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ZELMAC (tegaserod) Presentation to

GI Advisory Committee

June 26, 2000

Raymond E. Joseph MDMedical Officer

HFD-180

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Zelmac Background

Proposed Indication:

Indicated for the treatment of irritable bowel syndrome (IBS) in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms

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Zelmac NDA Submission

2 Phase II-double-blind trials:• Study 251: (n=547) 45 sites in North America

and Europe; dose-ranging with 4 dose levels of tegaserod or PL for 12 weeks

• Study 202: (n=123) 16 sites in Europe and Canada; dose-titration with 4 dose levels of tegaserod or PL for 20 weeks

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Summary of Phase II Studies• Study 251

1mg/d =PL; 4mg/d most effective dose

No dose response seen over the range of

4 to 24 mg/d

• Study 202

Increased response rates observed during

dose-titration from 4 to 12 mg/d

Doses of 4 and 12 mg/d chosen for Phase III trials

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Phase III Trials -2521 PtsSimilarities

PL-controlled, double-blind, randomized, three parallel groups with dose levels of 4, 12 mg vs placebo with 4 week baseline and 12 -week treatment period

Study 351

Study 301

Study 307

(Dose titration- 4 to 12 mg/d at 1 mo)

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Phase III TrialsStudy 351(n=799)

• First of the three Phase III studies to be completed

• The protocol pre-specified analysis failed to demonstrate efficacy

• Subsequently

a) the definition of responder in the SGA of relief was

changed to incorporate “somewhat” relieved 100% of

the time

b) the SGA of abd. discomfort/pain was changed to a

secondary efficacy variable

• Post-hoc analyses incorporating the above changes demonstrated efficacy for the 12 mg/d dose level

Led to protocol amendments for studies 301 and 307

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Responder Rates for SGA of Relief

Study Placebo4 12 or 4 to12

351 Responder Rate (%) 38.9 45.7 33.3

Therapeutic Gain 6.0 12.4

p-value N.S. 0.004

301 Responder Rate (%) 38.80 38.40 30.20

Therapeutic Gain 8.60 8.30

p-value 0.018 0.033

307 Responder Rate (%) 38.30 42.20 37.00

Therapeutic Gain 1.30 5.20

p-value N.S. N.S.

New Definition of SGA of Relief

Tegaserod (mg/d)

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Efficacy Issues

1. Pain not adequately assessed as an efficacy

endpoint

2. Overall difference between drug and PL group is 8%

3. Efficacy in males not established

4. Potential affect of laxatives

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Abdominal Pain

• Pain is an essential component of IBS• When analyzed as a component of SGA of

relief along with well-being and altered bowel function was statistically significant for studies 351 and 301

• However, when analyzed independently no statistical difference was seen in studies 301 and 307

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Responder Rates for SGA of Abdominal Discomfort/Pain

Study Placebo 4 12 or 4 to12 351 Responder Rate (%) 23.4 25.1 18.7

Therapeutic Gain 4.8 6.4p-value N.S. N.S.

301 Responder Rate (%) 29.8 29.9 22.6 Therapeutic Gain 7.2 7.3

p-value N.S. 0.044

307 Responder Rate (%) 25.5 27.6 30.6 Therapeutic Gain NONE NONE

p-value N.S. N.S.

Tegaserod (mg/d)

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Overall Efficacy 8-11 %

• Discussion Factors:

a) effect of gender in this study group

b) effect of long-standing disease

• Are results clinically meaningful?

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Efficacy in Males

• Studies included 15% males • Response to Zelmac in males was not different

compared to placebo• Lack of differentiation from placebo

– inadequate sample size – may raise the question whether the disease is

different in males

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Laxative Use

1. In the clinical trails, laxative use including bulking-agents was allowed

2. The use and timing of laxatives may influence the response of the SGA of relief

3. There was similar qualitative consumption between groups

Quantitative differences not assessed may be affecting outcome in constipation study patients

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Efficacy Summary

1. Overall efficacy was shown in one of the pivotal studies (301) for both the 4 mg and 12 mg dose levels ; supportive study 351 showed efficacy for the 12 mg dose level only; efficacy not replicated in 307

2. Efficacy in males not demonstrated

3. Laxative usage may have had an affect on efficacy

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Most Frequently Reported AEs in Phase III

In Phase II and long term results are similar

Adverse Event % Tegaserod % Placebo(n=1679) (n=837)

Headache 21.3 21.1Abd. Pain 19.8 18.2Diarrhea 11.7 5.4Nausea 9.2 8.6Flatulence 7.4 6.6Back Pain 6.7 5.4

