EF 1 Efficacy and Safety Martin P. Lefkowitz, MD Director, Clinical Research Martin P. Lefkowitz, MD Director, Clinical Research

EF 2 Overview of Clinical Results  Totality of data provides convincing evidence of efficacy for tegaserod 12 mg/d on global relief measure and secondary parameters of efficacy  Safe and well tolerated  Favorable benefit-to-risk profile in constipation- predominant IBS, a disorder with no proven therapeutic options  Totality of data provides convincing evidence of efficacy for tegaserod 12 mg/d on global relief measure and secondary parameters of efficacy  Safe and well tolerated  Favorable benefit-to-risk profile in constipation- predominant IBS, a disorder with no proven therapeutic options

EF 3 Tegaserod Clinical Program in Constipation-Predominant IBS StudyDose, mg/d*NLocation (% of patients) Phase II dose-ranging B US (54%), Europe (43%), Canada Phase III efficacy/safety B3514, 12799US (97%), Canada B3014, 12881Europe (90%), US, S Africa B307 4, US (66%), Europe (32%), Canada Long-term safety B Europe (50%), US (41%), Canada StudyDose, mg/d*NLocation (% of patients) Phase II dose-ranging B US (54%), Europe (43%), Canada Phase III efficacy/safety B3514, 12799US (97%), Canada B3014, 12881Europe (90%), US, S Africa B307 4, US (66%), Europe (32%), Canada Long-term safety B Europe (50%), US (41%), Canada 1 *Divided into 2 daily doses.

EF 4 Efficacy Presentation  Phase II  Phase III –Design and endpoints –Results  Summary  Phase II  Phase III –Design and endpoints –Results  Summary

EF 5 24 mg/d; n = mg/d; n = mg/d; n = mg/d; n = 107 Placebo; n = 113 Baseline Week –4 Randomization Week 4 Week 8 Week 12 Week 0 Phase II Study Design (B251) 1

EF 6 Phase II Subject’s Global Assessment (SGA) of Overall GI Symptoms (B251) 1

EF 7 1 Phase III Design Considerations Outcome Measures in IBS Trials (1) No consensus  No consensus on primary outcome measure  Assessment variable –Overall measure that integrates IBS symptoms –Specific symptom measure: abdominal discomfort/pain  Measurement –Ordinal and visual analog scales (VAS) No consensus  No consensus on primary outcome measure  Assessment variable –Overall measure that integrates IBS symptoms –Specific symptom measure: abdominal discomfort/pain  Measurement –Ordinal and visual analog scales (VAS)

EF 8 1 Outcome Measures in IBS Trials (2) General consensus  Responder approach for primary efficacy variable  Frequency: at least weekly  Self-administered by patient General consensus  Responder approach for primary efficacy variable  Frequency: at least weekly  Self-administered by patient

EF 9 Phase III Study Designs 1 B351 4 mg/d 12 mg/d Placebo 12 weeks 4 weeks Baseline 4 mg/d 12 mg/d Placebo 12 weeks 4 weeks B301 Baseline B307 4 mg/d 12 mg/d Placebo 12 weeks 4 weeks 4 mg/d Baseline

EF 10 1 Inclusion Criteria  Males and females  18 years of age (B351:  12 years)  Colon evaluated within last 5 years  Rome criteria Continuous or recurrent discomfort/pain in lower abdomen in last 3 months Discomfort/pain Relieved by BM (1 of 3) Associated with change in frequency of BMs Associated with change in consistency of stool  25% of the time < 3 BMs/week (2 of 3) Hard or lumpy stool Straining  Males and females  18 years of age (B351:  12 years)  Colon evaluated within last 5 years  Rome criteria Continuous or recurrent discomfort/pain in lower abdomen in last 3 months Discomfort/pain Relieved by BM (1 of 3) Associated with change in frequency of BMs Associated with change in consistency of stool  25% of the time < 3 BMs/week (2 of 3) Hard or lumpy stool Straining

