ce-1 zelnorm ® (tegaserod maleate) efficacy and safety in chronic constipation eslie dennis, md...

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Zelnorm®

(tegaserod maleate)

Efficacy and Safety in Chronic Constipation

Zelnorm®

(tegaserod maleate)

Efficacy and Safety in Chronic Constipation

Eslie Dennis, MD

Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs

Novartis Pharmaceuticals Corporation

Eslie Dennis, MD

Senior Medical Director: Gastroenterology Clinical Development and Medical Affairs

Novartis Pharmaceuticals Corporation

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OutlineOutline

Rationale Study objectives Study design Patient population Efficacy

– Primary

– Secondary Safety and tolerability

– 12-wk double-blind, placebo-controlled

– 13 months extension, double-blind, uncontrolled

Rationale Study objectives Study design Patient population Efficacy

– Primary

– Secondary Safety and tolerability

– 12-wk double-blind, placebo-controlled

– 13 months extension, double-blind, uncontrolled

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NH

NH2

OH

Serotonin Tegaserod

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Rationale for Drug DesignSimilarity to Serotonin (5-HT)Rationale for Drug DesignSimilarity to Serotonin (5-HT)

An aminoguanidine indole, designed to act specifically at 5-HT4 receptors in the GI tract

An aminoguanidine indole, designed to act specifically at 5-HT4 receptors in the GI tract

NH

NNH

ONH

NH

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Rationale for Zelnorm® in Chronic Constipation ProgramRationale for Zelnorm® in Chronic Constipation Program

#Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276.§Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148.‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888.

#Nguyen A, et al. J Pharmacol Exp Ther. 1997;280:1270-1276.§Weber E, et al. Gastroenterology. 2004; 126(Suppl 2):A147-A148.‡Novick J et al. Aliment Pharmacol Ther. 2002;16:1877-1888.

In IBS-C clinical studies: Increases stool frequency‡

Improves stool consistency‡

Improves straining‡

In IBS-C clinical studies: Increases stool frequency‡

Improves stool consistency‡

Improves straining‡

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Mechanism of action: Enhances gut motility#

Decreases transit time#

Increases chloride and water secretion§

Mechanism of action: Enhances gut motility#

Decreases transit time#

Increases chloride and water secretion§

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Phase III Chronic ConstipationPhase III Chronic Constipation

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Study ObjectivesPivotal Studies E2301, E2302Study ObjectivesPivotal Studies E2301, E2302

To evaluate efficacy, tolerability, and safety of Zelnorm® in patients with chronic constipation

– 2 mg and 6 mg BID vs placebo

– 12-wk treatment period

To evaluate efficacy, tolerability, and safety of Zelnorm® in patients with chronic constipation

– 2 mg and 6 mg BID vs placebo

– 12-wk treatment period

19 CSRs E2301, E2302; Sections 2

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Study DesignsStudy Designs

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Study DesignStudy E2301Study E2301Study DesignStudy E2301Study E2301

11 2.5 Clinical Overview F1-1

12-wkTreatment periodScreening

Zelnorm® 2 mg BID

Placebo

Zelnorm 6 mg BID

N = 1264

Europe, Australia, South AfricaEurope, Australia, South Africa

2-wkBaseline

Nostudy drug

CE-9CE-9

Study DesignStudies E2301, E2301EStudies E2301, E2301EStudy DesignStudies E2301, E2301EStudies E2301, E2301E

11 2.5 Clinical Overview F1-1

12-wkTreatment periodScreening

Nostudy drug

Zelnorm® 2 mg BID

Placebo

Zelnorm 6 mg BID

N = 1264

Europe, Australia, South AfricaEurope, Australia, South Africa

n = 842

Zelnorm 2 mg BID

Zelnorm 6 mg BID

13-moExtension period

E2301E1

2-wkBaseline

Zelnorm 6 mg BID

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Study DesignStudy E2302Study E2302Study DesignStudy E2302Study E2302

11 2.5 Clinical Overview F1-1

12-wkTreatment periodScreening

Zelnorm® 2 mg BID

Placebo

Zelnorm 6 mg BID

N = 1348

North and South AmericaNorth and South America

4-wkWithdrawal

Nostudy drug

2-wkBaseline

Nostudy drug

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CSBM Is the Basis for Patient Inclusion and Endpoints CSBM Is the Basis for Patient Inclusion and Endpoints

