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Aranesp® (darbepoetin alfa) Therapy for Oncology Patients

Oncologic Drugs Advisory CommitteeMay 4, 2004

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Amgen Guests

Jeffrey Crawford, MD Professor of Medicine Duke University School of Medicine

David DeMets, PhD Professor and Chair of BiostatisticsUniversity of Wisconsin

John Glaspy, MD, MPH Professor of MedicineUniversity of California at Los Angeles School of Medicine

Harvey Lodish, PhD Professor of Biology and Professor of Bioengineering at MITMember of Whitehead Institute

Douglas Losordo, MD Associate Professor of MedicineTufts University School of Medicine

Marc Pfeffer, MD, PhD Senior Physician in CardiologyProfessor of MedicineBrigham and Women’s Hospital

Joseph Eschbach, MD Senior Research AdvisorNorthwest Kidney CenterClinical Professor MedicineUniversity of Washington

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Independent Investigators

Principal Investigator Study Group Institution

J. Overgaard, MD The Danish Head Dept. Experimental Clinical Oncology and Neck Cancer Aarhus University HospitalStudy Group Aarhus C. Denmark(DAHANCA)

R. Delarue, MD Groupe d’Etude des Adult Hematology DeptLymphomes de l’Adulte Hospital Necker, Paris, France

A. Bosley, MD (GELA) Hematology Dept.UCL Mont Godinne, Belgium

U. Nitz, MD Westdeutschen Gynecological ClinicStudiengruppe (WSG) Dusseldorf University

Dusseldorf, Germany

S. Kahlert, MD Gynecological Clinic and Polyclinic for Oncology Study Obstetrics and Gynecology,Group (AGO) Grosshadern Clinic, Ludwig-

Maximillian UniversityMunich, Germany

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Presentation Outline

Background Dawn Viveash, MDVP of Regulatory Affairs and Safety

EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT

Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment

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Distinct Properties of Aranesp

Altered amino Altered amino acid sequence acid sequence permits permits attachment ofattachment of2 additional 2 additional carbohydrate carbohydrate side chains side chains

Increase in Increase in negative negative chargecharge

Increase in Increase in molecular molecular weight weight and sizeand size

5-fold reduction in 5-fold reduction in receptor binding receptor binding affinityaffinity

3-fold increase in 3-fold increase in serum half lifeserum half life

Leads to improved Leads to improved in vivo biological in vivo biological activityactivity

Molecular Differences Compared

with Epoetin

Physical Differences Compared

with Epoetin

Biological Differences Compared

with Epoetin

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Aranesp Approvals

September 2001 US Nephrology Approval– Aranesp is indicated for the treatment of anemia

associated with chronic renal failure, including patients on dialysis and patients not on dialysis

July 2002 US Oncology Approval – Aranesp is indicated for the treatment of anemia in

patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy

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Aranesp Product Labeling

Warnings: Cardiovascular events (including thrombotic events)– Association with high hemoglobin and rate of rise

– Description of Besarab1 study including mortality

Guidance regarding hemoglobin target and rate of rise– Adjust dose to achieve and maintain a target Hb 12 g/dL and rate of rise

of Hb not to exceed 1 g/dL in two weeks

Precautions: Theoretical concern regarding growth factor potential

Adverse reactions: Thrombotic events– Overall incidence 6.2% for Aranesp and 4.1% for placebo; specific

mention of pulmonary embolism and thrombosis

1Besarab et al. NEJM. 339(9):584;1998.

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Comprehensive Risk Assessment:Preclinical Data with Darbepoetin alfa

Not genotoxic1

No proliferative or hyperplastic signals inlong-term animal toxicology studies1

No tumor progression in tumor xenograft models2,3

Beneficial effect (decrease in tumor progression) in association with radiotherapy3

1Amgen data on file.2Kirkpatrick et al. 2003.3Ning et al. 2003.

