Two Randomized Trials of Linaclotide for Chronic Constipation

We know that, Linaclotide (BELOW STRUCTURE) is an experimental peptide agonist of guanylate cyclase 2C that is undergoing clinical trials for use in treating abdominal pain in patients with irritable bowel syndrome (IBS) accompanied by constipation. The drug was developed by Ironwood Pharmaceuticals, based in Cambridge, Massachusetts. 

 Now researchers lead by, Dr. Anthony J. Lembo, an associate professor of medicine at Harvard Medical School and director of the GI Motility Center at Beth Israel Deaconess Medical Center in Boston, have come up with interesting claim  that "people who received the drug had improvement in symptoms, and the treatment was generally well-tolerated". 

Researchers conclude that, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation (2 trials). Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation...

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1010863

Positive results from phase 3 clinical trials of Linoclotide ....

Ironwood Pharmaceuticals, Inc. and Forest Laboratories, Inc. recently announced positive top‐line results from two Phase 3 clinical trials assessing the safety and efficacy of once‐daily dosing of the investigational drug linaclotide in patients with chronic constipation (CC). Analyses of the data indicate that in both multicenter, randomized, double‐blind, placebo‐controlled trials, statistical significance was achieved for the primary endpoint of 12‐week complete spontaneous bowel movement (CSBM) overall responder at the two doses studied in each trial (133 mcg/day: p‐values≤0.0012 and 266 mcg/day: p‐values<0.0001). In both trials, statistical significance (p<0.01) was achieved for all prespecified secondary endpoints, which included measures of bloating, abdominal discomfort, and average weekly CSBMs.

About Linaclotide :

Linaclotide (see the structure) is an orally delivered peptide that acts locally in the gut with no detectable systemic exposure at therapeutic doses and is intended for once‐daily administration. Linaclotide can be synthesized by solid-phase technology using Fmoc protections. Amino acids are coupled using DCC/HOBT and Fmoc groups are removed by means piperidne .Cysteinethiol groups are protected with trityl and cleavage of the peptide from the resin is done by TFA.

Mode of action :

Linoclotide acts agonist of guanylate cyclase type‐C (GC‐C), a receptor found on the lining of the intestine. Activation of GC‐C leads to increases in intracellular and extracellular cGMP. In preclinical models, extracellular cGMP inhibited afferent nerve firing and positively affected markers of abdominal pain, while intracellular cGMP led to activation of anion channels which stimulated anion and fluid secretion into the intestine, leading to accelerated intestinal transit. Linaclotide is a first‐in‐class compound in Phase 3 clinical development for the treatment of IBS‐C and CC.

Ref : http://www.ironwoodpharma.com/newsPDF/Linaclotide.Ph3.CC.results.11.02.09.pdf