BM: Bowel Movement SBM: Spontaneous Bowel Movement

– Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM

CSBM: Complete Spontaneous Bowel Movement– Complete: BM that results in sensation of

complete evacuation– Measure of quality and frequency

BM: Bowel Movement SBM: Spontaneous Bowel Movement

– Spontaneous: non–laxative-induced stool; no laxative or enema in 24 hr preceding BM

CSBM: Complete Spontaneous Bowel Movement– Complete: BM that results in sensation of

complete evacuation– Measure of quality and frequency

C Protocol CSR E2301, E2302, Sections 2, Pages 8 -9

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Current Concepts: Chronic ConstipationLembo, Camilleri N Engl J Med 2003; 349:1360-8Current Concepts: Chronic ConstipationLembo, Camilleri N Engl J Med 2003; 349:1360-8

“An epidemiologic study of constipation in the United States identified it as an inability to evacuate stool completely and spontaneously three or more times per week”‡

“An epidemiologic study of constipation in the United States identified it as an inability to evacuate stool completely and spontaneously three or more times per week”‡

‡Stewart et al. Am J Gastroenterol. 1999;94;3530-3540

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Main Inclusion CriteriaPivotal Studies E2301, E2302Main Inclusion CriteriaPivotal Studies E2301, E2302

Male or female, ≥ 18 yr of age Chronic constipation#

– Chronic: ≥ 6 months of constipation symptoms– Constipation: < 3 CSBM/wk and ≥ 1 of the following

(≥ 25% of occurrences):• Hard/very hard stools • Sensation of incomplete evacuation• Straining

Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms– No alarm features

Male or female, ≥ 18 yr of age Chronic constipation#

– Chronic: ≥ 6 months of constipation symptoms– Constipation: < 3 CSBM/wk and ≥ 1 of the following

(≥ 25% of occurrences):• Hard/very hard stools • Sensation of incomplete evacuation• Straining

Normal endoscopic/radiologic bowel evaluation within past 5 yr and after onset of symptoms– No alarm features

1919 CSRs E2301, E2302; Sections 3.3.2; 2.5 Clinical Overview, Section 4.3

CSBM = Complete spontaneous bowel movement.#Modified Rome II criteria.

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Main Exclusion CriteriaPivotal Studies E2301, E2302Main Exclusion CriteriaPivotal Studies E2301, E2302

Constipation due to:– Organic disease of the colon– Known mechanical outlet dysfunction– Bowel or gynecologic surgery– Metabolic disturbances– Neurologic disturbances

Concomitant medications Fecal impaction requiring surgical or

manual intervention Significant medical disorder that could interfere with

completion of study

Constipation due to:– Organic disease of the colon– Known mechanical outlet dysfunction– Bowel or gynecologic surgery– Metabolic disturbances– Neurologic disturbances

Concomitant medications Fecal impaction requiring surgical or

manual intervention Significant medical disorder that could interfere with

completion of study

1919CSRs E2301, E2302; Section 3.3.2

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Exclusion Criteria at RandomizationPivotal Studies E2301, E2302Exclusion Criteria at RandomizationPivotal Studies E2301, E2302

Patients excluded if

During the 14-day baseline period

– Constipation not confirmed by diary data

– Loose or watery stools > 3 days

– Laxatives > 2 days outside of guidelines

– Noncompliant with completion of diary (< 11 days)

Patients excluded if

During the 14-day baseline period

– Constipation not confirmed by diary data

– Loose or watery stools > 3 days

– Laxatives > 2 days outside of guidelines

– Noncompliant with completion of diary (< 11 days)

C Protocol E2301, E2302; Sections 3.3.2

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Data CollectedPivotal Studies E2301, E2302Data CollectedPivotal Studies E2301, E2302

Daily per bowel movement– Straining – Stool frequency– Stool form– Complete/incomplete evacuation

Weekly – Satisfaction with bowel habits – Bothersomeness of

• Constipation • Distension/bloating• Abdominal discomfort/pain

Daily per bowel movement– Straining – Stool frequency– Stool form– Complete/incomplete evacuation

Weekly – Satisfaction with bowel habits – Bothersomeness of

• Constipation • Distension/bloating• Abdominal discomfort/pain

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Patient DispositionPatient Disposition

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Patient Disposition—ITT PopulationPivotal Studies E2301, E2302—Pooled Patient Disposition—ITT PopulationPivotal Studies E2301, E2302—Pooled

