Irritable bowel syndrome (IBS) involves daytime abdominal pain, bloating and discomfort and altered bowel habits (that is, either constipation (IBS-c), diarrhoea (IBS-d) or both (alternating IBS)) without progressive deterioration or detectable structural, mechanical, biochemical or overt inflammatory abnormalities. It afflicts 
12% of adults in the US, and has an incidence among women twice as high as men, and onset after the age of 50 is unusual1. Although not life threatening, IBS can seriously impair overall quality of life, and as a result it is one of the most common reasons for visits to primary care physicians and gastroenterologists in the US. Its pathogenesis remains unclear, although much progress has been made in recent years on this issue.
IBS has received considerable attention recently for both its costs in terms of societal expenditures and for the realization that an effective therapy is possible. The economic consequences of IBS are substantial not only because of direct medical care costs, but also as a result of time and productivity lost at work. The annual direct and indirect medical costs of IBS management in the US have been reported to be as high as US$8 billion and $25 billion respectively2. These costs place IBS among the 10 most expensive gastrointestinal (GI) diseases in the US3. Yet only 6% of the direct costs are attributed to medication (compare this to gastroesophageal reflux disease (GERD), for which drug costs are estimated at 63% of total direct costs)3, making IBS a relatively under-penetrated market (Fig. 1). Given its 12% prevalence and assuming 50% penetration, 7 (30-day) prescriptions per year and pricing in line with Novartis' tegaserod, IBS could represent a market on par with the current GERD ($15 billion) and depression ($14 billion) markets4.
Current treatment options
First-line therapy for all forms of IBS includes education, reassurance, exercise, trigger avoidance and dietary modifications. Failing that, fibre supplements and osmotic laxatives are prescribed for IBS-c and antidiarrhoeal agents such as loperamide for IBS-d. The pain associated with IBS can be addressed with antispasmodics such as dicyclomine and hyoscyamine. In addition, low-dose tricyclic antidepressants such as amitriptyline and desipramine have also found utility in treating a variety of IBS-related symptoms. However, these treatments do not provide satisfactory overall relief and are often associated with adverse effects, some of which mimic IBS symptoms.
Newer therapies that provide global relief for IBS are on the rise. The 5-HT3 antagonist alosetron (Lotronex; GlaxoSmithKline) is effective in relieving pain, normalizing bowel frequency and reducing urgency in patients with IBS-d, and was approved by the US FDA in February 2000. It quickly became the treatment of choice with sales of $56 million (in a period of 9 months). However, soon after its introduction, 70 cases of adverse reactions to the drug were seen in which the main concern was the potential for damage to the intestine from either ischaemic colitis or severe constipation. Following this, GlaxoSmithKline voluntarily withdrew alosetron from the US market in November 2000. However, as a result of intense lobbying efforts by patient advocacy groups to have the drug placed back on the market, the FDA approved a supplemental New Drug Application (sNDA) for alosetron on 7 June 2002 that allowed restricted marketing only to women with severe IBS-d who are unresponsive to other therapies. For IBS-c, the FDA approved tegaserod (Zelnorm (US)/Zelmac (Europe); Novartis) in July 2002. This drug relieves constipation, bloating and pain in patients with IBS-c by activating the 5-HT4 receptors in the GI tract. As with alosetron, tegaserod is indicated in IBS for women only. Its side effects are generally mild, with diarrhoea being the most prominent, and the drug is being monitored closely for any cases of ischaemic colitis. Worldwide sales of tegaserod through September of 2005 were $295 million and are expected to reach $640 million for IBS by 20094.
Possible future therapies
As the pathophysiology of IBS becomes better understood, newer compounds with novel mechanisms of action are increasingly being seen in clinical development (Table 1). For example, renzapride (Alizyme) and E-3620 (Eisai), compounds with combined 5-HT4 agonist and 5-HT3 antagonist mechanisms of action, are in late-stage clinical trails for IBS-c. Ramosetron (Astellas Pharma), a 5-HT3 receptor antagonist, is currently in trials for IBS-d in Japan and Europe. Pivotal trials in the US for ramosetron are planned with an anticipated NDA filing date in the first half of 2008. DDP733 (pumosetrag; Dynogen), a minimally absorbed, locally acting 5-HT3 partial agonist, and DDP225 (Dynogen), a single small molecule with combined noradrenaline-reuptake inhibition and 5-HT3 antagonist properties, are currently in Phase IIa trials for IBS-c and IBS-d, respectively. Other potential treatment options in clinical development currently include opioid modulators, CCK-A antagonists, chloride channel modulators and neurokinin antagonists.
Conclusions
The IBS market is large and under-penetrated and is therefore attractive for novel, safe and efficacious therapies. Furthermore, the response of patient advocacy groups to the withdrawal of alosetron in 2000 and the subsequent reinstatement of this drug underscores the level of unmet medical need in this area. In the near future, we will likely see second-generation agents in these classes and several other compounds and classes of compounds for IBS.
Market indicators
IBS is an attractive market because it is large and under-penetrated (Fig. 1). Approximately 80% of the most severe cases involve women (Fig. 2a) and approximately one-third of IBS sufferers experience diarrhoea as their primary bowel syndrome, one-third experience constipation (IBS-c) and the remaining third alternate between these two extremes (Fig. 2b). The attractiveness of the IBS market, coupled with increasing understanding of its pathophysiology, gives it the potential to grow and evolve in a manner similar to how the antihypertensive and GERD markets matured over the past several decades (Fig. 3).
Figure 2 | Irritable bowel syndrome epidemiology.
a | Percentage of men and women with severe IBS. Source: Ref. 1. b | Percentage of patients within each IBS subtype. Source: Ref. 2.
Figure 3 | The growth potential of the irritable bowel syndrome market.
As recently as the 1960s, the only treatment options available for patients with hypertension were diuretics, such as trichlormethiazide and the anti-adrenergic reserpine. Since then several new drug classes for this disease have been introduced and also several agents within each of these classes. Similarly, the only treatment available for gastroesophageal reflux disease (GERD) until recently were oral antacids, which have been used since the time of ancient Greece. However, today four drug classes are marketed for GERD and also several drugs within each of these classes. Despite the apparent maturity of these markets, novel approaches continue to be pursued.