EF 11 1 Exclusion Criteria  Diarrhea associated with IBS  25% of the time  Other relevant GI conditions  Concurrent use of –Narcotics, motility agents –Laxative use except as rescue  Diarrhea associated with IBS  25% of the time  Other relevant GI conditions  Concurrent use of –Narcotics, motility agents –Laxative use except as rescue

EF 12 1 Randomization Criteria  Abdominal discomfort/pain –Mean baseline score  35 mm on 100-mm VAS –No upper limit cutoff for pain severity  Stool consistency –No specific mean score  Eligibility based on clinical history Abdominal discomfort/pain Constipation  Abdominal discomfort/pain –Mean baseline score  35 mm on 100-mm VAS –No upper limit cutoff for pain severity  Stool consistency –No specific mean score  Eligibility based on clinical history Abdominal discomfort/pain Constipation VAS = Visual analogue scale.

EF 13 Primary Efficacy Variable SGA of Relief (B351) Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain, and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief symptoms during the past week:  Completely relieved  Considerably relieved  Somewhat relieved  Unchanged  Worse Response:  50% complete/considerable relief at study endpoint Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain, and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief symptoms during the past week:  Completely relieved  Considerably relieved  Somewhat relieved  Unchanged  Worse Response:  50% complete/considerable relief at study endpoint 1

EF 14 Response:  40% reduction and at least 20-mm absolute reduction from baseline at study endpoint “How much of a problem was your abdominal discomfort/pain over the last week?” AbsentVeryMildModerateSevereVery mildsevere 100 mm Primary Efficacy Variable SGA of Abdominal Discomfort/Pain (B351) 1

EF 15 1 Statistical Methodology for Primary Efficacy Variables  Study endpoint: last 4 available weekly scores  Treatment comparisons by Mantel-Haenszel test stratified by center  A multiple comparison procedure was used to ensure the overall 2-sided type I error rate of  <.05  Study endpoint: last 4 available weekly scores  Treatment comparisons by Mantel-Haenszel test stratified by center  A multiple comparison procedure was used to ensure the overall 2-sided type I error rate of  <.05

EF 16 Adjustment Rules Applied to primary efficacy variables at endpoint:  Patient defined as nonresponder if –No postrandomization SGA assessment –< 28 days treatment –Laxative intake > 5 days overall or any use in last 4 weeks of study Applied to primary efficacy variables at endpoint:  Patient defined as nonresponder if –No postrandomization SGA assessment –< 28 days treatment –Laxative intake > 5 days overall or any use in last 4 weeks of study 1

EF 17 Secondary Efficacy Assessments Weekly:SGA of bowel habit (VAS) Daily:Intensity of abdominal discomfort/pain (6-point scale) Intensity of bloating (6-point scale) Number of bowel movements Stool consistency (7-point scale) Weekly:SGA of bowel habit (VAS) Daily:Intensity of abdominal discomfort/pain (6-point scale) Intensity of bloating (6-point scale) Number of bowel movements Stool consistency (7-point scale) Intensity scale 0 = none 1 = very mild 2 = mild 3 = moderate 4 = severe 5 = very severe Intensity scale 0 = none 1 = very mild 2 = mild 3 = moderate 4 = severe 5 = very severe Stool consistency scale 1 = watery 2 = loose 3 = somewhat loose 4 = neither loose nor hard 5 = somewhat hard 6 = hard 7 = very hard Stool consistency scale 1 = watery 2 = loose 3 = somewhat loose 4 = neither loose nor hard 5 = somewhat hard 6 = hard 7 = very hard

EF 18 Patient Disposition B351B301B307 Enrolled1,0931,1221,163 Discontinued 292 (27)240 (21)313 (27) during baseline Randomized Completed633 (79)751 (85)680 (80) Discontinued during 166 (21)130 (15)165 (20) double-blind period B351B301B307 Enrolled1,0931,1221,163 Discontinued 292 (27)240 (21)313 (27) during baseline Randomized Completed633 (79)751 (85)680 (80) Discontinued during 166 (21)130 (15)165 (20) double-blind period 1 Patients, n (%)