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Comprehensive Risk Assessment:Clinical Data

Epidemiological analysis of thrombotic events

Review of completed and ongoing Aranesp trials

Post-marketing oncology experience

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Aranesp Safety Observations

No detrimental effect on survival

No tumor progression signal

Thrombotic event rate consistent across pre-and post-approval studies

Product label appropriately represents relevant safety information

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Presentation Outline

Background Dawn Viveash, MDVP of Regulatory Affairs and Safety

EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT

Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment

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Characteristics of Established Oncogenes

Chromosome translocation

Gene amplification

Gene mutation

Protein over-expression

Protein truncation

Auto-phosphorylation

Signaling in absence of ligand

Transforming

Prognostic indicator

Therapeutic target

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The EPO-R and Tumorgenicity

The EPO-R is not an oncogene– No amplification of the EPO-R gene in any tumor except

for 2 erythroleukemic cell lines– No activating EPO-R point mutations in any human or

animal tumor

Humans with EPO-R truncations are hypersensitive to EPO but have no increase in tumor incidence

EPO transgenic mice and humans over-expressing EPO are polycythemic but have no increase in tumor incidence

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EPO-R Expression in Erythroid Cells

Over 90% of receptors are in the cytoplasm, not on the cell surface

Only 1000 - 2000 receptors are present on the cell surface

Surface expression requires JAK-2 and possibly other accessory proteins

2 EPO-R:1 EPO complex is required for signaling

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Measuring EPO-R in Fixed or Frozen Primary Tumor Biopsies

RT-PCR – Measures EPO-R transcripts, not functional EPO-R

mRNA, EPO-R protein, or functional receptor– Requires separation of tumor from other cells

Immunohistochemistry– Measures EPO-R in the cytoplasm and on the cell

surface– Too insensitive to detect cell surface EPO-R– Existing antibodies not sufficiently specific

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Measuring EPO-R in Fresh Primary Tumor Biopsies All methods require purifying tumor cells from other cells and at least 108 cells

per sample

Binding with radio-labeled EPO– Difficult to detect specific, saturable binding to EPO-R versus non-specific, non-

saturable binding– Difficult to detect low numbers of low-affinity

(Kd >1 nM) receptors

Proliferation in response to EPO– Fresh tumor cells generally are not viable in culture

EPO-induced signal transduction pathways– EPO-induced phosphorylation of EPO-R, JAK-2, STAT-5, etc– Requires immunoprecipitation – Western blot analysis– Very insensitive, low signal to background ratio in

non-erythroid cells

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Presentation Outline

Background Dawn Viveash, MDVP of Regulatory Affairs and Safety

EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT

Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment

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Clinical Observations

Benefits associated with treatment of anemia

Thrombotic Events Analyses in Oncology– Epidemiology

– Clinical trials

Survival Analyses of Aranesp Clinical Trials

Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored

– Independent-investigator sponsored

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Anemia is a Significant Complication of Chemotherapy Treatment in Patients with Cancer

Anemia is a highly prevalent comorbidity1-5 – ~90% of chemotherapy patients will develop anemia (grade

1-4)– Up to 30% of patients develop grade 3-4 anemia

Anemia has a significant impact in quality of life and commonly results in transfusions6

– 40 - 60% of anemic patients will require transfusions7,8

– 61% of patients believe fatigue affects their quality of life more than pain

– 78% of patients with cancer experience fatigue

1Chau L, et al. Br J Haem. 2003;120:970-977; 2Louvet C, et al. J Clin Oncol. 2002;20:4543-4548; 3Scheithauer W, et al. J Clin Oncol. 2003;21:1307-1312; 4Hitt R, et al. Ann Oncol. 2002;13:1665-1673; 5Schiller JH, et al. N Engl J Med 2002;346:92-98; 6 Vogelzang N, et al. Semin Hematol. 1997;34(suppl 2):4–12; 7Tandem audit; 8Amgen data on file.

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Aranesp Increases Hemoglobin and Reduces Transfusions

RBC Transfusions from week 5 to 13

314 1487 77315N =

PlaceboQWK

Q2WKQ3WK

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n +

95%

CI

328 1462 81330N = 0.0

0.2

0.4

0.6

0.8

1.0

PlaceboQWK

Q2WKQ3WK

Pro

po

rtio

n +

95%

CI

Hematopoietic response

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Evidence-Based Clinical Practice Guidelines by ASH/ASCO and NCCN

Confirmed the benefits of anemia treatment regarding transfusion requirements and improvement in HRQOL1-5

Guidelines provide recommendations regarding:– Hemoglobin target (11 – 12 g/dL)4

– Thresholds for withholding erythropoietic protein therapy

Amgen supports these independent evidence-based guidelines– They are consistent with the US package insert

for Aranesp

1Seidenfeld et al. 2001; 2Bohlius. 2003; 3Crawford et al. 2002; 4Sabbatini et al. 2004; 5Rizzo et al. 2001.

