Evolving Safety Issues Associated With Erythropoietin Products
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Evolving Safety Issues Associated With Erythropoietin Products Oncology Drugs Advisory Committee May 4, 2004 Harvey Luksenburg, M.D. Division of Therapeutic Biological Oncology Products, ODE 6/OND/CDER. FDA Team. Harvey Luksenburg, M.D., Clinical Kaushik Shastri, M.D., Clinical

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Slide1 l.jpg

Evolving Safety Issues Associated With Erythropoietin Products Oncology Drugs Advisory CommitteeMay 4, 2004

Harvey Luksenburg, M.D. Division of Therapeutic Biological Oncology Products,ODE 6/OND/CDER


Fda team l.jpg
FDA Team Products

Harvey Luksenburg, M.D., Clinical

Kaushik Shastri, M.D., Clinical

Ellis Unger, M.D., Clinical

Andrea Weir, Ph.D., Pharm/Tox

Clare Gnecco, Ph.D., Statistics

Mark Rothmann, Ph.D., Statistics

Ruth Wager, Ph.D., Product

Emily Shacter, Ph.D., Product


Background l.jpg
Background Products

  • Two large randomized studies in cancer patients on chemotherapy ± EPO have shown

    • Shorter OS

    • Shorter PFS

    •  incidence of thrombotic/cardiovascular events

      in the groups assigned to EPO


Slide4 l.jpg

Background Products

  • The EPO products used in these two studies are not licensed in U.S.

  • Used a treatment strategy to achieve hemoglobin  12 gm/dL [higher than recommended in the labeling for U.S. licensed products]


Background5 l.jpg
Background Products

  • Clinical trials for U.S. licensed EPO products were not designed to assess impact on

    • Response rate

      (except N93-004)

    • TTP/PFS

    • OS


Goals 1 l.jpg
Goals (1) Products

  • Safety issues observed with EPREX and NeoRecormon may also apply to U.S. licensed products

  • Review results of trials with EPREX and NeoRecormon (non-U.S. licensed) regarding safety concerns


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Goals (2) Products

  • Review data available regarding safety from trials of EPOGEN / Procrit and Aranesp (U.S. licensed)

  • To come to agreement on design of future studies regarding safety


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Safety Issues With Recombinant Erythropoietins Products

  • Thrombotic and cardiovascular adverse events

  • Tumor progression

  • Survival


Recombinant epo products u s licensed l.jpg
Recombinant EPO Products (U.S. Licensed) Products

  • Epoetin alfa manufactured by Amgen

    • EPOGEN (marketed by Amgen Inc.)

    • Procrit (marketed by Ortho BioTech L.P.)

  • Darbepoetin alfa

    (Aranesp; Amgen, Inc.)


Recombinant epo products not licensed in u s l.jpg
Recombinant EPO Products Products (Not Licensed in U.S.)

  • Epoetin alfa (EPREX, Ortho Biologics)

  • Epoetin beta (NeoRecormon; Hoffmann-La Roche)


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EPOs as a Class Products

  • FDA considers all of these products members of the same product class

  • These evolving safety issues are assumed to apply to all products unless adequate and well-controlled trials demonstrate otherwise


Differences l.jpg
Differences Products

  • Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

  • Aranesp differs in amino acid sequence (5) and degree of glycosylation


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Similarities Products

  • All exert principal clinical effect by binding to the EPO receptor

  • All have similar pharmacodynamic effects when used at recommended dosages

  • Similar toxicity profile across products (except PRCA)


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Target Hemoglobin: Background Products

  • Labels for EPOGEN/Procrit and Aranesp have dosage guidelines based on safety data from registration studies performed in patients with chronic renal failure (CRF)


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Recommended Hgb/Hct Products

  • EPOGEN/Procrit

    • “Suggested Target Hct. Range: 30% to 36%”

  • Aranesp

    • “The dose should be adjusted for each patient to achieve and maintain a target hemoglobin not to exceed 12 g/dL”


Dosing recommendations l.jpg
Dosing Recommendations Products

  • For rapid increase in Hgb greater than 1.0 g/dL (or 4 points in Hct) in any 2 week period dose should be reduced

  • Hold if Hgb > 13 g/dL, until Hgb falls < 12 g/dL, and restart dose at 25% belowprevious dose.



