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Drug Product Name:

LINZESS Rx

Pharmacological Class:
Guanylate cyclase-C agonist.

Active Ingredient(s):
Linaclotide 145mcg, 290mcg; capsules.

Company
Forest and Ironwood

Indication(s):

Irritable bowel syndrome with constipation (IBS-C). Chronic idiopathic constipation (CIC).

Pharmacology:

Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.

Clinical Trials:

The efficacy of Linzess for the management of symptoms of IBS-C was established in two placebo-controlled trials. A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with Linzess 290mcg or placebo once daily and were evaluated for efficacy. Efficacy of Linzess was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. In both trials, the proportion of patients who were responders to Linzess 290mcg was statistically significantly higher than with placebo. Improvement from baseline in abdominal pain and complete spontaneous bowel movements (CSBM) frequency was seen over the first 12-weeks of the treatment periods. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). For the change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs per week in both trials.

The efficacy of Linzess for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adults (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with Linzess 145mcg, 290mcg, or placebo once daily and were evaluated for efficacy. Efficacy of Linzess was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. During the individual double-blind placebo-controlled trials, Linzess 290mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with Linzess 145mcg. The proportion of patients who were CSBM responders was statistically significantly greater with the Linzess 145mcg dose than with placebo. CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs. On average, patients who received Linzess across the two trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).