A 2 Alosetron 2000 6/26 Allen Mangel, M.D., Ph.D. International Director Gastroenterology International Product Development Leader, Alosetron Safety &

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Alosetron 2000 6/26

Allen Mangel, M.D., Ph.D.Allen Mangel, M.D., Ph.D.International DirectorInternational Director

Gastroenterology Gastroenterology International Product Development International Product Development

Leader, AlosetronLeader, Alosetron

Safety & Efficacy Safety & Efficacy of Alosetronof Alosetron

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AlosetronAlosetron

•Potent and Selective 5HTPotent and Selective 5HT33 receptor antagonistreceptor antagonist

•5HT5HT33 receptors participate receptors participate in motor and sensory in motor and sensory processes in the gutprocesses in the gut

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Alosetron 2000 6/26

2 weeks 2 weeks 4 weeks 4 weeks 12 weeks 12 weeks

Treatment (BID)Treatment (BID)PlaceboPlacebo

Alosetron 1 mg Alosetron 1 mg

Screening Screening Follow-upFollow-up(No treatment) (No treatment)

Study Design Study Design (S3BA3001/S3BA3002)(S3BA3001/S3BA3002)

Diarrhea-Diarrhea-predominapredominantnt

AlternatinAlternating bowel g bowel patternpatternFemale Female OnlyOnly

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Primary EndpointPrimary Endpoint

Adequate relief of IBS pain and Adequate relief of IBS pain and discomfort:discomfort:

““In the past seven days have In the past seven days have you had adequate relief of you had adequate relief of your irritable bowel syndrome your irritable bowel syndrome pain and discomfort?”pain and discomfort?”

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(Diarrhea-Predominant)(Diarrhea-Predominant)

*p<0.05*p<0.05

S3BA30S3BA3001 01

% W

ith

Ad

eq

uate

%

Wit

h A

deq

uate

R

elief

Relief

S3BA30S3BA3002 02 Follow-upFollow-up

**

TreatmentTreatment

** ****** **

**** ** **

TreatmentTreatment

**

Follow-upFollow-up

** ** ** ** ** ** **** ** **

WeekWeek WeekWeek

LOCF LOCF

““In the Past Seven Days Have You Had In the Past Seven Days Have You Had Adequate Relief of Your Irritable Bowel Adequate Relief of Your Irritable Bowel

Syndrome Pain and Discomfort?”Syndrome Pain and Discomfort?”

placebo placebo alosetronalosetron

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*p<0.05*p<0.05LOCF LOCF


% D

ays

% D

ays

Follow-up

WeekWeek

Treatment Follow-up

WeekWeek

Treatment

**

* * * * * * * **

S3BA30S3BA3001 01

S3BA30S3BA3002 02


* * * * * * * * *

** *

““Have You Felt or Experienced a Have You Felt or Experienced a Sense of Urgency Today?”Sense of Urgency Today?”

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1

2

3

4

0 1 2 3 4 5 6 7 8 9 10111213141516



0 1 2 3 4 5 6 7 8 9 10111213141516

Follow-upFollow-up

WeekWeek

Treatment

Sto

ols

/Day

Sto

ols

/Day

WeekWeek

Treatment

S3BA30S3BA3001 01

S3BA30S3BA3002 02


* * * * * * * * * * * * * * * * * * * * * * * *

““Please Enter the Number of Please Enter the Number of Times You Have Passed Stool Times You Have Passed Stool

Today”Today”

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Follow-upFollow-up

WeekWeek

Treatment

WeekWeek

Treatment

Fir

mer

Con

sis

ten

cy S

core

Fir

mer

Con

sis

ten

cy S

core



S3BA30S3BA3001 01

S3BA30S3BA3002 02


** * * * * * * * * * * * * * * * * * * * * * *

““Please Rate the Consistency OfPlease Rate the Consistency OfYour Stool Today”Your Stool Today”

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Efficacy Efficacy UpdateUpdate

A A 1111

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International ComparatorInternational Comparator

•Two studies: 600 patients Two studies: 600 patients eacheach

•Compare alosetron to Compare alosetron to mebeverine mebeverine (antispasmodic) or (antispasmodic) or trimebutine (opioid acting trimebutine (opioid acting agent)agent)

A A 1212

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In the past seven days have you had In the past seven days have you had adequate relief of adequate relief of

your irritable bowel syndrome pain and your irritable bowel syndrome pain and discomfort?discomfort?

