New Therapies in Irritable Bowel Syndrome: What Works and When

Orla Craig

Disclosures

Curr Opin Gastroenterol. 2018;34(1):50-56. 

In This Article

Irritable Bowel Syndrome With Constipation

For those meeting criteria for IBS-C in whom laxatives have failed there are a number of new therapeutic options. The pro-secretory agents are a class of drug, which bind to receptors on enterocytes causing chloride and bicarbonate secretion, this leads to an increase in intestinal fluid secretion and accelerates transit.[46] We now have several years of clinical experience with Linaclotide and Lubiprotostone with Plecanatide the most recent addition to this class recently come to the market.

Linaclotide is a minimally absorbed agonist of guanylate cyclase C. Activation of this receptor results in an increase in cyclic guanosine monophosphate, which in turn activates the cystic fibrosis transmembrane regulator. Activation of this ion channel results in the secretion of chloride and bicarbonate causing increased intestinal fluid secretion and accelerated transit. It also appears to have a pain-modulating effect by desensitizing afferent pain fibres.[47] In two large phase-3 trials, Linaclotide 290 μg was found to be more effective than placebo at improving abdominal pain and bowel pattern in IBS-C patients at both 12 and 26 weeks.[48,49] Linaclotide is licenced in both Europe and the United States for the treatment of IBS-C.

Lubiprostone activates ClC-2 channels located on the apical side of intestinal epithelial cells inducing fluid secretion. There is also some evidence to suggest that it enhances intestinal barrier function.[50] Like Linaclotide, it has low systemic availability. In two large, placebo-controlled, randomized studies, Lubiprostone 8 μg twice daily resulted in significantly higher overall symptom response compared with placebo during 12 weeks of treatment.[51] It is FDA-approved for the treatment of IBS-C at this dose but its European licence extends only to use in chronic idiopathic constipation at a dose of 24 μg twice daily. Nausea is a common side effect of Lubiprostone. This occurs more frequently in those taking the 24 μg dose[52] and may be reduced somewhat by taking it with food.

Serotonin plays an important role in gut motility, reduced 5-HT reuptake has been demonstrated in IBS-D and impaired release associated with IBS-C.[53] Therefore, the serotonin receptor is an attractive target for drug development in IBS. Nonselective 5-HT4 receptor agonists, such as Cisapride and Tegaserod, although effective for the treatment of constipation,[54,55] were associated with adverse cardiovascular events largely through their affinity for the hERG-encoding potassium channel.[56] This ultimately led to their withdrawal from the market.

Highly selective 5-HT4 agonists Prucalopride, Velusetrag and Naronapride do not exhibit affinity for the hERG channel and are not known to be associated with cardiovascular side effects.[57] An integrated analysis of six randomized, controlled trials involving almost 2500 patients demonstrated that Prucalopride is well tolerated and efficacious in the treatment of chronic idiopathic constipation.[58] It is licenced for the treatment of chronic constipation but could be considered in IBS-C wherever pro-secretory agents have failed. The recommended dose is 2 mg, reduced to 1 mg is those over 65 years of age.

A recent meta-analysis of newer pharmacological treatments in IBS including Linaclotide, Lubiprostone and Prucalopride has identified that although these agents are superior to placebo in treating constipation, a majority of patients on active treatment remained constipated,[59] therefore, there remains an unmet need for new drug therapies for patients with IBS-C.

Plecanatide is a peptide analogue of uroguanylin. Like Linaclotide, it activates intestinal guanylate cyclase receptors but it is thought to act in a pH-sensitive manner, targeting GC-C receptors primarily in the small intestine coinciding with areas of fluid secretion. This in theory would lessen the likelihood of diarrhoea as a limiting side effect.[60,61] It has recently been licenced by the FDA for the treatment of chronic idiopathic constipation. A large phase three trial published earlier this year demonstrated that Plecanatide 3 mg and 6 mg significantly improved constipation and its related symptoms with a low rate of adverse events. (21% of those on 3 mg, 19.5% of those on 6 mg achieved the primary outcome compared with 10% of controls)[62] Trials in IBS-C are ongoing.

Tenapanor is a small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3 with minimal systemic absorption. It reduces the absorption of sodium and phosphate and enhances intestinal fluid volume and transit.[63] Results of a recent phase II trial have shown that Tenapanor 50 mg b.i.d. improved constipation and associated symptoms including bloating and pain compared with placebo in patients with IBS-C.[64*] There was no significant change in serum sodium or phosphate levels. Phase III trials are ongoing.

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