EF 19 Demographics Variable (mean)B351B301B307 Age, years Gender, % female Race, % Caucasian Weight, kg Smoking, % Duration of IBS, years Use of bulking agents, % Fiber score, g Variable (mean)B351B301B307 Age, years Gender, % female Race, % Caucasian Weight, kg Smoking, % Duration of IBS, years Use of bulking agents, % Fiber score, g

EF 20 Baseline Characteristics Variable (mean) B351B301B307 Abdominal discomfort/pain VAS score, mm Bowel habit VAS score, mm Days with significant abdominal discomfort/pain, % Days with significant bloating, % Number of bowel movements/week Days without bowel movements, % Days with hard stools, % Stool consistency score Variable (mean) B351B301B307 Abdominal discomfort/pain VAS score, mm Bowel habit VAS score, mm Days with significant abdominal discomfort/pain, % Days with significant bloating, % Number of bowel movements/week Days without bowel movements, % Days with hard stools, % Stool consistency score

EF 21 Efficacy Results Presentation Overview  Efficacy results of study B351  Modification of primary efficacy variable for studies B301 and B307  Efficacy results of study B301  Efficacy results of study B307  Summary  Efficacy results of study B351  Modification of primary efficacy variable for studies B301 and B307  Efficacy results of study B301  Efficacy results of study B307  Summary

EF 22 SGA Data Presentation Response, % Weekly response Monthly response Endpoint: Last 4 available SGA values Adjustment rules* 1 Week *No SGAs, < 28 d treatment, laxative use.

EF 23 Primary Efficacy Variables at Endpoint (B351) P =.05.27P =

EF 24 Complete or Considerable Relief by Week (B351) 1 † † * * * * * * * * * * *P <.05 versus placebo. † P <.01 versus placebo. Placebo4 mg/d12 mg/d † † † †

EF 25 SGA of Abdominal Discomfort/Pain by Week (B351) 9 * * Placebo4 mg/d12 mg/d *P <.05 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS.

EF 26 SGA of Bowel Habit (B351) *P <.05 versus placebo. † P <.01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS. * * Placebo4 mg/d12 mg/d Weekly * * † † * *

EF 27 Daily Diary: Abdominal Discomfort/Pain (B351) Improvement *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale. * * * * * * * * * * * * * Placebo4 mg/d12 mg/d † † † † † † Pain score

EF 28 Daily Diary: Bloating (B351) Improvement *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale. † * * * * * * * * * * * * * * * * * * † † † † Bloating score Placebo4 mg/d12 mg/d

EF 29 Number of Bowel Movements and Stool Consistency by Week (B351) 1 Placebo4 mg/d12 mg/d *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). * * † † † † * * * * * * * * † † † † † † † † * * * * * * † † † † † † † † † † † † * * * * * * † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † * * † † † † † † † † † † † † † † † † † † Bowel movements Stool consistency

EF 30 1 Summary (B351)  No statistically significant differences in primary efficacy variables –Low placebo response rates: SGA of relief 22% SGA of abdominal discomfort/pain 19%  Significant treatment differences observed in daily diary variables  Consistent pattern of improvement for tegaserod across primary and secondary variables  No statistically significant differences in primary efficacy variables –Low placebo response rates: SGA of relief 22% SGA of abdominal discomfort/pain 19%  Significant treatment differences observed in daily diary variables  Consistent pattern of improvement for tegaserod across primary and secondary variables

EF 31 B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B301/B307 SGA of relief Complete or considerable relief at least 50% of the time at study endpoint OR At least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint 1 Modification of Primary Efficacy Variables

