1. OC 1 Review of Ovarian Cysts Bruce Carr, MD Director, Division of Reproductive Endocrinology The University of Texas Southwestern Medical Center Bruce Carr, MD Director, Division of Reproductive Endocrinology The University of Texas Southwestern Medical Center

2. OC 2 Safety  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications

3. OC 3 Safety  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications

4. OC 4 1 Corpus luteum Graafian follicle Primary follicles Growth and Development of Ovarian Follicles

6. OC 6 n = 2 on tegaserod n = 1 on placebo n = 2: with history of OCs n = 3: newly occurring n = 4*: not confirmed n = 5: OC confirmed n = 9 "ovarian cysts” (n = 8 tegaserod, n = 1 placebo) Further Analysis of “Ovarian Cysts” *Revised diagnosis: – Cystadenofibroma – Peritubal cyst – Pelvic adhesions – Ruptured ovarian cyst n = 2 on tegaserod – Adenomyosis/OC – Appendicitis Recurring/OC – Cyst/follicle – Polycystic ovary

7. OC 7 Female Patients With Ovarian Cysts PlaceboTegaserod Controlled studies Phase III1/707 (0.14)1/1,419 (0.07) Phase II0/140 (0.0) 2/456 (0.44) Phase II/III 1/847 (0.12) 3/1,875 (0.16) Uncontrolled, long-term – 1/611 (0.16) studies PlaceboTegaserod Controlled studies Phase III1/707 (0.14)1/1,419 (0.07) Phase II0/140 (0.0) 2/456 (0.44) Phase II/III 1/847 (0.12) 3/1,875 (0.16) Uncontrolled, long-term – 1/611 (0.16) studies Patients, n (%)

8. OC 8 Estimated Ovarian Cyst Frequency in Women Aged < 50 Years (Pooled Phase II/III and Long-term Studies) Estimated Exposure frequency per (women- No. of 1,000 women- Total N days) cysts years (95% CI) Tegaserod1,649203,3234 7.2 (2.1 - 18.4) Placebo 607 49,73417.3 (0 - 40.6) Estimated Exposure frequency per (women- No. of 1,000 women- Total N days) cysts years (95% CI) Tegaserod1,649203,3234 7.2 (2.1 - 18.4) Placebo 607 49,73417.3 (0 - 40.6) 11

9. OC 9 Patients With History of Ovarian Diseases or Ovarian Surgery at Baseline Patients, n (%) Phase II/IIILong-term PlaceboTegaserodTegaserod History (n = 847)(n = 1,875)(n = 611) Ovarian surgery4 (0.5)23 (1.2) 3 (0.5) Ovarian cysts41 (4.8)85 (4.5) 36 (5.9) Patients, n (%) Phase II/IIILong-term PlaceboTegaserodTegaserod History (n = 847)(n = 1,875)(n = 611) Ovarian surgery4 (0.5)23 (1.2) 3 (0.5) Ovarian cysts41 (4.8)85 (4.5) 36 (5.9)

10. OC 10 Prevalence of Simple Cysts and Polycystic Ovaries Detected by Ultrasound in Asymptomatic/healthy Populations  Postmenopausal:6.6% –23% resolved spontaneously by 2 years (Conway, 1998)  Women 25-40 years:6.6% –82% disappeared after 3 months (Borgfeldt, 1999)  Adolescent girls: 12% –65% disappeared after 3 months (Porcu, 1994)  Postmenopausal:6.6% –23% resolved spontaneously by 2 years (Conway, 1998)  Women 25-40 years:6.6% –82% disappeared after 3 months (Borgfeldt, 1999)  Adolescent girls: 12% –65% disappeared after 3 months (Porcu, 1994) 27

11. OC 11 Preclinical Studies With Tegaserod  No treatment-related ovarian cysts in –Rat toxicity studies up to 6 months –Dog toxicity studies up to 12 months –Mouse carcinogenicity study or after reevaluation in the rat carcinogenicity study  No histopathological evidence of hormonal perturbation in any studies  No treatment-related ovarian cysts in –Rat toxicity studies up to 6 months –Dog toxicity studies up to 12 months –Mouse carcinogenicity study or after reevaluation in the rat carcinogenicity study  No histopathological evidence of hormonal perturbation in any studies

12. OC 12 Summary  No evidence of a link between tegaserod and the development of ovarian pathology –Clinical studies –Preclinical/toxicology studies  No evidence of a link between tegaserod and the development of ovarian pathology –Clinical studies –Preclinical/toxicology studies

13. OC 13 Safety  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications  Ovarian cysts: human and animal data  Laparotomies in patients due to gynecological and GI indications

14. OC 14 Gynecology Surgery for “Ovarian Cysts” *Revised diagnosis: – Cystadenofibroma – Peritubal cyst – Pelvic adhesions – Ruptured ovarian cyst – Adenomyosis/OC – Appendicitis Recurring/OC – Cyst/follicle – Polycystic ovary n = 2 on tegaserod n = 1 on placebo n = 2: with history of OCs n = 3: newly occurring n = 4*: not confirmed n = 5: OC confirmed n = 9 "ovarian cysts” (n = 8 tegaserod, n = 1 placebo) n = 2 on tegaserod

15. OC 15 Patients Undergoing Laparotomy for GI Indications Dose Time Patient mg/d (days)(gender/age)Adverse eventComments PBO75301/209/13AppendicitisAppendectomy (34F) PBO207351/518/19Perforated cecumPerforated cecal ulcer 4 (27F) months after last dose. Partial cecectomy. 118251/42/7Ileus Incarcerated hernia; (42F) previous abdominal surgery 436301/112/9Benign pancreatic Exploratory laparotomy and (71F) cyst cystectomy 12183209/28/6Small bowel History of small bowel (58F)obstruction obstruction after hysterectomy. Adhesiolysis and reduction of internal hernia. Dose Time Patient mg/d (days)(gender/age)Adverse eventComments PBO75301/209/13AppendicitisAppendectomy (34F) PBO207351/518/19Perforated cecumPerforated cecal ulcer 4 (27F) months after last dose. Partial cecectomy. 118251/42/7Ileus Incarcerated hernia; (42F) previous abdominal surgery 436301/112/9Benign pancreatic Exploratory laparotomy and (71F) cyst cystectomy 12183209/28/6Small bowel History of small bowel (58F)obstruction obstruction after hysterectomy. Adhesiolysis and reduction of internal hernia.

16. OC 16 Frequency of Laparotomies by Year in NDA Database Placebo Tegaserod Frequency per Frequency per n/Npatient yearn/Npatient year Phase II/III2/9880.00914/21980.0083 Long-term--4/6750.0097 Placebo Tegaserod Frequency per Frequency per n/Npatient yearn/Npatient year Phase II/III2/9880.00914/21980.0083 Long-term--4/6750.0097

17. OC 17 Summary: Tegaserod and Laparotomies  In the study population a variety of different gynecological and GI disorders led to laparotomies  Frequency of laparotomies by exposure duration similar for tegaserod and placebo  No obvious causal relationship or signal that tegaserod affects the frequency of laparotomies