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

A 3 Alosetron /26Alosetron Potent and Selective 5HT 3 receptor antagonistPotent and Selective 5HT 3 receptor antagonist 5HT 3 receptors participate in motor and sensory processes in the gut5HT 3 receptors participate in motor and sensory processes in the gut

A 4 Alosetron /26 2 weeks 4 weeks 12 weeks Treatment (BID) Placebo Alosetron 1 mg Screening Follow-up (No treatment) Study Design (S3BA3001/S3BA3002) Diarrhea- predominan t Alternating bowel pattern Female Only

A 5 Alosetron /26 Primary Endpoint Adequate relief of IBS pain and discomfort: “In the past seven days have you had adequate relief of your irritable bowel syndrome pain and discomfort?”

A 6 Alosetron /26(Diarrhea-Predominant) *p<0.05 S3BA300 1 % With Adequate Relief S3BA300 2 Follow-up * Treatment * * * * * * * * * Treatment * Follow-up * * * * * * * * * * WeekWeek LOCF “In the Past Seven Days Have You Had Adequate Relief of Your Irritable Bowel Syndrome Pain and Discomfort?” placebo alosetron

A 7 Alosetron /26*p<0.05 LOCF (Diarrhea-Predominant) % Days Follow-up Week Treatment Follow-up Week Treatment * * * * * * * ** * * S3BA3001S3BA3002 placebo alosetron * * * * * * * * * * * * “Have You Felt or Experienced a Sense of Urgency Today?”

A 8 Alosetron /26 *p<0.05 LOCF (Diarrhea-Predominant) Follow-up Week Treatment Stools/Day Week S3BA300 1 S3BA300 2 placebo alosetron * * * * * * * * ** * * * * ** * * ** * * * * “Please Enter the Number of Times You Have Passed Stool Today”

A 9 Alosetron /26 Follow-up Week Treatment Week Firmer Consistency Score *p<0.05 LOCF (Diarrhea-Predominant) S3BA300 1 S3BA300 2 placebo alosetron * * * * * * * ** * * * * * * * * * ** * * * * “Please Rate the Consistency Of Your Stool Today”

A 10 Alosetron /26 Efficacy Update

A 11 Alosetron /26 International Comparator Two studies: 600 patients eachTwo studies: 600 patients each Compare alosetron to mebeverine (antispasmodic) or trimebutine (opioid acting agent)Compare alosetron to mebeverine (antispasmodic) or trimebutine (opioid acting agent)

A 12 Alosetron /26 In the past seven days have you had adequate relief of your irritable bowel syndrome pain and discomfort? (Diarrhea-Predominant) % With Adequate Relief Week Treatment Follow-up % With Adequate Relief Week Treatment Follow-up S3BB300 1 S3BB300 2

A 13 Alosetron /26S3B30011 Recently completedRecently completed 783 female diarrhea predominant IBS patients783 female diarrhea predominant IBS patients Twelve week treatment phaseTwelve week treatment phase 2:1 (alosetron : placebo) randomization2:1 (alosetron : placebo) randomization

A 14 Alosetron /26 IBS Global Improvement Question “Compared to the way you usually felt during the 3 months before you entered the study, are your IBS symptoms over the past 4 weeks”: Substantially worseSubstantially worse Moderately worseModerately worse Slightly worseSlightly worse No changeNo change Slightly improvedSlightly improved Moderately improvedModerately improved Substantially improvedSubstantially improved

A 15 Alosetron /26 Global Improvement Responder Month * p<0.05 * * * % Responders

A 16 Alosetron /26 Efficacy Conclusion IBS is a multidimensional disorderIBS is a multidimensional disorder In diarrhea-predominant female patients alosetron produces robust improvement on multiple endpointsIn diarrhea-predominant female patients alosetron produces robust improvement on multiple endpoints

A 17 Alosetron /26Safety Constipation Ischemic Colitis Hepatic Functio n

A 18 Alosetron /26 Agreements With FDA Prior To June 27, 2000 No change in frequency and/or severity of ischemic colitis since approval of alosetronNo change in frequency and/or severity of ischemic colitis since approval of alosetron Number of cases of ischemic colitis and serious constipation reconciledNumber of cases of ischemic colitis and serious constipation reconciled At the November 16, 1999 Advisory Committee meeting alternative etiologies for some of the cases for ischemic colitis were presented. However, at the request of the FDA, pathology of ischemic colitis would not be discussed.At the November 16, 1999 Advisory Committee meeting alternative etiologies for some of the cases for ischemic colitis were presented. However, at the request of the FDA, pathology of ischemic colitis would not be discussed.

A 19 Alosetron /26 2 Databases (June 1, 2000) Clinical TrialsClinical Trials –3000 subjects at approval –6852 subjects as of June 1, 2000 Post-Marketing SpontaneousPost-Marketing Spontaneous –130,000 prescriptions

A 20 Alosetron /26Constipation Potential Complications ImpactionImpaction ObstructionObstruction IleusIleus MegacolonMegacolon PerforationPerforation

A 21 Alosetron /26 Constipation (Phase II/III) 27% of patients developed constipation (5% placebo patients)27% of patients developed constipation (5% placebo patients) Of the patients who became constipated, 65% reported mild to moderate constipationOf the patients who became constipated, 65% reported mild to moderate constipation 75% of constipated patients had only one episode75% of constipated patients had only one episode 10% of patients in Phase II/III withdrew secondary to constipation10% of patients in Phase II/III withdrew secondary to constipation

