# Presentation: 413854

## sNDA 21-156: CELEBREXTM

**INDICATION**
**Reduction and Regression of Adenomatous Colorectal Polyps in Familial Adenomatous Polyposis Patients**
**FDA ODAC Presentation**
**December 14, 1999**
**Bethesda, MD**

## CDER/DODP Review Team

**Medical Reviewers: ****	****Judy H. Chiao , M.D.**
**	****	****	****	****Julie Beitz, M.D. (TL)**
**Statisticians: ****	****	****John Lawrence, Ph.D.**
**	****	****	****	****Gang Chen, Ph.D. (TL)**
**Biopharm:****	****	****John Duan, Ph.D.**
**	****	****	****	****Atiqur Rahman, Ph.D. (TL)**
**Pharm/Tox:****	****	****Wendelyn Schmidt, Ph.D.**
**	****	****	****	****Paul Andrews, Ph.D. (TL)**
**Chemistry:****	****	****Sung Kwang Kim, Ph.D.**
**	****	****	****	****Rebecca Wood,  Ph.D. (TL)**
**GI Consultants: ****	****	****James Lewis, M.D (SGE),                                                           ****	****	****	****Mark Avigan, M.D., John Senior, M.D. (FDA)**
**CSO:****	****	****	****Paul Zimmerman****	****	****	**
**DSI: ****	****	****	****Gus Turner, Ph.D.**

## FDA Presentation Outline

**Regulatory requirements for accelerated approval**
**GI Issues in FAP**
**FDA Review of Study 001**
**Conclusions**
**Unresolved Issues and Points to Consider**

## Accelerated Approval Requirements

**Serious or life-threatening illness***** ***
***Meaningful therapeutic benefits over existing treatments***
***Surrogate endpoints likely to predict clinical benefit in the above patient population***
**Post-marketing studies to demonstrate clinical benefit must be carried out with “due diligence”**

## Familial Adenomatous PolyposisGenotype vs. Phenotype

**Autosomal dominant genetic disease with 80-100% penetrance**
**Germline mutation of APC gene (tumor suppressor gene) **
**Attenuated FAP (AFAP) is a heterogeneous clinical entity, characterized by fewer than 100 colorectal polyps and later age of onset of colon cancer **
**AFAP is associated with 3’ or 5’APC mutations**

## Familial Adenomatous PolyposisClinical Phenotype

**Hallmark of FAP colorectal polyposis**
**>100 colorectal adenomatous polyps (tubular adenomas); 100% colon cancer unless the colon is removed**
**45 y/o: 83% developed cancer**
**50 y/o: 93% developed cancer**
**Upper GI polyps and increased risk for periampullary cancer**
**Extraintestinal manifestations**

## Familial Adenomatous PolyposisCurrent Management

**Prophylactic colectomy **
**could prevent colon cancer in persons known to be at risk of FAP**

## Familial Adenomatous PolyposisTypes of Prophylactic GI Surgery

**  ****Subtotal Colectomy w/ Ileorectal Anastomosis**
**Need vigilant f/u q 6-12 mos**
**Risk of rectal cancer 13-25% at 20 yrs**
**Repeated polypectomies causing scarring**
**25-30% may need rectal stump removed**

## Familial Adenomatous PolyposisTypes of Prophylactic GI Surgery

** **
**  ****Colectomy with Mucosal Proctectomy followed by Ileoanal Anastomosis**
**? Functionally less desirable**
**Polyps in the pouch: ? malignant potential**

## Familial Adenomatous PolyposisUnresolved GI Issues

**Upper GI polyps in 30-100%**
**Difficult to manage **
**Risk of death from duodenal cancer >rectal cancer**

## Study 001 in FAP Patients

**Study Design: Randomized, DB, placebo-controlled 3-arm study (placebo vs. 100 mg bid vs. 400 mg bid); N=83 **
**Hypothesis: Celebrex ******** colorectal polyps**
**Primary efficacy endpoint: *****mean***** percent change in the number of colorectal polyps**
**Secondary efficacy endpoint: *****mean***** percent change in the duodenal plaque-like areas**

