CAMPATH alemtuzumab: Status of Phase IV Postmarketing Commitments

1
CAMPATH (alemtuzumab) Status of Phase IV
Post-marketing Commitments

• Oncology Drugs Advisory Committee
• 8 Nov 2005
• Cynthia Sirard, MD

2
Genzyme Participants

• Susan Beardslee Principal Medical
  Writer, Scientific Reporting
• Stephen Eckert, Ph.D. Senior Director,
  Biostatistics
• Mark Goldberg, M.D. Senior Vice President,
  Clinical Research
• Mark Hayes, Ph.D. Vice President,
  Regulatory Affairs
• Jeanne Jones, RN, MSN Director, Clinical
  Research
• Tracie Reed Senior Associate, Regulatory
  Affairs
• Cynthia Sirard, M.D. Medical Director,
  Clinical Research

3
Agenda

• Overview of treatment options for CLL
• CAMPATH Review of data supporting approval
• Review and status of post-approval commitments
  CAM307
• Resolving challenges in meeting post-approval
  commitments

4
Chronic Lymphocytic Leukemia (CLL)

• Most common form of adult leukemia in U.S.
• Incidence 9,730 patients/year
• Prevalence 60,000 patients
• Progressive and often fatal disease
• Deaths 4,600/year
• No current therapy is curative
• No therapy has demonstrated prolonged survival

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What is CLL and How is it Treated?
Disease Characteristics
1st line therapy 9,730 Incidence

• Evolving standards of care
• Alkylator-based
• Fludarabine
• Rituximab
• Combination

• Chronic disease
• Variable clinical course
• Often asymptomatic at dx (no treatment
  required)
• Requires multiple sequential treatments
• Treatment goal
• Palliative
• Curative?
• MRD

No response
Relapsed/ refractory therapy 60,000 Prevalence

• Re-tx with 1st line agents
• Fludarabine
• Rituximab
• CAMPATH
• 2nd line cytotoxic
• PBSCT/ BMT
• Clinical trials

Response
Remission
Relapse/ progression
6
CAMPATH-1H (alemtuzumab)

• Humanized monoclonal antibody directed against
  CD52 antigen
• Expressed on B T lymphocytes, NK cells, DCs,
  Mono/Mac, plasma cells, Thymocytes
• Not expressed on bone marrow progenitor cells

Carbohydrate
Human IgG1 construct
Murine CDRs
7
Mechanism of action

• Lyses lymphocytes via
• Complement fixation
• Antibody dependent cell mediated cytotoxicity
• Induction of apoptosis
• Different mechanism of action from available
  cytotoxic chemotherapeutic agents

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Pivotal and Supportive Studies for
ApprovalPatient Population
9
Pivotal and Supportive Studies for
ApprovalEfficacy Results
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Pivotal and Supportive Studies for ApprovalSafety

• Most common adverse events are acute
  infusion-related events that decline with
  subsequent infusions
• Variety of opportunistic infections reported
  anti-infective prophylaxis is recommended on
  initiation of therapy
• Hematologic toxicity which can be severe emerges
  on treatment in some patients, but is usually
  transient
• Reasonable and manageable safety profile in this
  immunocompromised, refractory disease population

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Accelerated Approval Granted 7 May 2001

• Indication
• CAMPATH is indicated for the treatment of B-cell
  chronic lymphocytic leukemia (CLL) in patients
  who have been treated with alkylating agents and
  who have failed fludarabine therapy
• Nine post-approval commitments
• Five completed
• Four are ongoing
• Three will be completed in Q1 2006 at the
  conclusion of randomized phase III study (CAM307)
  initiated in 2001
• Final commitment to be completed in a study being
  initiated in 2005 (CAM203)

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CAMPATH Post-marketing CommitmentsCompleted
13
CAMPATH Post-marketing CommitmentsOngoing
14
CAM307Overview