Patients, %

Placebon = 863

Zelnorm®

2 mg BIDn = 867

Zelnorm6 mg BIDn = 882

Completed 81.5 84.2 83.1

Discontinued 18.5 15.8 16.9

Reason for discontinuation

Unsatisfactory therapeutic effect

7.2 4.4 3.7

Adverse event(s) 3.7 3.2 5.3

Withdrew consent 3.0 3.3 4.3

Other 4.6 4.8 3.5

Summary of Clinical Efficacy T 3-8C

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ResultsResults

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Demographic InformationPivotal Studies E2301, E2302Demographic InformationPivotal Studies E2301, E2302

CSR E2301, PTT 7.3-1, 7.6-5; CSR E2302, PTT 7.3-1, 7.6-5

E2301N = 1264

E2302N = 1348

Female 86% 90%

Age (mean, yr) 46 47

Range, yr 18 - 86 18 - 88

≥ 65 yr 14% 12%

Postmenopausal# 43% 48%

Caucasians 98% 85%

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#Female population (E2301, n = 1091; E2302, n = 1213).

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Constipation Symptoms Prior to Start of TreatmentConstipation Symptoms Prior to Start of Treatment

E2301 (N = 1264) E2302 (N = 1348)

Mean MeanHistory

Duration of symptoms, yr 14.7 19.5

Hard/very hard stools 73.9% 77.0%

Average SBM/wk, n 1.4 1.4

Diary data (14-day baseline)

CSBM/wk, n 0.5 0.6

SBM/wk, n 3.1 3.6

SBM with straining/wk, n 2.6 3.1

Stool form 2.6 2.9

C CRS E2301,E2302 PTTS 7.5-1, 7.6-5

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Constipation Symptoms Prior to Start of TreatmentConstipation Symptoms Prior to Start of Treatment

E2301 (N = 1264) E2302 (N = 1348)

Mean Median Mean MedianHistory

Duration of symptoms, yr 14.7 10.0 19.5 15.3Hard/very hard stools 73.9% 90% 77.0% 90%Average SBM/wk, n 1.4 1 1.4 1

Diary data (14-day baseline)

CSBM/wk, n 0.5 0 0.6 0SBM/wk, n 3.1 2.5 3.6 2.9SBM with straining/wk, n 2.6 2.0 3.1 2.5Stool form 2.6 2.5 2.9 2.8

CCRS E2301,E2302 PTTS 7.5-1, 7.6-5

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Primary Efficacy VariablePrimary Efficacy Variable

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Primary Efficacy VariablePivotal Studies E2301, E2302Primary Efficacy VariablePivotal Studies E2301, E2302

Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12

2-wkdrug-freebaseline 12-wk treatment

Responder

– Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline

– ≥ 7 days of treatment

Responder

– Increase of ≥ 1 CSBM/wk during the first 4 wk of treatment compared with baseline

– ≥ 7 days of treatment

CSBM = Complete spontaneous bowel movement.

19CSR E2301, F 3-1; E2302 pages 22-23

CE-25CE-25

26.7

35.640.2

0

10

20

30

40

50

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

Primary Efficacy VariablePivotal Studies E2301, E2302Primary Efficacy VariablePivotal Studies E2301, E2302

*P < .05, ***P < .0001Responder = Increase of ≥ 1 CSBM/wk during Wk 1- 4 and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.

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E2301

****

CSRs E2301, E2302 PTT 9.1-1

n = 416

25.1

41.4 43.2

0

10

20

30

40

50

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

E2302*** ***

n = 450n = 447 n = 451n = 417 n = 431

CE-26CE-26Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1 - 12Pivotal Studies E2301, E2302

Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1 - 12Pivotal Studies E2301, E2302

Responder – Increase of ≥ 1 CSBM/wk during the

entire 12-wk treatment period compared with baseline#

Responder – Increase of ≥ 1 CSBM/wk during the

entire 12-wk treatment period compared with baseline#

18

CSBM = Complete spontaneous bowel movement.# ≥ 7 days of treatment.

Protocol E2301 Amendment 3, Sections 1, 2

Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12

2-wk drug-freebaseline

12-wk treatment

CE-27CE-27Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1- 12 Pivotal Studies E2301, E2302

Secondary Efficacy Variable: Increase of ≥ 1 CSBM/wk During Wk 1- 12 Pivotal Studies E2301, E2302

***P < .0001Responder = Increase of ≥ 1 CSBM/wk during Wk 1 - 12 and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.

