Linaclotide, Novel Therapy for the Treatment of Chronic Idiopathic Constipation

Chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are common gastrointestinal (GI) disorders. The overall prevalence of CC in the general population is approximately 20%. CC is defined by infrequent bowel movements (less than three bowel movements per week) with associated straining or the sense of incomplete emptying of the bowel. IBS-C is defined by constipation with recurrent abdominal pain that is generally relieved by defecation.

Treatments for CC in the current US market include nonprescription and prescription medications. Nonprescription medications include stool softeners, fiber supplements, osmotic and stimulant laxatives, such as polyethylene glycol and milk of magnesia and bisacodyl, respectively. Lubiprostone is the only prescription medication approved in the US for CC and IBS-C. Tegaserod was a previously approved medication for IBS-C that, although effective, was withdrawn from the US market due to reported adverse effects. Overall, these treatments have variable benefit and efficacy, and there is still great demand for more efficacious and safer treatments for these chronic conditions. Newer therapies for CC and IBS-C have been developed with novel mechanism of actions. Other agents that are either in clinical trials or approved in Europe to treat CC or IBS-C include the uroguanylin (UG) analog plecanatide; prokinetics such as prucalopride, velusetrag, and naronapride; and the ileal bile acid transporter inhibitor, elobixibat, which increases bile acid concentration in the colon leading to accelerated colonic transit.

Linaclotide is a 14-amino acid peptide with three disulfide bonds with a structure analogous to the endogenous peptides GN and UG. Linaclotide is stabilized by three intramolecular disulfide bonds, similar to the two disulfide bonds in GN and UG. However, the UG sequence has two N-terminal aspartate residues that are not in the amino acid sequence of linaclotide. Linaclotide is a guanylin (GN) and UG analog that activates the guanylate cyclase-C (GC-C) receptor. GN and UG are endogenous peptides of the GN peptide family that are produced by the enteroendocrine cells and activate the GC-C receptor, increasing intestinal fluid secretion. The GC-C receptor is expressed in enterocytes from the small intestine to the distal colon and it is the transmembrane receptor for the heat stable enterotoxin (STa) responsible for acute secretory diarrhea. Activation of the GC-C receptor on the lumen of intestinal epithelial cells stimulates the intrinsic GC-C activity that leads to increases in intracellular cyclic guanosine monophosphate (cGMP), which in turn leads to phosphorylation of a cGMP-dependent protein kinase II and phosphorylation of the cystic fibrosis transmembrane conduction regulator (CFTR). Activation of the CFTR channel results in chloride and fluid secretion into the lumen that leads to increased colonic transit.

Mechanism of Action
Linaclotide binds to the GC-C receptor and stimulates intestinal secretion by increasing the production of cGMP. Increased intracellular cGMP leads to phosphorylation of a cGMP-dependent protein kinase II and phosphorylation of the CFTR, which results in chloride anion and fluid secretion into the intestinal lumen. The GC-C receptor is the key receptor for the STa. These enterotoxins are produced by organisms, such as Escherichia coli, and activate the GC-C receptor causing an acute secretory diarrhea. The specific function of this receptor has been confirmed in GC-C null mice, which fail to elicit the STa stimulation of fluid accumulation within the intestines, evidence of the function of this receptor in intestinal fluid secretion. In vitro studies using human carcinoma T84 cells have demonstrated that the binding of linaclotide occurs in the luminal side of the intestine. The selective binding of linaclotide to the GC-C receptor was studied with a competitive radioligand-binding assay using a radiolabeled heat-stable enterotoxin [125I]-STa in GC-C wild-type and null mice. In wild-type mice, linaclotide inhibited binding of [125I]-STa in a concentration-dependent manner. However, in GC-C null mice a low level of residual binding of [125I]-STa to intestinal mucosa was demonstrated, an effect that was inhibited by linaclotide. This is evidence that linaclotide binds to the GC-C receptor and that this effect is abolished in GC-C null mice.



Maria I. Vazquez-Roque · Ernest P. Bouras. Adv Ther (2013) 30(3):203–11.