CLOLAR

1
CLOLAR(clofarabine) Pediatric Subcommittee ODAC
Meeting

• 20 October 2005

2
Genzyme participants

• Rekha Abichandani, MD Medical Director, Clinical
  Research
• Marie Bonneterre, MD Medical Director, Clinical
  Research
• Stephen Eckert, PhD Senior Director,
  Biostatistics
• Manny Fernandez Manager, Clinical Research
• Mark Hayes, PhD Vice President, Regulatory
  Affairs
• Edda Tschirhart Associate, Regulatory Affairs
• Mike Vasconcelles, MD Vice President, Clinical
  Research

3
Agenda

• Introduction
• Pre-approval clinical development highlights
• Post-approval clinical development plans
• Clinical development risks and challenges
• Summary

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Relapsed and refractory pediatric leukemia

• Treatments for newly diagnosed patients with ALL
  use aggressive multi-drug regimens
• 21 ALL have relapsed/refractory disease
• Relapsed leukemia is the third most common
  childhood cancer

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Annual incidence of pediatric ALL (SEER)
2,470Pediatric ALL
2,34795 CR
124 5 Refractory
37516 Relapse
499 Pediatric ALL Patients
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Challenges in relapsed and refractoryPediatric
leukemia

• Heterogeneous population
• Multi-drug resistance is common in leukemia
  cells, particularly at relapse
• Dose intensification with combination therapies
  has resulted in significant co-morbidities and
  organ dysfunction
• Transplant is the best curative option but
  requires disease control and time to identify
  donor

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Approved agents for relapsed or Refractory
pediatric leukemia

• Clofarabine is the first drug specifically
  approved for pediatric leukemia in 20 years
• Most commonly used agents approved many years ago
• methotrexate (1953)
• 6-mercaptopurine (1953)
• vincristine (1963)
• Ara-C (1969)
• doxorubicin (1974)
• Development of new pediatric oncology agents has
  lagged behind adult oncology drug development

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Nucleoside analogsdAdo and its analogs
Resistant to Deamination
Resistant to Phosphorolysis
deoxyadenosine cladribine fludarabine
clofarabine
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Mechanism of action
Inhibition of DNA synthesis/ repair
5NT
dCK
clofarabine
Transporter
CELL DEATH
clofarabine
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Agenda

• Introduction
• Pre-approval clinical development highlights
• Post-approval clinical development plans
• Clinical development risks and challenges
• Summary

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Pre-approval development timeline

• Phase II AML (BIVN-121)
• (N65)

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Key regulatory milestones forPediatric acute
leukemia
2003 2003 2004 2004 2004 2004
Feb Jul Mar Aug Dec 01 Dec 28
Orphan drug designation Fast track
designation Rolling NDA submission
completed Efficacy update submitted ODAC
recommends accelerated approval (in relapsed
and refractory pediatric ALL) FDA grants approval
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Basis for approval

• Efficacy
• Single Phase II study of 49 patients (CLO 212)
• Pediatric ALL Second or subsequent relapse
  and/or refractory
• Clofarabine single agent
• Endpoint overall response (CR CRp20)
• Safety
• 113 pediatric leukemia patients (includes AML
  patients)

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Approved indication

• On 28 Dec 2004, FDA granted marketing approval
  for clofarabine for the treatment of pediatric
  patients 1 to 21 years old with relapsed or
  refractory ALL after at least two prior regimens
• Approval was
• under provisions of accelerated approval
  regulations, and
• based on the induction of complete responses
• Sponsor required to conduct a randomized, Phase
  III post-marketing study demonstrating clinical
  benefit

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Agenda

• Introduction
• Pre-approval clinical development highlights
• Post-approval clinical development plans
• Clinical development risks and challenges
• Summary

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Initial pediatric ALL post-approval Clinical
development plan

