Linaclotide shows efficacy in Phase IIb chronic constipation trial

Linaclotide, an investigational peptide agonist of the guanylate cyclase-C receptor, is associated with rapid and sustained improvement in bowel habits and abdominal symptoms in patients with chronic constipation, according to data from a Phase IIb study. Researchers randomized 310 patients with chronic constipation to receive 1 of 4 doses of linaclotide (75 mcg, 150 mcg, 300 mcg, or 600 mcg) or placebo once daily. The primary endpoint of the study was the change in the mean weekly...

Linaclotide, an investigational peptide agonist of the guanylate cyclase-C receptor, is associated with rapid and sustained improvement in bowel habits and abdominal symptoms in patients with chronic constipation, according to data from a Phase IIb study.

Researchers randomized 310 patients with chronic constipation to receive 1 of 4 doses of linaclotide (75 mcg, 150 mcg, 300 mcg, or 600 mcg) or placebo once daily. The primary endpoint of the study was the change in the mean weekly frequency of spontaneous bowel movements (SBMs) during the 4-week treatment period, compared with a 2-week pretreatment baseline period.

Data for the efficacy population (n=307) showed that, on average, the weekly rate of SBMs increased by 2.6 with the 75 mcg dose of linaclotide, by 3.3 with the 150 mcg dose, by 3.6 with the 300 mcg dose, and by 4.3 with the 600 mcg dose, compared with an increase of 1.5 SBMs per week with placebo (P<=.05 for all doses vs placebo).

Moreover, greater proportions of the linaclotide-treated patients achieved a first SBM within 24 hours of starting treatment, from 50.8% with the 75 mcg dose to 75.8% with the 600 mcg dose, versus 36.8% with placebo (P<=.05 for all doses vs placebo except the 75 mcg dose). The median time to the first SBM was 24.0 hours with the 75 mcg dose, 21.9 hours with the 150 mcg dose, 23.1 hours with the 300 mcg dose, 13.0 hours with the 600 mcg dose, and 32.6 hours with placebo.

Similar results were observed for the secondary endpoint of complete SBMs, defined as SBMs associated with a sensation of complete emptying of the bowels.

Additional analysis of secondary endpoints showed that, relative to placebo, some or all doses of linaclotide were associated with significantly greater improvement in ratings of stool consistence, straining during bowel movements, abdominal discomfort, bloating, constipation severity, relief of constipation, treatment satisfaction, and quality of life.

The investigators also noted that, during 14 days of posttreatment follow-up, there was no evidence of rebound worsening of constipation after linaclotide was discontinued.

Adverse events occurred in 33.8% of the linaclotide-treated patients and in 31.9% of the placebo group. The study authors noted that adverse events were somewhat more common with linaclotide 600 mcg (38.1% of patients) than with the lower doses of the drug (29.0%-35.0%). The most common adverse event and the only dose-related adverse event was diarrhea, which led to treatment discontinuation in 6 patients (1 in the linaclotide 150 mcg group, 2 in the 300 mcg group, and 3 in the 600 mcg group). Approximately half of the reports of diarrhea occurred within 2 days of starting treatment.

Based on these results, the researchers suggested that the 150 mcg and 300 mcg doses of linaclotide provide an appropriate balance between symptom improvement and adverse events. (Lembo AJ, et al. Gastroenterology 2010;138:886-895.)

Ironwood Pharmaceuticals Inc. funded this study.

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