CHICAGO – The investigational agent linaclotide brought relief from the symptoms of irritable bowel syndrome with constipation in a randomized phase III trial of 800 patients.
Linaclotide significantly improved all 4 primary efficacy end points and all 10 secondary efficacy end points when it was compared with placebo in the 16-week trial, Dr. Satish S.C. Rao reported at the annual Digestive Disease Week.
The study sponsors (Ironwood Pharmaceuticals and Forest Laboratories) reported that they are on track to submit a New Drug Application later this year to the Food and Drug Administration for the indications of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. European partner Almirall S.A. is expected to file for the IBS-C indication in Europe in the second half of 2011. During the 2-week pretreatment baseline period, patients in the study met modified Rome II criteria for IBS-C, and had an average of fewer than three complete spontaneous bowel movements (CSBMs) per week, and five or fewer spontaneous bowel movements per week, plus abdominal pain rated as a 3 or higher on a 10-point severity scale. Most (91%) of the 800 patients were female, and 77% were white. During the pretreatment period, 88% of patients experienced abdominal pain every day.
Patients were randomized to linaclotide 266 mcg or placebo (405 and 395 patients, respectively) once daily for 12 weeks, followed by a 4-week randomized withdrawal period during which the linaclotide group either continued on treatment or switched to placebo, and placebo patients switched to active treatment.
In all, 19.5% of patients on linaclotide were able to have at least three CSBMs and at least one additional bowel movement per week for at least 9 of 12 weeks, compared with only 6.3% of patients on placebo (P less than .0001), reported Dr. Rao, professor and director of neurogastroenterology and motility at the University of Iowa in Iowa City.
For at least 9 of 12 weeks, 34.3% of linaclotide-treated patients experienced at least a 30% reduction in abdominal pain, as did 27.1% of controls, a significant difference (P less than .05).
Both of these end points were achieved for at least 9 of 12 weeks by 12% of the linaclotide patients and 5% of controls (P less than .001).
The fourth primary end point, created by the FDA last year to provide guidance for the industry, required at least a 30% reduction in abdominal pain and an increase of at least one CSBM per week, both for at least 6 of 12 weeks. In all, 33.6% of the linaclotide patients and 21% of controls achieved this end point (P less than .0001).
The linaclotide group experienced significant improvements, compared with the placebo group, on all secondary end points including bloating severity scores, abdominal discomfort severity scores, CSBMs per week, and straining scores, he said.
Patients who continued on or switched to linaclotide improved, whereas patients who switched from linaclotide to placebo showed a relapse of symptoms.
Linaclotide is a 14–amino acid investigational peptide that increases generation of cyclic guanosine monophosphate (cGMP) in patients with IBS. Based on preclinical data, cGMP is thought to increase luminal fluid secretion and also to enhance intestinal transit and reduce visceral pain by modulating the activity of afferent nerves, Dr. Rao explained.
The only other FDA-approved drug for this disorder is lubiprostone (Amitiza), which is a chloride channel activator. The mechanism of action, efficacy, and adverse events associated with linaclotide appear to be different from those of lubiprostone, Dr. Rao said in an interview.
Diarrhea was the most common adverse event, occurring in 19.5% of linaclotide and 3.5% of placebo patients. Rates of other adverse events were similar with linaclotide and placebo, including abdominal pain (5.4% vs. 2.5%), headache (5% vs. 3.5%), and flatulence (5% vs. 1.5%).
Dr. Rao said that patients in clinical practice would need to remain on continuous linaclotide, but noted that a long-term study, also presented at DDW, included data for 6 months showing persistent improvement.
Ironwood Pharmaceuticals and Forest Laboratories sponsored the trial. Dr. Rao disclosed consulting and serving as an advisor or review panel member for Forest, Takeda Pharmaceuticals, and the Dannon Co. His coauthors reported financial relationships with Ironwood and Forest.