• Step 1
• Phase I / II dose-escalation study of CLO plus
  Ara-C and L-asparaginase (L-asp) in refractory or
  relapsed ALL
• Step 2
• Randomized Phase III study of (Ara-C L-asp)
  CLO in pediatric ALL in first relapse
• Concepts from COG protocol AALL01P2
• Innovative, yet complicated, multi-agent design

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Original proposed Phase III designFirst relapse
Block 3-A Ara-C L-asp
Block 2 etoposidecyclophosphamideIT
methotrexate
Block 1 vincristineprednisonePEG-asparaginasedo
xorubicinIT cytarabineIT methotrexate
Block 3-B clofarabine Ara-C L-asp
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FDA comments on Proposed development plan

• Agreed to step 1 (Phase I / II combination)
• Stated that step 2 (Phase III) does not appear
  to have a realistic chance of showing a clinical
  benefit of clofarabine in children with ALL in
  first relapse
• COG AALL01P2 designed to identify optimal
  combination therapies for patients with ALL
• Genzymes understanding is that the complex
  multi-agent design would make it difficult to
  isolate the clinical benefit of clofarabine

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Additional issue with Proposed development plan

• Combination CLO Ara-C L-asp did not have wide
  investigator support
• Potential toxicity concerns
• Ara-C L-asp already maximally toxic
• Thus, may not be able to effectively
  dose-escalate clofarabine

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Revised pediatric ALL post-approvalClinical
development plan

• Step 1
• Conduct at least two Phase I / II combination
  studies
• CLO cyclophosphamide etoposide(protocol CLO
  21800205)
• CLO Ara-C(protocol COG AAML0523)
• Step 2
• Build from Phase II results to design appropriate
  randomized Phase III study to demonstrate
  clinical benefit

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Potential Phase III study design

• Randomized Phase III Study of combination
  selected based on the results of the Phase I/II
  studies
• Patient population
• 1st relapse
• 2nd/Subsequent relapse
• Potential endpoints
• Event free survival
• Remission rate/duration of remission
• Overall survival
• FDA/Genzyme to discuss details of the Phase III
  study design once data available from the Phase
  I/II studies

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Pediatric leukemia development timelinePost-appro
val
2005
2006
2007
New pediatric studies
? Phase I / II CLOetoposidecyclophosphamide
(CLO 21800205) (N39)
? Phase II CLOAra-C (COG AAML0523) (N70)

? Phase III comparator CLO (NTBD)
New adult studies
? Phase 3 Ara-C /- CLO (CLO 34100405) (N360)
? Phase 3 CLO vs low dose Ara-C (CLO-34200505)
(N360)
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Agenda

• Introduction
• Pre-approval clinical development highlights
• Post-approval clinical development plans
• Clinical development risks and challenges
• Summary

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Risks and challenges withPediatric ALL
development proposal

• No standard chemotherapeutic options in second or
  subsequent relapsed or refractory disease
• Challenge No standard comparator arm
• Defining an appropriate primary endpoint for a
  Phase III study
• Allogeneic SCT only potentially curative option
• Challenge SCT may confound remission duration
  and potentially other endpoints
• Small patient population (500 per year)
• Competing clinical trials
• Challenge Difficult to enroll Phase III trial in
  reasonable timeframe

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Agenda

• Introduction
• Pre-approval clinical development highlights
• Post-approval clinical development plans
• Clinical development risks and challenges
• Summary

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Summary

• In the 10 months since receiving approval,
  Genzyme has made progress toward meeting
  post-marketing commitments
• Initial plan proposed and required revision
• One Phase I / II trial initiated CLO 21800205
• Second Phase II protocol (collaboration with COG)
  finalized AAML0523
• Many challenges to designing an appropriate
  confirmatory trial, particularly in relapsed or
  refractory ALL
• Genzyme looks forward to collaborating with FDA
  and COG to face these challenges

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CLOLAR(clofarabine) Pediatric Subcommittee ODAC
Meeting

• 20 October 2005