# Presentation: 008558

## Celecoxib (CELEBREX®) Adjunctive Therapy of Familial Adenomatous Polyposis(FAP) Subpart H ApprovalDaniel R. Vlock, MD

**ODAC**
**March 12-13, 2003**

**Notes:**
Thank-you, Madam Chairperson, Advisory committee members, and representatives of the FDA.  My name is Daniel Vlock and I am Senior Director of Clinical Research at Pharmacia.

Today we are here to provide an update on the status of our subpart H post-approval commitments for Celebrex in the treatment of Familial Adenomatous Polyposis or FAP 

## ODAC MeetingPharmacia Attendees

**Langdon Miller, MD**
**	****Vice President, Clinical Research**
**Kenneth Verburg, MD**
**	****Vice President, Clinical Research**
**P.K. Narang, PhD**
**	****Senior Director, Regulatory Affairs**
**Kerry Barker, PhD**
**	****Director, Biostatistics**
**Bernard Levin, MD (consultant)**
**	****UT MD Anderson Cancer Center**
**Patrick Lynch, MD (consultant)**
**	****UT**** ****MD Anderson Cancer Center**

**Notes:**
Besides myself the following individuals will be able to answer any questions from the committee:
Dr. Langdon Miller, and Kenneth Verburg both in Clinical Research at Pharmacia

Drs. Bernard Levin and Patrick Lynch of the MD Anderson Cancer Center

## Summary

**Pharmacia is committed to fulfilling Subpart H requirements **

**Successful completion of ZINECARD****®****, CAMPTOSAR****®**** commitments**
**CELEBREX FAP post-approval program underway**

**Notes:**
Pharmacia is fully dedicated to completing its post-approval commitments

As you heard yesterday from the FDA, Pharmacia has completed subpart H requirements for ZINECARD and CAMPTOSAR. 

We are similarly dedicated to ensuring completion of our commitments for celecoxib in FAP and our post-approval  program is underway.

## Presentation Agenda

**FAP overview **
**Basis for celecoxib approval**
**Indication**
**Subpart H commitments**
**Conclusions **

## FAP Overview

**Rare, life-threatening disease**
**Autosomal dominant inheritance**
**Germline APC mutations (5q21)**
**~ 300 new patients/year in US**
**Accounts for 1% of all colorectal cancers**

## Natural History

**Natural History**

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

## Disease Management

**Lifetime endoscopic surveillance**
**Initial colon resection 18-20 years of age**
**Repeated surgeries**
**Interest in developing medical treatment as an adjunct to surgery**

## Pivotal Registration TrialBasis 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**

## Results of Pivotal Trial

**Largest prospective,  randomized trial conducted in FAP**
**2 years to complete **
**83 patients**
**Efficacy: 400 mg BID**
**28% reduction in mean polyp number compared to baseline**
**Secondary endpoints confirmatory**
**Safety: 400 mg BID**
**Well tolerated**

## FAP Indication

**To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (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 CELEBREX is discontinued  **
**The efficacy and safety of CELEBREX treatment in patients with FAP beyond six months have not been studied**

## Subpart H Commitments 

** **
**FAP phenotype suppression study**
**Designed to verify clinical benefit**
**Placebo-controlled trial in patients who are genotypically positive (have APC mutation) but phenotypically negative (have not yet developed polyps)**
**FAP registry**
**Determine both efficacy and safety parameters associated with short and long-term exposure**

## Subpart H Commitments 

** **
**FAP phenotype suppression study**
**Placebo-controlled trial in patients who are genotypically positive (have APC mutation) but phenotypically negative (have not yet developed polyps)**
**FAP registry**
**A long-term registry of clinical outcomes**

## Phenotype Suppression Study Proposed Design

**Phenotype Suppression Study**** Proposed Design**

**Description:****	****Phase III study of celecoxib in genotype-positive, phenotype negative children with FAP**
**Treatment groups:****	****Placebo**
**	****Celecoxib (400 mg po BID)**
**	****1:2 randomization **
**Sample size:****	****N = 231**
**Duration of therapy:****	****5 years**
**Primary endpoint:****	****Time to first adenoma**

## Phenotype Suppression StudyBrief Chronology of Events

## Phenotype Suppression StudyBrief Chronology of Events

## Phenotype Suppression Study Phase I Design

**Phenotype Suppression Study**** Phase I Design**

**Description:****	****Phase I study of celecoxib in genotype-positive children with FAP**
**Sites:****	****U.T. M.D. Anderson, ****Texas Children's Hospital, Cleveland Clinic**
**Design:****	****Dose escalation trial in successive cohorts of 6 patients**
**Treatment groups:****	****Placebo**
**	****Celecoxib (2, 4, 8 mg/kg po BID) **
**Sample size:****	****N = 18**
**Duration of therapy:****	****3 months for each cohort**
**Primary endpoint:****	****Safe dose in children****  **

## Phenotype Suppression StudiesBrief Chronology of Events

**Phenotype Suppression Studies****Brief Chronology of Events**

## Subpart H Commitments 

** **
**FAP phenotype suppression study**
**Placebo-controlled trial in patients who are genotypically positive (have APC mutation) but phenotypically negative (have not yet developed polyps)**
**FAP registry**
**A long-term registry of clinical outcomes**

## FAP RegistryInitial Design

**FAP Registry****Initial Design**

**Description:****	****Observational**
**Patient Population:****	****Patients receiving celecoxib Historical controls **
**Primary Endpoints:****	****Time to FAP-related events**
**	****Adverse events**

## FAP RegistryBrief Chronology of Events

## FAP RegistryBrief Chronology of Events

**FDA feedback  **
**Proposed DFMO study did not address Subpart H commitments**
**FDA still considered a registry worthwhile**
**Acknowledged that new therapies and differences in clinical practice may confound analysis**
**Efforts refocused on FAP registry**

**4/01**

## FAP RegistryBrief Chronology of Events

**FAP Registry****Brief Chronology of Events**

## FAP RegistryBrief Chronology of Events

**FAP Registry****Brief Chronology of Events**

## FAP RegistryProposed Design

**FAP Registry****Proposed Design**

**Description:****	****Observational **
**Patient Population:****	****Patients receiving celecoxib**
**	****Historical controls**
**Sites under consideration:****	****Established FAP registries**
**Objectives:****	****-  Describe characteristics of patients **
** ****	****    ****who receive celecoxib in clinical practice**
**	****-  Describe patterns of celecoxib use in **
** ****	****   ****disease management **
**	****-  Evaluate long-term safety of celecoxib **
**	****-  Assess whether celecoxib use may alter       **
**	****   ****management of FAP**
**	****-  Determine impact on incidence of FAP-related **
**	****    ****events (eg, polypectomy, surgery, cancer, **
**	****    ****desmoids, death)**

## Conclusions

**Pharmacia is committed to fulfilling Subpart H requirements**

**Phenotype suppression program to**** verify clinical benefit has begun **
**Continuing progress in implementing a revised FAP registry**