EF 32 Associations Between SGA of Relief and Other Efficacy Variables (B351) Efficacy variable % change from baselineResponderNonresponder VAS score: SGA abd discomfort/pain–48 –6 Days with significant pain–35 9 Daily pain score–40 –0.2 Days with significant bloating–32 3 Daily bloating score–38 –2 VAS score: SGA bowel habit–47 –6 Days with no bowel movement–44 –15 Days with hard or very hard stool–66–23 Efficacy variable % change from baselineResponderNonresponder VAS score: SGA abd discomfort/pain–48 –6 Days with significant pain–35 9 Daily pain score–40 –0.2 Days with significant bloating–32 3 Daily bloating score–38 –2 VAS score: SGA bowel habit–47 –6 Days with no bowel movement–44 –15 Days with hard or very hard stool–66–23 1 All comparisons significant (P <.001) Response:  50% complete/considerable or 100% at least somewhat relief.

EF 33 Associations Between SGA of Relief and Other Efficacy Variables (B351) Efficacy variable CompleteConsiderableSomewhatUnchangedWorse % change from baseline (n = 48)(n = 164)(n = 222)(n = 256)(n = 61) VAS score: SGA abd –79–50–23–58 discomfort/pain Days with significant pain –73–40 –7183 Daily pain score –72–44–16 48 Days with significant –61–37 –7 63 bloating Daily bloating score –64–41–16 17 VAS score: SGA bowel –75–50–23–36 habit Days with no bowel –62–46–28–10 –16 movement Days with hard or –71–70–50–19 3 very hard stool Efficacy variable CompleteConsiderableSomewhatUnchangedWorse % change from baseline (n = 48)(n = 164)(n = 222)(n = 256)(n = 61) VAS score: SGA abd –79–50–23–58 discomfort/pain Days with significant pain –73–40 –7183 Daily pain score –72–44–16 48 Days with significant –61–37 –7 63 bloating Daily bloating score –64–41–16 17 VAS score: SGA bowel –75–50–23–36 habit Days with no bowel –62–46–28–10 –16 movement Days with hard or –71–70–50–19 3 very hard stool 1 Last study week

EF 34 B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B351 Original SGA of relief Complete or considerable relief at least 50% of the time at study endpoint B301/B307 SGA of relief Complete or considerable relief at least 50% of the time at study endpoint OR At least somewhat (complete, considerable, or somewhat) relief for 100% of the time at study endpoint 1 Modification of Primary Efficacy Variables for Studies B301/B307 SGA of abdominal discomfort/pain  40% reduction and at least 20-mm absolute reduction from baseline SGA of abdominal discomfort/pain  40% reduction and at least 20-mm absolute reduction from baseline Secondary efficacy variable

EF 35 Efficacy Results SGA of Relief (B351) P =.05.27P = SGA of relief (retrospective analysis) Original SGA of relief

EF 36 Study B301 Efficacy Results

EF 37 4 mg/d 12 mg/d Placebo Baseline Week –4 Randomization Week 4 Week 8 Week 12 Week 0 1 Study Design (B351 and B301)

EF 38 SGA of Relief at Endpoint (B301) *Statistically significant. Response:  50% complete/considerable or 100% at least somewhat relief. 1 P =.018*.033*

EF 39 SGA of Relief at Endpoint B301 *Statistically significant. Response:  50% complete/considerable or 100% at least somewhat relief. 1 P =.018*.033*P =.007*.003* B351 (retrospective analysis) P = *P = * Placebo4 mg/d12 mg/d

EF 40 Monthly SGA of Relief B301 *P <.05 versus placebo; † P < 0.01 versus placebo. Response:  50% complete/considerable or 100% at least somewhat relief. 1 B351 (retrospective analysis) † † † † † † * Placebo4 mg/d12 mg/d

EF 41 At Least Somewhat Relief by Week 1 Placebo4 mg/d12 mg/d B301 * * * * * * * * * * † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † B351 * * * * * * † † † † † † † † † † *P <.05 versus placebo. † P <.01 versus placebo.

