Background

Irritable Bowel Syndrome (IBS), not to be confused with Inflammatory Bowel Disease (IBD), represents a group of symptoms characterized by abdominal pain and discomfort and changes in bowel movement patterns. There are two key types of IBS, depending on the predominant changes in stool consistency, i.e., IBS with constipation, or IBS-C; and IBS with diarrhea, or IBS-D. In addition, there are two other types of IBS, i.e., mixed IBS, or IBS-M; and unsubtyped IBS, or IBS-U.

IBS is a functional gastrointestinal disorder, without any evidence of underlying large intestinal damage, including no radiologic or endoscopic abnormalities. The cause(s) and pathogenesis of IBS have not been established, although clearly there is an interplay between various facors and abnormal GI motility. Recent meta-analyses have reported an average prevalence of about 11% worldwide, with some differences by regions. It can occur both in women and men, but is reported more frequently in women.

Drug Approvals

Since 2000, there have been a total of 6 drug approvals for IBS — 3 for IBS-C predominant and 3 for IBS-D predominant. Refer to the accompanying chart below (click here for a larger graph).

The new drug approvals are listed below separately for IBS-D predominant and IBS-C predominant, based on the most recent product labels as listed on Drugs@FDA:

Approvals for IBS-D predominant:

• Serotonin 5-HT3 Receptor Antagonist: Lotronex (alosetron, 2000), for IBS-D predominant, indicated for women only.
• mu-Opioid Receptor Antagonist: Viberzi (eluxadoline, 2015), indicated for both women and men.
• Rifamycin Antibacterial: Xifaxan (rifaximin, 2015), indicated for both women and men. Also approved for traveler’s diarrhea and hepatic encephalopathy.

Approvals for IBS-C predominant:

• Serotonin 5-HT4 Receptor Agonist: Zelnorm (tegaserod, 2002), for IBS-C predominant, was indicated for women only. Was also approved for chronic idiopathic constipation. Zelnorm was withdrawn from the market in 2007 due to increased risk of heart attacks and strokes.
• Prostaglandin E-1 Metabolite Analog: Amitiza (lubiprostone), indicated for women only. Also approved for chronic idiopathic constipation and opiod-induced constipation.
• Guanylate Cyclase-C Receptor Agonist: Linzess (linaclotide, 2012), indicated for both women and men. Also approved for chronic idiopathic constipation.

Comments

A few general comments are in order:

1. The approved treatments for IBS todate are symptomatic, aimed at relieving the abdominal pain and discomfort and the abnormal patterns of bowel movement.
2. Treatments approved between 2000 and 2010 were based on single-item patient-reported rating of overall change in condition as the primary efficacy endpoint, involving questions regarding adequate or satisfactory relief and subject global assessment of relief (Table 1, in reference 1).
3. A recently issued Guidance for Industry (1), in recognition of the limitations of single-item patient-reported rating of overall change, outlines the development of a multi-item patient-reported outcome (PRO) measures as primary endpoints for IBS clinical trials. It is emphasized that the recommendations contained therein, regarding primary endpoints, trial design, patient entry criteria and responder definitions, are provisional, considering the time-consuming task of developing the most appropriate PRO instruments and the need for continued efforts to develop more effective therapies for IBS.
4. The current lack of an understanding of the cause(s) and pathogenesis of IBS is clearly hampering the development of new and more effective drugs for IBS. It is noted that the average patient responder rates for the more recently approved IBS drugs is generally approximately within the second quartile of responder rates (25% to 50%, but with a few endpoints lower and higher), with significant placebo response (2). There is therefore a significant need for more fundamental research on the cause(s) of IBS to guide new drug discovery and development efforts.
5. To this date, no reliable biomarker for IBS has been identified. Thus, this is another area of needed fundamental research to facilitate future drug development for IBS.

References

1. Guidance for Industry. Irritable Bowel Syndrome – Clinical Evaluation of Drugs for Treatment. FDA, May 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf
2. Most recent product labels, as listed for the individual drugs on Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, accessed in August 31, 2016.

Refer to page 16 of Progression of Modern Therapeutics (2015 Report) available under Reports on this website; this report also includes the methodology used.