• Title
• A Phase III Study to Evaluate the Efficacy and
  Safety of Front-Line Therapy with CAMPATH
  (alemtuzumab) versus Chlorambucil in Patients
  with Progressive B-Cell Chronic Lymphocytic
  Leukemia
• Purpose
• Verify the clinical benefit of CAMPATH therapy
• General design
• Open label, multi-center, randomized, active
  controlled trial

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CAM307Objectives

• Primary objective
• To demonstrate that CAMPATH is superior to
  chlorambucil as front-line therapy in patients
  with progressive B-CLL as measured by progression
  free survival (PFS)
• Secondary objectives are to compare treatment
  arms with respect to
• Overall survival
• CR and overall response rates
• Duration of response (not statistically compared)
• Time to treatment failure
• Time to alternative therapy
• Safety

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CAM307Inclusion Criteria

• Histopathologically confirmed diagnosis of B-CLL
  with CD5, CD19 and CD23 positive clone
• Rai stage I through IV disease with evidence of
  progression
• No previous chemotherapy for B-CLL
• WHO performance status of 0, 1, or 2
• Serum creatinine 2.0 X the institutional upper
  limit of normal
• Adequate liver function

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CAM307Exclusion Criteria

• ANC lt 0.5 x 109/L or platelet count lt 10 x 109/L
• Autoimmune thrombocytopenia
• Active infection
• Serious cardiac or pulmonary disease
• Central nervous system involvement with CLL
• Positive quantitative CMV by PCR assay

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CAM307Treatment Arms

• Patients randomized 11 to receive either
• CAMPATH
• 30 mg/day IV
• Dosing is 3 times per week, up to 12 total weeks,
  inclusive of any dose escalation period
• or
• Chlorambucil
• 40 mg/m2 PO
• Dosing once every 28 days for a maximum of 12
  months

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CAM307Accrual Status

• Total Enrollment 297 patients
• 149 patients enrolled on CAMPATH
• 148 patients enrolled on Chlorambucil
• Last patient enrolled 15 Jul 2004
• Accruing / active sites
• 45 / 68 Total
• 9 / 20 US sites

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CAM307Patient Accrual Distribution

• Poland
• Croatia
• Czech Republic
• Serbia
• United States
• Slovakia
• Netherlands
• Lithuania
• France
• Italy
• United Kingdom
• Estonia
• Ireland

117 47 39 28 24 12 9 8 4 3 3 2 1
21
CAM307Statistical Design

• Randomization 11 by Interactive Voice Response
  System (IVRS)
• Primary endpoint assumption
• 50 improvement in PFS
• (21 months vs. 14 months)
• Sample size
• 284 patients (142 per treatment arm)

22
CAM307Interim and Final Analyses

• April 2004
• First interim analysis (safety only) was
  conducted after 50 patients per arm reached 4
  months following randomization
• August 2005
• Second interim analysis (safety and efficacy) was
  completed after 95 patients progressed (or died)
  
• Q2 2006 (projected)
• Final analysis planned after a total of 190
  failures (progressed/died)

23
CAM307Status and Timelines
24
CAM307Difficulties Encountered

• Initial enrollment at U.S. sites slow, likely due
  to alternative first-line therapeutic options for
  CLL patients in U.S.
• Enrollment increased substantially following
  opening of sites outside United States
  (particularly in eastern Europe)

25
CAM307Difficulties Encountered

• Logistical difficulties encountered in
  immunological function assessment cohort. Data
  captured for only 4 patients in CAM307.
• In a recent discussion with the Division of
  Oncology Drug Products (29 July 2005), Genzyme
  will fulfill this commitment in a new trial
  CAM203

26
CAM203

• A Phase II, open-label, prospective,
  multi-center study to evaluate the efficacy and
  safety of subcutaneously administered CAMPATH as
  therapy for patients with relapsed or refractory
  B-CLL who have previously received treatment with
  an alkylating agent and failed fludarabine

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Summary

• CAMPATH has emerged as an important treatment
  option for CLL
• Post-marketing commitments will be fully met
  following completion of CAM307 and CAM203 trials
• These trials will further provide support for
  CAMPATH use in first line CLL (CAM307) and for
  the subcutaneous route of administration (CAM203)