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Clinical Observations

Benefits associated with treatment of anemia

Thrombotic Events Analyses in Oncology– Epidemiology

– Clinical trials

Survival Analyses of Aranesp Clinical Trials

Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored

– Independent-investigator sponsored

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Analysis of Thrombotic Events in Oncology Patients

Thrombotic event terms as defined in approved US product label

Methods:– Analysis of epidemiologic databases

• General Practice Research Database (108,000 patient-years)

• Medstat Marketscan Database (~7,000 patient years)

– Analysis of Amgen clinical trial data• 11 Aranesp oncology trials completed by November 2003

• 1,807 Aranesp and 444 Placebo subjects

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Patients with Cancer Receiving Epoetin alfa and Epoetin beta Have a Higher than Background Risk of Thrombotic Events

Amgen analysis of Medstat Claims Database(1,305 patients)– Adjusted RR1 = 1.40 [95% CI: 0.90-2.16]

Bohlius et al. [2003]2 meta-analysis: 12 controlled trials (1,737 patients)– RR = 1.55 [95% CI: 0.93-2.59]– Does not include BEST or ENHANCE studies

Amgen analysis (Aranesp)– Confirms stable rate since approval– Prior TE history and poor performance status are independent risk

factors

1Adjusted for age, sex, cancer type, and comorbidities2Bohlius, et al. Blood. 2003;102:203a. Abstract 709.

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Clinical Observations

Benefits associated with treatment of anemia

Thrombotic Events Analyses in Oncology– Epidemiology

– Clinical trials

Survival Analyses of Aranesp Clinical Trials

Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored

– Independent-investigator sponsored

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Survival Analysis in Aranesp Randomized, Placebo-Controlled Trials in CIA

1Vansteenkiste J, et al. J Natl Cancer Inst. 2002;94:1211-1220. (Study 980297)2Hedenus M, et al. Br J Haematol. 2003;122:394-403. (Study 20000161)3Hedenus M, et al. Br J Haematol. 2002;119:79-86. (Study 980291)4Kotasek D, et al. Eur J Cancer. 2003;39:2026-2034. (Study 990114)

Studies: Characteristics:

Lung cancer1 N = 314 Homogeneous patient populationPlatinum-based therapyLong-term follow-up

Lymphoid malignancies2 N = 344 Less homogeneous patient populationsLong-term follow-up

Mixed solid tumor3 N = 405 Heterogeneous patient populationLymphoid malignancies4 N = 66 Follow-up (16 weeks)

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Aranesp Lung Cancer Study

RandomizationN = 314

Chemotherapy1

Aranesp 2.25 µg/kg/week

for 12 weeks

Chemotherapy1 Placebo

for 12 weeks

Endpoint

RBC

Transfusion

Long-termFollow-up

for Survival And Progression

Median follow up time:16 months

Placebo Aranesp

Number of patients 159 155

HistologyNSCLC 114 (72%) 108 (70%)SCLC 45 (28%) 47 (30%)

1Platinum-basedStudy 980297

Hb entry: 11 g/dLWithhold dose: Hb >14g/dL

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Aranesp

Placebo

Pe

rce

nt

20

40

60

80

100

Months from 1st Dose0 3 6 9 12 15 18 21 24

Subjects at risk:

PlaceboAranesp

159155

114116

5063

2635

1416

713

46

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Progression-free Survival in Lung Cancer Patients

Study 9802971Adjusted for histology

Total Events

Aranesp 155 131

Placebo 159 145

Hazard Ratio1

0.81 (95% CI: 0.64, 1.03)

0

01

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Overall Survival in Lung Cancer Patients

Placebo

Aranesp

20

40

60

80

100

0 3 6 9 12 15 18 21 24

Subjects at risk:

PlaceboAranesp

159155

127133

8694

5874

4449

3034

1616

37

Total Deaths

Aranesp 155 100

Placebo 159 119

Hazard Ratio1

0.78 (95% CI: 0.60, 1.01)Pe

rce

nt

Months from 1st Dose

0

01

Study 9802971Adjusted for histology

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Aranesp Lymphoid Malignancy Study

Median follow-up time:27 months

Placebo Aranesp

Number of patients 169 175NHL 45 (27%) 39 (22%)

HD 9 (5%) 12 (7%)CLL 26 (15%) 29 (17%)MM 83 (49%) 90 (51%)Waldenstrom’s 6 (4%) 5 (3%)

RandomizationN = 344

Chemotherapy +Aranesp

2.25 µg/kg/weekfor 12 weeks

Chemotherapy +Placebo

for 12 weeks

Endpoint

RBC

Transfusion

Long-termFollow-up

for Survival And Progression

Study 20000161

Hb entry: 11 g/dLWithhold dose: Hb >14g/dL

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Aranesp Lymphoid Malignancy Study: Baseline Characteristics

