There are few currently available therapies for chronic constipation that have been shown to be effective and safe in well-controlled, long-term trials, and many persons affected by this problem are not completely satisfied with their current treatment options.

Linaclotide is a 14-amino-acid synthetic peptide that is structurally related to the endogenous guanylin peptide family. It binds to and activates the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium, which sets off a chain of reactions resulting in secretion of chloride and bicarbonate into the intestinal lumen, increasing luminal fluid secretion and accelerating intestinal transit. In animal models, linaclotide has been shown to increase gastrointestinal transit and to reduce visceral pain.

Two phase III placebo controlled trials (Trial 303 and Trial 01) have assessed the efficacy and safety of once-daily administration of 145-μg and 290-μg doses of linaclotide for 12 weeks to 1276 patients with chronic constipation. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored.

• For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (p < 0.01 for all comparisons of linaclotide with placebo).

• Improvements in all secondary end points were statistically significantly greater in both linaclotide groups than in the placebo groups.

• The incidence of adverse events was similar among all study groups, with the exception of diarrhoea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups.

In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation.

The researchers conclude from these preliminary findings that in patients with chronic constipation, linaclotide increased the percentage of patients who reached the primary end point of three or more CSBMs per week, with an increase from baseline of at least one CSBM per week for 9 or more weeks of the 12-week treatment period. They call for additional studies to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation.

A supplemental New Drug Application has been submitted to the FDA requesting approval of linaclotide for the treatment of irritable bowel syndrome with constipation and chronic constipation