Improving Standards of Care in Irritable Bowel Syndrome

Definition of Irritable Bowel Syndrome (IBS) IBS is a chronic, episodic medical condition characterized by abdominal pain or discomfort associated with altered bowel function IBS with constipation is abdominal pain/discomfort associated with at least 2 of the 3: - < 3 bowel movements per week - Hard or lumpy stools - Straining with a bowel movement Drossman et al, Gastroenterology 1997; 112: 2120

Overall prevalence of IBS greater in females Drossman et al, Dig Dis Sci 1993; 38: 1569 Ages (years) Prevalence (%) –3435–44> Female Male

Prevalence by IBS subgroups Adapted from Talley et al, Am J Epidemiol 1995; 142: 76 Survey respondents (%) IBS- constipation IBS- diarrhea Overall Females Males 3022 residents surveyed in Minnesota 536 respondents IBS- alternating

IBS patients suffer  In a recent survey (n = 350) conducted by the International Foundation for Functional Gastrointestinal Disorders, it was found that: 42% of respondents reported having symptoms for 10 years or more 43% reported symptoms as 'severe', 40% described them as 'moderate' two-thirds of IBS sufferers describe their symptoms as extremely or very bothersome in press

IBS patients with constipation (abc-ibs) suffer from abdominal pain/discomfort, bloating, and constipation Lieberman Research Inc. 2000, GI Sufferer Study Rectal pain Sudden urges to have BM Heartburn / acid reflux Inability to have BM Bloating / distension Incomplete evacuation after BM Hard / lumpy stool Abdominal pain / discomfort Straining with BM Constipation Gas / gas pain % IBS patients that suffer once a week or more General US population IBS with constipation

Who treats IBS? Mitchell et al, Gastroenterology, 1987; 92: 1282 Drossman, Gastroenterology 1997; 112: 2120 Mitchell et al, Gastroenterology, 1987; 92: 1282 Drossman, Gastroenterology 1997; 112: 2120 Primary care Gastroenterology All other diagnoses 88% 12% IBS 28% IBS is a common diagnosis in primary care and gastroenterology practices All other diagnoses 72%

Impact of IBS on work or school Adapted from Drossman et al, Dig Dis Sci 1993; 38: 1569 Days missed from work or school in past year ***p< *** Non-IBS patients IBS patients

Mechanisms in IBS Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11:3 Enhanced perception Sympathetic Vagalnuclei 5-HT Altered motility Visceral hypersensitivity

Physiologic distribution of 5-HT Kim and Camilleri, Am J Gastroenterol 2000; 95: 2698 CNS: 5% GI tract: 95%

Summary of Hypotheses on the Pathophysiology of IBS IBS is characterized by changes in motility in response to environmental or enteric stimuli 1 Visceral hypersensitivity is well documented in IBS patients 2 Serotonin, which has both motility and sensory modulating properties, could represent a common factor linking the symptoms of IBS 3 1 AGA Patient Care Committee Gastroenterology 1997;112: Adapted from Camilleri and Choi et al., Aliment Pharmacol Ther 1997; 11: 3 3 Kim and Camilleri et al., Am J Gastroenterol 2000; 95(10): AGA Patient Care Committee Gastroenterology 1997;112: Adapted from Camilleri and Choi et al., Aliment Pharmacol Ther 1997; 11: 3 3 Kim and Camilleri et al., Am J Gastroenterol 2000; 95(10): 2698

Identify Red Flags Adapted from A technical review, Gastroenterology 1997; 112: 2120 Paterson et al., Can Med Assoc J 1999; 161: 154 Camilleri et al., Aliment Pharmacol Ther 1997; 11: 3 Adapted from A technical review, Gastroenterology 1997; 112: 2120 Paterson et al., Can Med Assoc J 1999; 161: 154 Camilleri et al., Aliment Pharmacol Ther 1997; 11: 3 l Physical - Abnormal exams - Rectal bleeding/obstruction - Positive FOBT/flex. sigmoidoscopy or colonoscopy (>50 years) l History - Unintentional Weight loss -Onset in older patient (>50 years) - Family history of cancer or IBD l Initial Labs -  HGB -  WBC -  ESR - Abnormal chemistry -  TSH Red Flags

IBS: An enduring diagnosis No change in diagnosis: 97% Most have no change in diagnosis after initial evaluation Owens et al, Ann Intern Med 1995; 122: consecutive Olmstead County residents first diagnosed with IBS during 1961–63. Median follow-up: 29 years (range 1–32 years)