EF 42 SGA of Abdominal Discomfort/Pain (B301) *P <.05 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS. * * * * * * * * * * * Placebo4 mg/d12 mg/d Weekly

EF 43 SGA of Bowel Habit (B301) *P <.05 versus placebo. † P <.01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS. Placebo4 mg/d12 mg/d * * * * * * * * * * * * * * * * * * * * * * * * † † Weekly

EF 44 Daily Diary: Abdominal Discomfort/Pain (B301) Improvement *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale. * * * * * * * * * * * * * * † † † † † † † † † † † † † † † † † † † † † † † † † † Placebo4 mg/d12 mg/d Pain score

EF 45 Daily Diary: Bloating (B301) Improvement *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). Significant: at least mild;  2 on a 6-point scale. * * * * * * * * * * * * * * * * * * † † † † † † † † † † † † † † Bloating score Placebo4 mg/d12 mg/d

EF 46 Number of Bowel Movements and Stool Consistency by Week (B301) 1 Placebo4 mg/d12 mg/d † † † † * * * * * * * * † † † † † † † † † † † † † † † † † † † † † † *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † † * * † † Bowel movements Stool consistency

EF 47 Summary Study B301  Clear evidence of efficacy –Significant treatment differences for SGA of relief –Consistent positive findings on secondary efficacy variables  Clear evidence of efficacy –Significant treatment differences for SGA of relief –Consistent positive findings on secondary efficacy variables

EF 48 Study B307 Efficacy Results

EF 49 Nonresponder: 12 mg/d (65%) 4 mg/d Placebo Baseline Week –4 Randomization Week 4 Week 8 Week 12 Week 0 1 Study Design (B307) 4 mg/d Responder: 4 mg/d (35%)

EF 50 SGA of Relief (B307) 1 Endpoint Monthly † * *P <.05 versus placebo; † P <.01 versus placebo. Response:  50% complete/considerable or 100% at least somewhat relief.

EF 51 At Least Somewhat Relief by Week (B307) 1 *P <.05 versus placebo. † P <.01 versus placebo. * * †*†* †*†* † † †*†* †*†*

EF 52 SGA of Abdominal Discomfort/Pain (B307) *P <.05 versus placebo; † P <.01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS. * * * * † † Placebo4 mg/d4-12 mg/d Weekly

EF 53 SGA of Bowel Habit (B307) *P <.05 versus placebo; † P <.01 versus placebo. Response:  40% reduction and at least 20-mm absolute reduction from baseline on 100-mm VAS. * * † † * * Placebo4 mg/d4-12 mg/d Weekly

EF 54 Number of Bowel Movements and Stool Consistency by Week (B307) 1 * * † † † † † † * * † † † † † † *P <.05 versus placebo; † P <.01 versus placebo (change from baseline). * * † † * * † † * * † † † † † † * * † † † † † † † † Placebo4 mg/d4-12 mg/d † † † † † † † † † † † † † † † † † † † † † † † † Bowel movements Stool consistency

EF 55 Summary Study B307  Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint  Not statistically significant for primary efficacy variable  Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint  Not statistically significant for primary efficacy variable

EF 56 Comparative Efficacy Summary

EF 57 Phase III Studies At Least Somewhat Relief B351 B301 B307 *P <.05 versus placebo. † P <.01 versus placebo. * * * * † † † * * * * * * † † * * † * † * *

EF 58 Phase III Studies Complete/Considerable Relief B351 B301 B307 *P <.05 versus placebo. † P <.01 versus placebo. * † * * * * † * * † † † † † † † †

