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FDA ODAC Meeting November 8, 2005

FDA ODAC Meeting November 8, 2005. Celecoxib (CELEBREX ® ) Therapy for Familial Adenomatous Polyposis (FAP) Subpart H Phase IV Commitments. Agenda. Familial Adenomatous Polyposis (FAP) Basis for Celebrex approval in FAP Subpart H commitments Status of Subpart H commitments

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FDA ODAC Meeting November 8, 2005

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  1. 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

  3. 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

  6. 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

  7. Placebo Celecoxib 100 mg BID Celecoxib 400 mg BID 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

  8. 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

  9. 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

  10. Phase III Genotype Positive FAP Study

  11. 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

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

  14. 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

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

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

  17. FAP Phase I – Adverse Events

  18. 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)

  19. FAP Phase I: Polyp Count Difference Wilcoxon p-value=0.011 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

  20. Genotype Positive StudyBrief Chronology of Events 12/04 • 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 • CV Safety Data (December 17th) 03/05 04/05 06/05 08/05 01/06

  21. 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) 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

  22. FAP Registry Study

  23. 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

  24. FAP Registry StudyBrief Chronology of Events 12/99 • 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 02/00 12/00 04/01 06/01 08/01 10/01

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

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

  27. 05/05 FAP Registry StudyBrief Chronology of Events (cont’d.) • 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 • Study re-activated at Cleveland Clinic • Combined assessment and site initiation visit at Mount Sinai (Toronto), Canada • Second semi-annual report submitted to EMEA 01/05 03/05 06/05

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

  29. Study Subjects in Activated Registries*Number 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

  30. 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

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