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)