Linaclotide Effective and Safe for Chronic Constipation

Nancy A. Melville

August 11, 2011

August 11, 2011 — The investigative drug linaclotide has been shown in 2 phase 3 placebo-controlled trials to safely and effectively reduce bowel and abdominal symptoms associated with chronic constipation, according to data published this week in the New England Journal of Medicine.

In the 2 parallel-group 12-week, double-blind, multicenter trials, 1276 patients with chronic constipation were randomized to receive either placebo or linaclotide 145 μg or 290 μg once daily.

The results indicated that at week 12, the primary endpoint of 3 or more complete spontaneous bowel movements (CSBMs) per week and an increase of 1 or more CSBMs from baseline during at least 9 of the 12 weeks was reached by 21.2% and 16.0%, respectively, of the patients who received 145 μg of linaclotide and by 19.4% and 21.3%, respectively, of the patients who received 290 μg of linaclotide.

In the placebo group, only 3.3% and 6.0% reached the endpoints, respectively, (P < .01 for all comparisons of linaclotide with placebo).

The study authors noted that, although the proportion of patients appeared low, the rate of patients achieving spontaneous bowel movements (SBMs) and CSBMs was impressive.

"Because of the rigor of the primary endpoint, only about 20% of the patients who received linaclotide and 5% of those who received placebo were considered to have had a response," they wrote.

"Of perhaps greater clinical relevance, the mean stool frequency in the 2 trials increased to 5.1 and 5.6 SBMs per week and to 2.2 and 2.9 CSBMs per week in the linaclotide-treated patients, as compared with 3.0 and 3.2 SBMs per week and 0.9 and 0.9 CSBMs per week in the placebo-treated patients."

The drug's effects were rapid, observed within the first 24 hours, and sustained through 16 weeks.

Importantly, patients also reported improvements in stool consistency, reduced straining, and reduced abdominal symptoms, such as bloating and discomfort, which are common concerns with chronic constipation, the study authors reported.

The drug's most common adverse effect was diarrhea, which was mostly mild or moderate in severity, and resulted in 4.2% of linoclotide-treated patients discontinuing the trial, compared with 0.5% of patients receiving placebo.

Linaclotide is a 14–amino acid, synthetic, minimally absorbed, peptide agonist of the endogenous guanylin family and binds to an activates the cyclise C receptor. The study authors speculated that the improvements result from various factors, including increased fluid in the lumen and accelerated intestinal transit.

"Although the improvement in bowel function with linaclotide treatment is most likely a consequence of increased luminal fluid, with an acceleration of intestinal transit, additional mechanisms may contribute to the improvement in abdominal symptoms," they wrote.

"In fact, linaclotide has been shown to reduce visceral hypersensitivity in animal models by means of a guanylate cyclase C–cGMP mechanism.”

"The observation that diarrhea occurred more commonly with linaclotide than with placebo is not surprising, " the study authors continue, "since diarrhea is an extension of linaclotide's pharmacologic effects."

According to Brennan M. R. Spiegel, MD, MSHS, associate professor of medicine at the VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA in California, the rate of adverse effects is not unusual with constipation medications. "That rate is consistent with other therapies, and the 4% discontinuation rate is about what has been seen with other drugs, so I would say it's acceptable," he explained in an interview with Medscape Medical News.

Dr. Spiegel, who was not involved in the studies, noted that the drug's improvement in CSBMs is impressive. "The CSBM rate is probably the most important thing in this condition, so it's important that there were improvements in that," he stated. .

Dr. Spiegel explained that the drug has a unique mechanism that sets it apart from other constipation drugs, while resulting in a similar effect of increased luminal fluid.

"All of the drugs tend to increase fluid secretion one way or another. For instance, Miralax boosts secretion, although passively through osmotic load, whereas linaclotide does it actively by actively pumping chloride into the lumen through the CFTR [cystic fibrosis transmembrane conductance regulator] channel and then water gets pumped into the lumen actively," Dr. Spiegel said.

"What is interesting is it works with this guanylate cyclase, which is its unique mechanism of action. But the net result is not really all that unique."

Dr. Spiegel noted that linaclotide has been shown in additional, earlier-stage clinical trials to also have efficacy in treating irritable bowel syndrome (IBS), a condition that, according to Dr. Spiegel, is even more in need of an effective therapy.

"The data have been positive from what I have seen from this study, but I'm more enthusiastic about its studies on IBS," he explained.

"The reason I say that, is we have several therapies already available to us for chronic constipation that generally work well, whereas for IBS, it [is] a much different story. In that regard it looks very promising, not just for constipation but abdominal bloating and pain and a lot of other features, and there aren't many other effective therapies.

"But, if the price point puts it in line with existing therapies, linaclotide could really prove to be one of the first-line agents for difficult to treat chronic constipation."

The study was funded by Ironwood Pharmaceuticals and Forest Research Institute.. Several study authors are employed by and receive stock or stock options from Ironwood Pharmaceuticals. Several other study authors are employed by and receive stock or stock options from Forest Research Institute. One study author has served as a consultant for Ironwood Pharmaceuticals, Salix, Prometheus, Glaxo-Smith-Kline, Alkermes, Ardelyx, and Theravance. Dr. Spiegel disclosed that he has served on an independent advisory board for Ironwood Pharmaceuticals, but it was not related to linaclotide.

N Engl J Med. Published August 11, 2011.


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