A 22 Alosetron /26 Constipation (Phase III) Management Four consecutive days without a bowel movementFour consecutive days without a bowel movement –Brief (up to 4 days) interruption of alosetron –Occurred in 9% of alosetron treated patients –88% of patients resumed bowel movement during the interruption

A 23 Alosetron /26Constipation At approvalAt approval No serious events June 1, 2000June 1, 2000 –2 reports in clinical development –4 reports in spontaneous database No deathsNo deaths

A 24 Alosetron /26 Constipation - Clinical Trials (Hospitalized) Duration of Alosetron EventAge(Days)Other Factors Impaction547Previously disimpacted Constipation Colectomy5627Constipation (Obstruction,Dense abdominal megacolon, 2 o ischemia) adhesions

A 25 Alosetron /26 Constipation - Spontaneous Reports (Hospitalized) Duration of Alosetron EventAge(Days)Other Factors Stercoral ulcer487History of idiopathic constipation Impaction/SBO5021 Loop colostomy682Sigmoid stricture & (18 days after d/ccolitis Alosetron) Sigmoid perforation7217Hydrocodone No report of constipation before surgery

A 26 Alosetron /26 Constipation Conclusion Most frequent adverse eventMost frequent adverse event Rare reports of complications of constipation have been reported since approvalRare reports of complications of constipation have been reported since approval Pre-existing constipation was reportedPre-existing constipation was reported No deathsNo deaths

A 27 Alosetron /26 Ischemic Colitis

A 28 Alosetron /26 Ischemic Colitis - Clinical Trials At approval (clinical development)At approval (clinical development) 4 reports/3000 subjects (1:750) June 1, 2000June 1, New reports 7 Total reports/6852 subjects (1:979) Acute, transient ischemic colitisAcute, transient ischemic colitis No sequelae/no change in severityNo sequelae/no change in severity No deathsNo deaths

A 29 Alosetron /26 Ischemic Colitis - Spontaneous (June 1, 2000) 130,000 prescriptions dispensed130,000 prescriptions dispensed Spontaneous Reports: 5Spontaneous Reports: 5 –Acute, transient and self limiting –No sequelae –No deaths

A 30 Alosetron /26 Chronic Colitis Colonic Surgery Date Unknown Initiate Alosetron 3/16/00 Stop Alosetron 3/22/00 Initiate Prednisone 4/00 Colonic Surgery 6/4/00

A 31 Alosetron /26 Ischemic Colitis Three large private GI practices (5/95-5/2000)Three large private GI practices (5/95-5/2000) –110,000 patients –188 cases of ischemic colitis Duke Database (7/93-11/99)Duke Database (7/93-11/99) –14,478 colonoscopies –130 cases of ischemic colitis

A 32 Alosetron /26 Ischemic Colitis Conclusion No change in frequency and/or severity of ischemic colitisNo change in frequency and/or severity of ischemic colitis All cases represented acute, transient ischemic colitisAll cases represented acute, transient ischemic colitis No sequelae notedNo sequelae noted No deathsNo deaths

A 33 Alosetron /26 Hepatic Function

A 34 Alosetron /26 ALT (>3x Normal) TimePlaceboAlosetron Pre-approval0.4%0.5% Post-approval0.9%0.4% Total0.43%0.42%

A 35 Alosetron /26 Alkaline Phosphatase/ Bilirubin ParameterPlaceboAlosetron Alk Phos0.07%0.09% (≥2X Normal) Bilirubin 0.29%0.12% (≥2X Normal) No alosetron treated subjects had ALT >3X and Bili >2X

A 36 Alosetron /26 Elevated Liver Enzymes One patient with hepatitis (without jaundice) in label at time of approvalOne patient with hepatitis (without jaundice) in label at time of approval Two additional narratives from spontaneous reports in briefing document; one case with multiple confounding factorsTwo additional narratives from spontaneous reports in briefing document; one case with multiple confounding factors

A 37 Alosetron /26 Hepatic Function Conclusions No signalNo signal Rates similar to placeboRates similar to placebo

A 38 Alosetron /26 “Other” Serious Events (21 Total - 11 Reviewed) (130,000 Prescriptions) Abdominal Pain(n=2)Abdominal Pain(n=2) Overdose Other Medications(n=2)Overdose Other Medications(n=2) Syncope(n=1)Syncope(n=1) CVA(n=1)CVA(n=1) Bloody Diarrhea(n=1)Bloody Diarrhea(n=1) Chest Pain(n=1)Chest Pain(n=1) Acute Enteritis(n=1)Acute Enteritis(n=1) Viral Meningitis(n=1)Viral Meningitis(n=1)

A 39 Alosetron /26 Overall Conclusion IBS is a significant disease with a large burden of illness for the individual patientIBS is a significant disease with a large burden of illness for the individual patient Alosetron produces robust multidimensional improvement (pain, urgency, frequency, consistency), in the treatment of female diarrhea-predominant IBS patientsAlosetron produces robust multidimensional improvement (pain, urgency, frequency, consistency), in the treatment of female diarrhea-predominant IBS patients

A 40 Alosetron /26 Overall Conclusion (continued) No change in the frequency and/or severity of ischemic colitis since approvalNo change in the frequency and/or severity of ischemic colitis since approval Rare complications of constipation have been observedRare complications of constipation have been observed Overall risk-benefit shows clear benefits of alosetronOverall risk-benefit shows clear benefits of alosetron