Placebo AranespN = 169 N = 175n (%) n (%)

Non-Hodgkin’s lymphoma 45 (27) 39 (22)Indolent 29 (64) 20 (51)Aggressive 16 (36) 17 (44)

International Prognostic Index0 – 2 30 (67) 22 (56)3 – 5 15 (33) 17 (44)

Multiple myeloma 83 (49) 90 (51)Stage I + II 28 (34) 36 (40)Stage IIIA + B 55 (66) 54 (60)

Chronic lymphocytic leukemia 26 (15) 29 (17)Stage A + B 14 (54) 11 (34)Stage C 11 (42) 17 (59)

Study 20000161

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Progression-free Survival in Patients with Lymphoid Malignancies

Study 200001611Adjusted for disease type, stage and IPI score

Aranesp

Placebo

Pe

rce

nt

20

40

60

80

100

Months from 1st Dose0 3 6 9 12 15 18 21 24

Subjects at risk:

PlaceboAranesp

169175

150146

119125

104109

96100

8585

7172

6360

Total Events

Aranesp 175 120

Placebo 169 113

Hazard Ratio1

1.11 (95% CI: 0.85, 1.44)

0

4943

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Overall Survival in Patients withLymphoid Malignancies

Aranesp

Placebo

20

40

60

80

100

0 3 6 9 12 15 18 21 24

Subjects at risk:

PlaceboAranesp

169175

160162

146150

135136

132126

124122

116117

113101

Total Deaths

Aranesp 175 80

Placebo 169 61Hazard Ratio1

1.33 (95% CI: 0.95, 1.86)

Pe

rce

nt

Months from 1st Dose

0

Study 200001611Adjusted for disease type, stage and IPI score

9376

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Number of Patients Tumor Type

314 Lung cancer

410 Lymphoid cancer

405 Mixed Solid Tumor

1,129

(708 Aranesp, 421 Placebo)

933 Patient-years of follow-up

Pooled Analysis of Four Amgen Completed Trials Concerning Tumor Progression and Survival

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Progression-free Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data

Pe

rce

nt

80

85

90

95

100

Weeks After 1st Dose0 4 8 12 16

Subjects at risk:

PlaceboAranesp

421708

405680

372642

349572

Placebo

Aranesp

Hazard Ratio2

1.02 (95% CI: 0.78, 1.33)

1Studies 980297, 20000161, 980291, 9901142Adjusted for study, disease type, stage and IPI score

0

252313

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Overall Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data

Placebo

Aranesp

80

85

90

95

100

Weeks After 1st Dose0 4 8 12 16

Subjects at risk:

PlaceboAranesp

421708

411687

387660

368600

294358

Hazard Ratio2

1.02 (95% CI: 0.67, 1.54)

0

Pe

rce

nt

1Studies 980297, 20000161, 980291, 9901142Adjusted for study, disease type, stage and IPI score

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Pooled1 Analyses: Progression-free Survival Hazard Ratios Associated with Aranesp (A) vs Placebo (P) by Tumor Type

1Studies 980297, 20000161, 980291, 990114

Hazard Ratio (95% CI)0.1 1.0 10

Ovarian (A = 11/49, P = 3/12)

Breast (A = 16/94, P = 6/23)

GI Other (A = 15/54, P = 4/13)

SCLC (A = 40/60, P = 42/47)

NSCLC (A = 99/146, P = 109/130)

Lymphoma (A = 29/70, P = 32/60)

Myeloma (A = 66/105, P = 57/86)

CLL (A = 26/39, P = 22/28)

Other (A = 23/91, P = 5/22)

Overall (A = 325/708, P = 280/421)

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No Negative Impact on Progression or Survival Outcomes with Hb 13 g/dL or 1 g/dL in 14 Days

Pooled analyses of Aranesp trials; Studies 980297, 20000161, 980291, 990114;Models stratified by study; adjusted for treatment therapy and baseline Hb value;Hb increase and Hb target were time-dependent covariates; Hb values within 28 days of a transfusion are excluded.