Thrombotic events with epo l.jpg
Thrombotic Events with EPO Products

  • Licensing studies for EPOGEN

    / Procrit and Aranesp demonstrated baseline risk of thrombotic & cardiovascular adverse events at labeled target Hgb (10-12 g/dL)


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“Normal Hematocrit Study” (Besarab et al, Products NEJM 1998)

  • 1,233 patients with chronic renal failure on dialysis with clinical evidence of CHF or ischemic heart disease

  • EPOGEN at baseline in order to achieve/maintain Hct 27-33%


Normal hematocrit study l.jpg
“Normal Hematocrit Study” Products

  • Both arms received EPOGEN but randomized to different treatment strategies

    • Achieve Hct of 42% (±3) (“normal Hct”)

    • Maintain Hct of 30% (±3)

      (“low Hct”)




Breast cancer erythropoietin trial best eprex epoetin alfa l.jpg
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

  • Randomized, DB, Placebo controlled

  • 939 women w/ metastatic breast cancer

    • 1st line therapy

    • +/- EPREX for 12 mos

    • Therapy started Hgb < 13 g/dL


Best trial l.jpg
BEST Trial alfa])

  • Primary objective to demonstrate superior survival at 12 months.

  • Target Hgb 12-14 g/dL

  • Stopped by IDMC based on first 4 mos safety data


Best trial27 l.jpg
BEST Trial alfa])

At 4 months

  •  incidence of fatal thrombotic and cardiovascular events

    EPREX 2.3%

    Placebo 0.4%


Henke et al lancet 2003 neorecormon epoetin beta l.jpg
Henke et al ( alfa])Lancet 2003) (NeoRecormon [Epoetin beta])

  • Randomized, DB, PC

    • 351 patients w/ head and neck cancer

    • Concurrent radiotherapy

    • Anemic < 12 g/dL women

      < 13 g/dL men


Henke et al l.jpg
Henke et al alfa])

  • Primary Objective

    To demonstrate superior locoregional PFS

  • Target Hgb ≤14 g/dL women

    ≤15 g/dL men


Henke et al30 l.jpg
Henke et al alfa])

  • Hypertension, hemorrhage, venous thrombosis, pulmonary embolism, CVA

    Epoetin beta 11%

    Placebo 5%

  • Patients who died of “cardiac disorders”

    Epoetin beta 5.5%

    Placebo 3%


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Registration Studies-Procrit alfa])

  • Pooled analyses of six multicenter, randomized, DB, placebo-controlled studies

  • 131 patients

    – Various primary cancers

    • Platinum (n=59) & non-platinum (n=72)

    • Anemic

    • Primary endpoint: Proportion patients tranfused


Registration studies procrit33 l.jpg
Registration Studies-Procrit alfa])

  • Incidence of thrombotic & cardiovascular events (pooled data)

  • Placebo 12% (8/68)

  • Procrit 3% (2/63)


Study n93 004 procrit epoetin alfa l.jpg
Study N93-004 alfa])(Procrit [Epoetin alfa])

  • Post-marketing commitment

  • Randomized, DB, PC, non-inferiority study

  • Intended to enroll 400 patients with SCLC

    • First line therapy

    • Baseline Hgb < 14 g/dL


Study n93 004 l.jpg
Study N93-004 alfa])

  • Primary Endpoint: Objective RR after 3 cycles chemo to rule out decrement of 15% in ORR with Procrit

  • No target Hgb, Procrit dose reduced for Hgb > 16 g/dL

  • Study terminated for poor accrual at 224 patients


Study n93 00436 l.jpg
Study N93-004 alfa])

Incidence of Thrombotic Vascular Events

  • Procrit 22% (24/109)

  • Placebo 23% (27/115)

  • Includes “chest pain”, MI, angina, stroke, cardiac arrest, peripheral ischemia, cardiovascular disorder, thrombosis, DVT, PE, phlebitis



Aranesp 980297 l.jpg
Aranesp 980297 alfa])

  • Randomized, DB, PC

  • 320 pts with lung cancer

    • Platinum-containing chemotherapy

    • Anemic (< 11 g/dL)


Aranesp 98029739 l.jpg
Aranesp 980297 alfa])

  • Primary endpoint: Proportion transfused between week 5 and week 12 or end of treatment period (EOTP)

  • Aranesp held for Hgb > 14 g/dL women & Hgb > 15 g/dL men


Aranesp 98029740 l.jpg
Aranesp 980297 alfa])

Thrombotic events

  • Aranesp 5% (7/155)

  • Placebo 3% (5/159)


Slide41 l.jpg

Thrombotic/Vascular Events alfa])

Studies w/ Signal


Slide42 l.jpg

Thrombotic/Vascular Events alfa])

