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

2 Oncologic Drugs Advisory Committee Meeting Ligand Attendees Ligand: –Andrés Negro-Vilar, M.D., Ph.D. Exec. Vice President, Research & Development Chief 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 L (prior to 1999, ) Study L (prior to 1999, ) –Difficulties encountered

4 ONTAK ® Structure 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 Diptheria toxin Enzyme Activity Cleavage Domain Diptheria toxin Translocation Function |S|S||S|S| IL-2 Receptor Binding Domain RVRR |S|S||S|S| Fusion Junction

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

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 ( ): 37% response rate –Phase III study of 9  g/kg vs 18  g/kg ( ): 30% response rate

8 ONTAK  Clinical Commitments for Final Approval Completion of a 3 arm, blinded, placebo controlled study of 9  g/kg and 18  g/kg in CTCL patients (now L ) (n=195) Completion of an open label study of 18  g/kg in CTCL patients (now L ) (n=86) –Companion study to L , including 3 subgroups: CD25(-) patients (target = 29 patients) Placebo cross-over patients from study L Retreatment patients from studies , and -11 (prior to 1999)

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

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

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

12 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 Challenges Encountered in Conduct of L

13 Site Enrollment Efforts to Complete Protocol L From 1999 Through October 2005

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

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

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

17 Site Enrollment Efforts to Complete Protocol L in 2000 UK: 2 Germany: 3 Canada: 2 USA: 3 Australia: 2 # of Active Sites Cumulative # of Pts. 12 # of Pts. Enrolled9 82 France: 6

18 Site Enrollment Efforts to Complete Protocol L in 2003 UK: 3 Germany: 4 Canada: 3(1) USA: 1 Australia: 1 Poland: 5(1) Russia: 5 Austria: 2 Netherlands: 1 Cumulative # of Pts. # of Pts. Screened # of Active Sites25 48 # of Pts. Enrolled16 114

19 Site Enrollment Efforts to Complete Protocol L in 2004 UK: 3 Germany: 3 Australia: 2(1) Poland: 5(1) Russia: 6(1) Austria: 2 Argentina: 7 Brazil: 9 Canada: 2 Cumulative # of Pts. # of Pts. Screened # of Active Sites23 70 # of Pts. Enrolled14 128

20 Site Enrollment Efforts to Complete Protocol L in 2005 UK: 3 Germany: 3 Canada: 2 Australia: 4(2) Poland: 5 Russia: 5 Austria: 2 Switzerland: 1 Cumulative # of Pts. # of Pts. Screened # of Active Sites25 31 # of Pts. Enrolled9 137

21 Summary of Patient Recruitment Efforts Since % 26% 21%

22 Summary of Patient Recruitment Efforts Since % 21%

23 Post-approval Commitment For Protocol L TargetEnrolled Total number of pts8690 Number of CD25(-) pts2932 CD25(+) pts (58) – Two distinct subgroups contributing important additional information Prior placebo treatment crossover Retreatment after relapse  Status: Enrollment goals met

24 Summary With Ligand’s intensive efforts: L –Total accrual to date is 137 patients –Enrollment averages about 12 pts/year or 0.5 pts/site/year L –Met enrollment goal (86 targeted, 90 enrolled) –Continues to accrue, offering L 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 L and L studies.