EF 59 Efficacy Variables at Endpoint B351 B301 B307 Efficacy variable4 mg/d12 mg/d4 mg/d12 mg/d4 mg/d4-12 mg/d SGA efficacy variables SGA of relief+<.01<.05< Original SGA of relief<.05 + < SGA of abdominal <.05-- discomfort/pain SGA of bowel habits Daily diary variables Days with significant: Abdominal pain + < Abdominal bloating + < Number of: Bowel movements <.01<.001<.001<.01<.05<.001 Days without BMs + <.01<.05<.05 + <.05 % days with hard stools + < B351 B301 B307 Efficacy variable4 mg/d12 mg/d4 mg/d12 mg/d4 mg/d4-12 mg/d SGA efficacy variables SGA of relief+<.01<.05< Original SGA of relief<.05 + < SGA of abdominal <.05-- discomfort/pain SGA of bowel habits Daily diary variables Days with significant: Abdominal pain + < Abdominal bloating + < Number of: Bowel movements <.01<.001<.001<.01<.05<.001 Days without BMs + <.01<.05<.05 + <.05 % days with hard stools + < = Positive direction for tegaserod, P >.05 versus placebo. - = Negative direction for tegaserod, P >.05 versus placebo.

EF 60 Additional Analyses

EF 61 Pooled Analysis Prespecified primary efficacy variables  B351: Original SGA of relief and SGA of abdominal discomfort/pain  B301/B307: SGA of relief Endpoint analysis Longitudinal analysis P value versus placebo P value versus placebo 12 mg/d 12 mg/d 4 mg/d(4-12 mg/d)4 mg/d(4-12 mg/d) <.0001 Prespecified primary efficacy variables  B351: Original SGA of relief and SGA of abdominal discomfort/pain  B301/B307: SGA of relief Endpoint analysis Longitudinal analysis P value versus placebo P value versus placebo 12 mg/d 12 mg/d 4 mg/d(4-12 mg/d)4 mg/d(4-12 mg/d) <.0001

EF 62 Number of Months With Positive Response for SGA of Relief § P value versus placebo 12 mg/d Study 4 mg/d (4-12 mg/d) B351Original SGA of relief B351 SGA of relief * B301 SGA of relief.008* <.001* B307 SGA of relief * P value versus placebo 12 mg/d Study 4 mg/d (4-12 mg/d) B351Original SGA of relief B351 SGA of relief * B301 SGA of relief.008* <.001* B307 SGA of relief * 1 *Statistically significant with adjustment for multiple comparisons. § Primary analysis of alosetron data. Gastrointestinal Drug Advisory Committee meeting, November 16, 1999.

EF 63 % Weeks With At Least Somewhat Relief Placebo4 mg/d12 mg/d4-12 mg/d 4 P =.021 <.001P =.005 <.001P =

EF 64 SGA of Relief by Gender Pooled Results: B351/B301/B307 1 (n = 2,025)(n = 2,037)(n = 373)(n = 373) Male Female *P <.05 versus placebo; † P <.01 versus placebo mg/d group pooled with 4 mg/d group at Month 1 and with 12 mg/d group at endpoint. * † † †

EF 65 SGA of Relief at Endpoint Placebo-Subtracted Values by Gender 4 mg/d12 mg/d4-12 mg/d B351 B301 B307 * † † *P <.05 versus placebo. † P <.01 versus placebo. (n = 102)(n = 697)(n = 150)(n = 731)(n = 138)(n = 703)

EF 66 Summary of Efficacy (1)  Study B301: clear evidence of efficacy –Significant treatment differences for SGA of relief –Consistent positive findings on secondary efficacy variables  Study B351: although not statistically significant on prespecified primary efficacy endpoints, overall results strongly supportive of efficacy –Daily diary variables statistically significant in favor of tegaserod –Positive trends for all SGA assessments  Study B301: clear evidence of efficacy –Significant treatment differences for SGA of relief –Consistent positive findings on secondary efficacy variables  Study B351: although not statistically significant on prespecified primary efficacy endpoints, overall results strongly supportive of efficacy –Daily diary variables statistically significant in favor of tegaserod –Positive trends for all SGA assessments

