Irritable bowel syndrome (IBS) is a common disorder characterised by abdominal discomfort associated with altered bowel function. It is defined as recurrent abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least three months. The individual symptoms of IBS have limited accuracy for the purpose of establishing a diagnosis of the disorder, and it is therefore considered a symptom complex.

The aetiology of IBS is complicated and not well understood. It is generally accepted that a combination of genetic and environmental factors play a role in its development. The evidence to date suggests that while patients with a family history of IBS are more likely to develop the disorder, no specific genetic loci have been well characterised and linked with the syndrome.

Other factors that are believed to cause IBS include disturbances in gastrointestinal (GI) motility, mucosal barrier disruption, visceral hypersensitivity, food sensitivity, dysfunction of the gut-brain axis (that is, neurohormonal interactions between the central nervous system [CNS] and the gut), and a stress response involving neurotransmitters.

Mind how you go

There is an association between IBS and psychological disorders (for example, anxiety, depression, and post-traumatic stress disorder [PTSD]), with up to two thirds of IBS patients in tertiary care centres having a concurrent psychological disorder. Dysbiosis of the gut microbiota is also believed to be implicated in the pathogenesis of IBS. Reduced numbers of bifidobacteria and lactobacilli in the lumen, reduced numbers of bifidobacteria in the mucosa, and lower diversity in both the lumen and mucosa have been reported in patients with IBS compared with healthy individuals. In addition, infectious gastroenteritis has been shown to be associated with an increased risk of developing IBS.

There are no specific biomarkers for the syndrome, but an increased understanding of the aetiology and pathophysiology of the disorder has led to the identification of a wide variety of targets to treat it. Current IBS products target the ClC-2 chloride channel (Sucampo/Takeda/Abbott's Amitiza [lubiprostone]), guanylate cyclase-C (GC-C) (Ironwood/Actavis/Almirall/Astellas' Linzess [linaclotide]), and the 5-HT3 receptor (Prometheus's Lotronex and Astellas' Irribow [ramosetron hydrochloride]). The late-stage pipeline candidates that are included in the analysis target the opioid receptors, the tachykinin NK2 receptor, bacterial overgrowth, GC-C and the sodium transporter, NHE3.

As of October 2014, the early-stage pipeline candidates target the bombesin BB2 receptor, the 5-HT4 receptor, the intestinal bile acid transporter (IBAT), the translocator protein (TSPO), the adrenergic beta-3 receptor and the zonulin receptor.

IBS is classified into three main subtypes, according to the predominant bowel habit: constipation-predominant IBS (IBS-C), diarrhoea-predominant IBS (IBS-D), and mixed-presentation IBS (IBS-M). IBS-M patients present with a mixed pattern of bowel habits, with alternating symptoms of constipation and diarrhoea over time. In some studies, IBS patients who do not fall into one of these three subtypes are classified as having unsubtyped IBS (IBS-U). However, the literature is inconsistent with regard to the existence of the IBS-U subtype, and it is therefore not included in this report.

Seven up

GlobalData estimates that the drug sales for IBS in 2013 were approximately $589.6 million across the seven major markets (7MM) covered in its report. By the end of the forecast period in 2023, IBS sales will increase to approximately $1.5 billion, at a compound annual growth rate (CAGR) of 9.89%.

GlobalData forecasts that IBS-related sales will follow a growing trend until 2023. The steady and continuous growth in this market will be driven by:

  • the increasing uptake of Ironwood/Actavis/Almirall/Astellas' Linzess, and its anticipated launch in Japan in 2017
  • the anticipated label expansion of Salix/Alfa Wassermann/Norgine/Bama-Geve's Xifaxan for diarrhoea-predominant IBS (IBS-D)
  • the potential introduction of four late-stage pipeline products into the IBS market
  • the increasing number of prevalent cases of IBS.

