CA-1 Preclinical Studies Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation Philip Bentley, PhD Vice President Toxicology/Pathology Novartis Pharmaceuticals Corporation

CA-2 Tegaserod Carcinogenicity Studies Rat study: No tumor increase Mouse study: One tumor type increased Rat study: No tumor increase Mouse study: One tumor type increased

CA-3 Increased Incidence of Intestinal Tumors in Tegaserod Mouse Carcinogenicity Study Dose, mg/kg SexMFMFMFMF No. of intestines examined AdenocarcinomaSmall intestine Mucosal hyperplasiaSmall intestine Dose, mg/kg SexMFMFMFMF No. of intestines examined AdenocarcinomaSmall intestine Mucosal hyperplasiaSmall intestine mg/kg = 34 times human exposure (AUC); 80 fold human dose (BSA) 600 mg/kg = 70 times human exposure (AUC); 240 fold human dose (BSA)

CA-4 Mouse Small Intestinal Tumors  Increased incidence at high dose only, which caused severe inhibition of body weight gain and exceeded the Maximal Tolerated Dose (MTD)  Associated with sustained hyperplasia of small intestinal mucosa  Increased incidence at high dose only, which caused severe inhibition of body weight gain and exceeded the Maximal Tolerated Dose (MTD)  Associated with sustained hyperplasia of small intestinal mucosa

CA-5 Body Weight Curves in the Tegaserod Mouse Carcinogenicity Study

CA-6 Tegaserod Has No Mutagenic Potential  In vitro assays –Ames test, Salmonella typhimurium –Chromosomal aberration, V-79 cells –HGPRT gene mutation, V-79 cells –DNA repair (UDS), rat hepatocytes  In vivo assay –Bone marrow micronucleus, CD-1 mouse  In vitro assays –Ames test, Salmonella typhimurium –Chromosomal aberration, V-79 cells –HGPRT gene mutation, V-79 cells –DNA repair (UDS), rat hepatocytes  In vivo assay –Bone marrow micronucleus, CD-1 mouse

CA-7 Tegaserod Induces Reversible Hyperplasia in Mouse Intestinal Mucosa Incidence of Study week Dose, mg/kgBrdU LIhyperplasia After 13-week /10 treatment *2/ *6/10 After 4-week026.90/10 recovery / /10 Incidence of Study week Dose, mg/kgBrdU LIhyperplasia After 13-week /10 treatment *2/ *6/10 After 4-week026.90/10 recovery / /10

CA-8 Tumors Result From Epigenetic Effects  Short-term treatment of mice resulted in reversible hyperplasia of small intestinal mucosa  Long-term treatment at very high doses resulted in sustained mucosal hyperplasia as observed in the mouse carcinogenicity study  Short-term treatment of mice resulted in reversible hyperplasia of small intestinal mucosa  Long-term treatment at very high doses resulted in sustained mucosal hyperplasia as observed in the mouse carcinogenicity study

CA-9 Threshold Sustained Hyperplasia Is Required for Tumor Formation Hyperplasia Tumor 200 mg/kg 600 mg/kg

CA-10 The Tumor Incidence Was Only Increased at a Very High Tegaserod Dose  The dose of 600 mg/kg was above the MTD: –1,800-fold human dose (240 fold BSA) –70-fold expected human exposure (AUC) –570-fold estimated local intestinal concentration  The no-effect level of 200 mg/kg was at the MTD: –600-fold human dose (80 fold BSA) –34-fold expected human exposure (AUC) –190-fold estimated local intestinal concentration  The dose of 600 mg/kg was above the MTD: –1,800-fold human dose (240 fold BSA) –70-fold expected human exposure (AUC) –570-fold estimated local intestinal concentration  The no-effect level of 200 mg/kg was at the MTD: –600-fold human dose (80 fold BSA) –34-fold expected human exposure (AUC) –190-fold estimated local intestinal concentration BSA = Body surface area

CA-11 Tegaserod Therapy Poses No Carcinogenic Risk  Tegaserod is not mutagenic  Tumor incidences only increased at single site  No intestinal mucosal hyperplasia in dogs or rats  Initial hyperplasia in mice reversible  No carcinogenic effects in rats  Tumors only at the high dose in the mouse –Very high safety margin  Tegaserod is not mutagenic  Tumor incidences only increased at single site  No intestinal mucosal hyperplasia in dogs or rats  Initial hyperplasia in mice reversible  No carcinogenic effects in rats  Tumors only at the high dose in the mouse –Very high safety margin