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30.6

35.9

43.2

0

10

20

30

40

50

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

26.9

40.344.8

0

10

20

30

40

50

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

E2301 E2302***

******

CSRs E2301, E2302 PTT 9.1-5

n = 416 n = 450n = 447 n = 451n = 417 n = 431

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0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

Re

sp

on

de

rs, %

1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4

Time, wk

Weekly Responder RatePivotal Studies E2301, E2302Weekly Responder RatePivotal Studies E2301, E2302

CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4

E2301N = 1264

E2302N = 1348

48

P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo,Cochran-Mantel-Haenszel test.Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment.EOT = End of treatment; W = Withdrawal.

Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID

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0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

Re

sp

on

de

rs, %

1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4

Time, wk

Weekly Responder RatePivotal Studies E2301, E2302Weekly Responder RatePivotal Studies E2301, E2302

CSR E2301, PTT 9.1-4; CSR E2302, PTT 9.1-4

E2301N = 1264

E2302N = 1348

48

P < .05 vs placebo, Cochran-Mantel-Haenszel test.Responder = Increase of ≥ 1 CSBM/wk and ≥ 7 days of treatment.EOT = End of treatment; W = Withdrawal.

Placebo Zelnorm 6 mg BID

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

–2 –1 1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

Nu

mb

er

of

CS

BM

/wk

–2 –1 1 2 3 4 5 6 7 8 9 10 11 12 EOTW1W2W3W4

Time, wk

Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302

E2301N = 1264

E2302N = 1348

48

P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo, van Elteren test.Mean data.CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal.

Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID

CSR E2301, E2302, PTTs 9.2-2

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0.0

0.5

1.0

1.5

2.0

2.5

3.0

–2 –1 1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

Nu

mb

er

of

CS

BM

/wk

–2 –1 1 2 3 4 5 6 7 8 9 10 11 12 EOTW1W2W3W4

Time, wk

Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302Complete Spontaneous Bowel Movements Pivotal Studies E2301, E2302

E2301N = 1264

E2302N = 1348

48

Placebo Zelnorm® 6 mg BID

P < .05 vs placebo, van Elteren test.Mean data.CSBM = Complete spontaneous bowel movement; EOT = End of treatment; W = Withdrawal.

CSR E2301, E2302, PTTs 9.2-2

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Further a priori Secondary VariablesFurther a priori Secondary Variables

CE-33CE-33Satisfaction With Bowel HabitsWk 1 - 12Pivotal Studies E2301, E2302

Satisfaction With Bowel HabitsWk 1 - 12Pivotal Studies E2301, E2302

31.7 30.6

39.443.5

40.642.9

0

10

20

30

40

50

E2301 E2302

Re

sp

on

de

rs,

%

Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID

*P < .05; **P < .001Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline, Wk 1 - 12.Scale 0 - 4, 0 = a very great deal satisfied, 4 = not at all satisfied.

* *** **

48

n = 416 417 431 447 450 451

SCE T 3-18

CE-34CE-34Stool FormChange From BaselinePivotal Studies E2301, E2302

Stool FormChange From BaselinePivotal Studies E2301, E2302

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

Ch

an

ge

fro

m b

as

elin

e s

co

re

1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4

Time, wk

P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo.Mean data.EOT = End of treatment; W = Withdrawal.Scale 1- 7, 1 = hard, 7 = watery.

CSRs E2301, E2302 PTTs 9.2-532

Placebo

Zelnorm® 2 mg BID

Zelnorm 6 mg BID

E2301N = 1264

E2302N = 1348

CE-35CE-35Straining Score of Spontaneous Bowel Movements—Change From BaselinePivotal Studies E2301, E2302

Straining Score of Spontaneous Bowel Movements—Change From BaselinePivotal Studies E2301, E2302

0.0

0.1

0.2

0.3

0.4

0.5

1 2 3 4 5 6 7 8 9 10 11 12

Time, wk

De

cre

as

e in

sc

ore

1 2 3 4 5 6 7 8 9 10 11 12 EOT W1 W2 W3 W4

Time, wk

P < .05, Zelnorm 2 mg BID vs placebo; P < .05, Zelnorm 6 mg BID vs placebo.Mean data.EOT = End of treatment; W = Withdrawal.Scale 0 - 2, 0 = no straining, 1 = acceptable straining, 2 = too much straining.

