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Romiplostim

Romiplostim. Safety review--MDS progression Study 20050159 (phase 1/2 study [n=44]) March 12, 2008 Oncology Drugs Advisory Committee Meeting BLA 125268 Steven Lemery-DBOP Clinical Reviewer Faranak Jamali-Primary BLA clinical reviewer. Why Evaluate MDS Progression?.

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Romiplostim

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  1. Romiplostim Safety review--MDS progression Study 20050159 (phase 1/2 study [n=44]) March 12, 2008 Oncology Drugs Advisory Committee Meeting BLA 125268 Steven Lemery-DBOP Clinical Reviewer Faranak Jamali-Primary BLA clinical reviewer

  2. Why Evaluate MDS Progression? • c-Mpl expressed on hematopoietic progenitor cells • Detection of increased c-Mpl on blasts in AML or MDS • Demonstration of in-vitro proliferation after exposure to TPO • Results from clinical study 20050159

  3. Risk of AML Progression • The inclusion criteria specified that patients have low or intermediate-1 risk MDS • Low risk: 25% median progression to AML of 9.4 years • Intermediate-1 risk: 25% median progression to AML of 3.3 years Source: Greenberg et al. 1997

  4. 20050159 • N = 44, open label, dose escalation study • Doses: 300 to 1,500 mcg SC per week • Eligibility: platelets ≤ 50,000/mcl • G-CSF was not allowed

  5. Patient Demographics

  6. FDA’s Review: 22 Cases • Increased blasts • cytogenetics progression (for example: good to intermediate or poor risk)

  7. Potential AML cases • 84-year-old man with chloroma • 71-year-old man (AML) • 76-year-old man with an average blast count > 20% • 72-year-old man developed AML 6 weeks after stopping romiplostim

  8. AML or Rapid MDS Progression • Two patients died after rapid MDS progression • One patient started azacytidine with blasts > 20%

  9. Additional Patients with Increased Blasts • Blasts ≥ 20%: 4 • Blasts ≥ 10% to < 20%: 3 • Other: 4 • Cytogenetics progression: 4

  10. Limitations • Study 20050159 was uncontrolled • MDS: different disease • Unknown AML risk after detection of elevated blasts

  11. Summary • Rapid MDS progression and AML • Additional cases of MDS progression or transient blast count elevations • Fifteen of the 22 events within approximately 3 months • All of the 22 events initially within approximately 9 months

  12. Summary: Risk of AML Progression • Low risk: 25% median progression to AML of 9.4 years • Intermediate-1 risk: 25% median progression to AML of 3.3 years

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