Goals of Pharmacotherapy in IBS with Constipation Overall Relief (including impact on patients’ overall well-being)4 Multi-symptom relief 4  Abdominal pain  Bloating  Constipation 4 Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead,WE eds. Rome II The Functional Gastrointestinal Disorders 2nd ed. McLean, Va 2000:355,360,

Dietary advice  Patients often relate their functional symptoms to certain foods  Dietary restrictions are common, but may be inappropriate dairy products, sorbitol, caffeine, alcohol, citrus fruit, gas-forming vegetables, grains dairy products, sorbitol, caffeine, alcohol, citrus fruit, gas-forming vegetables, grains Jones et al, Gut 2000; 47(suppl. II): 1

Traditional therapies focused on individual symptoms of IBS with constipation Bloating and distention  Dietary modifications  Antispasmodics  Antiflatulants  Digestive enzymes  Antibiotics Abdominal pain / discomfort  Antispasmodics  Tricyclics  Analgesics Constipation  Fiber  Laxatives Abdominal pain / discomfort Bloating / distention Constipation  None of these medications effectively treat the multiple symptoms of IBS. May exacerbate individual symptoms e.g., fiber and bloating; antispasmodics and constipation

Tegaserod: Indication and Dosage Zelnorm (tegaserod maleate) is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation The safety and effectiveness in men have not been established Recommended dosage: tegaserod (Zelnorm) 6 mg twice daily orally before meals for 4–6 weeks For patients who respond to therapy at 4–6 weeks, an additional 4–6 weeks can be considered Efficacy of tegaserod beyond 12 weeks has not been established Novartis, data on file

Tegaserod: A New Class of Compound Tegaserod is a 5-HT 4 receptor agonist new class of compound: aminoguanidine indoles Structure similar to serotonin Camilleri, Aliment Pharmacol Ther 2001; 15: 277 Serotonin (5-HT) NH OH NH 2 Tegaserod O N NH

Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ther. 2001; 15: Tegaserod: Pharmacological Effects Stimulates 5-HT 4 receptors and improves GI function Stimulates the peristaltic reflex Alters the chloride secretion in the intestine Reduces visceral sensitivity * * animal data

Subject’s Global Assessment of relief % Responders *p<0.05 Responders are defined as at least “somewhat relieved” ITT population Weeks * * * * * * * * * * * Placebo (n = 288) Tegaserod 6 mg bid (n = 294) Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655 B301 0

Mean relief in abdominal pain / discomfort score * p<0.05 (6 mg bid vs placebo) ITT analysis. 100mm Visual Analogue Scale with 6 descriptors: none to very severe Baseline pain score: placebo = 2.77; tegaserod = 2.78 * Change from baseline (pain score) * * * * * * ** * * 0 Week Baseline Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655 B Placebo (n = 288) Tegaserod 6 mg bid (n = 294)

Change in number of bowel movements Change from baseline (number of weekly bowel movements) *p<0.05 (6 mg bid vs placebo) ITT analysis Placebo (n = 288)Tegaserod 6 mg bid (n = 294) * * * * Week * * * ** * * Baseline Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655 B301  Improvement seen on Day 1

Mean change in bloating score *p<0.05 (6 mg bid vs placebo) ITT analysis 6-point scale: 0 = none to 6 = very severe Baseline bloating score: placebo = 2.67; tegaserod = 2.72 Change from baseline (bloating score) Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655 * * * * * Week * * * * Baseline B PlaceboTegaserod 6 mg bid

Summary of Tegaserod Efficacy Significant improvement in Subject's Global Assessment of relief Relief of individual IBS symptoms: - Abdominal pain / discomfort - Bloating - Constipation Müller-Lissner et al., Aliment Pharmacol Ther 2001; 15: 1655

Zelnorm: Safety Data

Adverse events occurring >1% Novartis, data on file Musculoskeletal disorders Back pain Arthropathy 2 <1 3 1 Body as a whole – general disorders Accidental trauma Leg pain Central and peripheral nervous system Headache Dizziness Migraine Gastrointestinal system disorders Abdominal pain Diarrhea Nausea Flatulence Placebo (n = 1305) % Zelnorm 6 mg bid (n = 1327) % System / adverse experience