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Most Frequently AEs Led to Discontinuation in Phase II & III

Body System/Adverse Event % Tegaserod % Placebo(n=2198) (n=988)

GI 4.7 3.4 Diarrhea 2.1 0.6 Abd. Pain 1.7 1.9 Flatulence 1.1 0.7 Nausea 0.4 0.8CNS 1.7 2.0 Dizziness 0.7 1.2 Headache 0.7 0.9General 0.9 0.7

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Duration (Days) % Tegaserod(n=675)

>= 1 100.0>= 85 72.9>=180 55.9>=270 48.7>=365 27.4

Duration of Exposure

Pooled L-T Studies

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Safety in Generaln =1679

• Approx. 72% phase III pts experienced one AE Only diarrhea was statistically significantly different from PL 11.7% vs 5.4%

(p <0.0001)• AEs only marginally greater in tegaserod

groups vs placebo • SAEs incidence-tegaserod (1.8%) = PL

profiles were similar

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Safety (Cont.)

• One death- in study 301-Patient with 14y Hx of depression; committed suicide on day 36 of drug

• 5 SAEs in tegaserod pts-possibly related to test medication– abdominal pain [n=2]– gastritis [n=1]– SVT [n=1]– hypoglycemia [n=1]

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Safety Issues

1. Diarrhea (> 3 BMs/d, loose, watery

with a sense of urgency)

2. Syncope tegaserod (n=8) vs PL (n=1) p=(NS)

3.”Ovarian Cysts”

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Diarrhea• Incidence: 11.7% tegaserod vs 5.4% PL

p value <0.0001

• In alternators (18-36% at baseline) 21%• Discontinuation secondary to diarrhea was 2.1%

in tegaserod vs 0.6% in PL

p value = 0.002• 50% occurred during the first week; contributing

factors?• In long-term study 209, 14.6% experienced

diarrhea leading to discontinuation in 3.5 %

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Possible Ovarian Cysts

YES NO TOTAL

Tegaserod 5 3 8

Placebo 0 1 1

Total 5 4 9

Went to Surgery

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Pts Undergoing Surgery

• All 5 cases on 12 mg/d dose of drug

– 3 in study 209 ( ie. long- term)

– 1 in study 307

– 1 in study 351

• None from placebo groups

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Case No. 1 (12 mg)

• 50y WF 10y Hx. of ovarian cyst

no abdominal pain

• Elective surgery performed on day

334 of drug

• Surgery: benign tumor; no cyst

Not associated with test med.

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Case No. 2 (12 mg)

• 45y WF with past Hx. of hysterectomy experienced abdominal pain;

went to OR on day 261 of drug

• Surgery:

– bilateral salpingo-oophorectomy

– post-op diagnosis: adhesions

– there is no mention of a cyst

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Case No. 3 (12 mg)

• 37y BF with past Hx. of hysterectomy abdominal pain on day 100 of drug

• CT scan: 2.7 cm right ovarian cyst• Surgery: due to continue pain

(performed 5 weeks later)

right salpingo-oophorectomy,

lysis of adhesions, appendectomy• Pathology: 1cm peritubal cyst, adhesions,

normal appendix

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Case No. 4 (12 mg)• 35y F presented with unknown Hx

• Surgery: day 306 of drug

• Pathology: multiple ovarian cysts,

including 3.5cm partially luteinized follicle cyst and adenomyosis of the uterus

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Case No. 5 (12mg)• 13y WF with past Hx. of bilateral ovarian cysts

Presented on day 87 of drug

with right-sided abdominal pain

• Surgery: laparoscopic resection of a right ovarian cyst (4 to 5cm) and appendectomy. Ovarian cyst seen at surgery-lysed and drained

• Pathology: early appendicitis

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Surgery Summary• Relationship between drug and ovarian

cysts is unknown

• 3 of the 5 had previous pelvic surgery

– Adhesion were seen in 2

–One had early appendicitis

• Pharmacologic effects -

lower abdomen and pelvis

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Ovarian Cysts In Ongoing Studies

One case- (Tx. group=blinded)• 43y F with Hx. of tubal ligation with

reversal

• Diagnosed with ovarian cyst via sonogram on day 23 of drug

• Discontinued from the trial due to nausea and flatulence

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Safety Summary

AEs occurring more frequently in the tegaserod group

• Syncope p=(NS)• Diarrhea p< 0.0001• Ovarian cyst - the significance of which is

unclear at present• Relationship of Zelmac to risk of

abdominal pathology leading to surgery unknown