## Study 001 in FAP patientsPatient Characteristics-1

- <date/time>

**Study 001 in FAP patients****Patient Characteristics-1**

## Study 001 in FAP patientsPatient Characteristics-2

## Study 001 in FAP PatientsMethodology

**1****o ****efficacy endpoint**
**Polyp count is based on tattoo or marked areas assessed at 6 mos by one investigator **
**Committee review of videotapes (*****qualitative***** global assessment)**
**2****o**** efficacy endpoint**
**mean of one high- and one low-density plaque-like areas in the duodenum assessed at 6 mos**

## Efficacy Results of Study 001:       Applicant’s Dataset

## FDA Verification of the primary efficacy data

**Rectal polyps were counted from still color photos taken at baseline and 6 mos**
**Blinded to patient treatment assignments**
**28 patients with varied responses from the St. Mark’s Hospital site reviewed**
**FDA’s counts for patients on the Celebrex 400 mg arm are very similar to  the Applicant’s**

## Primary Efficacy VerificationFDA vs. Applicant

## Safety Results of Study 001

## Safety Profile in Arthritis Patients

**Exposure**
**OA: N=4200 up to 3 months**
**RA: N=2100 up to 6 months**
**ADRs:**
**Incidence of GI ulceration detected by endoscopy: 3.4-7.6% (vs  2-2.3% in placebo)**

## Exploratory analysis of Study 001

**Question: **
**What proportion of  patients had**
**at least a 25%******** or 25%********  in colorectal polyp counts in focal area(s)?**
**	****	**

## Exploratory analysis of Study 001

## Exploratory analysis of Study 001

**Question:**
- 	**Does a decrease in *****rectal***** polyps in the tattoo area predict for an improvement in the entire rectum? **

## Rectal Video Assessment-1

**Rectal video: N=74**
**3 reviewer consensus in 72 patients **
**4 reviewer consensus in 52 patients**

## Rectal Video assessment-2

## Rectal Video assessment-3

## Rectal Video assessment vs. Rectal polyp count change (%) in one tattoo area

## Rectal Video assessment vs. Rectal polyp count change (%) in one tattoo area

**	**
**	****Among 22 patients who had >=25%  decrease in rectal polyp count in one area, only 6 patients (27%) had an overall improvement of the entire rectum  by video assessment**

## Conclusions-1 

**Study 001 enrolled a heterogeneous patient population**
**Mean % change in colorectal polyp count is ****-28% in the 400 mg group (p=0.003 when compared to placebo group) **
**More patients in the 400 mg group had >=25% decrease in colorectal polyp count in focal area(s) when compared to placebo group**
**More patients in the 400 mg group had a “better” rating of rectal video by 4 committee members**

## Conclusions-2:

**Celebrex at 400 mg BID was well tolerated for 6 months but safety data for this dose beyond 6 months is not available at the present time.**
**% change in rectal polyps in one area does not appear to predict for changes in the entire rectum when the entire rectum is assessed by videotapes by 5 viewers.**
**The durability of Celebrex effects on colorectal polyps cannot be assessed due to the short treatment duration of 6 months.**

## Unresolved Issue-1

**Question:**
**Is reduction in polyps in FAP patients a surrogate *****likely***** to predict clinical benefit in these patients? **

## Unresolved Issue-2

**Clinical benefits in FAP:**
**Reduction in rectal cancer**
**Reduction in duodenal cancer**
**Reduction in other FAP-related cancers**
**Preservation of rectal stump without increasing risk for rectal cancer**
**Delay of prophylactic colectomy without increasing the risk for colorectal cancer**

## Points to Consider

**Without a complete regression of all colorectal polyps, reduction in polyps may not result in a decrease in colorectal cancer incidence in FAP patients**
**The entire GI mucosa is at risk for developing cancer due to the germline APC mutation**
**Cancer may arise from the remaining polyps or non-polypoid areas**

## Points to Consider

**The clinical significance of a partial reduction in colorectal polyps in FAP patients is difficult to assess from Study 001**** **
**If ODAC recommends accelerated approval, Celebrex treatment should be considered only *****as an adjunct***** to the usual care of FAP patients (e.g., surgery, endoscopy)**