Overall Safety and Tolerability of Tegaserod Tegaserod was generally well tolerated. Side effects reported significantly more often with tegaserod than with placebo were headache (15% vs 12%) and diarrhea (9% vs 4%) Novartis, data on file

Overall Safety and Tolerability of Tegaserod Diarrhea: tegaserod 9% vs placebo 4% In most cases, diarrhea occurred within the first week of treatment Typically, diarrhea resolved with continued therapy Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the tegaserod-treated patients Novartis, data on file

Summary of Drug–Drug Interactions In vitro: no inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 No clinically relevant drug–drug interactions were observed in healthy volunteers with: theophylline dextromethorphan Digoxin 3 Warfarin 4 oral contraceptives 5  Dose adjustment is not required for any of the above drugs co-administered with tegaserod 1 Zhou, et al., Am J Gastroenterol 1999; 94: 2623: Kalbag, et al., Gastroenterology 2000; 118 (suppl. 2): A1179: Zhou, et al., J Pharm Sci 1999; 1: A Ledford, et al., Gastroenterology 2000; 118 (suppl. 2): A1184: Zhou, et al., Gastroenterology 2000; 118 (suppl. 2): A1207: Zhou, et al., Am J Gastroenterol 1999; 94: 2623: Kalbag, et al., Gastroenterology 2000; 118 (suppl. 2): A1179: Zhou, et al., J Pharm Sci 1999; 1: A Ledford, et al., Gastroenterology 2000; 118 (suppl. 2): A1184: Zhou, et al., Gastroenterology 2000; 118 (suppl. 2): A1207: 5539

Conclusions Tegaserod is the first treatment proven to provide multi-symptom IBS relief of: - Abdominal pain/discomfort - Bloating - Constipation Favorable tolerability demonstrated in well-controlled clinical trials with more than 2,600 IBS patients

Digestive Diseases Week Key Findings Orlando, FL May 17-22, 2003

Tegaserod Improves Gastric Emptying in Patients with Gastroparesis and Dyspeptic Symptoms Tougas G et al. Oral Presentation, DDW 2003

Objective  To evaluate whether 8 weeks of tegaserod can improve abnormally delayed gastric emptying in patients with dyspeptic symptoms and delayed gastric emptying Tougas G et al. Oral Presentation, DDW 2003

Gastric retention (%) of meal at 2 hours post meal Placebo *p=0.077 vs placebo; **p=0.003 vs placebo ** * *‘normal’ gastric retention rate at 2 hours is 40% Retention (%) at 2 hours post meal Tegaserod dose ↓ 24%↓ 35%↓ 15%↓ 6% Tougas G et al. Oral Presentation, DDW 2003

Results and Conclusions Gastric retention was reduced consistently with tegaserod, especially at 2 and 4 hours after meal Tegaserod 18mg/day and 24mg/day decreased food retention in late phase emptying by 2x over placebo 80% of patients given 18mg/day developed normal gastric emptying vs. 50% of placebo patients Tegaserod improves gastric emptying in patients with gastroparesis and dyspeptic symptoms Tougas G et al. Oral Presentation, DDW 2003

Efficacy and Safety of Tegaserod in Patients with Chronic Constipation

Conclusions  Significant improvement as compared to placebo: Number of complete, spontaneous bowel movements Time to first complete, spontaneous bowel movement Straining Distention and bloating Abdominal discomfort/pain Satisfaction with bowel habits Bothersome constipation  Additional evidence for safety Most frequent adverse effects leading to discontinuation included nausea, diarrhea, abdominal pain, headache No serious adverse events were noted with the use of tegaserod for up to 12 weeks in pts with CC. Johanson J, et al. Oral presentation. DDW 2003.

Tegaserod provides rapid, effective relief of abdominal pain/discomfort, bloating and constipation in Chinese patients with irritable bowel syndrome with constipation (IBS-C) Lin S, et al. Poster S1017.DDW 2003.

Results and Conclusions Adverse events were reported in 10% of patients on tegaserod and 6% on placebo. The most common adverse events seen in tegaserod group were diarrhea, abdominal pain and dizziness (frequency <3%). They did not result in discontinuation. Tegaserod provided rapid relief of IBS-C symptoms including abdominal pain, bloating and constipation and was well tolerated in Chinese patients with IBS-C.  Lin S, et al. Poster S1017. DDW 2003.

