FDA ODAC Meeting November 8, 2005

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FDA ODAC MeetingNovember 8, 2005

• Celecoxib (CELEBREX) Therapy forFamilial
  Adenomatous Polyposis (FAP)
• Subpart H Phase IV Commitments

2
Agenda

• Familial Adenomatous Polyposis (FAP)
• Basis for Celebrex approval in FAP
• Subpart H commitments
• Status of Subpart H commitments
• FAP Phenotype Suppression Study
• FAP Registry Study
• Summary

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FAP Disease Overview

• Rare inherited disease
• Annual incidence rate 1-2 cases per 1 000 000
• Prevalence rate 2.6 to 4.7 per 100 000

4
FAP Disease Natural History

• Adenomas begin to develop in adolescence
• 100-5000 colorectal adenomas
• Cancer risk increases with number of adenomas
• If untreated
• 100 colorectal cancer risk
• Median life expectancy 42 years

5
FAP Disease Management

• Lifetime endoscopic surveillance
• Initial colon resection 18-20 years of age
• Repeated surgeries
• Surgical prophylaxis has dramatically reduced
  this cancer risk, albeit with substantial
  morbidity
• Interest in developing medical treatment as an
  adjunct to surgery

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Pivotal Registration TrialBasis for Approval

• Description Double-blind, placebo-controlled
  study of celecoxib in patients with FAP
• Sites U.T. M.D. Anderson, St. Marks (UK)
• Treatment Groups Placebo
• celecoxib (100, 400 mg po BID)
• Primary Endpoint Percent change in the number of
  colorectal adenomas
• Duration of Therapy 6 months

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Celebrex Efficacy in FAPDouble-blind,
placebo-controlled Phase II Study
Patients N 81 (17 placebo, 32 100 mg BID, 32
400 mg BID) Duration of Therapy 6 months
RESULTS
Duodenal N 50
Colorectal N 77
P 0.003
Change Baseline
400 mg BID versus placebo
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FAP Indication

• Celecoxib (CELEBREX ) in FAP approved December
  1999 under 21 CFR Subpart H to reduce the number
  of adenomatous colorectal polyps in FAP as an
  adjunct to usual care (e.g., endoscopic
  surveillance, surgery)
• It is not known whether there is a clinical
  benefit from a reduction in the number of
  colorectal polyps in FAP patients.
• It is not known whether the effects of CELEBREX
  treatment will persist after treatment
  discontinuation
• The efficacy and safety of CELEBREX treatment in
  patients with FAP beyond six months have not been
  studied

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Subpart H Phase IV Commitments

• Post-approval Commitments under Subpart H
• Phase III placebo-controlled trial of celecoxib
  in genotype positive, phenotype negative subjects
  with FAP
• Registry-based observational study assessing
  clinical outcomes in FAP patients receiving
  celecoxib compared with control patients

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Phase III Genotype Positive FAP Study
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Genotype Positive StudyBrief Chronology of Events
12/99

• FDA agrees with study concept
• NCI/Pharmacia collaboration
• NCI issues request for proposals (RFP)
• Pharmacia to provide drug and monetary support
• NCI contract awarded
• MD Anderson - lead institution
• Creighton University
• Memorial Sloan Kettering Cancer Center
• Cleveland Clinic
• Texas Children Hospital
• University of California San Francisco
• Mt Sinai Hospital (Toronto)
• St Marks Hospital (England)

04/00
07/00
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Genotype Positive StudyBrief Chronology of
Events (contd.)
08/00

• Consideration of issues before Phase III
• Celecoxib dosing in children
• Pilot dose-ranging trial needed
• Draft Phase I protocol developed
• Phase I/III program submitted to FDA
• Three Phase I Protocol revisions required
• Primary issue need for placebo control in Phase
  I setting
• Phase I Protocol approved by NCI

10/00
01/01
02/01
01/02
13
Genotype Positive StudyBrief Chronology of
Events (contd.)
02/02

• MDACC IRB approval
• Final Phase I protocol submitted to FDA
• Use of investigational 50mg orally dispersible
  tablets not achieved
• Protocol revised to use commercial capsule
  formulation
• First patient enrolled in Phase I study