(Diarrhea-Predominant) (Diarrhea-Predominant)

% W

ith

Ad

eq

uate

%

Wit

h A

deq

uate

R

elief

Relief

Week

Treatment Follow-up

% W

ith

Ad

eq

uate

%

Wit

h A

deq

uate

R

elief

Relief

Week

Treatment Follow-up

S3BB30S3BB3001 01

S3BB30S3BB3002 02

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S3B30011S3B30011

•Recently completedRecently completed

•783 female diarrhea 783 female diarrhea predominant IBS patientspredominant IBS patients

•Twelve week treatment Twelve week treatment phasephase

•2:1 (alosetron : placebo) 2:1 (alosetron : placebo) randomizationrandomization

A A 1414

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IBS Global Improvement IBS Global Improvement QuestionQuestion““Compared to the way you usually felt during the 3 Compared to the way you usually felt during the 3

months before you entered the study, are your months before you entered the study, are your IBS IBS symptomssymptoms over the past 4 weeks”: over the past 4 weeks”:

•Substantially worseSubstantially worse•Moderately worseModerately worse•Slightly worseSlightly worse•No changeNo change•Slightly improved Slightly improved •Moderately improvedModerately improved•Substantially improvedSubstantially improved

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0

10

20

30

40

50

60

70

80

90

1 2 3

PlaceboAlosetron

Global Improvement Global Improvement ResponderResponder

MontMonthh

* * p<0.05p<0.05

* *

*

%

%

Resp

on

de

Resp

on

de

rsrs

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Efficacy ConclusionEfficacy Conclusion

•IBS is a multidimensional IBS is a multidimensional disorderdisorder

•In diarrhea-predominant In diarrhea-predominant female patients alosetron female patients alosetron produces robust produces robust improvement on multiple improvement on multiple endpointsendpoints

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SafetySafety

ConstipationConstipation IschemIschemic ic

ColitisColitis

HepatiHepatic c

FunctiFunctionon

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Agreements With FDA Agreements With FDA Prior To June 27, 2000Prior To June 27, 2000

• No change in frequency and/or severity of No change in frequency and/or severity of ischemic colitis since approval of ischemic colitis since approval of alosetronalosetron

• Number of cases of ischemic colitis and Number of cases of ischemic colitis and serious constipation reconciledserious constipation reconciled

• At the November 16, 1999 Advisory At the November 16, 1999 Advisory Committee meeting alternative etiologies Committee meeting alternative etiologies for some of the cases for ischemic colitis for some of the cases for ischemic colitis were presented. However, at the request were presented. However, at the request of the FDA, pathology of ischemic colitis of the FDA, pathology of ischemic colitis would not be discussed.would not be discussed.

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2 Databases (June 1, 2 Databases (June 1, 2000)2000)

•Clinical TrialsClinical Trials– 3000 subjects at approval3000 subjects at approval

– 6852 subjects as of June 1, 6852 subjects as of June 1, 20002000

•Post-Marketing Post-Marketing SpontaneousSpontaneous– 130,000 prescriptions130,000 prescriptions

A A 2020

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ConstipationConstipation

Potential ComplicationsPotential Complications• ImpactionImpaction• ObstructionObstruction• IleusIleus• MegacolonMegacolon• PerforationPerforation

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Constipation (Phase Constipation (Phase II/III)II/III)• 27% of patients developed 27% of patients developed

constipation (5% placebo patients)constipation (5% placebo patients)

• Of the patients who became Of the patients who became constipated, 65% reported mild to constipated, 65% reported mild to moderate constipationmoderate constipation

