CHICAGO – Plecanatide, a drug recently approved for chronic idiopathic constipation, bested placebo in two randomized studies evaluating its effect in irritable bowel syndrome with constipation.
Results of the identical, 12-week, phase III studies propelled plecanatide (Trulance; Synergy Pharmaceuticals) into a supplemental new drug application for adult irritable bowel syndrome–constipation predominant (IBS-C), Ronald Fogel, MD, said at the annual Digestive Disease Week®.
During the question-and-answer period, though, clinicians didn’t quite echo the corporate enthusiasm for plecanatide. Several pointed out that overall responder rates were somewhat low for both the 3-mg and 6-mg dose (study -04, 30% both doses; study -05, 21% and 24%), with a drug-placebo differential of about 12% and 7%, respectively. When questioned, Dr. Fogel didn’t have data on the number needed to treat to improve one case. But, he asserted, such response numbers are typical for drug trials in patients with functional bowel disorders and meaningful to those who did respond.
“The differences were statistically significant, and, as someone who was there for both trials, I would say they are also clinically significant,” said Dr. Fogel, founder of the Digestive Health Center of Michigan, Chesterfield. “Patients who did respond were very happy.”
The drug was also quite well-tolerated, with diarrhea as the only important treatment-related adverse event and. This occurred in less than 2% of patients, and only about 1% of either cohort discontinued the medication because of severe diarrhea.
Plecanatide, structurally, is almost identical to uroguanylin, a peptide that regulates sodium and bicarbonate secretion into the intestine but with 8 times greater binding potential to the guanylate cyclase-C receptor. Both the natural and manmade molecules promote fluid secretion into the lumen and inhibit fluid absorption. Uroguanylin is most active in an acidic environment; therefore, plecanatide exerts most of its action in the proximal small intestine.
Synergy also asserts on its website that activation of the GC-C-receptor “may lead to decreased inflammation and pain sensation in the GI tract.” Abdominal pain was not a primary outcome in the pivotal trials for plecanatide’s idiopathic constipation studies, but it was a coprimary endpoint, with stool frequency, for the IBS-C trials.
The studies enrolled a total of 2,189 patients with a diagnosis of IBS-S. They were equally randomized to placebo or plecanatide 3 mg or 6 mg, once daily. Most (75%) were women. The mean age was about 43 years. At baseline, they reported less than one complete, spontaneous bowel movement per week. They also completed an 11-point scale on abdominal symptoms of pain (mean, 6), discomfort (mean, 6.2), and bloating (mean, 6.5).
The study included a 2-week pretreatment assessment period, 12 weeks of daily therapy during which patients filled out an electronic diary of stool frequency and abdominal pain/discomfort, and a 2-week follow-up. The primary endpoint was the number of overall responders, who had to experience both a decrease of at least 30% in their weekly abdominal pain score and an increase of at least one complete, spontaneous bowel movement per week.
Both studies posted statistically significant overall responder rates, relative to placebo, in both doses.
In study -04, the final overall placebo response rate was 17.8%, compared with 30% in the plecanatide 3-mg group and 29.5% in the plecanatide 6-mg group. In study -05, the placebo responder rate was 14%, compared with 21.5% in the 3-mg group and 24% in the 6-mg group.
Dr. Fogel showed stool frequency data but not abdominal pain data. About 41% of patients taking the study drug had increased bowel movements for at least 6 weeks of treatment, compared with 31.4% of those taking placebo. This 9% absolute difference was remarked on during the question-and-answer period as a surprisingly small separation. However, Dr. Fogel said that it was clinically significant as well as statistically so, with a P value of less than 0.001.
Plecanatide worked quickly. By the end of treatment week 1, the placebo and both active groups had already significantly separated, and that separation remained significant throughout the entire treatment period. During the 2-week follow-up period, the effect of both active doses tailed off and fell to the same as placebo by the end of 2 weeks.
One of the drug’s strongest points was its low rate of treatment-related diarrhea. Any diarrhea occurred in about 4% of both dosage groups, compared to 1% of the placebo group. Severe diarrhea occurred in 1% of the 3-mg and 0.4% of the 6-mg group, compared with 0.1% of the placebo group. This caused about 1% of patients to discontinue the study medication.
The adverse event profile was notably better than that of linaclotide (Linzess; Allergan), plecanatide’s close competitor. Also a guanylate cyclase–C agonist, linaclotide provoked diarrhea in almost 20% of patients in its pivotal phase III trials. Symptoms were severe in 2%. Lincalotide’s effectiveness in promoting bowel movements was slightly higher than that of plecanatide (about 48% in the pivotal trials), with a similar placebo response rate.
Plecanatide was approved earlier this year for chronic idiopathic constipation in adults.
Synergy Pharmaceuticals sponsored the study. Dr. Fogel has no financial interest in the company or in plecanatide.
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