Deborah Brauser

October 10, 2008

October 10, 2008 (Orlando, Florida) — Linaclotide appears to significantly improve abdominal pain and relieve constipation and other symptoms in adults with irritable bowel syndrome with constipation (IBS-C), according to results from a large phase 2b study presented here at the American College of Gastroenterology (ACG) 2008 Annual Scientific Meeting and Postgraduate Course.

According to the study, presented in a plenary session by Jeffrey Johnston, MD, vice president and chief medical officer at Ironwood Pharmaceuticals, in Cambridge, Massachusetts, this multicenter trial was designed to evaluate the safety and efficacy of a daily regimen of 75-, 150-, 300- or 600-μg doses of linaclotide or placebo in adults with IBS-C. The study's primary end point was the change from baseline for complete spontaneous bowel-movement (CSBM) frequency.

Of the 420 patients enrolled in 89 centers across the United States, 419 were in the intent-to-treat (ITT) population, and 337 completed the study — which comprised a 2-week baseline evaluation, a 12-week treatment period, and a 2-week posttreatment phase. During his presentation, Dr. Johnston reported that the mean age of the ITT population was 44.4 years, and that 92% of the patients were female and 8% were male.

All patients used an interactive voice-response system to make daily assessments of bowel habits and symptom severity, and weekly global assessments, using a rating scale from 5 (very severe) to 1 (none). During the baseline period, patients had to report less than 3 CSBMs per week and mean daily abdominal pain of at least mild severity. Treatment effects were estimated using an analysis of covariance and the Cochran–Mantel–Haenszel test.

"At the end of the treatment period," reported Dr. Johnston, "the primary end point, as well as all secondary end points, was met." The change from baseline, compared with placebo, for CSBM frequency was significant in all linaclotide groups. In addition, abdominal pain showed clinically and statistically significant improvement for all treated patients. For patients with severe or very severe baseline abdominal pain, the improvement was even more dramatic. Its dose breakdown for change from baseline was –0.8 for 75 μg (P = .0236), –1.0 for 150 μg (P = .0018), –1.2 for 300 μg (P = .0002), and –1.3 for 600 μg (P =< .0001), compared with placebo (–0.2 change). In the 300-μg and 600-μg dosage groups, results were statistically significant for straining, bloating, IBS symptom severity, and global assessments.

Effects from all dosage groups were apparent within the first week of treatment and were maintained throughout the full 12-week treatment period. In his presentation, Dr. Johnston said that diarrhea was the most common adverse event reported, although discontinuation for this reason was low, at only 1% to 6%.

When asked by Medscape Gastroenterology what he found to be the most exciting finding of this study, Dr. Johnston said: "That would be the effect on abdominal pain. We were pretty confident that we would get good effects on bowel habits [based on previous studies], but we really didn't know about pain. We knew that preclinically we should see an effect on abdominal pain, but it was really exciting to see the actual data and see how dramatic the magnitude of the effect was."

He continued: "The number 1 takeaway [message] is that linaclotide has the potential, based on these phase 2b data, to affect both the pain and discomfort of IBS, as well as to alter the bowel habit and constipation of IBS-C."

During the question-and-answer event immediately after the presentation, session moderator Nicholas Talley, MD, professor of medicine at Mayo Clinic Jacksonville, in Florida, and coeditor ofACG's American Journal of Gastroenterology, expressed surprise about the makeup of the trial population. Looking at the data presented, he asked: "Most of these patients were very constipated at baseline — did you ever consider excluding them from your study?" When Dr. Johnston answered that he hadn't, Dr. Talley replied: "That could have been interesting."

Later, Dr. Talley explained to Medscape Gastroenterology that "the devil's in the details. I would like to have seen the trial exclude patients with pelvic-outlet obstruction, especially since drugs don't usually work in these types of patients. [The investigators] may have seen even more positive results if not for that issue."

Overall, though, Dr. Talley said he was optimistic. "Clearly, this is a novel drug, especially in its motor action. There were significant improvements in multiple types of symptoms in IBS patients. And I didn't see any safety issues. It's good news for the field if the results are confirmed in phase 3 trials."

This study was supported by an industry grant from Ironwood Pharmaceuticals. Dr. Johnston is an employee of Ironwood. Dr. Talley has consulted for Ironwood in the past.

American College of Gastroenterology (ACG) 2008 Annual Scientific Meeting and Postgraduate Course: Abstract 35. Presented October 6, 2008.

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