The main corporate strategy trend in the IBS market is for companies to enter into partnerships to develop and market products in different markets. Examples include the partnerships of Sucombo, Takeda and Abbot Japan for Amitiza (lubiprostone); of Ironwood, Actavis, Almirall and Astellas for Linzess; of Salix and Alfa Wassermann for Xifaxan; and of AstraZeneca and Ardelyx for tenapanor. With only a small number of products indicated for IBS that were initially developed by small pharmaceutical companies, GlobalData expects these alliances and partnerships to continue as medium or large pharmaceutical companies attempt to bring new products into the IBS market.

Other key strategies that the players in the IBS market are pursuing include the development of a complementary portfolio of products for the treatment of different IBS subtypes, and the development of products with novel mechanisms of action.

GlobalData anticipates that five new products have the potential to enter the IBS market during the 2013-2023 forecast period. This includes the anticipated label expansion of the antibiotic, Xifaxan, for IBS-D, the introduction of two additional products for IBS-D (Furiex's [Actavis] eluxadoline and Menarini's ibodutant), and two products for IBS-C (Synergy's plecanatide and AstraZeneca/Ardelyx's tenapanor).

Most importantly, these therapies will increase the available treatment options for patients with IBS-D, and they will also, in part, address some of the significant unmet needs in this market. Furiex's (Actavis) eluxadoline has the potential to become the first IBS-D drug without prescription restrictions in the US, and GlobalData foresees that it could generate the highest sales among the current pipeline products by 2023 in the 7MM, reaching sales of approximately $236.9 million. In addition, GlobalData estimates that the sales of products that are currently in late-stage development could reach approximately $993.8 million by 2023.

What do physicians think?

The majority of doctors interviewed for this piece had a positive perception of Ironwood/Actavis/Almirall/Astellas' Linzess, which they considered the best single product for treating IBS-C.

"I think Linzess is a little bit better than Amitiza in terms of improving constipation and pain symptoms, but that is, at least, my clinical impression from treating patients over the last year and a half with this medication," said a US-based physician. "I seem to think that I have more patients who get some exuberant diarrhoea on it, which is not a side effect, but is a known [problem related to its] mechanism of action. I often have to titrate down a little bit more than I do with Amitiza. I think if I had to choose one or the other, I would choose Linzess," Others agreed that Linzess was probably the best single agent out currently available for IBS-C.

The label expansion of the currently used off-label therapy, Salix/Alfa Wassermann/Norgine/Bama-Geve's Xifaxan, for IBS will increase its uptake, mainly due to increased use by primary care physicians (PCPs). However, Xifaxan is not expected to significantly change the treatment paradigm for IBS.

"I think Xifaxan would definitely be picked up more by local GI [gastrointestinal] doctors and by community providers, because they do not only use it for IBS, and if it is FDA-approved, they would be much more likely to use it. I think use of Xifaxan will definitely go up," expressed another interviewee.

However, a European doctor opined that Xifaxan was not a suitable treatment for IBS sufferers: "First, there is the issue with the drug's efficacy, as it has only been demonstrated in patients with IBS-D, and I am not sure that any IBS-D patient is a candidate for the drug. Patients with small intestinal bacterial growth or abnormal microbiota would probably be good candidates for this drug. I believe that is a new and interesting option."

As noted earlier, the IBS market is characterised by a number of significant unmet needs. The most significant include the need for treatments with improved efficacy to control the majority of symptoms, treatments for IBS-D and IBS-M patients, and an improved diagnosis rate.

"There is no one, outstanding drug. Different ones work a little bit, but nothing is really fantastic," said the European contributor.

"I think none of the drugs so far are satisfactory in controlling IBS symptoms. There is a need for drugs, not only to control the bowel movement[s], but to also control the symptoms of pain and bloating," said a KOL from Japan.

Most interviewees expressed a need for better criteria and biomarkers for the diagnosis of the conditions. In view of the significant unmet needs in the IBS market, physicians are anticipating new products to become available for treating
patients with IBS.