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

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

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  1. 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

  2. FDA Team 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

  3. Background • 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

  4. Background • 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]

  5. Background • Clinical trials for U.S. licensed EPO products were not designed to assess impact on • Response rate (except N93-004) • TTP/PFS • OS

  6. Goals (1) • 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

  7. Goals (2) • 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

  8. Safety Issues With Recombinant Erythropoietins • Thrombotic and cardiovascular adverse events • Tumor progression • Survival

  9. Recombinant EPO Products (U.S. Licensed) • Epoetin alfa manufactured by Amgen • EPOGEN (marketed by Amgen Inc.) • Procrit (marketed by Ortho BioTech L.P.) • Darbepoetin alfa (Aranesp; Amgen, Inc.)

  10. Recombinant EPO Products(Not Licensed in U.S.) • Epoetin alfa (EPREX, Ortho Biologics) • Epoetin beta (NeoRecormon; Hoffmann-La Roche)

  11. EPOs as a Class • 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

  12. Differences • Epoetin alfa and beta have same amino acid sequence but differ in glycosylation • Aranesp differs in amino acid sequence (5) and degree of glycosylation

  13. Similarities • 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)

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

  15. Recommended Hgb/Hct • 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”

  16. Dosing Recommendations • 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.

  17. Thrombotic and Cardiovascular Adverse Events

  18. Thrombotic Events with EPO • Licensing studies for EPOGEN / Procrit and Aranesp demonstrated baseline risk of thrombotic & cardiovascular adverse events at labeled target Hgb (10-12 g/dL)

  19. “Normal Hematocrit Study” (Besarab et al, 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%

  20. “Normal Hematocrit Study” • Both arms received EPOGEN but randomized to different treatment strategies • Achieve Hct of 42% (±3) (“normal Hct”) • Maintain Hct of 30% (±3) (“low Hct”)

  21. “Normal Hematocrit Study”

  22. Probability of Death/Non-Fatal MI

  23. 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

  24. BEST Trial • 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

  25. BEST Trial At 4 months •  incidence of fatal thrombotic and cardiovascular events EPREX 2.3% Placebo 0.4%

  26. Henke et al (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

  27. Henke et al • Primary Objective To demonstrate superior locoregional PFS • Target Hgb ≤14 g/dL women ≤15 g/dL men

  28. Henke et al • Hypertension, hemorrhage, venous thrombosis, pulmonary embolism, CVA Epoetin beta 11% Placebo 5% • Patients who died of “cardiac disorders” Epoetin beta 5.5% Placebo 3%

  29. Registration Studies-Procrit • 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

  30. Registration Studies-Procrit • Incidence of thrombotic & cardiovascular events (pooled data) • Placebo 12% (8/68) • Procrit 3% (2/63)

  31. Study N93-004 (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

  32. Study N93-004 • 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

  33. Study N93-004 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

  34. Thrombotic / Vascular Events

  35. Aranesp 980297 • Randomized, DB, PC • 320 pts with lung cancer • Platinum-containing chemotherapy • Anemic (< 11 g/dL)

  36. Aranesp 980297 • 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

  37. Aranesp 980297 Thrombotic events • Aranesp 5% (7/155) • Placebo 3% (5/159)

  38. Thrombotic/Vascular Events Studies w/ Signal

  39. Thrombotic/Vascular Events Studies w/o Signal

  40. Higher Target Hemoglobin • 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

  41. Higher Target Hemoglobin

  42. Tumor progression

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

  44. Preclinical Studies EPO is reported to • Inhibit apoptosis • Stimulate angiogenesis; endothelial cell growth, migration, and proliferation • Reduce survival in tumor xenograft models

  45. Tumor Stimulation • 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

  46. 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

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