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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

THANK YOU!

Peter Yorgin, MDpyorgin@ucsd.edu