05/02
06/02
08/02
12/02
Expected completion of Phase I study Q3-4 2004
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Genotype Positive StudyPhase I Design

• Description Phase I Pilot Toxicity/Methods
  Validation Study of Celecoxib in Genotype or
  Phenotype-Positive Children with Familial
  Adenomatous Polyposis
• Sites U.T. M.D. Anderson and Cleveland Clinic
• Patient population Patients 10-14 years old
  with known polyp burden or confirmed APC mutation
  
• Design Dose escalation trial in successive
  cohorts of 6 patients (4 celecoxib, 2 placebo)
• Treatment groups Celecoxib (4, 8, 16 mg/kg/day
  po), Placebo
• Sample size N 18 ( 3 cohorts of 6 patients)
• Duration of therapy 3 months
• Primary endpoint Safe dose in this patient
  population

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Genotype Positive StudyBrief Chronology of
Events (contd.)
04/03

• Pfizer assumes responsibility for the Phase IV
  commitments from Pharmacia
• Phase III protocol design re-evaluated given
  updates on Phase I study
• Limitations of phenotype negative population
  identified
• Single center review of cases within age range
• Clinically meaningful endpoint phenotype
  expression, define uniform threshold for
  endoscopic polyp removal
• Last subject enrolled in third cohort of the
  Phase I study

09/03
02/04
05/04
06/04
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Genotype Positive StudyBrief Chronology of
Events (contd.)
09/04

• Evaluate the consistency of measurement, number
  of possible patients per center, clinical
  practice standards site feasibility globally
  for Phase III
• DSMB of Phase I study meets Dec 16th for safety
  review 16mg/kg/day dose was safe appropriate
  for Phase III

12/04
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FAP Phase I Adverse Events
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FAP Phase I Adverse Events

• Grade 1 94.7 of all reported AEs
• Grade 2 5.3 of all reported AEs
• No CV AEs reported
• 21 (28) events were gastrointestinal
• Abdominal Pain 28.5 (Placebo-3, 4mg/kg-2,
  16mg/kg-1)
• Vomiting NOS 23.8 (4mg/kg-2, 8mg/kg-2,
  16mg/kg-1)
• Nausea 14.3 (Placebo-1, 8mg/kg-1, 16mg/kg-1)
• Rectal Bleeding 4.8 (Placebo-1)
• Diarrhea 4.8 (4mg/kg-1)
• Others 23.8 (4mg/kg-2, 16mg/kg-3)

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FAP Phase I Polyp Count Difference
Wilcoxon p-value0.011
Count
Placebo
4mg/kg
8mg/kg
16mg/kg
(N 6)
(N 4)
(N 4)
(N 4)
Celecoxib Dose
Difference in polyp count between baseline
end of treatment
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Genotype Positive StudyBrief Chronology of Events
12/04

• CV Safety Data (December 17th)

03/05

• Submission of briefing package to the FDA
• Meeting with FDA to present Phase III protocol
  design
• Special Protocol Assessment (SPA) for Phase III
  protocol submitted to FDA
• Comments from FDA regarding SPA received
• First patient to be enrolled in Phase III study

04/05
06/05
08/05
01/06
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Genotype Positive StudyProposed Design

• Description Phase III study of celecoxib in
  genotype-positive, early phenotype positive or
  negative subjects with FAP
• Treatment groups Placebo
• Celecoxib (16mg/kg/day, approximately 400mg BID)
• 11 randomization
• Sample size N 200
• Duration of therapy 5 years
• Primary endpoint Time to treatment failure
  defined as time from randomization to earliest
  occurrence of appearance of 20 polyps (gt2mm,
  visible without dye enhancement) at any
  colonoscopy during the study or diagnosis of
  colorectal malignancy

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FAP Registry Study
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FAP Registry-based Study

• Study Design Observational Registry-based Study
• Patient Population Patients receiving celecoxib
• Historical/Concurrent controls
• Participating Sites Established FAP registries
  in Canada, US, Denmark, Germany and Australia
• Objectives - Describe patterns of celecoxib use
  in
• disease management
• - Examine long-term benefits of celecoxib in
  prolonging time to FAP-related events
• - Evaluate long-term safety of celecoxib
• Study Timelines Study Initiation 3Q 2004 (US)
• First Study Status Report 4Q 2004
• Finalization of Study 4Q 2010

