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ONTAK ® (denileukin diftitox) Post-approval Clinical Commitment

ONTAK ® (denileukin diftitox) Post-approval Clinical Commitment. Oncologic Drugs Advisory Committee Meeting March 12-13, 2003 Bethesda, MD. ODAC Meeting Ligand Attendees. James L’Italien, Ph.D. Sr. Vice President, Regulatory Affairs & Compliance

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ONTAK ® (denileukin diftitox) Post-approval Clinical Commitment

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  1. ONTAK® (denileukin diftitox) Post-approval Clinical Commitment Oncologic Drugs Advisory Committee Meeting March 12-13, 2003 Bethesda, MD

  2. ODAC MeetingLigand Attendees • James L’Italien, Ph.D.Sr. Vice President, Regulatory Affairs & Compliance • Gordon Bray, M.D. (Speaker)Sr. Medical Director of Clinical Research • Andrés Negro-Vilar, M.D., Ph.D.Sr. Vice President, Research & DevelopmentChief Scientific Officer • Eric Groves, M.D., Ph.D.Vice-President, Project Management • Francine Foss, M.D. (Consultant) Professor of Medicine Tufts-New England Medical CenterBoston, MA

  3. Presentation Objectives • Review structure, mechanism of action and clinical characteristics of denileukin diftitox (ONTAK®) • Review clinical basis for accelerated approval and key development milestones • Describe the outstanding clinical commitment for final approval • progress to date • ongoing efforts to achieve completion of the study • challenges encountered • Summary

  4. Cleavage domain Diphtheria toxin enzyme activity S | S S | S IL-2 Diphtheria toxin translocation function Denileukin Diftitox Structure • Fusion protein that targets cytocidal activity of diphtheria toxin to tumor cells expressing the receptor for IL-2 (IL-2R) • Leukemic and lymphoma cells of B and T cell origin (including cutaneous T-cell lymphoma), constitutively express one or more subunits of IL-2R

  5. DT IL2 a g b IL2 protein synthesis Denileukin Diftitox (ONTAK)Mechanism of Action DT IL2 Cell exterior HIGH affinity IL2 receptor MEDIUM affinity IL2 receptor ONTAK® DT IL2 g b Cell membrane Cell interior Internalization of IL2R with bound toxin CELL DEATH DT IL2 DT Cleavage & Toxin release Protein synthesis terminated by toxin-mediated ADP ribosylation of elongation factor 2

  6. ONTAK – Clinical Characteristics • Indicated for the treatment of patients with persistent or recurrent, CD25 (+) cutaneous T-cell lymphoma (CTCL) • Acceptable safety profile • Minimal myelosuppression

  7. Clinical Data Supporting ONTAK Approval • Accelerated approval based on data in CTCL patients from 2 clinical studies: • 37% response rate (Phase I/II Study) • 30% response rate (Phase III Study) • Full approval requires completion of 3 arm, blinded, placebo controlled CTCL trial L4389-11

  8. Post-approval Clinical Commitment for ONTAK Study L4389-11 On target for submission of a final study report in early 2006, per prior communications with FDA

  9. Key Regulatory/Development Milestones Orphan Drug designation August 1996 BLA submitted by Seragen, Inc. December 1997 Accelerated approval granted Ligand Pharmaceuticals assumes all development responsibility February 1999

  10. L4389-11 Study Design (1) • Persistent/refractory CTCL • Disease Stage Ia-III • CD25 (+) • ≤ 3 prior therapies • Efficacy endpoints: • response rate • time-to-progression, response duration

  11. L4389-11 Study Design (2) • Following discussion with FDA during 1999, study population was increased from 120 (40:40:40) to 195 (39:78:78): • maintains original size of the placebo group • weights randomization toward active study drug to encourage enrollment

  12. L4389-11 Study Design (3) 5 daily treatments every 21 days; tumor burden is assessed at Baseline and Day 1 of each course after Course 1

  13. 110 100 90 80 70 60 Through 1999 2000 2001 2002 1Q 03 Approval 1Q 99 Enrollment in L4389-11 Progress to Date 105 98 89 Patients Enrolled 82 73 73 Year

  14. 30 20 10 0 1999 2000 2001 2002 1Q 03 Ongoing Efforts to Complete Study L4389-11 28 22 Cumulative Active Sites 9 10 1 Year

  15. Current Status of L4389-11 • Enrolled 105 of 195 patients needed to complete study • 28 active enrolling sites • Seven patients enrolled in the first two months of 2003 • We estimate that 29 of 39 required placebo patients have enrolled • On target for submission of a final study report in early 2006

  16. Challenges Encountered in Conduct of L4389-11 • Small population size; few large clinical research centers • Practice patterns for CTCL management • Impact of prior therapies on eligibility • Impact of the placebo arm

  17. Small Population Size • CTCL constitutes only 2.2% of all lymphoma cases in the U.S.* • Annual incidence – approximately 4 per million* • Approximately 1,100 new U.S. cases of CTCL reported per year* • Approximately 400 CTCL patients treated with ONTAK in 2002 *Surveillance, Epidemiology and End Results (SEER) data, NCI (1973 through 1992)

  18. topical therapies Ineligible for L4389-11 >3 therapies Prevalent Topical Therapies Nitrogen mustard, BCNU, bexarotene, UVB, PUVA, electron-beam therapy Prevalent Oral and Parenteral Therapies bexarotene,interferon α, ONTAK, oral MTX, purine analogues, combination chemotherapy Impact of Practice Patterns and Prior Therapies on Accrual Clinical Stage IA IB IIA IIB III IVA IVB Eligible for L4389-11

  19. Impact of the Placebo Arm • Patients often decline participation in placebo study due to symptoms/complications associated with CTCL (severe pruritis, ulcerations) • Investigators are reluctant to consider a placebo controlled study, especially for late stage patients • Governmental opposition – attempts to conduct study at six sites in France were unsuccessful • After approval by local Ethics Committees, the French MOH declined the clinical trial application, citing the revised Declaration of Helsinki

  20. Summary • Study enlarged from 120 to 195 patients to encourage patient enrollment while maintaining original size of placebo group • Multicenter, international expansion of study L4389-11 to a total of 28 study sites • 1.5 – 2.0 patients/site/yr will achieve the goal of completion by 2006 • On target for submission of a final study report in early 2006

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