1 FDA ODAC Meeting November 8, 2005 Celecoxib (CELEBREX ® ) Therapy for Familial Adenomatous Polyposis (FAP) Subpart H Phase IV Commitments.

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FDA ODAC MeetingNovember 8, 2005

Celecoxib (CELEBREX®) Therapy forFamilial Adenomatous Polyposis (FAP)

Subpart H Phase IV Commitments

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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

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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 riskMedian life expectancy – 42 years

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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. Mark’s (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

PlaceboCelecoxib 100 mg BIDCelecoxib 400 mg BID

-4.5

-11.9

-28

-35

-30

-25

-20

-15

-10

-5

0

-1.4-4.2

-14.5

-35

-30

-25

-20

-15

-10

-5

0

Patients: N = 81 (17 placebo, 32 100 mg BID, 32 400 mg BID)

Duration of Therapy: 6 months

RESULTS

Duodenal N = 50Duodenal N = 50ColorecColorectal tal N = 77 N = 77

% C

han

ge

Bas

elin

e%

Ch

ang

e B

asel

ine

****400 mg BID versus placebo400 mg BID versus placebo

P = 0.003P = 0.003****

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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

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)

07/00

04/00

12/99

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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

08/00

01/01

02/01

01/02

Genotype Positive StudyBrief Chronology of Events (cont’d.)

10/00

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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

02/02

08/02

12/02

05/02

06/02


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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05/04

02/04

06/04

09/03

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

04/03


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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

09/04

12/04

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FAP Phase I – Adverse Events

Number of Events

Grade 1 AEs

Grade 2AEs

Total # of AEs

Placebo

n=624 0 24

4mg/kg

n=422 2 24

8mg/kg

n=45 2 7

16mg/kg

n=421 0 21

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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)

FAP Phase I – Adverse Events

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FAP Phase I: Polyp Count Difference

Celecoxib Dose

Co

un

t*

(N= 6) (N= 4) (N= 4) (N= 4)

Wilcoxon p-value=0.011

Placebo 4mg/kg 8mg/kg 16mg/kg

* Difference in polyp count between baseline & end of treatment

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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

03/05

04/05

08/05

06/05

01/06

Genotype Positive StudyBrief Chronology of Events

• CV Safety Data (December 17th)12/04

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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: PlaceboCelecoxib (16mg/kg/day, approximately 400mg BID)1:1 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 (>2mm, 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

04/01

06/01

08/01

02/00

12/00

10/01

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FAP Registry StudyBrief Chronology of Events (cont’d.)

02/03

03/03

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

10/02

12/02

01/03

03/02

04/02

07/02

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10/04

11/04

09/04

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

02/04

05/04

09/03

04/03


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Study re-activated at Cleveland Clinic

Combined assessment and site initiation visit at Mount Sinai (Toronto), Canada

Second semi-annual report submitted to EMEA

05/05

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

01/05

12/04

03/05

06/05

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Study Status*

Site / Investigator Country Current Site Status

The Cleveland Clinic Foundation / Dr. James Church

USAInitiated:

Sept 1, 2004

Mount Sinai Hospital / Dr. Steven Gallinger

CanadaInitiated:

May 10, 2005

Hvidovre Univ. Hospital / Dr. Steffen Bulow

DenmarkInitiated:

Dec 6, 2004

Heinrich-Heine-Universitat, Dusseldorf /Dr. Gabriela Moeslein

Germany Initiation Delayed

The Cancer Council of Victoria / Dr. Finlay Macrae

Australia Initiation Delayed

* Pfizer Protocol Nº NQ4-00-02-012 Study Status Report June 13, 2005

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Study Subjects in Activated Registries*Number of Study subjects by Registry Site

Paramater Celecoxib Matched Control All Subjects

Number of FAP Subjects Entered to Data

United States 4 1 5

Canada 0 0 0

Denmark 4 0 4

Germany 0 0 0

Australia 0 0 0

Total 8 1 9

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

1 FDA ODAC Meeting November 8, 2005 Celecoxib (CELEBREX ® ) Therapy for Familial Adenomatous Polyposis (FAP) Subpart H Phase IV Commitments.

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