Studies w/o Signal


Slide43 l.jpg

Higher Target Hemoglobin alfa])

  • In September 2003 three placebo controlled clinical trials in oncology patients in which one arm received EPO to target a higher hemoglobin were terminated because of unexpected rates of thrombotic events in the EPO arm




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Preclinical alfa]) Studies

  • EPO receptors (EPO-R) are present on some tumor cell lines & tumor vasculature (endothelial cells)


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Preclinical alfa]) Studies

EPO is reported to

  • Inhibit apoptosis

  • Stimulate angiogenesis; endothelial cell growth, migration, and proliferation

  • Reduce survival in tumor xenograft models


Tumor stimulation l.jpg
Tumor Stimulation alfa])

  • Studies supporting approval of Procrit and Aranesp for the treatment of anemia in cancer patients on chemotherapy not designed to assess impact on

    • Tumor response

    • Tumor progression

    • Survival


Breast cancer erythropoietin trial best eprex epoetin alfa50 l.jpg
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

  • Randomized, DB, Placebo controlled

  • 939 women w/ metastatic breast cancer

    • 1st line therapy

    • +/- 12 mo EPREX

    • Therapy started Hgb < 13 g/dL


Breast cancer erythropoietin trial best eprex epoetin alfa51 l.jpg
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

  • Primary objective to demonstrate superior survival at 12 months.

  • Target Hgb 12-14 g/dL

  • Stopped by IDMC based on first 4 mos safety data


Best trial52 l.jpg
BEST Trial alfa])

At 4 months

  • 2-fold increase in disease progression

    EPREX 6% (28/469)

    Placebo 3% (13/470)


Best trial eprex epoetin alfa l.jpg
BEST Trial alfa]) (EPREX [Epoetin alfa])

At 4 months

  • 2.5-fold increase in early mortality

    EPREX 8.7% (41/469)

    Placebo 3.4% (16/470)


Henke et al lancet 2003 neorecormon epoetin beta54 l.jpg
Henke et al ( alfa])Lancet 2003) (NeoRecormon [Epoetin beta])

  • Randomized, DB, PC

    • 351 patients w/ head & neck cancer

    • Concurrent radiotherapy

    • Anemic: Hgb < 12 g/dL women

      Hgb < 13 g/dL men


Henke et al55 l.jpg
Henke et al alfa])

  • Primary Objective to demonstrate superior locoregional PFS

  • Target Hgb ≤ 14 g/dL women

    ≤ 15 g/dL men


Henke et al56 l.jpg
Henke et al alfa])

For Locoregional PFS

NeoRecormon vs. Placebo

RR 1.62

(95% CI 1.22, 2.14, p=0.0008)


Henke et al57 l.jpg
Henke et al alfa])

For Locoregional progression

NeoRecormon vs. Placebo

RR 1.69

(95% CI 1.16-2.47; p=0.007)


Study n93 004 procrit epoetin alfa58 l.jpg
Study N93-004 alfa])(Procrit [Epoetin alfa])

  • Post-marketing commitment

  • Randomized, DB, PC, non-inferiority study

  • Intended to enroll 400 patients with SCLC

    • First line therapy

    • Baseline Hgb < 14 g/dL


Study n93 00459 l.jpg
Study N93-004 alfa])

  • Primary Endpoint: Objective RR after 3 cycles chemo to rule out 15% decrement in ORR in Procrit arm

  • No target Hgb, Procrit dose reduced for Hgb > 16 g/dL

  • Study terminated at 225/400 for poor accrual


Procrit n93 004 l.jpg
Procrit N93-004 alfa])

  • Not designed to assess impact on TTP

  • Survival a secondary endpoint - no formal hypothesis testing



Aranesp 98029762 l.jpg
Aranesp 980297 alfa])

  • Randomized, DB, PC

  • 320 pts with lung cancer

    • Platinum-containing chemotherapy

    • Anemic (Hgb < 11 g/dL)


Aranesp 98029763 l.jpg
Aranesp 980297 alfa])

  • Primary endpoint: Proportion transfused between week 5 and week 12 (or EOTP)

  • Aranesp held for Hgb > 14 g/dL women & > 15 g/dL men


Aranesp 98029764 l.jpg
Aranesp 980297 alfa])

Median PFS (95% CI)

Aranesp 5 months (4, 7 mos)

Placebo 4 months (4, 5 mos)

Not designed to assess impact on PFS



Slide66 l.jpg

Tumor Stimulation alfa])

Studies w/ Signal


Slide67 l.jpg

Tumor Stimulation alfa])

Studies w/o Signal


Survival l.jpg

Survival alfa])


Breast cancer erythropoietin trial best eprex epoetin alfa70 l.jpg
Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

  • Randomized, DB, Placebo controlled

  • 939 women w/ metastatic breast cancer

    • 1st line therapy

    • +/- EPREX for 12 mos

    • Study drug started at Hgb < 13 g/dL


Best trial71 l.jpg
BEST Trial alfa])

  • Primary objective: To demonstrate superior survival at 12 months.