EF 67 Summary of Efficacy (2)  Studies B301 and B351 –B351 results largely replicated in study B301 –Consistent results between weekly SGA and daily diary variables –Tegaserod 12 mg/d group had most consistent effect across efficacy variables and over time  Study B307 –Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint –Not statistically significant for primary efficacy variable  Studies B301 and B351 –B351 results largely replicated in study B301 –Consistent results between weekly SGA and daily diary variables –Tegaserod 12 mg/d group had most consistent effect across efficacy variables and over time  Study B307 –Favorable effects for tegaserod at Months 1 and 2 with mixed results at endpoint –Not statistically significant for primary efficacy variable

EF 68 Summary of Efficacy (3)  Additional analyses (pooled analyses, number of months with positive response, % weeks with relief) reinforce findings of a positive treatment effect  Positive treatment effect primarily due to efficacy in women  Totality of data across multiple efficacy variables provides convincing evidence that tegaserod is effective in treatment of constipation-predominant IBS  Additional analyses (pooled analyses, number of months with positive response, % weeks with relief) reinforce findings of a positive treatment effect  Positive treatment effect primarily due to efficacy in women  Totality of data across multiple efficacy variables provides convincing evidence that tegaserod is effective in treatment of constipation-predominant IBS

EF 69 Safety 2

EF 70 Safety Overview  Exposure  Adverse events  Laboratory evaluations  ECG  Summary  Exposure  Adverse events  Laboratory evaluations  ECG  Summary

EF 71 Overall Exposure  3,510 healthy subjects or patients –Maximum daily dose up to 200 mg in healthy subjects  1,874 IBS patients for  85 days  302 IBS patients for  335 days  3,510 healthy subjects or patients –Maximum daily dose up to 200 mg in healthy subjects  1,874 IBS patients for  85 days  302 IBS patients for  335 days

EF 72 Serious Adverse Events Database Placebo Tegaserod Pooled phase II studies 5/1513.3%10/5191.9% Pooled phase III studies13/8371.6%30/1,6791.8% Pooled phase II/III studies18/9881.8%40/2,1981.8% Long-term studies 28/6754.1% Database Placebo Tegaserod Pooled phase II studies 5/1513.3%10/5191.9% Pooled phase III studies13/8371.6%30/1,6791.8% Pooled phase II/III studies18/9881.8%40/2,1981.8% Long-term studies 28/6754.1% 2

EF 73 Reasons for Discontinuations (Phase III) 2

EF 74 Overall Adverse Events (Phase III) 2

EF 75 Adverse Events > 5% (Phase III) % Placebo4 mg/d4-12 mg/d12 mg/d (n = 837) (n = 844)(n = 275)(n = 560) Headache Abdominal pain Diarrhea Nausea Flatulence Back pain Influenza-like symptoms Upper respiratory tract infections Dyspepsia Dizziness Pharyngitis % Placebo4 mg/d4-12 mg/d12 mg/d (n = 837) (n = 844)(n = 275)(n = 560) Headache Abdominal pain Diarrhea Nausea Flatulence Back pain Influenza-like symptoms Upper respiratory tract infections Dyspepsia Dizziness Pharyngitis

EF 76 Time to First Episode of Diarrhea (Phase III) - Majority (75%) single episode - Median duration, 2 days; mean duration, 7 days 2

EF 77 Adverse Events (  1%) Leading to Discontinuation (Phase III) % Placebo4 mg/d 4-12 mg/d12 mg/d Events(n = 837)(n = 844)(n = 275)(n = 560) Total Abdominal pain Diarrhea Flatulence Headache Dizziness % Placebo4 mg/d 4-12 mg/d12 mg/d Events(n = 837)(n = 844)(n = 275)(n = 560) Total Abdominal pain Diarrhea Flatulence Headache Dizziness

EF 78 Long-Term Safety Study (B209)  12-month, open label  4-12 mg/d dose titration –80% titrated to 12 mg/d  Enrolled: 579  Completed: 304  12-month, open label  4-12 mg/d dose titration –80% titrated to 12 mg/d  Enrolled: 579  Completed: 304

