ONTAK denileukin diftitox Postapproval Commitments

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• ONTAK (denileukin diftitox) Post-approval
  Commitments

Oncologic Drugs Advisory Committee
Meeting November 8, 2005 Holiday
Inn Gaithersburg, 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 LItalien, 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
S S
S S
Diptheria toxin Enzyme Activity
IL-2 Receptor Binding Domain
RVRR
Diptheria toxin Translocation Function
Fusion Junction
Cleavage Domain

• 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

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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
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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 mg/kg vs 18 mg/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 mg/kg and 18 mg/kg in CTCL
  patients 93-04-11 (now L4389-11) (n195)
• Completion of an open label study of 18 mg/kg in
  CTCL patients 93-04-14 (now L4389-14) (n86)
• 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)

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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
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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

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Study L4389-11Randomization Scheme
Original 120 pts (111)
Revised 195 pts (122)
Placebo (40 pts)
(39 pts)
Study 11 CD25()
9 ?g/kg (40 pts)
(78 pts)
18 ?g/kg (40 pts)
(78 pts)
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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

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Site Enrollment Efforts to Complete Protocol
L4389-11 From 1999 Through October 2005
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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 3963 2
Olsen et al. J Clin Oncol. 2001 19376 3 Kaye et
al. NEJ Med 1989 3211784
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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 3963 2
Olsen et al. J Clin Oncol. 2001 19376 3 Kaye et
al. NEJ Med 1989 3211784
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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 3963 2
Olsen et al. J Clin Oncol. 2001 19376 3 Kaye et
al. NEJM 1989 3211784
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Site Enrollment Efforts to Complete Protocol
L4389-11 in 2000
France 6
Canada 2
Germany 3
UK 2
USA 3
Australia 2
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Site Enrollment Efforts to Complete Protocol
L4389-11 in 2003
Netherlands 1
Germany 4
UK 3
Canada 3(1)
Austria 2
Poland 5(1)
USA 1
Russia 5
Australia 1
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Site Enrollment Efforts to Complete Protocol
L4389-11 in 2004
Germany 3
UK 3
Austria 2
Canada 2
Poland 5(1)
Russia 6(1)
Australia 2(1)
Brazil 9
Argentina 7
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Site Enrollment Efforts to Complete Protocol
L4389-11 in 2005
Switzerland 1
Germany 3
UK 3
Canada 2
Austria 2
Poland 5
Russia 5
Australia 4(2)
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Summary of Patient Recruitment Efforts Since 2003
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Summary of Patient Recruitment Efforts Since 2003
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Post-approval Commitment For Protocol L4389-14
Status Enrollment goals met
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Summary

• With Ligands 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.