Abdominal, Bowel Symptom Improvement From Linaclotide Meets FDA Standards for IBS-C

Patients taking linaclotide experience clinically meaningful improvement in abdominal and bowel symptoms, which closely correlate with the US Food and Drug Administration's new criteria for irritable bowel syndrome with constipation (IBS-C).

Patients taking linaclotide experience clinically meaningful improvement in abdominal and bowel symptoms, which closely correlate with the US Food and Drug Administration’s new criteria for irritable bowel syndrome with constipation (IBS-C), according to one poster presentation at Digestive Disease Week 2013, held May 18-21, 2013, in Orlando, Fla.

“There was great agreement between the two [standards],” said Jeffrey M. Johnston, MD, vice president and chief medical officer with the product’s developer, Ironwood Pharmaceuticals, in Cambridge, MA.

The use of adequate relief as a method to measure a drug’s effectiveness has been controversial, with the FDA moving to more symptom-based and specific measures, Johnston explained. This research poster displayed agreement between the thresholds for adequate relief and the government agency’s new weekly responder criteria, which includes a 30 percent reduction in worst abdominal pain and an increase in complete and spontaneous bowel movement of one or greater from baseline.

The FDA approved linacltide last year to treat adults suffering from IBS-C and chronic idiopathic constipation, based on originally agreed upon criteria. It is the first and only treatment in a new class of drugs called guanylate cyclase‐C agonists.

For the poster presentation, Michael Camilleri, MD, of the Mayo Clinic in Rochester, MN, and colleagues used combined data from two phase III, randomized clinical trials that observed 805 patients who received linaclotide and 797 who received placebo. Patients reported daily abdominal and bowel symptoms using an interactive voice response system diary. Additionally, they indicated on a weekly basis whether they had experienced adequate relief of their IBS-C symptoms.

Linaclotide-treated patients showed significantly greater rates of clinically meaningful improvement for all abdominal and bowel symptoms at 12 weeks compared to the placebo-treated patients. Fifty-five percent of the linaclotide group compared to 37 percent of the placebo group reported improved abdominal pain; 58 percent compared to 39 percent reported improved discomfort; 55 percent compared to 35 percent reported improved bloating; 59 percent compared to 39 percent reported improved abdominal fullness; and 51 percent compared to 35 percent reported improved cramping.

Bowel symptom responder rates on thresholds for clinically meaningful change anchored by adequate relief also showed beneficial outcomes, as 62 percent of the linaclotide patients compared to 27 percent of the placebo patients reported improved spontaneous bowel movements; 64 percent compared to 32 percent reported improved straining; and 76 percent compared to 35 percent reported improved stool consistency.

“In all cases, the differences between active and placebo responder changes were statistically significant,” Johnston said.

A Venn diagram illustrated a considerable level of agreement — greater than or equal to 70 percent — between the weekly FDA responder criteria and adequate relief. Johnston said the FDA criteria were more stringent, as more patients on the drug achieved adequate relief than the government agency’s weekly responder criteria.

For those taking linaclotide, the average percentage of weeks with adequate relief was 55 percent compared to 32 percent for those taking placebo. The average percentage of weeks in meeting FDA standards was 37 percent in the drug cohort and 20 percent in the control group, and the average percent of weeks with both adequate relief and meeting FDA standards was 31 percent in the linaclotide group and 14 percent in the placebo group. The average percentage of weeks without relief and without meeting the agency’s criteria was 39 percent in the intervention group and 62 percent in the control group.

“Using our large database, we could look at the comparison of the FDA measures to adequate relief and show that the FDA criteria is reasonable — and so is adequate relief,” Johnston concluded.