• 75% of constipated patients had 75% of constipated patients had only one episodeonly one episode

• 10% of patients in Phase II/III 10% of patients in Phase II/III withdrew secondary to constipationwithdrew secondary to constipation

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Constipation (Phase III)Constipation (Phase III)ManagementManagement

•Four consecutive days without Four consecutive days without a bowel movementa bowel movement– Brief (up to 4 days) interruption Brief (up to 4 days) interruption of alosetronof alosetron

– Occurred in 9% of alosetron Occurred in 9% of alosetron treated patientstreated patients

– 88% of patients resumed bowel 88% of patients resumed bowel movement during the movement during the interruptioninterruption

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ConstipationConstipation

•At approval At approval

No serious eventsNo serious events

•June 1, 2000 June 1, 2000 – 2 reports in clinical 2 reports in clinical developmentdevelopment

– 4 reports in spontaneous 4 reports in spontaneous databasedatabase

•No deathsNo deaths

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Constipation - Clinical Constipation - Clinical Trials Trials (Hospitalized)(Hospitalized)

Duration of Duration of AlosetronAlosetron

EventEvent AgeAge (Days)(Days) Other FactorsOther Factors

ImpactionImpaction 5454 77 Previously disimpactedPreviously disimpactedConstipationConstipation

ColectomyColectomy 5656 2727 ConstipationConstipation(Obstruction,(Obstruction, Dense abdominal Dense abdominal megacolon, 2megacolon, 2oo ischemia) ischemia) adhesionsadhesions

A A 2525

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Constipation - Constipation - Spontaneous Reports Spontaneous Reports

(Hospitalized)(Hospitalized)Duration of Duration of AlosetronAlosetron

EventEvent AgeAge (Days)(Days) Other FactorsOther Factors

Stercoral ulcerStercoral ulcer 4848 77 History of idiopathic History of idiopathic constipationconstipation

Impaction/SBOImpaction/SBO 5050 2121

Loop colostomyLoop colostomy 6868 22 Sigmoid stricture & Sigmoid stricture & (18 days after d/c(18 days after d/c colitiscolitisAlosetron)Alosetron)

Sigmoid perforationSigmoid perforation7272 1717 Hydrocodone Hydrocodone No report of constipationNo report of constipationbefore surgery before surgery

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Constipation ConclusionConstipation Conclusion

•Most frequent adverse eventMost frequent adverse event

•Rare reports of complications Rare reports of complications of constipation have been of constipation have been reported since approvalreported since approval

•Pre-existing constipation was Pre-existing constipation was reportedreported


A A 2727

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Ischemic ColitisIschemic Colitis

A A 2828

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Ischemic Colitis - Clinical Ischemic Colitis - Clinical TrialsTrials•At approval (clinical development) At approval (clinical development)

4 reports/3000 subjects (1:750)4 reports/3000 subjects (1:750)•June 1, 2000June 1, 2000

3 New reports3 New reports7 Total reports/6852 subjects 7 Total reports/6852 subjects

(1:979)(1:979)•Acute, transient ischemic colitisAcute, transient ischemic colitis•No sequelae/no change in severityNo sequelae/no change in severity•No deathsNo deaths

A A 2929

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Ischemic Colitis - Ischemic Colitis - SpontaneousSpontaneous(June 1, 2000)(June 1, 2000)

• 130,000 prescriptions 130,000 prescriptions dispenseddispensed

• Spontaneous Reports: 5Spontaneous Reports: 5– Acute, transient and self Acute, transient and self limitinglimiting

– No sequelaeNo sequelae

– No deathsNo deaths

A A 3030

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Chronic ColitisChronic Colitis

ColonicColonicSurgerySurgery

Date Date UnknownUnknown

InitiateInitiateAlosetronAlosetron3/16/003/16/00

StopStopAlosetronAlosetron3/22/003/22/00

InitiateInitiatePrednisonePrednisone

4/004/00

ColonicColonicSurgerySurgery6/4/006/4/00

A A 3131

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Ischemic ColitisIschemic Colitis

