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ONTAK ® (denileukin diftitox) Post-approval Commitments

ONTAK ® (denileukin diftitox) Post-approval Commitments. Oncologic Drugs Advisory Committee Meeting November 8, 2005 Holiday Inn Gaithersburg, Maryland. Oncologic Drugs Advisory Committee Meeting Ligand Attendees. Ligand:

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ONTAK ® (denileukin diftitox) Post-approval Commitments

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  1. ONTAK® (denileukin diftitox) Post-approval Commitments Oncologic Drugs Advisory Committee Meeting November 8, 2005 Holiday Inn Gaithersburg, Maryland

  2. Oncologic Drugs Advisory Committee MeetingLigand Attendees • Ligand: • Andrés Negro-Vilar, M.D., Ph.D.Exec. Vice President, Research & DevelopmentChief Scientific Officer • James L’Italien, Ph.D.Sr. Vice President, Regulatory Affairs & Compliance • Zofia Dziewanowska, M.D., Ph.D. Vice President, Clinical Research • Elyane Lombardy, M.D. Exec. Medical Director, Clinical Research • Eric Groves, M.D., Ph.D.Vice-President, Project Management • Expert Advisor and Clinical Investigator • Francine Foss M.D. • Professor of Medicine and Oncology, Yale Cancer Center

  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 • Study L4389-11 (prior to 1999, 93-04-11) • Study L4389-14 (prior to 1999, 93-04-14) • Difficulties encountered

  4. ONTAK® Structure | S | S | | S | S | Diptheria toxin Enzyme Activity • Fusion protein targets cytocidal activity of diphtheria toxin to tumor cells expressing the receptor for IL2 (IL2R) • Leukemic and lymphoma cells of T and B cell origin (including cutaneous T cell lymphoma) can constitutively express one or more subunits of IL-2R IL-2 Receptor Binding Domain RVRR Diptheria toxin Translocation Function Fusion Junction Cleavage Domain

  5. DT DT DT DT IL2 IL2 IL2 IL2 a g b Protein synthesis IL2 Denileukin Diftitox (ONTAK®) Mechanism of Action Cell exterior  = CD25  = CD122  = CD132 ONTAK INTERMEDIATE affinity IL2 receptor HIGH affinity IL2 receptor g b Cell membrane Internalization of IL2R with bound toxin CELL DEATH DT Cleavage & Toxin release Protein synthesis Terminated by toxin-mediated ADP ribosylation of elongation factor 2 Cell interior

  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 Accelerated Approval • February 1999: accelerated approval based on data in CTCL patients from 2 clinical studies • Phase I / II study (92-04-01): • 37% response rate • Phase III study of 9 mg/kg vs 18 mg/kg (93-04-10): • 30% response rate

  8. ONTAK Clinical Commitmentsfor Final Approval • Completion of a 3 arm, blinded, placebo controlled study of 9 mg/kg and 18 mg/kg in CTCL patients 93-04-11 (now L4389-11) (n=195) • Completion of an open label study of 18 mg/kg in CTCL patients 93-04-14 (now L4389-14) (n=86) • Companion study to L4389-11, including 3 subgroups: • CD25(-) patients (target = 29 patients) • Placebo cross-over patients from study L4389-11 • Retreatment patients from studies 92-04-01, • 93-04-10 and -11 (prior to 1999)

  9. Patient Selection and Randomization Schema ONTAK 9g/kg Study 11 195 pts ONTAK 18g/kg CTCL Patients Screened (Ia to III) (≤ 3 prior therapies) Placebo CD25(+) CD25(-) Placebo Progression or 8 cycles no response Study 14 86 pts Retreatment, CD25+

  10. R Up to 8 courses of A placebo S N C Primary D R Up to 8 courses of Endpoint: O E 9 g/kg/day Response M E Rate I N Up to 8 courses of Z 18 g/kg/day E L4389-11 Study Design • 5 daily treatments every 21 days; • Tumor burden is assessed at Baseline and Day 1 of each course after Course 1

  11. Study L4389-11Randomization Scheme Original 120 pts (1:1:1) Revised 195 pts (1:2:2) Placebo (40 pts) (39 pts) Study 11 CD25(+) 9 g/kg (40 pts) (78 pts) 18 g/kg (40 pts) (78 pts)

  12. Challenges Encountered inConduct of L4389-11 • Small population size (CTCL annual incidence – 4 per million; 1,100 new U.S. cases per year) • Few clinical research centers in each country see significant numbers of patients appropriate for this study • Impact of the placebo arm in a symptomatic patient population • Impact of number of prior therapies on eligibility

  13. Site Enrollment Efforts to Complete Protocol L4389-11 From 1999 Through October 2005

  14. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJ Med 1989 321:1784

  15. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJ Med 1989 321:1784

  16. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJM 1989 321:1784

  17. Site Enrollment Efforts to Complete Protocol L4389-11 in 2000 # of Active Sites 12 # of Pts. Enrolled 9 Cumulative # of Pts. 82 France: 6 Canada: 2 Germany: 3 UK: 2 USA: 3 Australia: 2

  18. Site Enrollment Efforts to Complete Protocol L4389-11 in 2003 # of Active Sites 25 # of Pts. Screened 48 # of Pts. Enrolled 16 Cumulative # of Pts. 114 Netherlands: 1 Germany: 4 Canada: 3(1) UK: 3 Austria: 2 Poland: 5(1) USA: 1 Russia: 5 Australia: 1

  19. Site Enrollment Efforts to Complete Protocol L4389-11 in 2004 # of Active Sites 23 # of Pts. Screened 70 # of Pts. Enrolled 14 Cumulative # of Pts. 128 Germany: 3 UK: 3 Austria: 2 Canada: 2 Poland: 5(1) Russia: 6(1) Australia: 2(1) Brazil: 9 Argentina: 7

  20. Site Enrollment Efforts to Complete Protocol L4389-11 in 2005 # of Active Sites 25 # of Pts. Screened 31 # of Pts. Enrolled 9 Cumulative # of Pts. 137 Switzerland: 1 Germany: 3 UK: 3 Canada: 2 Austria: 2 Poland: 5 Russia: 5 Australia: 4(2)

  21. Summary of Patient Recruitment Efforts Since 2003 26% 25% 21%

  22. Summary of Patient Recruitment Efforts Since 2003 26% 26% 21%

  23. Post-approval Commitment For Protocol L4389-14 Status:Enrollment goals met

  24. Summary With Ligand’s intensive efforts: • L4389-11 • Total accrual to date is 137 patients • Enrollment averages about 12 pts/year or 0.5 pts/site/year • L4389-14 • Met enrollment goal (86 targeted, 90 enrolled) • Continues to accrue, offering L4389-11 placebo patients the therapeutic option of receiving ONTAK

  25. Next Steps Ligand intends to open a dialogue with the FDA to discuss strategies to satisfy the requirements of our post-approval commitments, including the possibility of achieving an earlier study closure following an evaluation of total patient accrual from both the L4389-11 and L4389-14 studies.

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