ox.htm
ESA SCORECARDExogenous
erythropoietin
Prolyl Hydroxylase
Inhibitors
Erythropoietin receptor agonists
Erythrocyte replacement
therapies
COST +++ ++ ? ?ROUTE IV or SQ Oral SQ/Inhaled IV
Frequency EPO 3x/weekDarbepoeitin 1x/1-2 weeks
2-3 times per week
2-4 weeks Weeks
ADVERSE EFFECT PROFILE
HTN, Hyperkalemia
, Increased risk
of MI
Nausea, Headache
HTN Hepatic enzyme and
amylase elevation
BENEFITS Known performer
Better iron absorption
Less frequent dosing
Immediately available