EF 79 Adverse Events > 5% (Long-term Study: 12 Months) Event Headache30% Abdominal pain17% Upper respiratory 16% tract infection Diarrhea15% Back pain 9% Sinusitis 8% Nausea 8% Flatulence 8% Event Headache30% Abdominal pain17% Upper respiratory 16% tract infection Diarrhea15% Back pain 9% Sinusitis 8% Nausea 8% Flatulence 8% 2 Total patients, N = 567 (4-12 mg/d)

EF 80 Adverse Events (> 1%) Leading to Discontinuation (Long-term Study) Events Total11% Diarrhea4% Abdominal pain3% Flatulence3% Headache1% Events Total11% Diarrhea4% Abdominal pain3% Flatulence3% Headache1% 2 Total patients, N = 567 (4-12 mg/d)

EF 81 Laboratory Evaluations (Phase III)  Clinically relevant laboratory abnormalities in hematology and biochemistry values were rare and with similar frequency for tegaserod- and placebo-treated groups  Liver chemistries (LFTs) –ALT > 3-fold normal: tegaserod 0.4% versus placebo 0.2% –AST > 3-fold normal: tegaserod 0.1% versus placebo 0.1% –No simultaneous elevations in ALT/AST and bilirubin –No serious adverse event of hepatitis or elevated LFTs  No evidence of tegaserod-induced hepatotoxicity was noted  Clinically relevant laboratory abnormalities in hematology and biochemistry values were rare and with similar frequency for tegaserod- and placebo-treated groups  Liver chemistries (LFTs) –ALT > 3-fold normal: tegaserod 0.4% versus placebo 0.2% –AST > 3-fold normal: tegaserod 0.1% versus placebo 0.1% –No simultaneous elevations in ALT/AST and bilirubin –No serious adverse event of hepatitis or elevated LFTs  No evidence of tegaserod-induced hepatotoxicity was noted

EF 82 2 ECG Recording and Analysis  12-lead electrocardiograms (> 10,000 tracings)  Timepoint recording –Phase III: baseline, first dose (2 h), Months 1 and 3 (2 h) –Long-term: baseline; Months 2, 6, and 12  Analysis: –Central analysis by independent cardiologist –Intervals evaluated by SigmaScan technique  No effects on ECG (QTc intervals or arrhythmias)  12-lead electrocardiograms (> 10,000 tracings)  Timepoint recording –Phase III: baseline, first dose (2 h), Months 1 and 3 (2 h) –Long-term: baseline; Months 2, 6, and 12  Analysis: –Central analysis by independent cardiologist –Intervals evaluated by SigmaScan technique  No effects on ECG (QTc intervals or arrhythmias)

EF 83 2 Safety Summary  Tegaserod 4 and 12 mg/d –Well tolerated –Similar safety profile  Diarrhea: –Only adverse event with higher frequency than placebo –Low discontinuation rate (~ 2%)  No effects on ECG (QTc intervals or arrhythmias) or laboratory parameters  Tegaserod 4 and 12 mg/d –Well tolerated –Similar safety profile  Diarrhea: –Only adverse event with higher frequency than placebo –Low discontinuation rate (~ 2%)  No effects on ECG (QTc intervals or arrhythmias) or laboratory parameters

EF 84 Conclusions  Totality of data demonstrates that tegaserod is effective in the treatment of IBS in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms  Tegaserod 12 mg/d improves: –Abdominal discomfort/pain –Bloating –Constipation (stool frequency and stool consistency)  Favorable safety profile  Favorable benefit-to-risk profile  Totality of data demonstrates that tegaserod is effective in the treatment of IBS in patients who identify abdominal pain/discomfort and constipation as their predominant symptoms  Tegaserod 12 mg/d improves: –Abdominal discomfort/pain –Bloating –Constipation (stool frequency and stool consistency)  Favorable safety profile  Favorable benefit-to-risk profile