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ONTAKONTAK®® (denileukin diftitox) (denileukin diftitox) Post-approval CommitmentsPost-approval Commitments

Oncologic Drugs Advisory Committee MeetingNovember 8, 2005

Holiday InnGaithersburg, Maryland

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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

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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

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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| IL-2 Receptor

Binding Domain

RVRR

| S|S|

Fusion Junction

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Denileukin Diftitox (ONTAK®) Mechanism of Action

ONTAKHIGHaffinity IL2 receptor

INTERMEDIATE affinity IL2 receptor

Cleavage &Toxin release

IL2

DTProtein

synthesisCELLDEATH

Protein synthesisTerminated by toxin-mediated ADP ribosylation of elongation factor 2

Internalization of IL2R with bound toxin

Cell exterior

Cell interior

Cell membrane

IL2DT IL2DT

IL2DT

IL2DT

= CD25 = CD122 = CD132

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ONTAK – Clinical Characteristics

• Indicated for the treatment of patients with persistent or recurrent, CD25 (+) cutaneous T-cell lymphoma (CTCL)

• Acceptable safety profile

• Minimal myelosuppression

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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 g/kg vs 18 g/kg (93-04-10):

30% response rate

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ONTAK Clinical Commitmentsfor Final Approval

• Completion of a 3 arm, blinded, placebo controlled study of 9 g/kg and 18 g/kg in CTCL patients 93-04-11 (now L4389-11) (n=195)

• Completion of an open label study of 18 g/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

L4389-11Retreatment patients from studies 92-04-01,

93-04-10 and -11 (prior to 1999)

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Study 11

195 pts

Study 14

86 pts

CTCLPatients

Screened(Ia to III)(≤ 3 prior

therapies)

ONTAK 9g/kg

ONTAK 18g/kg

Placebo

Placebo Progressionor 8 cycles no response

CD25(+)

CD25(-)

Patient Selection and Randomization Schema

Retreatment, CD25+

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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

RANDOMIZE

PrimaryEndpoint:Response

Rate

SCREEN Up to 8 courses of

18 g/kg/day

Up to 8 courses of9 g/kg/day

Up to 8 courses ofplacebo

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Study 11

CD25(+)

Placebo (40 pts)

9 g/kg (40 pts)

18 g/kg (40 pts)

Original

120 pts (1:1:1)

Study L4389-11Randomization Scheme

(39 pts)

(78 pts)

(78 pts)

Revised

195 pts (1:2:2)

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• 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 L4389-11

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

90

3825

0

20

40

60

80

100

Evaluated Sites Opened Sites Active Sites

Num

ber

of S

ites

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Patient Enrollments for CTCL Studies

10390

136

71

35

0

20

40

60

80

100

120

140

92-04-01(Phase I/II)

93-04-10(Phase III)

L4389-11(Ligand)

L4389-14(Ligand)

Kaye et al.(NCI)

1 Saleh et al. J Am Acad Dermatol 1998 39:632 Olsen et al. J Clin Oncol. 2001 19:3763 Kaye et al. NEJ Med 1989 321:1784

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Prior to NDA Approval

Largest Prior Prospective CTCL Trial

Post Approval Studies

Nu

mb

er o

f P

atie

nts

/Tri

al

15

Patient Enrollments for CTCL Studies

10390

137

71

35

0

20

40

60

80

100

120

140

92-04-01(Phase I/II)

93-04-10(Phase III)

L4389-11(Ligand)

L4389-14(Ligand)

Kaye et al.(NCI)

1 Saleh et al. J Am Acad Dermatol 1998 39:632 Olsen et al. J Clin Oncol. 2001 19:3763 Kaye et al. NEJ Med 1989 321:1784

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Prior to NDA Approval

Largest Prior Prospective CTCL Trial

Post Approval Studies

Nu

mb

er o

f P

atie

nts

/Tri

al

16

Patient Enrollments for CTCL Studies

10390

137

71

35

0

20

40

60

80

100

120

140

92-04-01(Phase I/II)

93-04-10(Phase III)

L4389-11(Ligand)

L4389-14(Ligand)

Kaye et al.(NCI)

1 Saleh et al. J Am Acad Dermatol 1998 39:632 Olsen et al. J Clin Oncol. 2001 19:3763 Kaye et al. NEJM 1989 321:1784

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Prior to NDA Approval

Largest Prior Prospective CTCL Trial

Post Approval Studies

Nu

mb

er o

f P

atie

nts

/Tri

al

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Site Enrollment Efforts to Complete Protocol L4389-11 in 2000

UK: 2Germany: 3Canada: 2

USA: 3

Australia: 2

# of Active Sites

Cumulative # of Pts.

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# of Pts. Enrolled 9

82

France: 6

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Site Enrollment Efforts to Complete Protocol L4389-11 in 2003

UK: 3Germany: 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 Sites 25

48

# of Pts. Enrolled 16

114

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Site Enrollment Efforts to Complete Protocol L4389-11 in 2004

UK: 3Germany: 3

Australia: 2(1)

Poland: 5(1)Russia: 6(1)

Austria: 2

Argentina: 7Brazil: 9

Canada: 2

Cumulative # of Pts.

# of Pts. Screened

# of Active Sites 23

70

# of Pts. Enrolled 14

128

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Site Enrollment Efforts to Complete Protocol L4389-11 in 2005

UK: 3Germany: 3

Canada: 2

Australia: 4(2)

Poland: 5Russia: 5

Austria: 2

Switzerland: 1

Cumulative # of Pts.

# of Pts. Screened

# of Active Sites 25

31

# of Pts. Enrolled 9

137

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Summary of Patient Recruitment Efforts Since 2003

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

150

39 31

0

40

80

120

160

ScreenedPatients

L4389-11 L4389-14 Pivotal PhaseIII

Nu

mb

er o

f P

atie

nts

25%26%21%

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Summary of Patient Recruitment Efforts Since 2003

0%

20%

40%

60%

80%

100%

3139

150

0

40

80

120

160

ScreenedPatients

L4389-11 L4389-14 Pivotal PhaseIII

Nu

mb

er o

f P

atie

nts

26% 26%21%

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Post-approval Commitment For Protocol L4389-14

Target Enrolled

Total number of pts 86 90

Number of CD25(-) pts 29 32

CD25(+) pts (58) – Two distinct subgroups contributing important additional information

Prior placebo treatment crossover

Retreatment after relapse

31

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Status: Enrollment goals met

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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

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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.