Irritable bowel syndrome (IBS) in its various forms, such as IBS with constipation (IBS-C) and IBS with diarrhea (IBS-D), has proved to be difficult to diagnose and treat. Up until recently the number of therapies available to the physician also has been limited. However, there are potential therapies in the pipeline that are poised to enter the marketplace on the heels of Linzess (linaclotide), Ironwood Pharmaceutical Inc.'s guanylate cyclase-C agonist approved by the FDA last year for the treatment of both irritable bowel syndrome with constipation (IBS‐C) and chronic idiopathic constipation (CIC) in adults. (See BioWorld Today, Aug 31, 2012.)

Linzess is a once-daily capsule that helps relieve the abdominal pain and constipation associated with IBS‐-C. The drug is thought to work, the company says, by binding to the GC‐C receptor locally, within the intestinal epithelium. Activation of GC‐C results in increased intestinal fluid secretion and transit and a reduction in visceral pain, which is thought to be mediated by decreased activity of pain‐sensing nerves.

Ironwood and Forest Laboratories Inc., of New York, are co‐promoting the product in the U.S.

Strong Demand

Linaclotide also was approved by the European Commission for the treatment of adults in the European Union with IBS‐C and will be marketed under the brand name Constella through a license agreement with Almirall SA. Ironwood also has partnered linaclotide with Astellas Pharma Inc. for development and commercialization in Japan and with Astrazeneca plc for development and commercialization in China.

The company has seen strong initial demand for the drug since its launch with reported second-quarter net sales of $28.8 million with more than 125,000 prescriptions filled. (See BioWorld Today, July 24, 2013.)

With about 13 million suffering from IBS-C alone in U.S., the market potential is significant.

Philip Schoenfeld, director, Training Program in GI Epidemiology at the University of Michigan School of Medicine, told BioWorld Insight that treatment of IBS is guided by the patient's predominant symptoms because "at the level of the colon there are multiple reasons why the colon may dysfunction."

There is an unmet medical need for a therapeutic that could deal with all the major symptoms such as diarrhea, constipation and pain, Schoenfeld said, but for now the options for treatment are guided by the main symptomology of IBS.

He also noted that there are large ongoing studies that could bring new treatments options to the market next year.

Product Development

Salix Pharmaceuticals Ltd., of Raleigh, N.C., for example, is in the final stages of a Phase III retreatment study for Xifaxan (rifaximin) in patients with diarrhea-predominant IBS to satisfy issues cited in a 2011 FDA complete response letter. The trial was designed to test rifaximin 550 mg three times daily for 14 days in subjects with IBS-D who respond to an initial course of rifaximin for 14 days. The primary endpoint is the proportion of subjects who responded to repeat treatment in both IBS-related abdominal pain and stool consistency during the four-week treatment-free follow-up period compared to placebo.

Data are eanticipated at the end of the year or early in 2014 and, if positive, are expected to yield an FDA decision by around the middle of 2014. (See BioWorld Today, May 23, 2013.)

Salix is already marketing Xifaxan, a non-antibiotic antibacterial drug, for traveler's diarrhea and hepatic encephalopathy (HE). Sales have been increasing, with first-quarter prescriptions for Xifaxan in HE up 26 percent year over year.

Furiex Pharmaceuticals Inc., of Morrisville, N.C., said it completed enrollment of patients in two ongoing Phase III trials of eluxadoline, a first-in-class, locally acting mu opioid receptor agonist and delta opioid receptor antagonist, for diarrhea-predominant irritable bowel syndrome. Both trials will compare 75 mg eluxadoline twice a day, 100 mg eluxadoline twice a day and placebo. One study will have a 52-week duration, and one will have a 30-week duration. Top-line results are due in the first quarter of 2014. (See BioWorld Today, July 16, 2013.)

The company said that in vivo studies indicate that the activity of eluxadoline at the two different opioid receptors controls GI function as well as decreases pain and potentially mitigates the constipating effect of unopposed mu agonism.

In mid-stage development Synergy Pharmaceuticals Inc., of New York, reported that it had reached the halfway mark for total enrollment in an ongoing Phase II trial of plecanatide in patients with irritable bowel syndrome with constipation. Plecanatide is a guanylate cyclase C receptor agonist and an analogue of uroguanylin, which regulates ion and fluid transport in the intestine. The study is being carried out at 70 sites in the U.S. and will include 350 patients. The company expects to complete enrollment in the fourth quarter of 2013, and report topline data in the first quarter of 2014. (See BioWorld Today, July 18, 2013.)

Last year Astellas Pharma Inc., of Tokyo, entered a partnership with Drais Pharmaceuticals Inc., of Bridgewater, N.J., to develop and commercialize ASP7147, a bombesin BB2 receptor antagonist, for irritable bowel syndrome with diarrhea. Under the agreement, Astellas transfered ownership of the compound to Seldar Pharma Inc., a virtual company operated by Drais executives.

A number of other companies have IBS as an indication in their product porfolios. Galapagos NV, for example, which in May raised €53.9 million (US$70.7 million) in an over-subscribed placing. The company says that it intends to use the proceeds of the new funding to keep their product development programs in house for longer and develop them further. In particular, money will go into a cystic fibrosis program, and programs in breast cancer and IBD.

With a global market for IBD predicted to grow to be worth more than $3 billion in the next five years the competition for market share for new therapies will certainly increase.