CSRs E2301, E2302 PTTs 9.2-6

IIMMPPRROOVVEEMMEENNTT

32

Placebo

Zelnorm® 2 mg BID

Zelnorm 6 mg BID

E2301N = 1264

E2302N = 1348

CE-36CE-36Response Rates by Reduction of Bothersomeness - Wk 1 - 12Pivotal Studies E2301, E2302

Response Rates by Reduction of Bothersomeness - Wk 1 - 12Pivotal Studies E2301, E2302

Patients, %

Study E2301 Study E2302

Placebon = 416

Zelnorm®

2 mg BIDn = 417

Zelnorm6 mg BIDn = 431

Placebon = 447

Zelnorm®

2 mg BIDn = 450

Zelnorm6 mg BIDn = 451

Constipation 27.7 34.6* 40.9*** 25.7 35.1* 37.5**

Abdominal Distension/bloating

27.1 30.8 32.3 27.6 36.0* 35.4*

Abdominaldiscomfort/pain

22.5 27.8 28.3 21.4 31.8** 30.5*

*P < .05; **P < .001; ***P < .0001; Responder = Mean decrease of ≥ 1 point on a 5-point scale compared with baseline.Scale 0 to 4, where a lower score indicates less bother and greater satisfaction.

Summary of Clinical Efficacy T 3-18C

CE-37CE-37Association of CSBM and Improvement of Symptoms (Wk 1 - 4)Pivotal Studies E2301, E2302—Pooled

Association of CSBM and Improvement of Symptoms (Wk 1 - 4)Pivotal Studies E2301, E2302—Pooled

Median % change from baseline

Variable Responder Non-responder P value

Stool form of SBM 41.6 12.5 < .0001

Satisfaction with bowel habit –40.0 –6.7 < .0001

Constipation score –37.5 –8.3 < .0001

Straining score –37.6 –9.4 < .0001

Days with too much straining –50.0 –25.0 < .0001

Abdominal pain score –33.3 0 < .0001

Bloating score –33.3 –8.3 < .0001

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No DV

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Additional AnalysesAdditional Analyses

CE-39CE-39

Responder – ≥ 3 CSBM/wk during the first 4 wk of treatment‡ – No comparison with baseline

Responder – ≥ 3 CSBM/wk during the first 4 wk of treatment‡ – No comparison with baseline

CSBM = Complete spontaneous bowel movement.#FDA responder definition #1.‡ ≥ 7 days of treatment.

Protocol E2301 Amendment 3, Sections 1, 218

Wk 1 - 4Wk 1 - 4 Wk 5 - 8Wk 5 - 8 Wk 9 - 12Wk 9 - 12

2-wk drug-freebaseline

12-wk treatment

≥ ≥ 3 CSBM/wk3 CSBM/wk

Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#

Pivotal Studies E2301, E2302

Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#

Pivotal Studies E2301, E2302

CE-40CE-40Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#

Pivotal Studies E2301, E2302

Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 4#

Pivotal Studies E2301, E2302

C

12.9

18.8

22.2

0

5

10

15

20

25

30

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

12.9

23.021.8

0

5

10

15

20

25

30

Placebo Zelnorm® 2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

**

*

E2301 E2302

******

*P < .05; **P < .001; ***P < .0001.#FDA responder definition #1.

CSRs E2301, E2302 PTT 9.2-16

n = 412 n = 444n = 442 n = 449n = 410 n = 428

CE-41CE-41Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 12# Pivotal Studies E2301, E2302

Secondary Efficacy Variable: ≥ 3 CSBM/wk During Wk 1 - 12# Pivotal Studies E2301, E2302

14.3

17.1

25.2

0

5

10

15

20

25

30

Placebo Zelnorm®2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

13.1

22.7 22.0

0

5

10

15

20

25

Placebo Zelnorm®2 mg BID

Zelnorm 6 mg BID

Re

sp

on

de

rs,

%

****** ***

***P < .0001#FDA responder definition #2.

E2301 E2302

CCSRs E2301, E2302 PTT 9.2-17

CE-42CE-42

Responders by Baseline Bowel Movements/Wk

Responders by Baseline Bowel Movements/Wk

C

CE-43CE-43

Responders by Baseline Bowel Movements/wk Primary Efficacy VariablePivotal Studies E2301, E2302—Pooled

Responders by Baseline Bowel Movements/wk Primary Efficacy VariablePivotal Studies E2301, E2302—Pooled

