Aranesp darbepoetin alfa Therapy for Oncology Patients

1
Aranesp (darbepoetin alfa) Therapy for Oncology
Patients
Oncologic Drugs Advisory CommitteeMay 4, 2004
2
Amgen Guests

• Jeffrey Crawford, MD Professor of Medicine Duke
  University School of Medicine
• David DeMets, PhD Professor and Chair of
  Biostatistics University of Wisconsin
• John Glaspy, MD, MPH Professor of
  Medicine University of California at Los
  Angeles School of Medicine
• Harvey Lodish, PhD Professor of Biology and
  Professor of Bioengineering at MIT Member of
  Whitehead Institute
• Douglas Losordo, MD Associate Professor of
  Medicine Tufts University School of Medicine
• Marc Pfeffer, MD, PhD Senior Physician in
  Cardiology Professor of Medicine Brigham and
  Womens Hospital
• Joseph Eschbach, MD Senior Research
  Advisor Northwest Kidney Center Clinical
  Professor Medicine University of Washington

3
Independent Investigators
Principal Investigator Study Group Institution J.
Overgaard, MD The Danish Head Dept. Experimental
Clinical Oncology and Neck Cancer Aarhus
University Hospital Study Group Aarhus C.
Denmark (DAHANCA) R. Delarue, MD Groupe dEtude
des Adult Hematology Dept Lymphomes de
lAdulte Hospital Necker, Paris, FranceA.
Bosley, MD (GELA) Hematology Dept. UCL Mont
Godinne, Belgium U. Nitz, MD Westdeutschen Gynecol
ogical Clinic Studiengruppe (WSG) Dusseldorf
University Dusseldorf, Germany S. Kahlert,
MD Gynecological Clinic and Polyclinic for
Oncology Study Obstetrics and
Gynecology, Group (AGO) Grosshadern Clinic,
Ludwig- Maximillian University Munich, Germany
4
Presentation Outline

Background Dawn Viveash, MD VP of Regulatory
Affairs and Safety EPO-R Considerations Harvey
Lodish, PhD Professor of Biology
and Bioengineering - MIT Clinical
Observations David Parkinson, MD VP of Oncology
Clinical Development
5
Distinct Properties of Aranesp?
Molecular Differences Compared with Epoetin
Physical Differences Compared with Epoetin
Biological Differences Compared with Epoetin
5-fold reduction in receptor binding
affinity 3-fold increase in serum half life Leads
to improved in vivo biological activity
Altered amino acid sequence permits attachment
of2 additional carbohydrate side chains
Increase in negative charge Increase in molecular
weight and size
6
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

7
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)5841998.
8
Comprehensive Risk AssessmentPreclinical 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.
9
Comprehensive Risk AssessmentClinical Data

• Epidemiological analysis of thrombotic events
• Review of completed and ongoing Aranesp trials
• Post-marketing oncology experience

10
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

11
Presentation Outline

Background Dawn Viveash, MD VP of Regulatory
Affairs and Safety EPO-R Considerations Harvey
Lodish, PhD Professor of Biology
and Bioengineering - MIT Clinical
Observations David Parkinson, MD VP of Oncology
Clinical Development
12
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

13
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

14
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-R1 EPO complex is required for signaling

15
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

16
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 gt1 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

17
Presentation Outline

Background Dawn Viveash, MD VP of Regulatory
Affairs and Safety EPO-R Considerations Harvey
Lodish, PhD Professor of Biology
and Bioengineering - MIT Clinical
Observations David Parkinson, MD VP of Oncology
Clinical Development
18
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

19
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. 2003120970-977
2Louvet C, et al. J Clin Oncol.
2002204543-4548 3Scheithauer W, et al. J Clin
Oncol. 2003211307-1312 4Hitt R, et al. Ann
Oncol. 2002131665-1673 5Schiller JH, et al. N
Engl J Med 200234692-98 6 Vogelzang N, et al.
Semin Hematol. 199734(suppl 2)412 7Tandem
audit 8Amgen data on file.
20
Aranesp? Increases Hemoglobin and Reduces
Transfusions
21
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.
22
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

