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Title: Zelnorm (Tegaserod) Appears Effective in Repeated Treatment of Irritable Bowel Syndrome With Constipation: Presented at UEGW

"Zelnorm (Tegaserod) Appears Effective in Repeated Treatment of Irritable Bowel Syndrome With Constipation: Presented at UEGW"

BASEL, SWITZERLAND -- September 27, 2004 -- Data presented at the 2004 United European Gastroenterology Week (UEGW) congress show Zelnorm® (tegaserod) (a) is both effective and well-tolerated in the treatment of Irritable Bowel Syndrome with Constipation (IBS-C). [2] Novartis markets Zelnorm ® (tegaserod maleate) in the US, Canada, Philippines and South Africa; and under the trademark Zelmac (r) (tegaserod) in Switzerland, Latin America and Asia-Pacific regions. Zelnorm 6 mg, twice daily, provided patients with statistically significant improvement of their overall IBS symptoms as well as for the specific endpoint of improvement in abdominal discomfort or pain relief. [2] ZENSAA (Zelnorm in Europe, North and South America and Africa) is the largest trial of a dysmotility disorder like IBS-C ever conducted, having included more than 2,600 patients.[1,2] Highlights of ZENSAA include [2]: - Significant improvement with initial and repeated Zelnorm treatment for overall IBS and individual symptoms - Zelnorm significantly decreased abdominal discomfort or pain during both the initial treatment and re-treatment periods ( 9.1% (p<0.00001) and 15.9% (p<0.0001), respectively) - During the initial treatment period 33.7% of Zelnorm-treated patients experienced significant relief of overall IBS symptom relief during at least three weeks of the four-week treatment period compared with 24.2% of placebo-treated patients (p<0.0001) - In the second four-week treatment period, with repeated treatment two out of three (60.5%) patients taking Zelnorm experienced significantly improved relief of their overall IBS symptoms for at least two weeks compared with 42.8% of patients taking placebo (p< 0.0001) - Notable improvements in productivity and health outcome measures with Zelnorm treatment - More than three out of four Zelnorm-treated patients showed improvement in self-reported well-being (76.6% for Zelnorm-treated patients (p=0.013)) - Significant improvement in work productivity (reduced overall work impairment by 6.3% (p=0.0001)), including fewer sick days and a decrease in presenteeism was associated with Zelnorm treatment versus placebo "These positive results illustrate what we've known about Zelnorm all along; it has the distinction of treating the multiple dysmotility symptoms associated with IBS to the satisfaction of both physicians and patients," said Joerg Reinhardt, Head of Development, Novartis Pharma AG. "Because Zelnorm holds the promise of treating the tens of thousands of underserved people who now suffer from IBS-C, we remain committed to bringing Zelnorm to market in the European Union." Designed in line with the recommendations of the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Evaluation Agency (EMEA), ZENSAA was set up to assess initial and repeated Zelnorm treatment, as well as the effect on quality of life measures for women suffering from the multiple dysmotility symptoms of IBS-C. "The debilitating effects of IBS-C impact all aspects of a patient's quality of life - physical, social, emotional and ability to work," said lead investigator Professor Jan Tack, Associate Professor and Associate Head of Clinic, Department of Gastroenterology, University of Leuven, Belgium. "The exact trial design of ZENSAA, its broad scope and the volume of patients leave no doubt about the effectiveness of tegaserod in treating IBS with Constipation." The trial was also designed to mirror clinical practice as closely as possible within the clinical trial setting. The positive results from the ZENSAA trial will be used to support the upcoming EMEA filing of Zelnorm for the treatment of IBS-C in the European Union. More About ZENSAA [1] In this study, the adverse events profile of Zelnorm was similar to placebo, with the exception of diarrhoea. Diarrhoea was more frequent in patients taking Zelnorm (3.8%) vs placebo (0.6%) in treatment period 1. For tegaserod treated patients, diarrhoea rarely led to discontinuation (0.9%). There was a low incidence of serious adverse events in both treatment periods (0.1% in Period 1 and 0.6% in Period 2) for Zelnorm-treated patients. ZENSAA was a randomised, double-blind, placebo-controlled, multi-centre trial of 2,660 women with IBS-C. The trial was conducted in 262 centres in 24 countries including the UK, Germany, France, Italy, Spain, the US, New Zealand, Canada, Mexico and South Africa. The first treatment period comprised 2,135 patients taking 6 mg of Zelnorm twice daily and 525 patients taking placebo (4:1 ratio). Treatment was discontinued in all patients after a four-week period, followed by two to 12 weeks without treatment. Patients were then re-randomised after their symptoms recurred. In the second treatment period, 488 patients were given Zelnorm and 495 given placebo (1:1 ratio). The data were evaluated at the end of the trial. The primary efficacy endpoints were satisfactory relief of abdominal discomfort/pain and overall IBS relief for three of the four weeks of treatment, also referred to as the 75% rule. [3] The study data were also assessed using the 50% rule, satisfactory relief for two of the four weeks of treatment, for abdominal discomfort/pain and overall IBS relief. [2] ZENSAA was designed to assess the efficacy, safety and tolerability of Zelnorm during both short-term (4 week) treatment and re-treatment at recurrence of symptoms; daily and weekly symptom evaluation; quality of life including work productivity; and overall patient-reported satisfaction with treatment. For the work productivity measures, at the end of the trial, treatment with Zelnorm reduced absenteeism (work missed due to symptoms) by 2.6% vs. placebo (p= 0.0042) and reduced "presenteeism" (loss productivity while at work) by 5.4% (p=0.0001). About Irritable Bowel Syndrome with Constipation (IBS-C) Irritable Bowel Syndrome with constipation (IBS-C) is a chronic, recurrent dysmotility disorder characterised by the multiple symptoms of abdominal pain and discomfort, bloating, and constipation [4],[5],[6]. Serotonin (5HT), a naturally occurring chemical in the body that regulates motility and pain perception in the intestinal system, is thought to play an important role in the normal activities of the GI tract. Serotonin is believed to influence the movement of food and waste through the body [7],[8],[9]. There is currently no effective treatment available in Europe for the multiple dysmotility symptoms of IBS. Traditional treatment for the condition has included a constellation of symptom-specific approaches, which may worsen concurrent symptoms. About Zelnorm Zelnorm (tegaserod), a pro-motility agent, is the first in a newer class of medications known as serotonin-4 receptor agonists (5HT4 agonists) specifically developed to treat the multiple symptoms associated with dysmotility disorders like IBS-C. By activating 5HT4 receptors in the gastrointestinal tract, Zelnorm normalises delayed motility and reduces sensitivity of the intestinal tract [10],[11],[12],[13]. In clinical studies, significantly more patients experienced a general relief of symptoms when treated with Zelnorm, such as a decrease in abdominal pain, bloating and constipation [14],[15],[16],[17],[18]. In most patients, the onset of relief occurred within just one week 16. The medicine has been shown to be well tolerated and shows a profile of side effects similar to that of placebo with the exception of diarrhoea. The majority of patients reporting diarrhoea had a single episode and in most cases, diarrhoea occurred in the first week of treatment. Typically, diarrhoea resolved with continued therapy [1],[13],[14],[15],[16]. Zelnorm, discovered and developed by Novartis, is approved for the treatment of IBS in more than 50 countries including Australia, Switzerland, Canada, the United States, Mexico, China and Brazil. Zelnorm is also approved for the treatment of Chronic Constipation in more than 10 countries including the United States and Mexico. Zelnorm is being studied as a potential treatment for other important gastrointestinal disorders, such as gastroesophageal reflux disease (GERD) and dyspepsia (heartburn). For more information about IBS please visit http://www.IBSMediacentre.com. References: [1] Novartis Pharma AG. Press Release: Novartis initiates largest global clinical trial of Zelmac(R) in IBS. 2Dec2002. [2] Tack, Mueller-Lissner, Bytzer, Corinaldesi, Emmons, Pecher, Rueegg. Tegaserod provides rapid and sustained relief of abdominal discomfort/pain and overall symptoms when used as repeated treatment in women with IBS-C. Abstract UEGW 2004 [3] Committee for Proprietary Medicinal Products (CPMP). Points to consider on the evaluation of medicinal products for the treatment of irritable bowel syndrome. 2003 [4] Hungin AP, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40 000 subjects. Aliment Pharmacol Ther 2003;17(5):643-650 [5] Camilleri M, Choi MG. Review article: irritable bowel syndrome. Aliment Pharmacol Ther 1997;11(1):3-15 [6] Schuster MM. Defining and diagnosing irritable bowel syndrome. Am J Manag Care 2001;7(8 Suppl):S246-51. [7] Crowell MD. The role of serotonin in the pathophysiology of irritable bowel syndrome. Am J Manag Care 2001;7(8 Suppl):S252-260 [8] Hunt RH, Tougas G. Evolving concepts in functional gastrointestinal disorders: promising directions for novel pharmaceutical treatments. Best Pract Res Clin Gastroenterol 2002;16(6):869-883 [9] Jin JG, Foxx-Orenstein AE, Grider JR. Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 1999;288(1):93-97 [10] Novartis Data on File [11] Chey WD. Tegaserod and other serotonergic agents: what is the evidence" Rev Gastroenterol Disord 2003;3Suppl2:S35-40 [12] Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and CI secretion via afferent neurons and 5-HT4 receptors. Am J Physiol. 1999;277(3Pt1):G515-520 [13] Camilleri M. Serotonergic modulation of visceral sensation: lower gut. Gut 2002;51(Suppl)1:i81-86 [14] Novick J, Miner P, Krause R, Glebas K, Bliesath H, Ligozio G, et al. A randomised, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2002;16(11):1877-1888 [15] Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E, Nault B, et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms of irritable bowel syndrome in patients with abdominal pain, bloating and constipation. Aliment Pharacol Ther 2001;15:1655-1666 [16] Lefkowitz M, Shi Y, Schmitt C, Krumholz S, Tanghe J. The 5-HT4 partial agonist, tegaserod, improves abdominal discomfort/pain and normalises altered bowel function in irritable bowel syndrome (IBS) Am J Gastroenterol 1999;94(9):266 [17] Kellow J, Lee OY, Chang FY, Thongsawat S, Mazlam MZ, Yuen H, Gwee KA, Bak YT, Jones J, Wagner A. An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003;52(5):671-676 [18] Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther. 2001;15(3):277-289 SOURCE: Novartis International AG

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