25.3 26.2

37.6 39.238.643.4

0

10

20

30

40

50

< 3 ≥ 3

BM/wk at baseline

Res

po

nd

ers,

%

Placebo Zelnorm® 2 mg Zelnorm 6 mg

*P < .05; **P < .01; ***P < .0001Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment.BM = Bowel movement; CSBM = Complete spontaneous bowel movement.

n = 890 (34.4%) n = 1695 (65.6%)

SCE PTT 9.1-1c

***********

20

CE-44CE-44

0.1 1 10

Overall

< 65 yr

≥ 65 yr

Male

Female

Caucasian

Black

No baseline laxatives

Baseline laxatives

Responders by Subgroup Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled

Responders by Subgroup Primary Efficacy Variable Pivotal Studies E2301, E2302—Pooled

Patients, n

Zelnorm6 mg BIDPlacebo

32

805

771

106

88

789

877

33

780

761

93

117

737

854

Odds ratio

Zelnorm® 6 mg BID versus placebo, Wk 1 - 4

Responder = Increase of ≥ 1 CSBM/wk; CSBM = Complete spontaneous bowel movement.

470

407

438

416

CSCE Ts 3.12-13.13-1, 3.14-1, 3.15-1, 3.16-1, 3.17-1, 3.24-1

CE-45CE-45

Patients With IBS-Like Features Pivotal Studies E2301, E2302—PooledPatients With IBS-Like Features Pivotal Studies E2301, E2302—Pooled

Addendum to SCE T 3-1, ED June 8, 2004

Patients, n (%)

CriteriaPlacebon = 863

Zelnorm®

2 mg BIDn = 867

Zelnorm6 mg BIDn = 882

a. History of diagnosisof IBS

21 (2) 29 (3) 39 (4)

b. Abdominal discomfort/pain asmain complaint

102 (12) 108 (12) 109 (12)

c. Abdominal discomfort/pain > 0 and diarrhea#

82 (10) 89 (10) 78 (9)

d. Meets any of the above criteria

185 (21) 201 (23) 197 (22)

#Patients with ≥ 25% of SBM loose or watery (stool form 6 or 7) or> 3 SBM/day for ≥ 25% of days.SBM = Spontaneous bowel movement.

54

-1

CE-46CE-46Responders Without IBS-Like FeaturesPrimary Efficacy VariablePivotal Studies E2301, E2302—Pooled

Responders Without IBS-Like FeaturesPrimary Efficacy VariablePivotal Studies E2301, E2302—Pooled

*P < .05; ***P < .0001Responder = increase of ≥ 1 CSBM/wk, Wk 1 - 4, and ≥ 7 days of treatment.CSBM = Complete spontaneous bowel movement.

Addendum to Summary of Clinical Efficacy T 3-3C

Placebo Zelnorm® 2 mg BID Zelnorm 6 mg BID

CC patients without IBS-like features

n = 666n = 666 n = 651n = 651 n = 675n = 6750

10

20

30

40

50

Pat

ien

ts,

%

******

26

4044

CE-47CE-47

Efficacy SummaryEfficacy Summary

Efficacy demonstrated in patients who were chronically constipated

– Early onset of relief

– Sustained

– No rebound Efficacy demonstrated for the treatment of the

multiple symptoms of chronic constipation Zelnorm® 6 mg BID consistently more

efficacious than Zelnorm 2 mg BID

Efficacy demonstrated in patients who were chronically constipated

– Early onset of relief

– Sustained

– No rebound Efficacy demonstrated for the treatment of the

multiple symptoms of chronic constipation Zelnorm® 6 mg BID consistently more

efficacious than Zelnorm 2 mg BID

C

CE-48CE-48

Zelnorm®

(tegaserod maleate)Safety in Chronic Constipation

Zelnorm®

(tegaserod maleate)Safety in Chronic Constipation

C

CE-49CE-49

OverviewOverview

12-wk safety profile

– Exposure

– Adverse events profile

– Serious adverse events

– Laboratory evaluations

Long-term safety profile (16 months)

12-wk safety profile

– Exposure

– Adverse events profile

– Serious adverse events

– Laboratory evaluations

Long-term safety profile (16 months)

C

CE-50CE-50

Overall Exposure Pivotal Studies E2301, E2302—PooledOverall Exposure Pivotal Studies E2301, E2302—Pooled

