ONTAK denileukin diftitox Postapproval Clinical Commitment

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• ONTAK (denileukin diftitox) Post-approval
  Clinical Commitment

Oncologic Drugs Advisory Committee Meeting March
12-13, 2003 Bethesda, MD
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ODAC MeetingLigand Attendees

• James LItalien, 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

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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
• ongoing efforts to achieve completion of the
  study
• challenges encountered
• Summary

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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

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Denileukin Diftitox (ONTAK?) Mechanism of Action
DT
IL2
HIGH affinity IL2 receptor
Cell exterior
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
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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? 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

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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

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

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L4389-11 Study Design (2)

• Following discussion with FDA during 1999, study
  population was increased from 120 (404040) to
  195 (397878)
• maintains original size of the placebo group
• weights randomization toward active study drug to
  encourage enrollment

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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

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Enrollment in L4389-11 Progress to Date
105
98
89
Patients Enrolled
82
73
73
Year
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Ongoing Efforts to Complete Study L4389-11
28
22
Cumulative Active Sites
10
9
1
Year
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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

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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

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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)
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Impact of Practice Patterns and Prior Therapies
on Accrual
Clinical Stage
IA IB IIA
IIB III IVA IVB
Eligible for L4389-11
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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

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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