  • Target Hgb 12-14 g/dL

  • Stopped by IDMC based on 4 mo safety data


Best trial72 l.jpg
BEST Trial alfa])

Estimated 12-month survival

EPREX: 70% (148 deaths/469)

Placebo: 76% (115 deaths/470)

RR of death=1.4

(95% CI 1.07,1.74; p=0.012)



Henke et al lancet 2003 neorecormon epoetin beta74 l.jpg
Henke et al ( alfa])Lancet 2003) (NeoRecormon [Epoetin beta])

  • Randomized, DB, PC

    • 351 patients w/ head and neck cancer

    • Concurrent radiotherapy

    • Anemic < 12 Hgb g/dL women

      < 13 Hgb g/dL men


Henke et al75 l.jpg
Henke et al alfa])

  • RR of death: 1.4

    (95% CI 1.05-1.84, p=0.02 Cox)

  • Median overall survival

    NeoRecormon 605 days

    Placebo 928 days

    (p=0.09, logrank)


Study n93 004 procrit epoetin alfa76 l.jpg
Study N93-004 alfa])(Procrit [Epoetin alfa])

  • Randomized, DB, PC, non-inferiority study

  • Intended to enroll 400 patients with SCLC

    • First line therapy

    • Baseline Hgb < 14 g/dL

  • Not designed to assess impact on survival


Study n93 004 procrit epoetin alfa77 l.jpg
Study N93-004 alfa])(Procrit [Epoetin alfa])

Median survival

Procrit 10.5 months (95% CI: 9, 13)

Placebo 10.4 months (95% CI: 8, 13)

Overall mortality rate

Procrit 92% (100/109)

Placebo 88% (101/115)



Aranesp 98029779 l.jpg
Aranesp 980297 alfa])

Randomized, DB, PC

  • 320 pts with lung cancer

    • Platinum-containing chemotherapy

    • Anemic (< 11 g/dL)

  • Not designed to address impact on survival


Aranesp 98029780 l.jpg
Aranesp 980297 alfa])

Median overall survival

Aranesp 10 mos (95% CI: 9, 12 mos)

Placebo 8 mos (95% CI: 7, 9 mos)

Overall mortality rate

Aranesp 14% (22/155)

Placebo 12% (19/159)





Summary l.jpg
Summary alfa])

  • Two large, multicenter studies (BEST & Henke) designed to show superior survival or PFS demonstrated

    • Increased thrombotic events

    • Shorter PFS

    • Shorter OS

  • Used a treatment strategy to achieve hemoglobin levels > 12 g/dL


Summary85 l.jpg
Summary alfa])

  • Multicenter, placebo-controlled trials

    Procrit (N93-004) and Aranesp (980297)

    • Smaller in size

    • Not designed to assess impact on PFS or OS

    • Treatment strategy varied – Procrit held > Hgb 14 g/dL

      (label recommends 12 g/dL)


Conclusions l.jpg
Conclusions alfa])

  • Evolving safety concerns

  • Current dosing recommendations adequate to minimize risks of thrombotic events

  • Insufficient information for OS and PFS for U.S. licensed products at approved doses to assess risks

  • Amgen, Ortho Biotech and FDA agree on need for further studies


Fda recommended elements l.jpg
FDA Recommended Elements alfa])

  • Homogenous primary tumor type

  • Homogenous chemotherapy or radiotherapy regimens

  • Study designed to detect clinically meaningful decrements in response rate, PFS, and survival


Fda recommended elements88 l.jpg
FDA Recommended Elements alfa])

  • Prespecified definitions of cardiovascular and thrombotic events

  • DSMB oversight


Fda recommended elements89 l.jpg
FDA Recommended Elements alfa])

Determination of expression and

ligand affinity of EPO-R on

specific primary tumor types

  • Preferably through analysis of clinical tissue specimens or

  • Pre-existing tissue repositories representing common tumor types


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