HazardEndpoint ratio 95% CI

1 g/dL Hb Progression-increase in 14 days free Survival 0.51 0.42, 0.62

Survival 0.43 0.34, 0.56

Achieved Hb of Progression-13 g/dL free Survival 0.66 0.51, 0.84

Survival 0.56 0.40, 0.79

(857/1129)

(272/1129)

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Summary of Safety Experience with Aranesp®

Thrombotic event rate is appropriately represented in the Aranesp prescribing information

No effect on tumor progression or survival has been observed in Aranesp oncology clinical trials

Safety profile of Aranesp remains unchanged and excellent since its approval for oncology and nephrology indications

Benefit / Risk of Aranesp remains favorable

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Clinical Observations

Benefits associated with treatment of anemia

Thrombotic Events Analyses in Oncology– Epidemiology

– Clinical trials

Survival Analyses of Aranesp Clinical Trials

Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored

– Independent-investigator sponsored

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Rationale for the Investigation of Anemia Treatment on Tumor Progression and Survival

Well-established association between anemia and decreased survival in multiple malignancies– Overall increase in mortality risk: RR = 1.65 (1.54, 1.77)1

Pre-clinical correlations between anemia, tumor oxygenation, tumor response and survival in the setting of radiotherapy2-4

Trends toward improved survival in some chemotherapy induced anemia trials in oncology– Observed with Aranesp in SCLC [RR = 0.62 (0.38,1.01)]5

– Cochrane Meta-analysis with epoetin alfa and beta also suggest a benefit [RR = 0.80 (0.65, 1.00)]6

1 Caro et al. Cancer. 2001;91:2214; 2 Grogan M, et al. Cancer. 1999;86:1528–1536; 3 Overgaard J. Sem. Rad. Oncol. 1996;6:10-21; 4 Glaser CM. Int.J.Radiat.Oncol.Biol.Phys. 2001;50:705-715; 5 Vansteenkiste J, et al. J NCI 2002;94:1211-1220; 6 Bohlius et al, Blood. 2003;102:203a, abs 709.

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Amgen-Sponsored and Investigator-Initiated Studies of Aranesp in Oncology

Purpose:– Testing hypothesis of potential Aranesp survival benefit for multiple

oncology settings Process: – All Aranesp oncology studies worldwide reviewed

• Hemoglobin baseline, target, dosing algorithms• Safety monitoring• Design appropriateness for survival assessment

Outcome:– Five large randomized, controlled trials comprise a survival focused

clinical development program• One Amgen sponsored • Four investigator initiated, independently conducted, cooperative group trials

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Ongoing Survival Clinical Trials Program: Design Elements Randomized, controlled– Aranesp vs. placebo (double-blind) or

Aranesp vs. no epoetin (open-label) Aranesp administration during chemotherapy

or radiotherapy Progression and survival endpoints Safety endpoints monitored including thrombotic and

cardiovascular events Homogeneous populations Stratification for prognostic variables Long-term follow-up

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Ongoing Survival Clinical Trials Program: Sample Size and Tumor Type

Patient Population

Follow-up: over 9,000 patient-years

# of Patients Tumor Type

1,720 Breast cancer (2 trials)600 Head and neck cancer600 Lymphoma600 Small-cell lung cancer

3,520

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Amgen Small Cell Lung Cancer Study

RandomizationDouble-blind

N = 600

Cis/Carboplatin +Etoposide + Aranesp Endpoint

Survival

Follow-up

Study endpoints:• Survival• Change in Hb• FACT-F

Cis/Carboplatin +Etoposide + Placebo

Hb entry: 9 - 13 g/dLWithhold dose: Hb >14g/dL

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AGO Breast Cancer StudyDr. M. Untch et al.

RandomizationN = 720

SequentialTherapy(ECT)

SequentialDose-intensified

Therapy(ETCMF)

Endpoint

Relapse-freeand

OverallSurvival

Follow-up

Aranesp

Supportivecare

Aranesp S u

r g

e r

y

Study endpoints:• Relapse-free and overall survival• Complete pathological response• Quality of lifeE = epirubicin

C = cyclophosphamideT = paclitaxelM = methotrexateF = flourouracil

Withhold dose: Hb >14g/dL

Supportivecare

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WSG Adjuvant Breast Cancer StudyDr. U. Nitz et al.

RandomizationN = 1000

CEF or TAC+ radiotherapy

+ Aranesp

CEF or TAC + radiotherapy only

Endpoint

Relapse-freeSurvival

Follow-up

CEF = cyclophosphamide/epirubicin/5-floururacilTAC = taxotere/Adriamycin/cyclophosphamide

Study Endpoints:• Relapse-free survival• Overall survival• Hemoglobin response• Cognitive function

Surgery

Hb entry: 13.5 g/dLWithhold dose: Hb >14g/dL

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GELA Diffuse Large Cell Lymphoma StudyDr. R. Delarue, Dr. A. Bosley et al.