Summary of Clinical Safety PTT 2.1-114

Placebon = 861

Zelnorm®

2 mg BIDn = 861

Zelnorm6 mg BIDn = 881

Mean duration,days ± SD

79 ± 23 81 ± 21 80 ± 23

≥ 77 days, n 712 738 740

≥ 85 days, n 603 604 585

CE-51CE-51

Most Frequent Adverse Events Pivotal Studies E2301, E2302—PooledMost Frequent Adverse Events Pivotal Studies E2301, E2302—Pooled

5.2 3.7

10.1

5.1 4.2 6.0 4.8

11.07.2 6.6 4.7 4.7

7.23.0

59.6

13.2

56.3 57.1

0

10

20

30

40

50

60

Any AE Headache Nasopharyngitis Diarrhea Abdominal pain Nausea

Patie

nts,

%

Placebo (n = 861)Zelnorm® 2 mg BID (n = 861)Zelnorm 6 mg BID (n = 881)

Clinical Overview T5-2C

CE-52CE-52Most Frequent Adverse Events#

Leading to Discontinuation Pivotal Studies E2301, E2302—Pooled

Most Frequent Adverse Events#

Leading to Discontinuation Pivotal Studies E2301, E2302—Pooled

SCS Table 4-1218

Patients, %

Placebon = 861

Zelnorm®

2 mg BIDn = 861

Zelnorm6 mg BIDn = 881

Any AE 3.7 3.4 5.7

Abdominal pain NOS 0.6 1.0 0.8

Diarrhea NOS 0.2 0.3 0.9

Abdominal distension 0.2 0.2 0.6

Nausea 0.6 0.3 0.3

Headache NOS 0.2 0.2 0.3

NOS = Not otherwise specified.#≥ 5 patients treated with Zelnorm® any dose.

CE-53CE-53

Diarrhea EvaluationPivotal Studies E2301, E2302—PooledDiarrhea EvaluationPivotal Studies E2301, E2302—Pooled

Placebon = 861

Zelnorm®2 mg BIDn = 861

Zelnorm 6 mg BIDn = 881

Patients with diarrhea, n (%) 26 (3.0) 36 (4.2) 58 (6.6)

Diarrhea episodes per patient

1 episode, n (% of patients with diarrhea)

22 (84.6) 29 (80.6) 48 (82.8)

Duration of first episode, days (median)

2.0 2.0 2.5

Stool characteristics, first day of diarrhea (median)

Bowel movements 3.0 2.0 3.0

Stool form score# 5.7 6.0 6.3

SCS Table 8-1C

E2301&E2301 Diarrhea data.xls

#Bristol stool form scale.

CE-54CE-54

Diarrhea ManagementPivotal Studies E2301, E2302—PooledDiarrhea ManagementPivotal Studies E2301, E2302—Pooled

Patients, n

Placebon = 861

Zelnorm® 2 mg BIDn = 861

Zelnorm6 mg BIDn = 881

Diarrhea, n (%) 26 (3.0) 36 (4.2) 58 (6.6)

No action taken 19 24 30

Concomitant medication taken 3 5 6

Dose adjusted/interrupted 3 6 21

Dose permanently discontinued 2 3 8

Each AE occurrence counted.

C SCS T8-1 and SCS PTT 4.28-1

CE-55CE-55Diarrhea—No Clinically Significant ConsequencesPivotal Studies E2301, E2302

Diarrhea—No Clinically Significant ConsequencesPivotal Studies E2301, E2302

No clinically significant consequencesof diarrhea

None required IV hydration orelectrolyte replacement

No clinically significant consequencesof diarrhea

None required IV hydration orelectrolyte replacement

C

CE-56CE-56

Serious Adverse EventsPivotal Studies E2301, E2302—PooledSerious Adverse EventsPivotal Studies E2301, E2302—Pooled

Patients, n (%)

Placebon = 861

Zelnorm®

2 mg BIDn = 861

Zelnorm6 mg BIDn = 881

SAEs# 14 (1.6) 11 (1.3) 12 (1.4)

Discontinuations due to SAEs

3 (0.3) 4 (0.5) 3 (0.3)

Deaths‡ 0 1 (0.1) 0

Clinical Overview T5-3; SCS P13

#Excluding deaths.‡Patient 2521-9: 85-yr-old male with mesothelioma; died 67 days after last dose of Zelnorm 2 mg.