•Three large private GI Three large private GI practicespractices(5/95-5/2000)(5/95-5/2000)– 110,000 patients110,000 patients– 188 cases of ischemic colitis188 cases of ischemic colitis

•Duke Database (7/93-11/99)Duke Database (7/93-11/99)– 14,478 colonoscopies14,478 colonoscopies– 130 cases of ischemic colitis130 cases of ischemic colitis

A A 3232

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Ischemic Colitis Ischemic Colitis ConclusionConclusion

•No change in frequency No change in frequency and/or severity of ischemic and/or severity of ischemic colitiscolitis

•All cases represented acute, All cases represented acute, transient ischemic colitistransient ischemic colitis

•No sequelae notedNo sequelae noted


A A 3333

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Hepatic FunctionHepatic Function

A A 3434

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ALT (>3x Normal)ALT (>3x Normal)

TimeTime PlaceboPlacebo AlosetronAlosetron

Pre-approvalPre-approval 0.4%0.4% 0.5%0.5%

Post-approvalPost-approval 0.9%0.9% 0.4%0.4%

TotalTotal 0.43%0.43% 0.42%0.42%

A A 3535

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Alkaline Phosphatase/Alkaline Phosphatase/BilirubinBilirubin

ParameterParameter PlaceboPlacebo AlosetronAlosetron

Alk PhosAlk Phos 0.07%0.07% 0.09%0.09%

(≥2X Normal)(≥2X Normal)

BilirubinBilirubin 0.29% 0.29% 0.12%0.12%

(≥2X Normal)(≥2X Normal)

No alosetron treated subjects had ALT >3X and No alosetron treated subjects had ALT >3X and

Bili >2XBili >2X

A A 3636

Alosetron 2000 6/26

Elevated Liver EnzymesElevated Liver Enzymes

•One patient with hepatitis One patient with hepatitis (without jaundice) in label at (without jaundice) in label at time of approvaltime of approval

•Two additional narratives from Two additional narratives from spontaneous reports in spontaneous reports in briefing document; one case briefing document; one case with multiple confounding with multiple confounding factorsfactors

A A 3737

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Hepatic Function Hepatic Function ConclusionsConclusions

•No signal No signal

•Rates similar to placeboRates similar to placebo

A A 3838

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““Other” Serious EventsOther” Serious Events(21 Total - 11 Reviewed)(21 Total - 11 Reviewed)(130,000 Prescriptions)(130,000 Prescriptions)

•Abdominal PainAbdominal Pain (n=2)(n=2)•Overdose Other MedicationsOverdose Other Medications

(n=2)(n=2)•SyncopeSyncope (n=1)(n=1)•CVACVA (n=1)(n=1)•Bloody DiarrheaBloody Diarrhea (n=1)(n=1)•Chest PainChest Pain (n=1)(n=1)•Acute EnteritisAcute Enteritis (n=1)(n=1)•Viral MeningitisViral Meningitis (n=1)(n=1)

A A 3939

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Overall ConclusionOverall Conclusion

•IBS is a significant disease IBS is a significant disease with a large burden of illness with a large burden of illness for the individual patientfor the individual patient

•Alosetron produces robust Alosetron produces robust multidimensional multidimensional improvement (pain, urgency, improvement (pain, urgency, frequency, consistency), in the frequency, consistency), in the treatment of female diarrhea-treatment of female diarrhea-predominant IBS patientspredominant IBS patients

A A 4040

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Overall Conclusion Overall Conclusion (continued)(continued)

•No change in the frequency No change in the frequency and/or severity of ischemic and/or severity of ischemic colitis since approvalcolitis since approval

•Rare complications of Rare complications of constipation have been constipation have been observedobserved

•Overall risk-benefit shows Overall risk-benefit shows clear benefits of alosetronclear benefits of alosetron

Documents

A 2 Alosetron 2000 6/26 Allen Mangel, M.D., Ph.D. International Director Gastroenterology International Product Development Leader, Alosetron Safety &