23
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

24
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. 20032 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
comorbidities 2Bohlius, et al. Blood.
2003102203a. Abstract 709.
25
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

26
Survival Analysis in Aranesp? Randomized,
Placebo-Controlled Trials in CIA
Studies Characteristics Lung cancer1 N
314 Homogeneous patient population Platinum-base
d therapy Long-term follow-up Lymphoid
malignancies2 N 344 Less homogeneous patient
populations Long-term follow-up Mixed solid
tumor3 N 405 Heterogeneous patient
populationLymphoid malignancies4 N
66 Follow-up (16 weeks)
1Vansteenkiste J, et al. J Natl Cancer Inst.
2002941211-1220. (Study 980297) 2Hedenus M, et
al. Br J Haematol. 2003122394-403. (Study
20000161) 3Hedenus M, et al. Br J Haematol.
200211979-86. (Study 980291) 4Kotasek D, et al.
Eur J Cancer. 2003392026-2034. (Study 990114)
27
Aranesp? Lung Cancer Study
Chemotherapy1 Aranesp 2.25 µg/kg/week for 12
weeks
Long-term Follow-up for Survival And Progression
Endpoint RBC Transfusion
RandomizationN 314
Chemotherapy1 Placebo for 12 weeks
Median follow up time16 months
Placebo Aranesp Number of
patients 159 155 Histology NSCLC 114 (72) 108
(70) SCLC 45 (28) 47 (30)
Hb entry ?11 g/dL Withhold dose Hb gt14g/dL
1Platinum-based Study 980297
28
Progression-free Survival in Lung Cancer Patients
100
Total Events Aranesp 155 131 Placebo 159 145
80
60
Percent
Hazard Ratio1 0.81 (95 CI 0.64, 1.03)
Aranesp
40
Placebo
20
0
0
3
6
9
12
15
18
21
24
Months from 1st Dose
Subjects at risk
Aranesp
155
116
63
35
16
13
6
5
1
Placebo
159
114
50
26
14
7
4
1
0
Study 980297 1Adjusted for histology
29
Overall Survival in Lung Cancer Patients
100
Total Deaths Aranesp 155 100 Placebo 159 119
80
60
Percent
Hazard Ratio1 0.78 (95 CI 0.60, 1.01)
Placebo
40
20
0
0
3
6
9
12
15
18
21
24
Months from 1st Dose
Subjects at risk
Aranesp
155
133
94
74
49
34
16
7
1
Placebo
159
127
86
58
44
30
16
3
0
Study 980297 1Adjusted for histology
30
Aranesp? Lymphoid Malignancy Study
Chemotherapy Aranesp 2.25 µg/kg/week for 12
weeks
Long-term Follow-up for Survival And Progression
Endpoint RBC Transfusion
RandomizationN 344
Chemotherapy Placebo for 12 weeks
Median follow-up time27 months
Placebo Aranesp Number of patients 169 175 NHL
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)
Hb entry ?11 g/dL Withhold dose Hb gt14g/dL
Study 20000161
31
Aranesp? Lymphoid Malignancy Study Baseline
Characteristics
Placebo Aranesp N 169 N 175 n () n
() Non-Hodgkins lymphoma 45 (27) 39
(22) Indolent 29 (64) 20
(51) Aggressive 16 (36) 17
(44) International Prognostic Index 0 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
32
Progression-free Survival in Patients with
Lymphoid Malignancies
Total Events Aranesp 175 120 Placebo 169 113
100
80
Placebo
Hazard Ratio1 1.11 (95 CI 0.85, 1.44)
60
Percent
Aranesp
40
20
0
0
3
6
9
12
15
18
21
24
Months from 1st Dose
Subjects at risk
Aranesp
175
146
125
109
100
85
72
60
43
Placebo
169
150
119
104
96
85
71
63
49
Study 20000161 1Adjusted for disease type, stage
and IPI score
33
Overall Survival in Patients withLymphoid
Malignancies
100
Placebo
80
60
Percent
Total Deaths Aranesp 175 80 Placebo 169 61
40
Hazard Ratio1 1.33 (95 CI 0.95, 1.86)
20
0
0
3
6
9
12
15
18
21
24
Months from 1st Dose
Subjects at risk
Aranesp
175
162
150
136
126
122
117
101
76
Placebo
169
160
146
135
132
124
116
113
93
Study 20000161 1Adjusted for disease type, stage
and IPI score
34
Pooled Analysis of Four Amgen Completed Trials
Concerning Tumor Progression and Survival
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
35
Progression-free Survival in Four Pooled1 Placebo
Controlled Trials 16 Week Data
100
Hazard Ratio2 1.02 (95 CI 0.78, 1.33)
95
90
Percent
85
80
0
0
4
8
12
16
Weeks After 1st Dose
Subjects at risk
Aranesp
708
680
642
572
313
Placebo
421
405
372
349
252
1Studies 980297, 20000161, 980291,
990114 2Adjusted for study, disease type, stage
and IPI score
36
Overall Survival in Four Pooled1 Placebo
Controlled Trials 16 Week Data
100
95
90
Percent
Hazard Ratio2 1.02 (95 CI 0.67, 1.54)
85
80
0
0
4
8
12
16
Weeks After 1st Dose
Subjects at risk
Aranesp
708
687
660
600
358
Placebo
421
411
387
368
294
1Studies 980297, 20000161, 980291,
990114 2Adjusted for study, disease type, stage
and IPI score
37
Pooled1 Analyses Progression-free Survival
Hazard Ratios Associated with Aranesp? (A) vs
Placebo (P) by Tumor Type
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)
0.1
1.0
10
Hazard Ratio (95 CI)
1Studies 980297, 20000161, 980291, 990114
38
No Negative Impact on Progression or Survival
Outcomes with Hb ?13 g/dL or ?1 g/dL in 14 Days
Hazard Endpoint 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)
Pooled analyses of Aranesp trials Studies
980297, 20000161, 980291, 990114Models
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.
39
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

