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 PolyposisGenotype 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 PolyposisClinical 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 PolyposisCurrent Management

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

FAP

Familial Adenomatous PolyposisTypes 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 PolyposisTypes of Prophylactic GI Surgery

Colectomy with Mucosal

Proctectomy followed by Ileoanal Anastomosis

•? Functionally less desirable•Polyps in the pouch: ? malignant potential

Familial Adenomatous PolyposisUnresolved 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 patientsPatient Characteristics-1

PlaceboN=17

100 mg bidN=34

400 mg bidN=32

Median age (yrs)Percent of patients (%)

>=6041-59>31-40<=30

40

17.623.541.217.6

39

044.141.214.7

31

3.115.634.446.9

Median yrs from subtotal colectomyPercent of patients

>2010-205-10<=5

14.9N=10

208000

13.8N=2416.754.216.712.5

8.6N=18

044.438.916.7

Study 001 in FAP patientsPatient Characteristics-2

Percent of patientsPlacebo

N=17100 mg bid

N=34400 mg bid

N=32

w/ intact colon 29.4 23.5 37.5

w/ subtotal colectomy 58.8 73.5 56.5

w/ total colectomy 11.8 2.9 6.2

w/ Attenuated FAP 11.8 8.8 25

Study 001 in FAP PatientsMethodology

1o 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)

2o 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

PlaceboCelebrex

100 mg bidCelebrex

400 mg bid

Mean % incolorectal polyps

-4.5 -14.5 -28(p=0.003)

Mean % induodenal plaques

-1.4 +123.3 -16.5(p=0.402)

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 VerificationFDA vs. Applicant

Mean percentchange in polypcount

FDA Applicant

Placebo (N=4) +15% -11%

100 mg (N=11) +85.3% -2.2%

400 mg (N=13) -32.6% -33.3%

Safety Results of Study 001

Placebo(N=17)

Celebrex100 mg bid

(N=34)

Celebrex400 mg bid

(N=32)

Gr 2

GIDiarrhea

64.7(%)

35.211.8

47.1(%)

29.420.5

46.9 (%)

34.415.6

Gr 3 5.9 8.8 6.3

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

Placebo(N=15)

Celebrex100 mg bid

(N=33)

Celebrex400 mg bid

(N=30) polyps

>=50%25-49%less than 25%

0 (%) 6.7 40

12.1 (%) 21.2 24.2

16.6 (%)36.623.3

polyps>=50%25-49%less than 25%

00

20

36.19.1

00

6.7

No change 33.3 15.2 13.3

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

Number ofPatients w/

Consensus by 3 reviewersPlacebo 100 mg 400 mgN=15 N=30 N=29

Consensus by 4 reviewersPlacebo 100 mg 400 mgN=15 N=30 N=29

Better 0 5 8 0 2 6

Same 11 19 19 10 16 13

Worse 3 5 1 1 3 1

Unreadable 0 1 0 0 0 0

Noconsensus

1 0 1 4 9 9

Rectal Video assessment-3

4-memberconsensus

PlaceboN=15

100 mg(N=30)

400 mg(N=29)

Better 0 (%) 6.7 (%) 20.7(%)

Same 66.7 53.3 44.8

Worse 6.7 10 3.4

Unreadable 0 0 0

No consensus 26.7 30 31

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

4-memberconsensus

polyp count>=25 %

N=22

Polyp count(-24% to +24%)

N=38

polyp count>=25%

N=7Better 27.2 % (6) 5.3 % (2) 0 %

Same 22.7 % (5) 63.2 % (24) 42.9 % (3)

Worse 13.6 % (3) 5.3 % (2) 0 %

No consensus 36.4 % (8) 26.3 % (10) 57.1 % (4 )

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)