C

CE-57CE-57

Laboratory EvaluationsPivotal Studies E2301, E2302Laboratory EvaluationsPivotal Studies E2301, E2302

Low frequency of notable abnormalities

– Hematology

– Chemistry

– Liver function

– Renal function

Similar between Zelnorm® and placebo

Low frequency of notable abnormalities

– Hematology

– Chemistry

– Liver function

– Renal function

Similar between Zelnorm® and placebo

C Summary of Clinical Safety T 6-1

CE-58CE-58

Abdominal and Pelvic SurgeriesPivotal Studies E2301, E2302—PooledAbdominal and Pelvic SurgeriesPivotal Studies E2301, E2302—Pooled

Placebon = 861

Zelnorm®

2 mg BIDn = 861

Zelnorm6 mg BIDn = 881

All abdominal and pelvic surgeries, n (%)

8 (0.9) 3 (0.3) 6 (0.7)

Cholecystectomies, n 0 0 1

Other, n 8 3 5

C Clinical overview T 5-4, p 23

CE-59CE-59

Long-term Safety Studies E2301, E2301E1 (Long-term Safety Population)Long-term Safety Studies E2301, E2301E1 (Long-term Safety Population)

842 patients entered the extension trial Exposure

– 518 patients (61.7%) exposed to Zelnorm® ≥ 12 months

Discontinuation – 46% of patients discontinued

• 19% Unsatisfactory therapeutic response• 11% Withdrew consent• 10% Other (lost to follow-up, administrative

reasons, etc.)• 6% AE

842 patients entered the extension trial Exposure

– 518 patients (61.7%) exposed to Zelnorm® ≥ 12 months

Discontinuation – 46% of patients discontinued

• 19% Unsatisfactory therapeutic response• 11% Withdrew consent• 10% Other (lost to follow-up, administrative

reasons, etc.)• 6% AE

C CSR E2301E1 T 7-1, 8-1

CE-60CE-60

Adverse Events ≥ 5%Study E2301E1 (Long-term Safety Population)Adverse Events ≥ 5%Study E2301E1 (Long-term Safety Population)

Patients, %

Placebo -Zelnorm®

6 mg BIDn = 274

Zelnorm2 mg BID -2 mg BIDn = 283

Zelnorm6 mg BID -6 mg BIDn = 283

Headache 16.1 24.0 21.2Abdominal pain NOS 10.9 14.8 11.3Diarrhea NOS 10.6 8.1 9.9Nasopharyngitis 6.9 9.5 11.0Nausea 4.4 12.4 9.2Influenza 5.8 6.7 10.2Back pain 5.1 6.0 7.1Abdominal distension 4.0 5.7 7.8Abdominal pain upper 4.4 6.4 6.7Constipation 4.0 4.6 6.4Dyspepsia 3.3 7.4 3.9Flatulence 5.8 3.9 4.9Sinusitis NOS 2.2 5.7 4.9

C Summary of Clinical Safety T 4-5

CE-61CE-61

Conclusions—SafetyConclusions—Safety

Incidence of AEs on Zelnorm® similarto placebo

– Except diarrhea

Low discontinuation rate due to AEs

Long-term safety similar to pivotal studies

Zelnorm is safe and well tolerated in patients with chronic constipation

Incidence of AEs on Zelnorm® similarto placebo

– Except diarrhea

Low discontinuation rate due to AEs

Long-term safety similar to pivotal studies

Zelnorm is safe and well tolerated in patients with chronic constipation

C

CE-62CE-62

Final ConclusionsChronic ConstipationFinal ConclusionsChronic Constipation

Zelnorm® is effective in the treatment of multiple symptoms of chronic constipation

– 6 mg BID consistently more efficacious than 2 mg BID

Zelnorm improves

– Satisfaction with bowel habits

– Straining

– Stool form

– Stool frequency Zelnorm has a favorable safety profile

Zelnorm® is effective in the treatment of multiple symptoms of chronic constipation

– 6 mg BID consistently more efficacious than 2 mg BID

Zelnorm improves

– Satisfaction with bowel habits

– Straining

– Stool form

– Stool frequency Zelnorm has a favorable safety profile

C

CE-63CE-63

Proposed IndicationProposed Indication

Zelnorm® (tegaserod maleate) is indicated for the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation.

Zelnorm® (tegaserod maleate) is indicated for the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools, and infrequent defecation.

C Proposed Package Insert, 1 Oct 2003, p 8