40
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

41
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. 2001912214 2 Grogan M,
et al. Cancer. 19998615281536 3 Overgaard J.
Sem. Rad. Oncol. 1996610-21 4 Glaser CM.
Int.J.Radiat.Oncol.Biol.Phys. 200150705-715 5
Vansteenkiste J, et al. J NCI 2002941211-1220
6 Bohlius et al, Blood. 2003102203a, abs 709.
42
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

43
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

44
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 cancer 600 Lymphoma 600 Small-cell lung
cancer 3,520
45
Amgen Small Cell Lung Cancer Study
Cis/Carboplatin Etoposide Aranesp
Endpoint Survival
Follow-up
RandomizationDouble-blindN 600
Cis/Carboplatin Etoposide Placebo

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

Hb entry 9 - 13 g/dL Withhold dose Hb gt14g/dL
46
AGO Breast Cancer StudyDr. M. Untch et al.
Aranesp
SequentialTherapy(EC?T)
Endpoint Relapse-freeand OverallSurvival
Supportivecare
Follow-up
RandomizationN 720
S u r g e r y
SequentialDose-intensifiedTherapy(E?T?CMF)
Aranesp
Supportivecare

• Study endpoints
• Relapse-free and overall survival
• Complete pathological response
• Quality of life

E epirubicin C cyclophosphamide T
paclitaxel M methotrexate F flourouracil
Withhold dose Hb gt14g/dL
47
WSG Adjuvant Breast Cancer StudyDr. U. Nitz et
al.
Surgery
CEF or TAC radiotherapy Aranesp
Follow-up
Endpoint Relapse-freeSurvival
Randomization N 1000
CEF or TAC radiotherapy only