Tegaserod is an effective and safe therapy for irritable bowel syndrome in a Nordic population Nyhlin H, et al. Poster M1645. DDW In press, Gastroenterology.

Results and Conclusions The overall frequency of adverse events (AE) was comparable between treatments.  The most frequently reported AE was diarrhea : 9.2% tegaserod vs. 1.3% placebo.  Discontinuations due to diarrhea were 2.8% for tegaserod vs. 0% for placebo. Tegaserod 6mg bid is an effective, safe and well tolerated therapy in a Nordic population of IBS patients with non-D IBS.  Nyhlin H, et al. Poster M1645. DDW In press, Gastroenterology.

Results Tegaserod treated patients with less than 10 yrs duration of IBS symptoms had a gain in weekly therapeutic effect (range 10% to 26%) each week (p<0.05) over weeks Tegaserod significantly affected number of days with no bowel movements and days with >3 bowel movements for weeks 1-4 (p<0.0001).  Nyhlin H, et al. Poster M1645. DDW In press, Gastroenterology.

Relapse of Symptoms Following Withdrawal of Tegaserod Treatment in Irritable Bowel Syndrome with Constipation (IBS-C) Munoz V, et al, Poster T1804. DDW 2003.

Conclusions IBS-C patients respond favorably to initial treatment with tegaserod for 1 month (82%) IBS-C patients respond favorably to maintenance therapy with tegaserod for another 2 months (90%) Upon discontinuation of tegaserod, 2/3 of patients will relapse within 3 weeks 10% of maintenance treatment patients relapsed (p<0.0001) Patients who continue treatment 18x less likely to relapse Munoz V, et al, Poster T1804. DDW 2003.

Tegaserod Treatment for IBS: A Model of Indirect Costs Smith D, et al. Poster T1303. DDW 2003.

Conclusions IBS has substantial impact on worker productivity Net annual savings of $1,497 for employer per employee treated for IBS –Model can be tailored to match individual employers’ needs Treatment of IBS with tegaserod may be cost-effective in reducing indirect costs under a variety of scenarios, using a series of assumptions on wages, epidemiology, therapy, and costs –Further validation of this model is warranted  Smith D, et al. Poster T1303. DDW 2003.

Impact of IBS on Worker Productivity in an Employed U.S. Population Dean B, et al. Poster T 1302, DDW 2003.

Results and Conclusions  1,776 of 11,806 employees participated in both surveys  41% met Rome II criteria for IBS  Participants with IBS more likely to be female and Caucasian or Hispanic, otherwise similar to those without IBS Participants with IBS had work productivity losses of 19.8% due to GI symptoms compared with 5.6% among those without IBS This reduction is equivalent to working 4 days out of a 5-day work-week Reduced productivity of this magnitude may have substantial impact on employers. Dean B, et al. Poster T 1302, DDW 2003.

Conclusions  Employees with IBS  ~20% reduced work productivity due to GI Sx  ~14% reduced work productivity compared to non-IBS co-workers  Work less than 4 days out of total 5 day work week  May have substantial financial impact on employers Bonnie Dean, Daniel Aguilar, et al. Poster Presentation DDW 2003.

Tegaserod is Effective in the Retreatment of Irritable Bowel Syndrome with Constipation (IBS- C) Mueller-Lissner S., et al. Poster T1821. DDW 2003.

Conclusions High rate of recurrence of IBS symptoms was seen with discontinuation of tegaserod (84% of patients) Response rate achieved during re-treatment was similar to response rate achieved during initial treatment (85-88%) Therapy with tegaserod is highly effective and well-tolerated for initial treatment, as well as re-treatment in patients with IBS-C Mueller-Lissner S., et al. Poster T1821. DDW 2003.

Primary Efficacy Variable Johanson J, Tougas G, Chey W, et al. Oral presentation. DDW Increase ≥ 1 CSBM/Week

An Open Label Study to Determine the Efficacy and Tolerability of Tegaserod in the Treatment of Constipation Dominant Irritable Bowel Syndrome (IBS-C) Shah, S et al. Poster T1435. DDW 2003.

Conclusions Tegaserod 6mg BID is equally effective in male and females in relieving the symptoms of abdominal pain, bloating and straining at defecation. It increases the number of bowel movements per week in both sexes. This effect was more statistically more significant in males. This is the first study of tegaserod demonstrating significant efficacy in males.  Shah, S et al. Poster T1435. DDW 2003.