RandomizationN = 600

R-CHOP-14

R-CHOP-21

Endpoint

Relapse-freesurvival

Follow-up

Aranesp

Aranesp

Study endpoints:• Relapse-free survival• Overall survival• Disease-free survival• Response rateHb entry: 13 g/dLWithhold dose: Hb >14 g/dL

Supportivecare

Supportivecare

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DAHANCA Head and Neck Cancer StudyDr. J. Overgaard et al.

RandomizationN = 600

Radiotherapy+ Aranesp

Radiotherapyalone

Endpoint

Local-RegionalControl

Follow-up

Study endpoints:• Local-regional control (T+N)• Overall survival• Hemoglobin response

Hb entry: 13 g/dLWithhold dose: Hb >15 g/dL

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Amgen-Sponsored Trial and Independent-Investigator Trials

Accrual Detectable Sponsor/ Tumor through Projected DifferencesInvestigator type April ‘04 Control (80% power)

GELA/R. Delarue, NHL 22/600 62% atA. Bosley 3 years 11%

AGO/ Neo-adjuvant 80% atM.Untch Breast 400/720 5 years 10%

WSG/ Adjuvant 12/1000 75% atU. Nitz Breast 5 years 7%

DAHANCA/ Head/Neck 260/600 60% atJ. Overgaard 5 years 11%

Amgen SCLC 213/600 50% at9 months 11%

Overall Survival

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Amgen-Sponsored and Investigator-Initiated Trials

0

10

20

30

40

50

60

70

80

90

100

GELA

AGO

WSG

DAHANCA

Amgen

1.0 1.1 1.2 1.3 1.4 1.5

Po

we

r

Hazard Ratio

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Amgen-Sponsored and Investigator-Initiated Trials: Patient Experience

2003 2005 2007 2009 2011

1000

2000

3000

4000

5000

6000

7000

8000

9000

0

Projected Patients

Projected CumulativePatient-years of Follow-up

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Amgen-Sponsored and Investigator-Initiated Trials

Meta Analysis of all 5 trials

0

10

20

30

40

50

60

70

80

90

100

1.0 1.1 1.2 1.3 1.4 1.5

Po

we

r

Hazard Ratio

A meta-analysis with results from all five trials has 80% power to detect a hazard ratio of 1.15 or greater

BEST Survival HR = 1.31ENHANCE Survival HR = 1.39

Meta Analysis for the twobreast cancer studies

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Strengths of the Ongoing Aranesp Clinical Trials Program Design elements involve either double-blind, placebo-controlled or Aranesp

vs. no epoetin with pre-defined survival or tumor progression endpoints

Ongoing trials across multiple tumor types – 1700 breast cancer (2 studies)

– 600 head and neck cancer

Cumulative meta-analyses of 3500 patients will provide assessment over time of tumor progression and survival– Over 900 patients accrued to date

Studies include appropriate safety monitoring, including collection of thrombotic events– Head and neck study interim performed at 260 patients

AGO breast cancer trial incorporates tissue collection

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Conclusions

After detailed review of Aranesp pre-clinical and clinical experience, no significant survival or tumor progression signal observed

Benefits from treatment of CIA with Aranesp are well-established

Thrombotic event rate remains consistent with label

Substantial clinical trials program in place to further investigate survival outcomes

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Aranesp® (darbepoetin alfa) Therapy for Oncology Patients

Oncologic Drugs Advisory CommitteeMay 4, 2004

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Aranesp Group (Target hemoglobin 13 g/dL)

Placebo Group

Study Population• Hemoglobin 11 g/dL• GFR 20-60 mL/min/1.73m2

• Type 2 DM

N = 2000

N = 2000

Enrollment 1.5 years Follow-up period 2.5 years

Final Analysis

Baseline

Primary Endpoint- Time to the composite event, comprising:

• Mortality

• Non-fatal cardiovascular events: Myocardial infarction, acute myocardial ischemia, congestive heart failure, cerebrovascular accident

TREAT: Trial to Reduce Cardiovascular Events with Aranesp Therapy

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Pooled Oncology Analysis: Potential Interaction between Prior TE and Treatment

% of Subjects

NESP(N=1807)

Placebo(N=444)

No Prior Thrombotic Event

6%

(97/1703)

3%

(11/412)

Prior Thrombotic Event 13%

(14/104)

12%

(4/32)