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

Hb entry ?13.5 g/dL Withhold dose Hb gt14g/dL
CEF cyclophosphamide/epirubicin/5-floururacil TA
C taxotere/Adriamycin/cyclophosphamide
48
GELA Diffuse Large Cell Lymphoma StudyDr. R.
Delarue, Dr. A. Bosley et al.
Aranesp
R-CHOP-14
Follow-up
Supportivecare
Endpoint Relapse-freesurvival
RandomizationN 600
Aranesp
R-CHOP-21
Supportivecare

• Study endpoints
• Relapse-free survival
• Overall survival
• Disease-free survival
• Response rate

Hb entry ?13 g/dL Withhold dose Hb gt14 g/dL
49
DAHANCA Head and Neck Cancer StudyDr. J.
Overgaard et al.
Radiotherapy Aranesp
Endpoint Local-RegionalControl
Follow-up
Randomization N 600
Radiotherapyalone

• Study endpoints
• Local-regional control (TN)
• Overall survival
• Hemoglobin response

Hb entry ?13 g/dL Withhold dose Hb gt15 g/dL
50
Amgen-Sponsored Trial and Independent-Investigator
Trials
Overall Survival
Accrual Detectable Sponsor/ Tumor through Proj
ected DifferencesInvestigator type April
04 Control (80 power) GELA/ R. Delarue,
NHL 22/600 62 at A. Bosley 3
years 11 AGO/ Neo-adjuvant 80
at M.Untch Breast 400/720 5 years 10 WSG/ Adjuva
nt 12/1000 75 at U. Nitz Breast 5
years 7 DAHANCA/ Head/Neck 260/600 60 at J.
Overgaard 5 years 11 Amgen SCLC 213/600 50
at 9 months 11
51
Amgen-Sponsored and Investigator-Initiated Trials
Amgen
100
WSG
90
GELA
DAHANCA
80
70
Power
60
AGO
50
40
30
20
10
0
1.0
1.1
1.2
1.3
1.4
1.5
Hazard Ratio
52
Amgen-Sponsored and Investigator-Initiated
Trials Patient Experience
9000
8000
7000
Projected CumulativePatient-years of Follow-up
6000
5000
4000
3000
Projected Patients
2000
1000
0
2003
2005
2007
2009
2011
53
Amgen-Sponsored and Investigator-Initiated Trials
100
90
80
70
60
A meta-analysis with results from all five
trials has 80 power to detect a hazard ratio
of 1.15 or greater
Power
50
40
30
20
BEST Survival HR 1.31
10
ENHANCE Survival HR 1.39
0
1.0
1.1
1.2
1.3
1.4
1.5
Hazard Ratio
54
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

55
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

56
Aranesp (darbepoetin alfa) Therapy for Oncology
Patients
Oncologic Drugs Advisory CommitteeMay 4, 2004
57
TREAT Trial to Reduce Cardiovascular Events
with Aranesp Therapy
Aranesp Group (Target hemoglobin 13 g/dL)
N 2000

• Study Population
• Hemoglobin ? 11 g/dL
• GFR 20-60 mL/min/1.73m2
• Type 2 DM

Placebo Group
N 2000
Enrollment ? 1.5 years
Follow-up period ? 2.5 years
Baseline
Final Analysis

• Primary Endpoint- Time to the composite event,
  comprising
• Mortality
• Non-fatal cardiovascular events Myocardial
  infarction, acute myocardial ischemia, congestive
  heart failure, cerebrovascular accident

58
Pooled Oncology Analysis Potential Interaction
between Prior TE and Treatment
of Subjects

NESP(N1807)

Placebo(N444)

No Prior Thrombotic Event

6
3

(97
/
1703)

(11/412)

Prior Thrombotic Event

13

12

(14/104)

(4/32)