Linaclotide is a peptide agonist of guanylate cyclase type C, which is expressed on the epithelial cells that line the intestine. Activation of this receptor modulates abdominal pain sensation and secretion of fluid and electrolytes into the intestine.
The two trials, reported at this year's Digestive Disease Week, enrolled a total of 1,276 patients. Investigators randomised participants to receive 133 micrograms or 266 micrograms of linaclotide daily, or placebo, for 12 weeks. The study population was 89% female, with an average age of 48 years.
In both trials, the primary end point was achievement of three or more complete spontaneous bowel movements (CSBM) per week, with an increase from baseline of at least one CSBM per week for a minimum of nine weeks.
The results of the first trial showed that patients receiving linaclotide were more than twice as likely to respond to linaclotide as to placebo. The proportion of patients who achieved the primary end point was 16% in the group given 133 micrograms of linaclotide daily and 21.3% in the group on the 266 microgram dose, compared with 6% in the placebo group (p=0.0012 and p<0.0001, respectively, versus placebo).
In the second trial, the difference was even greater - 21.2% and 19.4% of patients receiving the lower and higher doses of linaclotide achieved the primary end point, respectively, compared with only 3.3% of those given placebo (p<0.0001 for both doses versus placebo).
Diarrhoea, flatulence and abdominal pain were the most commonly reported adverse events. At each dose of linaclotide, approximately 4% of patients discontinued treatment as a result of diarrhoea; the corresponding percentage in the placebo group was 0.5%.
Linaclotide, which is being developed in Europe by Almirall, is also undergoing Phase III testing for irritable bowel syndrome with constipation. Results from these trials are expected in the second
half of 2010.