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FAP Registry StudyBrief Chronology of Events

• FDA grants accelerated approval for celecoxib in
  FAP
• Discussion with experts initiated
• Submission of alternative proposal to FDA
• PHA meets with FDA to propose alternate
  controlled study of celecoxib vs.
  difluoromethylomithine (DFMO)
• FDA reiterates preference for a registry study
• MDACC confirms interest in setting up Registry,
  with grant from PHA
• MDACC sends copy of registry proposal written in
  June 2000, which is basis for current proposal
• CGA Meeting, protocol concept endorsed by CGA
  members

12/99
02/00
12/00
04/01
06/01
08/01
10/01
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FAP Registry StudyBrief Chronology of Events
(contd.)

• MDACC confirms that CGA will enter patient on
  registry study
• Protocol sent to CGA members to review
• As a result of lack of enthusiasm from the CGA
  physicians, the registry protocol was modified to
  include patients entering their own data
• Registry presented at CGA patient questionnaire
  sent to PHA
• Web-based Study prototype sent to PHA
• Submitted to MDACC IRB for approval
• MDACC IRB rejects web-based registry protocol
• Revised registry-based protocol under development
• Draft Study protocol submitted to FDA for review

03/02
04/02
07/02
10/02
12/02
01/03
02/03
03/03
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FAP Registry StudyBrief Chronology of Events
(contd.)

• Under preliminary review, FDA finds draft Study
  protocol acceptable
• First investigator meeting
• FAP Registry Planning Meeting to review draft
  protocol and finalize Study protocol for health
  authorities review
• Pfizer and CRO Study Kick-off meeting
• Final Study protocol submitted to FDA for review
• IRB approval from Cleveland Clinic
• Site initiation visit performed at Cleveland
  Clinic, and site activated
• Investigator Study Kick-off meeting
• Registry-based observational study protocol was
  amended (Amendment 1)
• First data transfer received from Cleveland
  Clinic
• Amendment 1 protocol submitted to FDA

04/03
09/03
02/04
05/04
09/04
10/04
11/04
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FAP Registry StudyBrief Chronology of Events
(contd.)

• Site initiation visit performed at Hvidovre Univ.
  Hospital, and site activated, first data transfer
  received
• Information on the CV safety of Celebrex based
  on results from two long-term cancer trials
  publicly released
• Health Canada suspended FAP Indication
• Cleveland Clinic investigator withholds Study
• First Study semi-annual report submitted to EMEA
• Pfizer agrees to a temporary suspension of launch
  of Celebrex for the FAP indication in Europe
  until finalization of EMEA assessment

12/04
01/05

• Study re-activated at Cleveland Clinic
• Combined assessment and site initiation visit at
  Mount Sinai (Toronto), Canada
• Second semi-annual report submitted to EMEA

03/05
06/05
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Study Status
Pfizer Protocol Nº NQ4-00-02-012 Study Status
Report June 13, 2005
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Study Subjects in Activated RegistriesNumber of
Study subjects by Registry Site
Percentages are based on the number of FAP
subjects entered in each study group through the
current reporting period. Information in this
table reflects data transfers through April 29,
2005 for the US Registry and December 16, 2004
for the Danish Registry. Additionally,
information in this table reflects recent verbal
confirmation from the Danish investigator
pertaining to one (1) subject (10030001) who
discontinued participation due to rash (assessed
as non-severe by the principal investigator).
Pfizer Protocol Nº NQ4-00-02-012 Study Status
Report June 13, 2005
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In Summary

• FAP is a rare life-threatening genetic disease
  with few therapeutic options
• Pfizer remains fully committed to compliance with
  subpart H requirements significant activity
  since previous ODAC March 2003
• Phase III FAP Pediatric Study
• FAP Registry Study initiated in 3Q 2004
• Despite challenges encountered
• Confirmatory Phase III Study ready to begin
• Multi-institutional FAP registry Study undertaken
  and in progress